Cancer.Net Podcast

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses.

In this podcast, Dr. Christopher Flowers covers highlights from the 2021 American Society of Hematology Annual Meeting, held December 11 to 14 in Atlanta, Georgia. He discusses new treatments for diffuse large B-cell lymphoma, advances in immunotherapy, and a session on improving inclusivity in clinical trials.

Dr. Flowers is the Chair of the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center and was appointed Division Head ad interim of Cancer Medicine in August 2020. He is also the 2022 Cancer.Net Associate Editor for Lymphoma.

View Dr. Flowers' disclosures at Cancer.Net.

Dr. Flowers: Hello. I'm Dr. Christopher Flowers, Chair of the Department of Lymphoma and Myeloma and Interim Division Head for Cancer Medicine at The University of Texas MD Anderson Cancer Center. And it's my pleasure to talk to you today about the highlights from this year's American Society of Hematology meeting. The ASH meeting this year was a very exciting meeting for lymphoma broadly across all of the lymphomas, with particular highlights around diffuse large B-cell lymphoma where there were some changes that may be changes in the standard of care in the year ahead. I was involved in one of these studies, the POLARIX study that I'll spend some time talking about, where I was the North American lead, and I've served as a consultant for Genentech-Roche in the conduct of that study and other studies related to drugs in their portfolio. The other set of studies that I will talk about are the studies around CAR T-cell therapy. And 2 of those studies, Dr. Jason Weston from my institution and MD Anderson were involved with and Dr. Weston was the senior leader on 2 of those 3 studies that I will talk about.

So let's first talk about the first line in diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma, as many of you may be aware of, is the most common type of lymphoma and the most common type of aggressive lymphoma. Back in the 1970s and 80s, the standard of care for CHOP therapy was developed. And that through the 90s, through a number of comparisons of clinical trials for chemotherapy, emerged as the de facto standard of care. In early 2000, the drug rituximab, the anti-CD20 antibody therapy, so our first form of immunotherapy, was added to CHOP. And R-CHOP therapy became the standard of care around 2002. And so it's really been about 20 years that that has been the standard of care for all patients or for most patients in the front line for diffuse large B-cell lymphoma. That's not been without challenges. There have been a number of clinical trials from 2002 to the present that have challenged R-CHOP, either by adding new therapies, like new targeted therapies looking at intensifying the CD20 antibody component, adding things like stem cell transplant or intensifying the chemotherapy-- and in some cases, focusing on subsets of diffuse large B-cell lymphoma, like the activated B-cell-like subset that are at poorer outcomes in the general population. However, none of those clinical trials really emerged to change the standard of care. And R-CHOP had remained the standard of care for patients.

This year, as one of the late breaking abstracts presented at the American Society of Hematology meeting and followed up by a publication in the New England Journal of Medicine, one of our top premier journals, there was a study that looked at the substitution of vincristine, one of the drugs in CHOP, for the drug polatuzumab vedotin. Polatuzumab vedotin is what we call an antibody-drug conjugate, where that antibody binds to a cell surface marker on the lymphoma cells CD79B. And with that, binding is internalized into the cell. And the conjugate is a form of chemotherapy, MMAE, that is then taken into the cell with the antibody. And that antibody-drug conjugate was substituted for vincristine in the study. In the POLARIX study, it showed that it met its primary endpoint for the study, which was an improvement in progression-free survival, where the patients who got the polatuzumab in their chemotherapy with R-CHP had an improvement in progression-free survival of approximately 26% over the group that got R-CHOP. This is the first time to show an improvement in front-line therapy for patients with diffuse large B-cell lymphoma. And regulatory bodies will be looking at this to see whether this is approved in the first line in the relatively near future.

The other major trials that were presented at this year's American Society of Hematology meeting in diffuse large B-cell lymphoma were trials looking at the second line of therapy for patients with diffuse large B-cell lymphoma. And in that second line, for patients who were fit and able, stem cell transplant has formed as standard of care for patients after R-CHOP therapy. As many of you may know, diffuse large B-cell lymphoma is a disease where the goal of treatment is cure. And with that first-line therapy, the therapies that are able to produce benefits in terms of progression-free survival are expected to go on to cure for those patients if those responses are durable in 5 years. Even when patients have relapse after their first-line therapy, there's the potential of cure in the second line. And stem cell transplant has been that curative approach that we've taken for many patients in the past.

In this year's ASH meeting, there were 3 trials that compared the concept of moving on, after first-line therapy, to intensive chemotherapy followed by a stem cell transplant or to performing CAR T-cell therapy as that second-line therapy. As some of you may know, CAR T-cell therapy has emerged as really an exciting form of immunotherapy, a cellular therapy, that is approved for patients who are with lymphomas and some leukemias and being explored in other diseases. CAR T-cell therapy is a form of immunotherapy where we actually re-engineer cells. So we take the cells from the patient and then genetically re-engineer those cells so they attack a marker on the cell surface. I talked about CD20 antibody therapy. All of these CAR T-cell therapies are cellular therapies against the marker on the lymphoma cells called CD19.

And so in these 3 trials that compared CD19 CAR T-cell therapy versus autologous stem cell transplant, 2 of those trials, 1 presented in the plenary session—and that was one of the ones that Dr. Weston participated in—was a study that showed that there was a benefit in progression-free survival for those patients who received CAR T-cell therapy over the approach to do stem cell transplant as that second-line therapy. There was a second trial, the TRANSFORM trial, that was also presented in one of the oral abstract sessions. That one presented interim analysis of their trial. They also showed a benefit in terms of progression-free survival. And then there was a third trial that was looked at in the late breaking abstract session. That one did not show a benefit for CAR T-cell therapy in that setting, using tisagenlecleucel as a form of CAR T-cell therapy in that study. And perhaps the reasons why that did not show a benefit or differences in the trial design between those 3 trials, not as many of the patients were able to go on to CAR T-cell therapy in that third trial. And that was really expertly described and compared by Alex Hariri in a discussion of the plenary session. So really, 4 major trials in diffuse large B-cell lymphoma that we expect will change the standard of care.

Likewise, there were a number of other exciting new immunotherapies that have been presented at this year's annual meeting, namely studies looking at bispecific antibodies. And so these are antibody-based therapies in a number of different trials that both engage a portion of the lymphoma cell. And then as the other portion of the bispecific, so meaning two, that other portion engages T cells. So it brings T cells into the tumor to be able to attack the lymphoma cells. And so there are a number of exciting therapies that are on the horizon for lymphomas looking at that. And those were also presented at the ASH meeting.

The last thing that I'd like to highlight from this year's annual society meeting was a joint session that looked at the role of clinical trials and ways that we can actually improve clinical trial design for patients-- 1, to increase the diversity, equity, and inclusion that we see across clinical trials to make sure that all patients who are eligible are having equal access to trials and being able to participate, but also in terms of being able to modify the eligibility criteria that we use for clinical trials. One of the things that we've explored, particularly for those challenges that I described without advances in the front line for diffuse large B-cell lymphoma in the past, have been that some of the eligibility criteria for our past trials really were not including all the patients who were most likely to benefit from trials. And so Tom Witzig at this year's annual society meeting really presented an outstanding look at the eligibility criteria that we use for lymphoma trials, and trying to be able to address those in ways that help to allow more patients to participate in trials, and those who are most likely to need a trial to be able to benefit from the activities that are engaged in a trial.

So I really appreciate all of your attention to this podcast. Exciting meeting this year for the American Society of Hematology Annual Meeting. And lots of things that will come to patients in the near future. And hope to be able to create advances that will help all of you in terms of your quality of life and well-being. So thank you all for your attention.

ASCO: Thank you, Dr. Flowers. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests statements on this podcast do not express the opinion of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In this podcast, Cancer.Net Associate Editor Dr. Norah Lynn Henry will discuss new research presented at the 2021 San Antonio Breast Cancer Symposium, held December 7-10. Dr. Henry is an Associate Professor in the University of Michigan's Division of Hematology/Oncology in the Department of Internal Medicine and is the Breast Oncology Disease Lead at the Rogel Cancer Center in Ann Arbor, Michigan.

View Dr. Henry's disclosures at Cancer.Net.

Dr. Henry: Hi, I'm Dr. Lynn Henry, a breast cancer oncologist from the University of Michigan Rogel Cancer Center. I'm here with exciting updates from the leading international breast cancer meeting, the San Antonio Breast Cancer Symposium, that was recently held in San Antonio, Texas, and online. I have no conflicts of interest for any of the trials that I will talk about. First, I'm going to give a very brief overview of the types of breast cancer, then talk about some research that was presented on both metastatic and early- stage breast cancer. Then to wrap it up, I'm going to mention an interesting study looking at lymphedema. As a reminder, there are multiple kinds of breast cancer. Some breast cancers are called hormone receptor-positive or estrogen receptor-positive, and are stimulated to grow by the hormone estrogen. We treat those cancers with antiestrogen treatments, which block estrogen or lower estrogen levels. Other breast cancers are called HER2-positive. These are often more aggressive cancers, but because they have extra copies of HER2, they often respond to treatments that block HER2. Finally, there are breast cancers that don't have hormone receptors or HER2. These are called triple-negative breast cancers and are also often aggressive cancers. So first, I'm going to talk about treatment for HER2-positive metastatic breast cancer. Many of the treatment regimens that we use for treating patients with HER2-positive breast cancer include the antibody trastuzumab, which is also called herceptin. More recently, 2 drugs have been approved that include trastuzumab linked to a chemotherapy drug. So they're sort of like smart drugs. One is called trastuzumab emtansine and the other is called trastuzumab deruxtecan. In the DESTINY-Breast03 trial, which was presented earlier this year, the deruxtecan drug was shown to be more effective than the emtansine one.

At this San Antonio meeting, the investigators look specifically at how well these 2 drugs worked in patients whose breast cancer had spread to their brain. And these exciting results, the deruxtecan drug was shown to greatly lengthen the time until cancer worsens compared to the emtansine drug, from 3 months on average to 15 months. In addition, on brain MRI, almost two-thirds of the patients had shrinkage of the brain lesions when they received the deruxtecan drug, compared to only about one-third who received emtansine. These important findings give us yet another potential treatment that we can use to help patients who have HER2-positive breast cancer that has spread to their brains.

So next, I'm going to switch gears and talk about treatment of metastatic hormone receptor-positive breast cancer. At this time, the initial treatments are generally with antihormone drugs, such as aromatase inhibitors or fulvestrant. Unfortunately, these drugs often stop working, and then patients have to switch to chemotherapy medication. The good news is, that there are a number of new antihormone drugs currently being developed in the EMERALD trial, which was presented at this meeting. Investigators tested a new antihormone medicine called elacestrant in postmenopausal women with metastatic breast cancer whose cancer had previously worsened during treatment with medicines called CDK4/6 inhibitors plus antihormone treatment. These findings are exciting because this new drug may work against some cancers that no longer respond to a currently available antihormone medicines. It might mean they don't yet need to switch to chemotherapy. However, the findings are still early, and this drug is not yet approved by the FDA. I'm sure we'll hear more about this drug and other similar ones in the months and years to come.

There were a lot of other research findings presented related to treatment for early- stage breast cancer at the meeting. And there were quite a number of updates from studies that were previously presented. For example, in patients with stage 2 and 3 triple-negative breast cancer, adding immunotherapy to neoadjuvant chemotherapy, which is chemotherapy given before surgery, improves event-free survival. Similarly, updated results from the RxPONDER clinical trial confirm that it is okay to not to give chemotherapy to postmenopausal women with hormone receptor-positive HER2-negative breast cancer who have 1 to 3 involved lymph nodes, and a 21-gene recurrence score of 25 or less.

Finally, there was a report of a large clinical trial examining whether the diabetes drug, metformin, can decrease the risk of breast cancer recurrence, especially in hormone receptor-positive breast cancer. Unfortunately, taking metformin did not lower the risk of breast cancer recurrence compared to placebo. So it is not recommended that patients take this drug specifically to try to lower their risk of breast cancer coming back.

In addition to these studies reporting findings about new medications, we also learn new information about an old problem, lymphedema. A group of women were followed over 2two years after they were diagnosed with breast cancer and underwent axillary lymph node dissection or removal of a large number of lymph nodes from under their armpit. Using a specific type of lymphedema measurement that looks at swelling in the arm, they found that almost 1 in 10 patients had developed lymphedema within 1 year of surgery, and almost 1 in 4 had lymphedema within 2 years. These are similar to what other studies had previously found. But importantly, patients who were Black were much more likely to develop lymphedema compared to white or Asian patients. This association with race hadn't been carefully looked at before and suggests that additional studies need to be done to figure out how best to monitor for, prevent, and treat lymphedema in all patients with breast cancer.

Importantly, at this meeting, we also got glimpses of the many new drugs on the horizon for the treatment of breast cancer. And we eagerly await the results of large randomized trials so that the drugs at work can be used to care for patients with breast cancer. But for now, that's it for this quick summary of important research from the 2021 San Antonio Breast Cancer Symposium. Overall, we continue on a fast track in breast cancer with many new and exciting therapies being actively studied, as well as research helping support our patients to do better than ever. Stay tuned to Cancer.Net for future updates from upcoming breast cancer conferences. Thank you.

ASCO: Thank you, Dr. Henry. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In this podcast, experts will discuss targeted therapy for lung cancer, including 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells, called an EGFR exon 20 insertion. They will explain how targeted therapy works to treat cancer, why this specific mutation is different from other, more common EGFR mutations, and what these 2 new treatments mean for people with this type of cancer.

This podcast will be led by Dr. Charu Aggarwal, Dr. Xiuning Le, Dr. Vamsidhar Velcheti, and Marcia Horn.

Dr. Charu Aggarwal is the Leslye Heisler Associate Professor of Medicine in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine in Philadelphia, Pennsylvania. She is also the Cancer.Net Associate Editor for Lung Cancer.

Dr. Xiuning Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at the University of Texas MD Anderson Cancer Center in Houston, Texas. She is also a Cancer.Net advisory panelist for lung cancer.

Dr. Vamsidhar Velcheti is the director of thoracic medical oncology at NYU Langone's Perlmutter Cancer Center in New York, New York, and is also a Cancer.Net advisory panelist for lung cancer.

Marcia Horn is the President and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group in Phoenix, Arizona.

View full disclosures for Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn at Cancer.Net.

Dr. Charu Aggarwal: Hello and welcome to this Cancer.Net podcast on new research in lung cancer. I'm Dr. Charu Aggarwal from the University of Pennsylvania. I'm also the Cancer.Net Associate Editor for Lung Cancer. I'm here today with my colleagues from the Cancer.Net Lung Cancer Panel. First is Dr. Xiuning Le from the University of Texas MD Anderson Cancer Center. Hi, Dr. Le.

Dr. Xiuning Le: Hi, everyone. This is Xiuning Le from MD Anderson. I'm happy to be here as one of the discussants.

Dr. Aggarwal: Next is Dr. Vamsi Velcheti from the NYU Langone Perlmutter Cancer Center. Vamsi?

Dr. Vamsidhar Velcheti: Hi, this is Vamsi Velcheti. I'm so glad to be here with you.

Dr. Aggarwal: And our special guest today is Marcia Horn, the president and CEO of the International Cancer Advocacy Network and the executive director of the Exon 20 Group. Hi Marcia.

Marcia Horn: Hi, everyone. Wonderful to be here.

Dr. Aggarwal: So good to have you all. Before we begin, we should mention that Marcia has consulted with both Takeda Oncology and Janssen on survey research for the Exon 20 Group. You can view full disclosures for this podcast at Cancer.Net.

Our podcast today is going to be about targeted therapy for non-small cell lung cancer, and specifically, 2 new treatments that target a specific type of mutation or change in the EGFR gene in some cancer cells. This mutation is called an EGFR exon 20 insertion. Dr. Velcheti, I'll start off with you. What is targeted therapy, and how does it work?

Dr. Velcheti: So thank you, Charu. Lung cancer is a very complex biological disease. There are a lot of genes in the tumor cells that could be mutated, and understanding the type of genetic changes or mutations in the DNA of these tumor cells helps us really develop treatments that are very focused on that particular patient's cancer. Having a specific gene alteration could render tumors more susceptible or vulnerable to certain treatments, and these are what we call targeted therapies. And in lung cancer, these are especially important because there are a lot of drugs developed for patients with certain unique genomic aberrations, or changes in the DNA, and it's ushered in a whole wave of new treatments for patients with lung cancer, and it's really an exciting time for patients with lung cancer.

Dr. Aggarwal: That's terrific. And I would like to focus on the mutation aspect a little bit more. Dr. Le, can you talk to us [about] whether all mutations found in lung cancer, can all of them be treated?

Dr. Le: Like Dr. Velcheti was talking about, lung cancer is really a complex disease. And oftentimes in 1 lung cancer, we can detect more than 1, multiple mutations. Some of them function as driving the cell growth. Some of them function as a brake. We call that a tumor suppressor to release the cell from being suppressed. Clinically, we usually classify all the mutations that can be detected in the lung cancer into the 2 groups. One is called actionable. The other group is called not actionable. Actionable, meaning when we detect a mutation, we, as clinicians, can actually offer a specific targeted therapy to act on the mutation. Therefore, detection of the actionable mutation oftentimes translates to the patient potentially having the opportunity to get targeted therapy targeting that potential actionable driver oncogene. As of today, we're talking, the development of lung cancer treatment has been so advanced. We have 9 actionable genetic alterations that can be detected in non-small cell lung cancer. Even since 2 years ago, there are 4 new additions, so a total of 9 as of today, and EGFR exon 20 is one of the newest being approved in 2021, so really good news.

Dr. Aggarwal: I know we've come a long way, and EGFR exon 20 insertions have been known for a long time. However, we've also known that they are not perhaps as sensitizing as the other EGFR mutations. Dr. Velcheti, could you shed some light on what is unique about these mutations in terms of testing as well as application of therapies?

Dr. Velcheti: We have known about EGFR mutations in lung cancer for a very long time, and there have been quite effective treatments for EGFR activating mutation-positive lung cancer patients. However, not all mutations in the EGFR gene are the same. Depending on the location of the sequence change in the gene, they could have a different degree of response to EGFR inhibitors. So when we talk about EGFR exon 20, we're talking about a subset of these EGFR gene mutations which is in an area of the EGFR gene, a change in the sequence of the EGFR gene, that doesn't necessarily respond so well to the novel EGFR inhibitors that we have been using for a long time.

So the clinical implications, and it's something to kind of think about and remember, is that the way we test for these mutations is very different. You could do comprehensive genomic profiling, or in some cases, there are some tests that actually test for a specific type of gene mutation. So it's something we call "hotspot panels." Those are tests using certain techniques that actually only pick up certain EGFR genes, and they don't pick up all the gene mutations that happen in the EGFR gene. So it is very important to kind of keep that in mind because now we have drugs approved for exon 20 mutations. If you don't actually pick them up on a test, then obviously, we can't identify those patients for treatment with these exciting new treatments.

And also, just as a quick plug, given that we have so many new drugs approved for different types of gene alterations in lung cancer, it is even more important now to focus on doing really good biomarker testing with comprehensive genomic profiling looking at a wide panel of genes, rather than focusing on certain kinds of gene mutations. So this is what we call comprehensive genomic profiling. That's absolutely critical in order to identify patients for the right treatment with targeted therapy. So it's extremely important to do that upfront so that we have patients kind of matched up to the right treatment.

Dr. Le: I do also want to add with Dr. Velcheti in that I fully agree that exon 20 is oftentimes not on the hotspot PCR-based testing, so please use a comprehensive, what we call, next-generation sequencing base. I also want to say that also, exon 20 can be detected in liquid biopsy. So it's not you have to do the tissue biopsy if the patient has the opportunity to get liquid biopsy. As long as it's a good, comprehensive panel, it should also be able to detect that.

Dr. Aggarwal: Absolutely, can never underemphasize the benefits and importance of comprehensive testing. Marcia, I'll turn to you. You lead a large group called the Exon 20 Group. How common is the EGFR exon 20 insertion-- how common is this mutation in people with lung cancer?

Marcia Horn: It's not at all common. In fact, EGFR exon 20 insertion mutations in non-small cell lung cancer are exceedingly rare, a total of about 2% of all NSCLC and about 9 to 10% of all EGFR mutations. And it's an insertion mutation that hits, for the most part, never-smokers and members of Asian populations, although we at the Exon 20 Group have seen diagnoses in virtually every racial and ethnic group imaginable.

The Exon 20 Group was established in 2017 as a special project of ICAN. It was founded by an EGFR exon 20 insertion patient, Kevin Hamlin, and his brother, Bob Hamlin, who's a senior lecturer at MIT. What we all wanted to do was get an international working group put together, and before we knew it, we had this huge global coalition of not only many hundreds of patients for EGFR exon 20 insertion and HER2 exon 20 insertion representing about 54 countries, but we had care partners, family members, several hundred leading thoracic oncologists, medical oncologists, and members of the community oncology setting as well, plus biotechs, pharmas with drugs in the exon 20 pipeline, and members from molecular profiling labs and the basic sciences in exon 20 bench science.

So altogether, we're working to turn this into a chronic and manageable disease, and for the last 4 and a half years, we've been connecting our patients to promising clinical trials, especially the 2 newly approved drugs, and our angel buddy program provides our patients with peer-to-peer counseling to help them through side effects. So we're all united in blasting this disease off the planet and making the patient journey far more manageable.

Dr. Aggarwal: Incredible. I'm just so proud of what all you've achieved, and you serve such an important mission in terms of patient advocacy and, more importantly, support. Dr. Velcheti, there have been 2 new recently approved targeted therapies to treat non-small cell lung cancer that harbors an EGFR exon 20 insertion mutation, and really, these drugs have come to us within the last few months. How does the first drug, mobocertinib, work to treat this cancer?

Dr. Velcheti: Yeah, definitely. I think this is a really exciting time for thoracic oncology as we have more to offer our patients, especially for exon 20 and EGFR exon 20 specifically. We have 2 drugs now, FDA-approved, and mobocertinib is a small-molecule inhibitor. It's an oral drug, and this has been approved for patients who have EGFR exon 20 mutation. This is for patients who have already had platinum-based chemotherapy, and they have progressed, and these patients could now be treated with mobocertinib. Certainly, the activity, it seems like a very active drug. It's very promising. It's kind of similar to the other small-molecule targeted therapies that we have, but it does have side effects. Patients could potentially have diarrhea, which is kind of similar to other EGFR small-molecule inhibitors or drugs in the class, so it's something to kind of know when patients are being treated with this drug. Certainly, it's really nice to have more treatment options for these patients. So I think now we haven't had any EGFR small-molecule inhibitors show significant efficacy in this patient population, so this is a really welcome approval for patients. And there's also a new drug, which I'm sure Dr. Le is going to be talking about, amivantamab, which could also be an option for these patients.

Dr. Aggarwal: Speaking of, let's turn to Dr. Le about amivantamab. Can you tell us a little bit more?

Dr. Le: Yeah, amivantamab, again, represents a very exciting approval. I think, like Dr. Velcheti was talking about, the small-molecule inhibitor, but amivantamab represents a brand-new class of potential agents for exon 20 and many other oncogene targets in lung cancer.

So amivantamab, as the name signifies, is an antibody drug. It's not an oral drug. It's an IV drug. The antibody has 2 heads, basically. One is targeting EGFR. The other is targeting another oncogene called MET. So it's a bispecific antibody. The mechanism of action is also different than the small-molecule inhibitor such as mobocertinib in that it's not disabling the ATP-binding kinase activity of EGFR, rather than its antibodies to go after the EGFR on the cell surface and disable or internalize the receptor a different way. So I say that we're excited because it represents a really brand-new group of targeted therapy that we're probably going to see coming in the next decade, not just limited to the small-molecule inhibitor, of course, from the research, and also opens opportunity for future combinations.

In terms of usage, so again, this medication is approved in patients who have EGFR exon 20 insertion, who had prior treatment. It's an IV treatment, and then the IV is rather frequent, every 2 weeks. The drug showed really great safety and then induced response in about 40% of the patients, a nice addition to the tools we have that we can battle the disease.

Dr. Aggarwal: It's amazing that we have 2 drugs in this space. Can you talk, in your personal experience, pros and cons of each approach and if there is any data to guide using 1 drug versus another or in sequence? We'll start with you, Dr. Le, and then we'll go to Dr. Velcheti.

Dr. Le: Yeah. So that's a very good question. I don't think we have the 1 perfect answer because we haven't conducted either head-to-head trials or sequential trials. When I'm in my clinic, I tell my patients that both of them are valid options. And most likely, 1 patient will be receiving 1 and the other because I think each of the medications also have a limit of after a certain time, the disease will continue to progress. So we shouldn't be ruling out either of them rather than thinking of them as being the sequential treatment. One thing I do also discuss with the patient is the drug administration - one is IV; one is oral - and then toxicity profile. The amivantamab, the most common issue is the infusion reaction in the first time that the patient's receiving it. However, after that's properly managed, the drug is really easy to tolerate down the line. So usually, I present both options to patients. I would have to say that numerically speaking, the response rate of amivantamab is higher than the reported of mobocertinib. So sometimes, together with the patients and family, we decide to go for amivantamab first and then save oral TKI as the next option, but really, there's no right or wrong. And then I tell the patient most likely, they will be receiving both in the end.

Dr. Aggarwal: Your thoughts, Dr. Velcheti, on that approach? Anything different that you do?

Dr. Velcheti: No, I completely agree with Dr. Le. Both of them are very different drugs. So Dr. Le mentioned they work in very different ways. They have, most importantly, very different adverse event profile. So we don't know about what the right sequencing should be. We don't have those studies to really inform us. But I do the same thing that Dr. Le just mentioned. Given slightly higher response rates, we tend to use amivantamab first, but again, it's really patient preference. I've had patients who said they don't want to have IV infusions. They prefer oral treatment. They don't want to come into the hospital that often. And there are some patients who are really concerned about the diarrhea. So it's really hard to kind of know what would be the perfect sequence, and especially, it's a rare population, so it's going to be really hard to do a trial, to kind of do a cross-trial comparison. That's all we have here in terms of making decisions.

The other thing to also consider is, do we use these 2 drugs, one after the other, if they progress? I think given that they work in a very different way mechanistically, I do think if you progress on mobocertinib that doesn't necessarily mean you will not respond to amivantamab and vice versa. So I would encourage trying sequential approach. And also the other thing to also keep in mind is there are a lot of clinical trials with exciting drugs which are in the pipeline, and, of course, some of the data has already been presented and those look really promising. So I highly encourage patients to kind of consider participating in clinical trials.

Dr. Aggarwal: That's such a fantastic summary. And Marcia, I will turn to you. What do these new drugs mean for patients with this rare subset of an actionable mutation?

Marcia Horn: I totally agree with Dr. Le and Dr. Velcheti and their comments based on their deep, deep experience with EGFR exon 20 insertion patients. No question that, from the point of view of the Exon 20 Group, we were totally thrilled at the FDA approvals of both amivantamab and mobocertinib. And we, like everyone else, affectionately call both drugs as ami and mobo. These drugs are providing a concrete lifeline of hope, for the first time, that patients' lives can be extended and patient journeys can be manageable in terms of side effects. So what we're really excited about in the Exon 20 Group is not only the continuing clinical development of ami and mobo and other promising drugs in the pipeline, as Dr. Velcheti said, but we're looking forward to seeing ami and mobo in combination with second drugs. We're awaiting data down the road, obviously, from the ongoing amivantamab plus lazertinib trial that is recruiting, in part, EGFR exon 20 insertion patients, and we're really excited about drugs that can be combined with mobocertinib as well. We want a robust pipeline of numerous choices and good compounds.

Dr. Aggarwal: And Marcia, given the amount of information in this subgroup, what questions should patients ask their doctors about these new treatments?

Marcia Horn: We really think it's important for patients on diagnosis to ask their clinicians what the method of communication is going to be between patient and physician. This is not only important on diagnosis of EGFR exon 20 insertion mutated cancer, but it's really, really important when the patient is accessing either ami or mobo or a drug in clinical trials. So patients need answers on who is going to be answering their questions about side effects when they write those questions into a patient portal, and they have to have the sense that somebody is going to be listening to them in the event that the collateral medications that an oncologist may be giving them in conjunction with a clinical trial drug or in tandem with either ami or mobo-- if those collateral medications are not tamping down on side effects to the extent that we all want to see, we, for sure, want that patient to be talking to the treatment team, the study team, or whoever, and getting some quick answers because frankly, nothing is more tragic than a patient withdrawing from a drug for failure to manage toxicities, and we never want to see that happen. We do everything possible at the Exon 20 Group to make sure patients are outfitted with angel buddies who have lived, battle-hardened experience with that particular drug, and these drugs are manageable.

Dr. Aggarwal: So much excitement going on in this space, and we are thrilled to be able to offer these approaches. But I will just summarize that we wouldn't be able to extend these benefits if we don't test, and comprehensive testing remains critical in diagnosing and delivering appropriate therapy. Thank you so much, Dr. Le, Dr. Vamsi Velcheti, as well as Marcia, for joining us today for this Cancer.Net podcast. You can learn more about lung cancer and how it's treated by visiting Cancer.Net. Thank you, everyone.

Dr. Le: Thank you.

Marcia Horn: Thank you.

ASCO: Thank you, Dr. Aggarwal, Dr. Le, Dr. Velcheti, and Ms. Horn. Learn more about lung cancer at www.cancer.net/lung. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

In this podcast, Dr. Tian Zhang and Dr. Afreen Shariff discuss common and sometimes serious side effects caused by a type of immunotherapy called "immune checkpoint inhibitors." They also explain why it is important for people with cancer to track the side effects they experience and discuss them with their health care team.

Dr. Zhang is an associate professor of Internal Medicine at UT Southwestern Medical Center and is a medical oncologist at the Harold C. Simmons Comprehensive Cancer Center. She is also a Cancer.Net Specialty Editor.

Dr. Shariff is an endocrinologist and assistant professor of medicine at Duke University School of Medicine and the Associate Director for the Multi-Disciplinary Toxicity Program at the Center for Cancer Immunotherapy at Duke Cancer Institute.

Together Dr. Zhang and Dr. Shariff host a podcast called Checkpoint NOW discussing a multidisciplinary approach to managing side effects of immunotherapy. Learn more and listen at www.checkpointnow.org.

View full disclosures for Dr. Zhang and Dr. Shariff at Cancer.Net.

Dr. Zhang: Hi, everyone. Thank you for joining. My name is Tian Zhang, and I specialize in treating patients with kidney, bladder, and prostate cancers. I'm happy today to be joined by my wonderful colleague at Duke, Dr. Afreen Shariff.

Dr. Shariff: Hello, everyone. I'm Dr. Afreen Shariff, endocrinologist, assistant professor of medicine, and associate director at the Center of Cancer Immunotherapy at Duke Cancer Institute. We're happy to talk today on the podcast Cancer.Net about immune checkpoint inhibitors and associated side effects that many patients often are concerned about. Neither of us have any disclosures related to this podcast content.

Dr. Zhang: Thanks, Afreen. With the increase in use of immune checkpoint inhibitors for patients with cancer and the prevalence of side effects and toxicities, we thought it was important for patients to understand what side effects to monitor for and when to contact their doctors for further guidance and management. We thought we would put together this particular podcast to focus on side effect monitoring from a patient perspective.

Dr. Shariff: I agree. We have some side effects that can potentially be attributed to multiple toxicities, but there are others that can be pretty straightforward. These are times when referrals to subspecialists like myself are necessary. And at other times, the treating oncologist primarily manages toxicities. The more patients know, the better prepared they will be when starting on immune checkpoint inhibitors. Tian, let's get started. When you are introducing a new start for immune checkpoint inhibitors to a patient in your clinic, what is your overall advice?

Dr. Zhang: Afreen, I think it's so important for patients to understand the general scope of side effects to monitor for. These include rashes and diarrhea, which are more common and relatively straightforward to attribute, but also other nonspecific symptoms like fatigue. I start with an overview about common side effects of rash and diarrhea, discuss a little bit more about rare side effects of inflammation in the lungs or liver, and then talk about potential endocrine side effects. And we do that all when the patient's starting immune checkpoint inhibitors in my clinic.

Dr. Shariff: Oh, that's great, Tian. What should patients know about diarrhea?

Dr. Zhang: Sure. So diarrhea is reflective of inflammation in the colon, what we call colitis. And this can occur in mild form or in a more severe form and is 1 of the most common side effects of immune checkpoint inhibitors. Changes in stool caliber, particularly loose or watery stools, and also frequency per day should be quantified and noted. Diarrhea does not often have blood, but bloody stools are also possible and should be reported. If bowel movements while on checkpoint inhibitors increase to 2 to 3 times more per day above baseline, patients should start reporting these to their treating oncologists for further management.

Dr. Shariff: Well, I'm sure our audience and some of the patients on immune checkpoint inhibitors will find this very useful. Now, skin rashes are seen quite commonly as well. For patients being treated with immune checkpoint inhibitors, what would you like them to know about these rashes?

Dr. Zhang: Sure. Of course, skin rashes vary from mild to severe and treatment varies with the diagnosis. If patients notice blisters and pain, this can certainly be an emergency and needs to be evaluated further by their oncologist who may then refer them to a skin doctor for more treatment. Large patches of red rashes can also be concerning. In general, we start with topical steroids for mild rashes and then add on oral steroids if topical ones are not controlling the rash.

Afreen, we see fatigue so often in patients treated with immune checkpoint inhibitors. Can you share some insight into different side effects that can cause fatigue?

Dr. Shariff: Tian, this is a very important question and common concern expressed by many patients. Now, often it is difficult to identify the cause if fatigue occurs in isolation without any other symptoms. Now, fatigue can result from immunotherapy and from cancer itself. But what I want to emphasize is the difference between ongoing fatigue and profound fatigue, which is a severe version affecting everyday activity levels. When patients experience profound fatigue, it's important to know what other symptoms are present that can help with identifying a cause.

Dr. Zhang: Great. And what other symptoms should patients be aware of?

Dr. Shariff: Sometimes this occurs with headaches and vision changes, indicating a side effect causing inflammatory changes of the pituitary gland in the brain. If this is a concern, your oncologist will advise further testing and a referral to a hormone doctor like myself called an endocrinologist. Now, if fatigue occurs with rapid weight loss, increased heart rate, and tremors, these can be signs of an overactive thyroid called hyperthyroidism. Now, in contrast, fatigue with weight gain can indicate an underactive thyroid. Both of these thyroid-related side effects will require lab evaluation to confirm a diagnosis.

Dr. Zhang: Afreen, fatigue is so common and also a presenting symptom for diabetes, as well. Can you tell us more about this?

Dr. Shariff: Yes. Fatigue and weight loss are common in new-onset or worsening diabetes. With immune checkpoint inhibitors, you can see a rare side effect of insulin deficiency, which is called type 1 diabetes. It's a rare side effect and needs treatment right away. What makes the symptoms a little different is that this fatigue is seen with increased thirst and appetite and a high blood sugar, which helps with the diagnosis. Now, Tian, we also see fatigue with shortness of breath. Now, what side effects can cause this?

Dr. Zhang: When a patient comes in with shortness of breath, we're often thinking about heart and lung toxicities from immune checkpoint inhibitors. Measuring oxygen saturation helps. Sometimes patients who have inflammation in their lungs, what we call pneumonitis, will have decreased oxygenation levels. In the clinic, if patients report shortness of breath on exertion, we will also obtain EKGs, echocardiograms, and other labs to evaluate for heart dysfunction. And often, subspecialists will help us in managing lung and heart toxicities from immune checkpoint inhibitors.

Dr. Shariff: Excellent. Now, what other complications can we see in a patient treated with immune checkpoint inhibitors?

Dr. Zhang: Liver dysfunction is 1 that we haven't talked about yet, and liver dysfunction is often without symptoms. Oncologists will monitor liver function generally every few weeks when patients are treated with immune checkpoint inhibitors. An elevation from baseline will spark suspicion that the immunotherapy is responsible, or other drugs. And often we will involve a liver specialist. And if, due to the immune therapy, we'll often treat that with steroids.

Dr. Shariff: That's very helpful. Now, what about other toxicities like kidney toxicity and toxicities to the nervous system?

Dr. Zhang: Sure. Certainly, these are rare forms of toxicities, the ones that affect the kidneys or neurologic toxicities. But they can certainly happen. For kidney toxicities, we would monitor kidney function on labs and sometimes would need to involve a kidney specialist. These are often primarily treated with steroids. Neurologic toxicities are rare but can be disabling and dangerous if diagnosed late. So patients can experience symptoms ranging from mild, like numbness and tingling, to more severe symptoms of weakness and paralysis. These situations often involve the input of a neurologist.

Dr. Shariff: Thanks, Tian, for your insight on these rare side effects. Interestingly, some side effects may be picked up on labs while patients may not have any symptoms. This is why oncologists are often checking blood work with every treatment. And it's important to bring up symptoms when you do experience them while on treatment. While these side effects are concerning, it's important to have a conversation with your treating oncologist to weigh your risk for each of these side effects. Most importantly, remember that a majority of these less severe side effects are manageable and do not need interruption of immune checkpoint inhibitors. This is a general guidance, and it's important to always refer to your treating clinician.

Dr. Zhang: Thanks, Afreen. I hope this session helps bring awareness for symptom management and side effects management for patients on immune checkpoint inhibitors. For other information on specific toxicities, there are several resources. You can follow us on Twitter at CheckpointnowMD, check out our podcast, Checkpoint Now, on Apple Podcast or Spotify, or also go onto the Cancer.Net website with more information on disease-specific treatments and toxicities.

ASCO: Thank you Dr. Zhang and Dr. Shariff.

To learn more about immunotherapy and its potential side effects, please visit www.cancer.net/immunotherapy. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, Cancer.Net Associate Editors discuss new research in brain tumors and gastrointestinal cancers presented at the 2021 ASCO Annual Meeting, held virtually June 4-8.

First, Dr. Glenn Lesser will discuss new research in 2 types of brain tumors, craniopharyngioma and glioblastoma.

Dr. Lesser is the Louise McMichael Miracle Professor and Associate Chief in the section on Hematology and Oncology in the Department of Internal Medicine at Wake Forest University, and is the Director of Medical Neuro-Oncology at the Atrium Health Wake Forest Baptist Comprehensive Cancer Center. He is also the Cancer.Net Associate Editor for central nervous system tumors.

View Dr. Lesser's disclosures at Cancer.Net.

Dr. Lesser: Hello. My name is Glenn Lesser, and I'm a professor of medical oncology and the Director of Medical Neuro-oncology at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina. I'm also the editor of the brain tumor section for ASCO's Cancer.Net. And today, I would like to briefly discuss 2 clinically relevant research studies involving patients with brain tumors that were presented at this year's ASCO's Virtual Scientific Program. I have no disclosures or relationships relevant to the second abstract I'll be discussing today. But by way of full disclosure, I have enrolled patients and I'm a co-investigator on the first study I'll describe.

As an introduction to those listeners not familiar with the current treatment options for patients with brain tumors, it's important to remember that patients with primary tumors of the brain have not seen the recent rapid advances in effective treatment strategies that patients with other malignancies have experienced. Thus, those of us who treat these patients really actively await the research results, which are presented and highlighted annually in several of our key national meetings, including ASCO, or the American Society of Clinical Oncology, Annual Meeting, which was, again, held virtually this year in light of the pandemic. I have selected several abstracts whose results, I believe, have immediate clinical relevance and can be used to modify our current standard of care therapies for the subgroups studied.

First abstract of interest was the presentation by Dr. Brastianos, who is the principal investigator of the Alliance A071601 study, which is a phase II trial of BRAF/MEK inhibition in patients with a tumor called a newly diagnosed papillary craniopharyngioma. A craniopharyngioma's a very uncommon tumor that can occur in both adults and children. And it typically arises in the region of the optic chiasm, a very important structure related to vision, and the pituitary gland, which is responsible for the production of a variety of hormones or compounds which stimulate other glands in the body to produce key hormones. These tumors often have cystic and solid components. And, as they grow, they compress the optic chiasm and the pituitary gland to produce symptoms, including loss of bilateral peripheral vision. Standard therapy for these lesions has included 1 or more surgeries and treatment with radiation therapy, including both external beam radiation and stereotactic radiosurgery.

Although these tumors are generally not felt to be malignant, their continued growth and compression of surrounding structures leads to significant morbidity and symptoms, which dramatically worsen the quality of life of patients who have them and which, rarely, can be fatal. In adults, the most common variant of these tumors is called a papillary craniopharyngioma. And Dr. Brastianos and others have previously shown that these papillary tumors almost always have a driver mutation known as a BRAF V600E mutation. Now, a driver mutation is a specific mutation in the DNA, the instruction manual of the tumor cells, that gives those cells a selective growth advantage and, thus, promotes the cancer's development and spread.

In contrast, passenger mutations are mutations that may be present in the cancer cells but don't directly promote their growth or survival. The tumors that contain these driver mutations have the potential to be selectively targeted and effectively controlled by drugs which have been developed against that particular characteristic mutation. So this study builds on earlier case reports showing fairly dramatic regressions of these tumors with the use of agents that have been developed to target the BRAF V600E mutation, which is a characteristic of the more common aggressive melanoma skin cancer.

Over the last decade, 3 sets of drugs have been developed and brought to market, which have great efficacy in killing cells with this specific mutation. These drugs include a BRAF inhibitor, which targets the BRAF gene, and a MEK inhibitor, which essentially blocks an escape mechanism that the tumor cells try to use when confronted by the BRAF inhibitor. This is the only example I know of in oncology where giving 2 drugs leads to actually fewer side effects than if only the BRAF inhibitor was given by itself. But this trial had 2 cohorts of patients, 1 where it involves 16 patients with newly diagnosed craniopharyngiomas and a second arm enrolled patients whose craniopharyngioma recurred after radiation plus or minus surgery. The drugs used in this trial were vemurafenib and cobimetinib. And the goal was to give patients at least 4 months of this oral combination therapy. Dr. Brastianos presented the results of the newly diagnosed cohort, or Cohort A, at this year's ASCO. Remarkably, 15 of the 16 treated patients, or 94% of those treated, had a volumetric response, meaning a significant shrinkage of the tumor based on a central, independent review of their brain MRI scans. In fact, the only patient who didn't respond only received 2 days of treatment before they had to stop the medications due to some drug-related toxicity. So not only did these patients respond, but the median reduction in their tumor size was about 91%. And, furthermore, these responses appeared to last a long time, with only 1 patient recurring at the time the data was analyzed for ASCO.

The estimated overall survival of the patients on Cohort A at 2 years was 100%, while their estimated progression-free survival at 2 years was 93%. Phenomenal results. These drugs do have a variety of side effects which can occur to someone commonly and may lead to drug discontinuation in as many as a third of patients, although not nearly that many discontinue these drugs due to toxicity on this particular trial. These results, I believe, really establish combination-drug therapy with BRAF and MEK inhibitors as an effective standard-of-care option for selected patients with these newly diagnosed papillary craniopharyngiomas that contain a BRAF mutation. We're anxiously awaiting both longer-term follow-up of this study to determine the durability of these responses as well as the presentation of the results of Cohort B, which treated patients with recurrent disease after radiation.

The second study I'd like to highlight was presented in the oral poster session by Dr. Domenech on behalf of her colleagues in the GEINO, the Spanish Neuro-oncology Cooperative Group Trial 14-01. She presented the long-term results of this prospective trial, which randomized patients with newly diagnosed glioblastoma to 6 cycles of adjuvant temozolomide versus continuing the temozolomide for up to 12 monthly cycles of therapy. But since the publication of Dr. Roger Stupp's landmark trial in the New England Journal of Medicine in 2005, the standard therapeutic approach around the world for patients with newly diagnosed glioblastoma has included concurrent radiation and temozolomide chemotherapy for about 6 weeks, so both given at the same time, followed by monthly adjuvant temozolomide for 6 to 12 months with the drug being given for 5 days in a row each month. We have learned much about the molecular subgroups of glioblastoma and the characteristic molecular findings that may predict a given patient's responsiveness to this therapy since this publication. To date, however, clinical trials have not convincingly determined whether the benefits seen by adding chemotherapy to radiation stem from the concurrent phase of therapy, the adjuvant or post-radiation phase of therapy, or the entirety of the concurrent followed by adjuvant temozolomide. Furthermore, although the initial pivotal study described only 6 months of adjuvant monthly temozolomide to patients, many practitioners have felt that, frankly, more is better, particularly with a well-tolerated drug like temozolomide. And many physicians routinely give up to 12, or even more, monthly cycles of the drug.

As a result, many clinical trials over the last 15 years have allowed investigators to treat to the duration of their choice. Those in favor of this approach believe that more anti-cancer therapy is better, while those who limit temozolomide to only 6 months cite the increased cost, the increased rate of side effects or toxicities, as well as the mutational stress that prolonged alkylating therapy might put on tumors, which can theoretically lead to a more resistant tumor at the time of recurrence.

GEINO 14-01, which enrolled 159 patients, is the only large, prospective attempt to randomize patients to 6 or 12 cycles of adjuvant temozolomide therapy. The presented findings clearly show that adding 6 cycles of temozolomide after the first 6 adjuvant cycles produced no additional benefit in overall survival. With a median follow-up of about 20 months, there was no difference in the percent of patients surviving at 2 years between the arms, nor was there a difference in the percent of long-term survivors defined as survival of at least 30 months from the diagnosis. Patients in the extended therapy arm did experience an increase in hematologic or blood count toxicities in addition to the added cost and additional doctor visits the extended treatment generated. The authors, somewhat respectfully, concluded that the results of this trial should be corroborated in a prospective phase III trial. However, it's unlikely that such a trial will ever be mounted. And these results are likely going to be the best data we have to guide our approach in the future. Although more data will be provided in the full publication of the results of this trial, the presented results indicate that in most patients with newly diagnosed glioblastoma, the standard of care should involve a maximum of 6 months of adjuvant temozolomide chemotherapy.

In conclusion, the investigative teams behind both of these studies I've just described are to be commended on their efforts, which provide guidance on how best to care for patients with craniopharyngiomas and newly diagnosed glioblastoma. These studies are also outstanding examples of why well-done clinical trials that carefully test and evaluate the beneficial effects, as well as the toxicities of new cancer treatments, are critical to our goal of optimizing the treatment of our patients with cancer. Thanks so much for listening today.

ASCO: Thank you Dr. Lesser.

Next, Dr. Jeffrey Meyerhardt will discuss new research in esophageal and colorectal cancer. Dr. Meyerhardt is the Douglas Gray Woodruff Chair in Colorectal Cancer Research, Clinical Director and Senior Physician at the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute, Deputy Clinical Research Officer at the Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School. He is also the Cancer.Net Associate Editor for gastrointestinal cancers.

View Dr. Meyerhardt's disclosures at Cancer.Net.

Dr. Meyerhardt: My name is Jeffrey Meyerhardt. I'm a gastrointestinal oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. I'm an Associate Editor of Cancer.Net, ASCO's patient information site. Today, I'm going to discuss research on gastrointestinal cancers that were presented at the 2021 ASCO Annual Meeting. I do not have any relationships to disclose related to these studies. I'm going to focus on some studies related to esophageal and gastric cancer as well as studies in colorectal cancer. For esophageal and gastric cancer, we saw a variety of studies for immunotherapy in different settings. I think some important background information in considering esophageal and gastric cancer is that there are similarities and differences between the 2 cancers. Esophageal cancers can be squamous cell or adenocarcinomas. Gastric cancers that'll be discussed here are adenocarcinomas. In between the esophagus and the stomach is the gastroesophageal junction, one of the cancers with increasing incidence overall. They are also typically adenocarcinomas. For non-metastatic disease, the location of disease is treated differently. But for metastatic disease, most standard chemotherapy trials lump all of these sites together and have mixed squamous cell carcinoma and adenocarcinoma of the esophagus together. However, with immunotherapy, there are differences emerging to rethink this concept. While there are challenges in finding reliable markers to determine efficacy of immunotherapy in all cancer types, 2 markers have emerged relevant to gastro and esophageal cancer, PD-L1, or the combined positive score, and tumor mutational burden, which signals immunogenicity of a cancer.

While there were a wealth of studies of immunotherapy, 1 study that was noteworthy at this year's ASCO was CheckMate 648. The CheckMate studies have focused on the PD-1 inhibitor nivolumab. Checkmate-648 was a randomized study comparing unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma, previously untreated, randomized to 1 of 3 treatments. Nivolumab with 2 standard chemotherapies, 5-FU and cisplatinum, versus nivolumab and ipilimumab, a no-chemotherapy, just-immunotherapy arm, or chemotherapy only with 5-FU and cisplatinum. Nivolumab and ipilimumab was superior to chemotherapy only alone for overall survival and progression-free survival, particularly in patients with PD-L1 scores greater than or equal to 1%. Of note, there are some patients that don't benefit early on, which has been seen in other studies comparing chemotherapy to immunotherapy. There was similar overall and progression-free survival for immunotherapy alone compared to nivolumab, 1 immunotherapy with chemotherapy. More immunotherapy-related toxicities were seen with the combined immunotherapy arm, but more GI toxicities were seen with nivolumab plus chemotherapy. Overall, this study provides a non-chemotherapy option for patients as initial therapy for esophageal squamous cell carcinoma.

Turning to colorectal cancers, there are 2 studies that I wanted to highlight. The first study was the DESTINY-CRC01 study. This was a phase II study of trastuzumab deruxtecan, T-DXd, which is an antibody-drug conjugate of humanized anti-HER2 antibody bound to a chemotherapy, a topoisomerase I inhibitor. A phase II study means all patients got the same drug. The study focused on a limited population of metastatic colorectal cancer patients who overexpressed a protein called HER2. As with other cancer types, it is important to have molecular testing of colorectal cancer that may determine certain treatment options for patients. The several molecular features in colorectal cancer that are proven most important in treatment decisions include microsatellite instability, a feature that predicts effectiveness of immunotherapy; KRAS and RAS mutations that the lack of efficacy of a class of drugs called epidermal growth factor inhibitors like cetuximab and panitumumab; BRAF, which has specific drugs that target this mutation; and HER2. HER2 overexpression was first targeted in breast cancer. And there are also overexpressing stomach cancers that benefit from HER2-directed therapy. Approximately 3 to 4 percent of metastatic colorectal cancers overexpressed HER2. The DESTINY trial focused on patients who had progressed on at least 2 prior lines of therapy. So a heavily-pretreated population, 45% of patients with significant overexpression had a response to therapy. And 83% had disease control with a median of greater than half a year.

Interestingly, the drug was meaningfully active in patients who had prior HER2-directed therapy. While the drug had some expected toxicities, 9% of patients also experienced something called interstitial lung disease, inflammation of the lungs, which would need to be monitored. However, this drug does show promise in the armamentarium of targeted therapies for metastatic colorectal cancer.

The last trial I wanted to focus on is FOCUS4. This trial compared maintenance therapy with capecitabine, an oral form of 5-FU, versus active monitoring for patients with metastatic colorectal cancer. This is a topic that I found so important over the years and have not received as much attention I think it deserves. Fortunately, there are multiple trials in this field. And I think it's important to highlight them when new ones result. The basic principle is that when treating colorectal cancer these days with combinations of different chemotherapies, it is not uncommon to have a patient experience good disease control for prolonged periods of time. Initially, trials for metastatic colorectal cancer decades ago just continued therapy for as long as the disease was controlled for undue toxicities. However, with more effective therapies, there also have been increasing cumulative toxicities that catch up with patients over time. And there has been interest in continuing and considering changing at some point from multiple combination regimens to either maintenance therapy, some people call "chemotherapy light," or giving a full holiday off therapy. And there have been multiple trials over the years that have looked at these strategies. What is clear from those trials is that patients don't do better just staying on combination therapy. However, maintenance therapy is still chemotherapy. And a key to understand, is that even necessary? Are patients compromising outcomes by taking periods off of treatment?

FOCUS4 was a trial in the U.K. that randomized patients with metastatic colorectal cancer whose disease was controlled after 16 weeks of first-line combination therapy. They received either capecitabine with a usual 2 weeks of pills followed by 1-week break--or active monitoring with scans every 8 weeks. While the time till this tumor grew was shorter fully off of chemotherapy, the overall survival was not different between the 2 arms. This lack of overall survival has proven out in other trials. It was recently seen in a meta-analysis published in the Journal of the American Medical Association of Oncology recently. Active monitoring may not be the best option for every patient. But I think it is an important discussion between patients and their oncologists to balance quality of life and continued disease control.

Thank you for listening to this brief summary of new research in gastrointestinal cancers from the 2021 ASCO Annual Meeting.

ASCO: Thank you, Dr. Meyerhardt. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

Brielle Gregory Collins: Hi, everyone. I'm Brielle Gregory Collins, a member of the Cancer.Net content team, and I'll be your host for today's Cancer.Net podcast. Cancer.Net is the patient information website of ASCO, the American Society of Clinical Oncology. Today, we're going to be discussing how parents can talk with their children about a metastatic cancer diagnosis and their prognosis. The information discussed in this podcast is based on a study published in JCO Oncology Practice titled, "Talking with Children About Prognosis: The Decisions and Experiences of Mothers with Metastatic Cancer." Our guests today are Dr. Eliza Park and Dr. Paula Rauch. Dr. Park served as the lead author on the study, and Dr. Rauch served as a co-author on the study. Dr. Park is the deputy director for the UNC Lineberger Comprehensive Cancer Support Program at the University of North Carolina at Chapel Hill in Chapel Hill, North Carolina. Thanks for joining us today, Dr. Park.

Dr. Eliza Park: Thank you for having me.

Brielle Gregory Collins: Dr. Rauch is the director of the Marjorie E. Korff Parenting At a Challenging Time, or PACT, program at Massachusetts General Hospital in Boston, Massachusetts. She is also a member of the Cancer.Net Psychosocial Oncology Advisory Panel. Thanks for joining us today, Dr. Rauch.

Dr. Paula Rauch: My pleasure.

Brielle Gregory Collins: Before we begin, we should mention that Dr. Rauch and Dr. Park do not have any relationships to disclose related to this podcast, but you can find their full disclosure statements on Cancer.Net. Now, to begin, Dr. Rauch, what are some of the challenges or fears parents with metastatic cancer have in talking with their children about their illness?

Dr. Rauch: I think as parents themselves are adjusting to their own diagnosis, whether it's the parent who is living with the cancer or their co-parent, they are hoping to not burden their children, to not worry them too much, and at the same time, they want to be sure to include their children in this very important event that's happening in the life of the family, and that is a tough balance for any parent.

Brielle Gregory Collins: And I recognize that these conversations might be different for parents who don't have metastatic cancer. So what ways are these discussions different when parents have non-metastatic cancer?

Dr. Rauch: I think for me, the easiest way to talk about this is to think about how we encourage parents to talk with their children about cancer, and that varies depending on the age of the child. But 1 way that we often talk with parents that they may explain cancer to younger children is to talk about the fact that our bodies are made up of millions and millions and millions of teeny-weeny, little cells that are kind of like Legos, and that what cancer cells are, they're kind of like Legos that are mixed up and don't fit together right and can't do their jobs right. When someone has an early-stage cancer, the goal of treatment by their medical team is to be able to get rid of the cancer completely. The goal of treatment when someone has metastatic disease, when those mixed-up cells are in more than 1 place in someone's body and the treatment can't make them go away completely, the goal is to keep those mixed-up cancer cells as small as possible and in as few places as possible so they don't interfere with a person's healthy cells.

Brielle Gregory Collins: Okay, thank you for explaining that. And what do parents with metastatic cancer need to know before talking with their children about their illness?

Dr. Rauch: I think parents generally know their children well. And so part of what they are thinking about is, first off, what is communication like typically in their household, what's the developmental stage of their child, what's their child's understanding of things, and also importantly, what their child's temperament is. You could think about temperament in children as being a little bit like personality in adults, but temperament is a way of capturing that kids have a typical way of adjusting to or understanding changes in their lives and in events that happen at home. And so taking all those things into consideration, parents may want to share information at a particular time, maybe at the beginning of a weekend when they have time to process with their child. They may have a good sense of what their child's understanding is. An older child may know a lot about cancer, a younger child, almost nothing. So we really think about parents as the expert on their own children. We have a lot of experience with the kinds of words that you can use in talking to children, but it's always a partnership of parents knowing their children and what their usual way of communicating is and then adapting this particular set of information to that knowledge base.

Brielle Gregory Collins: Okay. And I want to talk a little bit about prognosis and what parents should know about talking with their children about their prognosis. So first of all, just getting into that topic, why is it important for parents with cancer to know what their prognosis is?

Dr. Rauch: Well, you can't really explain anything to your child that you don't understand well yourself. Many parents will tell us that they find themselves asking really important questions of their oncology team because their children ask them really good questions or because even if they're not quite ready to describe fully something to their child, it's kind of like they want a script in their back pocket that they can draw upon if questions come up. When we have a sense of how we want to answer something, then it's easier to present a calm presence to children and really then to help them to feel their questions really are welcome.

Brielle Gregory Collins: Thank you, Dr. Rauch. And Dr. Park, branching into the study, you've described several different approaches that parents can use when talking about their prognosis with their children. So can you summarize for us what those strategies are?

Dr. Park: So that's a good question, and I would say, in taking a step back, kind of the overarching kind of goal of the study is that we know that these conversations can be nuanced and that they can be challenging. So given that we know that there's multiple decisions and challenges related to this, kind of how are the ways that parents who are remarkably resilient, thoughtful, find ways to kind of thread this needle in a way that makes sense for them and their families? And I think 1 of the main takeaways is to think about it is almost as, "What does honesty mean kind of when talking about cancer?" Because what can be an honest conversation in 1 family can look dramatically different from another's, and that's not to say that either way is better or worse, just different. So for some families, that meant discussing details about what their scans looked like and what that meant for their treatment and for the stage of their cancer, and for other people, it meant bringing up the possibility that their illness was chronic or may not be curable. And what we found is that for most parents, it was less about whether they should say something at all but rather a timing of when, and that takes a variety of decisions related to the factors that Dr. Rauch mentioned earlier.

Brielle Gregory Collins: I know in the study, there were several strategies that were outlined, so I want to go back to that for a minute. Do you mind just walking through what each of those strategies individually was and what they mean for parents who might be talking about this with their children?

Dr. Park: Absolutely. So as I mentioned before, there was many different strategies. So what I'm going to describe may not reflect everyone's experience, but the main 1 that we identified is parents simply wanted to be honest, and what that meant in terms of discussing their prognosis then took a variety of different forms. And so the strategies that came up most frequently that parents described using was, 1, kind of introducing the language of illness that might not get better in a way that can be fairly gentle. And so the language that many parents used was kind of, "Treatment for the rest of my life," and this was a way of signaling some of the changes that are going to be happening in their family moving forward but not necessarily including other statements that the children may not necessarily-- or the parents may not necessarily be ready to discuss right then and there.

The other common strategy that parents, I think, very instinctively used was having these many conversations over time. I think that the truth is this is not a 1 and done, to use a basketball analogy, conversation. This is something that happens kind of over the dinner table, at bedtime, in car rides, over the course of weeks, months, or most commonly, years, and there are a lot of children who grow up with a parent with cancer, and over time, the details can kind of emerge.

The third major way that parents would often approach these conversations was via questions, and the truth is that these conversations about prognosis were not always initiated by the parent. We had children as young as 4 who were asking questions about kind of what this means and what might happen next. And so parents often kind of look to their children's questions as kind of cues for cues of what they believe their child may be ready for in terms of specifics.

And I would say that the kind of last strategy is something that is just instinctual that I think every parent does without even thinking about it, which is just really reinforcing their love and their desire to help reassure their children that this may be information or news that is not desired but that they want the best for their children and to help their children feel secure, and I think that was probably the message that emerged in almost every description of parents' conversations with their children.

Brielle Gregory Collins: Thank you. And in the study, the most common barrier to having these discussions was that the parent didn't know what to expect in the future. So can you tell us a little bit more about that?

Dr. Park: Yes. So this was something that I think can be overlooked when we think about just, "What are the challenges in having these conversations?" I think we all understand that it can be emotionally taxing for parent or child, depending on what is happening with the illness, but this uncertainty about what happens in the future, I think, is a reflection of just how much progress has occurred in cancer therapies over the past decade. Many of our participants in the study had breast cancer, and these days, women can live with metastatic breast cancer for a decade or longer, and other individuals may not have quite the same expectation. And so because it can be so hard for patients as well as their providers to kind of be able to predict what happens next, it can be really challenging to figure out, "What does my child need to know next or even right now?"

Brielle Gregory Collins: Thank you for outlining all that. That's very helpful. And Dr. Rauch, is there anything that all parents should do when having these conversations about their prognosis with their children?

Dr. Rauch: I think most parents may not even think about this quite as prognosis but really more about what is going on with them. Just like any other family event, there is an illness that is underway within the parent, but there are also all kinds of changes in their home and things that will directly affect the child. So first, I think it's important to name the cancer because if you name it, then it can be talked about. If it's left as a euphemism, a bump, a lump, a boo-boo, that can be confusing. So I think the very beginning, even for children as young as 3, is to name it so it becomes something that is - I use a made-up word myself - talkaboutable so that there's the possibility and really the welcoming of questions in conversation. So I would say that's the first part.

And then, I think, a combination of what the goals are of treatment for the parent and also, what the impact is day to day, week to week, month to month for the child. And the amount of time that a child is thinking, and maybe it is really moment to moment for a preschooler, it may be a much longer amount of time for an older child. So thinking in terms of those bits of time that makes sense at different ages and then, I think, recognizing that children who are even 7 years old and older are not just getting their information from their parents, but they're getting information from lots of other places. Kids of all ages may overhear information at home, and that's the most confusing way to get clear information about cancer and about how the cancer is unfolding for the parent. So continuing to check in with kids, "What have you heard? What are you wondering about?" And certainly, for older kids, addressing the challenges of children getting information from the internet as opposed to directly from a parent.

Brielle Gregory Collins: Got it. So you definitely don't want it to be this elephant in the room. You want it to be an open discussion, and you want to be available to address the questions that your child might have and, of course, mitigate any fears that they might come across when they go on Google or talk with other people, things like that.

Dr. Rauch: Yeah, you want to give the message, "Don't worry alone." And I'll sometimes say to parents of adolescents, "Let your teenager know that you're going to either worry about them or worry with them." And if the teenager shares their concerns of what they're hearing, then the parent and the teenager can problem-solve together. If the child or teen doesn't share their information, then the parent's going to worry about them, and when a parent worries about instead of with their teenager, the parent is much more likely to be off the mark and frankly, more annoying to teenagers, and many teenagers will respond with a smile to that, "Oh, yeah. If you're guessing what's on my mind, you're going to annoy me more. If we can talk about it together, we can actually address the things that are front and center." And I think helping teenagers to recognize that what they read about on the web is about a large group of people and it's about the past. So it's neither about how things are going to be for the individual, their parent, nor is it representative of the future of cancer care. So the best guess about a parent's illness trajectory is going to come from talking with the parent and the parent talking with their medical team, and that's an important message to deliver to kids really in older elementary school age, middle school, and adolescents.

Brielle Gregory Collins: Definitely. That's helpful to know. And for parents who might be struggling with a child who doesn't want to talk about the illness, what advice do you have for people in that position if their children don't want to talk about it?

Dr. Rauch: So I think parents need to give updates to their child and say, "I want to be sure that you have the opportunity to hear, and I want you to hear from me. You might overhear me talking to your aunt about this or your grandparent or about that. So here's what's going on." Because, again, overhearing information is the worst way to have it communicated. It's not respectful to the child either to feel like, "Oh, my parent is talking to other people about the specifics of their illness and leaving me out." So communicating to a child, "I don't want you to worry alone. Here's what you might hear me talking about with others. Here's how my treatment or my illness may affect us at home and you, the child, in particular. I am eager to hear your questions, but it's up to you to let me know what's on your mind." And then I think for some kids, it's also giving them permission to talk to other caring adults, who are also a good source of information. Some kids can't bear to have the conversation with their parent because it's upsetting. They can see that their parent is upset or they feel upset themselves. But they might talk to their best friend's mom, or they might talk to another family member, or they might talk to a co-parent. And guiding children and teenagers to good resources, and by resources, I mean people who they can discuss the parent's cancer with, is also important.

Dr. Park: I would also add to that, as a clinician, I often ask patients, "What is helpful for you to know?" And what I might assume is helpful for them to know may be completely different than what is the truth, and we often find that that can be another way to help kind of open up some conversations to find out what are the kind of lingering questions or kind of unknowns in their child's mind.

Dr. Rauch: I also find that some teenagers who are not so eager to talk, if you ask them, "What's the dumbest thing anybody has said to you?", that sometimes is a gateway to a conversation.

Brielle Gregory Collins: That's a great question. And Dr. Park, going back to the study, many parents in the study were worried about upsetting their children by talking about their prognosis. So what can parents do to help if they're in this situation?

Dr. Park: Well, I think the truth is that parents are worried about upsetting their children because these conversations are hard for a good reason, and there is a need for balance and for weighing these different considerations. I think we find that parents can do things like kind of put their toe in the water. I don't think all this information needs to come out on the very first time they're telling their child about their diagnosis. If anything, we find that most parents take a more gradual approach. One of the things I often think about is that it takes time for adults to adjust to a cancer diagnosis and what that means. And similarly, it takes time for kids, too, and so there isn't necessarily a rush to kind of put it all out there on the very first conversation.

And the other things that I think that are helpful can be the more clear an individual is about kind of what they can expect with their illness and the different possibilities, I think, can at least reduce some of the uncertainty on the parent's end. It may not necessarily make the conversation less worrisome for the parent or the child in terms of that immediate moment, but I think oftentimes, parents can often then give additional information that they may not have known if they hadn't had more information from their provider about what the next treatment might be, if this 1 doesn't work the way we would like it to, or that things may not necessarily happen, things may not suddenly change on the drop of a dime tomorrow. I think that sometimes there can be uncertainty on the parent's end, and that is something that is very modifiable with having some conversations with their health care team.

Dr. Rauch: I think often parents can reassure their child that they're not expecting anything to happen this week or next week or this month or next month or today or tomorrow and that if things change, that they will update their child. And then the other thing I would just say is that parents are often very, very worried that when they share information with their child, their child will be so upset and sort of almost like that their childhood will stop at that moment. And in my experience, the vast majority of parents are surprised that their child accommodates as quickly as he or she does. It doesn't mean that it's not upsetting. It is upsetting, and actually, we would be worried if a child or a teenager wasn't upset by a parent's life-shortening cancer diagnosis. It is upsetting.

So using as the yardstick whether children are transiently or for a time upset is kind of the wrong yardstick. We would expect just lots of things upset kids, then they accommodate, and the parent is there to help them through that process. If parents wait too long to begin the conversation with their child, then they really have deprived their child or teenager of the opportunity to co-process this difficult news. Think about it like an elevator if you're starting at the penthouse, and you're going down a floor at a time. It's a lot easier to adjust to a gradual stepwise change than it is to go from the penthouse to the basement in free fall. So slowly having multiple conversations, as Dr. Park was discussing, but also not being afraid to let children be upset. Most parents have experienced their child's distress about a host of things. I've been watching my toddler grandchild start in daycare. He weeps when he starts in the morning, and then he's fine at the end of the day. I don't mean to minimize how different this challenge is, but part of what we do as parents and grandparents is to provide children with the opportunity to be safely upset with us.

Brielle Gregory Collins: Right. And I want to go back to this idea of the questions that children ask. I know we talked about the importance of addressing those questions. And Dr. Park, in the study, parents often relied on their children's questions to help guide these conversations, but are there any questions that parents should be asking their children when it comes to their illness?

Dr. Park: I think the truth is that we would like for parents to be listening even more than telling, and by that I mean that the main concern of parents, as Dr. Rauch mentioned earlier, is whether this is going to be too upsetting for their children, and that is not something that you can necessarily know or predict about how your child is kind of coping with this news by a single conversation or by you talking to them. Rather, I think it means kind of finding out kind of, "How does this impact their child's lives? What are the questions that they have been wondering about?" And really just, I think, being curious about how their child is thinking about this and what they understand, I would say, would be the kind of questions we would encourage all parents to think about. The other thing I also like to say is that children are remarkably curious people. I have young kids, and I think our dinner table conversations are essentially 1 long 20 questions pretty much every night, but not every child is necessarily going to feel comfortable asking some of these questions. And so having the parents at least find out what their children want to know, I think, can help put some of that expectation or pressure to ask these kind of bigger questions off their kids and perhaps kind of in the parent's hands.

Dr. Rauch: I have a couple of questions that I might suggest for parents of different ages. So I think parents of young children, whether it's the parent or a co-parent or someone else that asks to find out how young children understand why someone got cancer, it happens that sometimes in this early age where kids really feel like they caused the things that happen around them, they may have a misconception that they caused the parent's cancer or that when the parent is fatigued, that the fatigue is because the parent doesn't like them or is bored with them or irritable at them. So I think remembering that very young children are particularly self-centered, and that's developmentally normal to ask questions there. I think sometimes for older kids, just asking what someone who hasn't lived with a parent with cancer-- what other kids don't get about what it's like to be them can sometimes again be a way into having a child share what they feel isn't well understood by their peers or isn't well understood by the people around them.

Brielle Gregory Collins: Thank you for breaking those down. And thank you both so much for your time and for sharing your expertise today. It was so great having you.

Dr. Rauch: Thank you.

Dr. Park: Thank you.

Brielle Gregory Collins: For more information on this topic, please visit www.cancer.net/talkingwithchildren.

ASCO: If this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, 3 Cancer.Net Associate Editors discuss new research in cervical cancer, melanoma, and cancer in adults 65 and over, presented at the 2021 ASCO Annual Meeting, held virtually June 4th through 8th.

This episode has been adapted from the recording of a live Cancer.Net webinar, held August 9th, and led by Dr. Merry Jennifer Markham, Dr. Ryan Sullivan, and Dr. William Dale.

Dr. Markham is Chief of the Division of Hematology and Oncology and a clinical professor in the Department of Medicine at the University of Florida. She is also the Cancer.Net Associate Editor for Gynecologic Cancers.

Dr. Sullivan is board certified in medical oncology and an attending physician in the Division of Hematology/Oncology at Massachusetts General Hospital. He is also the Cancer.Net Associate Editor for Melanoma and Skin Cancer.

Dr. Dale is a clinical professor, the Arthur M. Coppola Family Chair in Supportive Care Medicine, and director of the Center for Cancer and Aging at City of Hope Comprehensive Cancer Center. He is also the Cancer.Net Associate Editor for Geriatric Oncology.

Full disclosures for Dr. Markham, Dr. Sullivan, and Dr. Dale are available at Cancer.Net.

Greg Guthrie: Good afternoon, everyone. I'm Greg Guthrie, and I'm a member of the Cancer.Net content team. And I'll be your host for today's Research Round Up webinar. This webinar will focus on gynecologic cancers, melanoma, and cancer in adults age 65 and older. Cancer.Net is the patient information website of the American Society of Clinical Oncology, also known as ASCO.

Our participants will be answering questions at the end of this webinar during the Q&A session. Please note that the participants cannot answer questions about anyone's personal medical situation. If you have specific questions about your cancer care, please contact a member of your health care team. Today we'll be addressing research from the 2021 ASCO Annual Meeting, which was held virtually in June, and our participants are members of the Cancer.Net Editorial Board. Now, they are Dr. Merry Jennifer Markham of the University of Florida Health. Dr. Markham is the Cancer.Net Associate Editor for gynecologic cancers. Dr. Ryan J. Sullivan of Massachusetts General Hospital Cancer Center, Harvard Medical School. Dr. Sullivan is the Cancer.Net Associate Editor for melanoma and skin cancer. Dr. William Dale of City of Hope Comprehensive Cancer Center. Dr. Dale is the Cancer.Net Associate Editor for geriatric oncology. And thank you, everyone, for joining us today. So starting us off today is Dr. Markham with highlights in gynecologic cancers.

Dr. Markham: Thank you so much, Greg. It's great to be here talking about a couple of studies that were presented at ASCO. Just to point out that I don't have any conflicts of interest for either of the 2 studies that I'll be presenting today. This first slide is a study that looked at a database to answer a question. And really, the primary question the study was trying to answer was whether HPV screening or cancer screening or HPV vaccination has made any difference in the United States over the last 15 years for HPV-associated cancers. And so the primary population that the results of this study really impact are any people, all people at risk for HPV-associated cancers, and these include oropharyngeal squamous cell carcinoma cancers. So head and neck cancers, anal and rectal squamous cell carcinomas, vulvar, vaginal, and cervical squamous cell carcinomas, and penile as well. So this study evaluated data from 2001 to 2017 in a database, the U.S. Cancer Statistics Database, and specifically tried to answer these questions. And the findings were rather complex, broken down by men and women, and so I'll walk you through.

In women, the overall incidence of HPV-related cancers was 13.68 per 100,000. And so of those cases, 52% were cervical cancer. What the authors found is that over the last 16 years, the incidence of cervical cancer decreased at an annual percent change of 1.03%. So a decrease annually by a little over a percent. And the incidence of cervical cancer in 2017 was 7.12 per 100,000. Over that same timeframe, the incidence rates of other HPV-associated cancers in women increased significantly. So rather than decrease, they went in the opposite direction. And specifically oropharyngeal, head and neck cancer, increased by 0.77% annually, anal and rectal cancer increased by 2.75% annually, and vulvar squamous cell carcinoma increased by 1.27% annually. Specifically in women over age 80, the incidence of anal and rectal cancer approached that of cervical cancer. The incidence of cervical cancer in that age population was 6.95 per 100,000, which was a decrease of 2.9% annually. Anal and rectal cancer incidence in women over 80 was 6.36 per 100,000 or 1.23% increase annually. So the authors did a projection model and found that the incidence in women of anal and rectal cancer was expected to surpass that of cervical cancer by the year 2025 for every age group over age 55.

Now if we switch to men, the incidence of all HPV-related cancers was 11 per 100,000 in the year 2017 and 81% were head and neck cancers. Over the last 16 years, there was an increase in HPV-related cancers in men 2.36% per year, with the highest increase in head and neck cancers, 2.71%, and in anal and rectal squamous cell carcinomas, 1.71% annual increase. Those who were at highest risk of head and neck cancer, the squamous cell carcinoma that I'm referring to, were older men. They were ages 65 to 69 with an incidence rate of 36.5 per 100,000 and an annual increase of 4.24%. White men actually had the highest incidence. So white men ages 65 to 69 had the highest incidence of head and neck squamous cell carcinoma at 41.6 per 100,000.

So it's a lot of numbers, a lot of data. Boiled down, what this really means is that cervical cancer has been decreasing. All other HPV-related cancers have been increasing. Now, the decrease in cervical cancer incidence is likely a combination of factors. Primarily, we have regular screening for cervical cancer, and we have HPV vaccination. Now, the risk for other HPV-related cancers, such as head and neck and anal and rectal squamous cell carcinoma, does remain high and is increasing, unfortunately. These are not cancers with routine screening. And so the authors concluded, and I think this makes sense, that screening and vaccination efforts, specifically HPV vaccination efforts, might help to impact those rising cancer numbers and help to decrease those rising incidence rates. So that is study 1. Greg, are we ready to go to the next one?

Greg Guthrie: Yeah, we are.

Dr. Markham: So this is the OUTBACK study. This is adjuvant chemotherapy following chemoradiation. That's primary treatment for locally advanced cervical cancer compared to chemoradiation alone. This was a phase III randomized study. We refer to it as the OUTBACK study, which was its official name. And this study sort of hits at the opposite end of that HPV cancer-related spectrum. So we're out of the prevention and in sort of incidence arena now in a realm of treatment. So this study impacts women who had locally advanced cervical cancer and specifically those who were able to be treated for cancer with chemoradiation. And just to clarify, chemoradiation, when that term is used together usually means chemotherapy and radiation given at the same time. And the chemotherapy is usually designed to make the radiation work better. So standard practice, the standard treatment that oncologists give for locally advanced cervical cancer is chemotherapy with a medicine called cisplatin and radiation, and this together is again chemoradiation.

So the question the authors wanted to ask in this study was whether adding chemotherapy at the end of chemoradiation helped to improve survival outcomes. So the study compared 2 groups, 1 group of women - and this was randomized - received chemoradiation alone. And that's absolutely standard of care practice. The other group, the experimental group, received chemoradiation, which was standard, but an additional 4 cycles of chemotherapy with a platinum and a taxane chemotherapy agent. The primary endpoint was overall survival. The study took a little bit of time to accrue. It recruited from 2011 to 2017, and ultimately 919 women with locally advanced cervical cancer were eligible and were analyzed in this dataset. Of those, 456 were assigned to chemoradiation, and 463 were assigned to chemoradiation followed by the additional 4 cycles of chemotherapy. What the study found is that overall survival at 5 years was similar in both groups. So 71% for the standard treatment arm and 72% for the arm that received the 4 additional cycles of chemotherapy. In addition, the progression-free survival was similar at the 5-year mark. So 61% compared to 63%. I think important to note is that this is a negative study. So the 4 additional cycles did not make a difference for these women. However, 81% of the women who were assigned to the chemoradiation and the chemotherapy had grade 3 to 5 adverse events within a year of being randomized, compared to only 62% of women who received the chemoradiation alone. So more women who received that experimental arm had more toxicity, more adverse events.

As we like to do in any randomized study, the authors did evaluate both groups of women to make sure there were no differences, and there were no statistical differences inherent between those 2 groups, and patterns of their cancer recurrence were similar in both groups. So what does this mean for our patients? For women with locally advanced cervical cancer, what we know now based on this study is that the standard treatment really does remain chemotherapy with radiation concurrent, so given simultaneously, and that we actually don't get any improvement in survival by adding additional chemotherapy. We do get extra side effects and extra toxicity. But women do not have better outcomes with this regimen. And that's it for these 2 studies, Greg.

Greg Guthrie: Thanks, Dr. Markham. I was wondering if you could really quickly give a sense of scope for how much do grade 3 through grade 5 adverse events affect somebody's well-being, quality of life.

Dr. Markham: Yes, absolutely. So typically, a side effect on a clinical trial are graded from 1 to 5. 5 is the absolute worst. That typically is death from a treatment. Grade 1 is very mild side effects such that you as a patient, if you're being treated with that, that treatment course may not really have much in the way of side effects or symptoms. But once we get to grade 3 and 4, there is some consequence. So, for example, for someone with anemia, they might actually require hospitalization or a blood transfusion. So it's definitely not a mild side effect. These are what we would consider significant or severe.

Greg Guthrie: Thanks, Dr. Markham. Now we'll move on to Dr. Sullivan with highlights in melanoma.

Dr. Sullivan: Greg, thanks so much for the introduction. It's a pleasure to be here today, and I'd like to thank Cancer.Net for the opportunity to provide highlights in melanoma from the Annual Meeting at ASCO. So I thought what I would do is show a few pictures and then describe what these pictures mean. So, the first study that I'm going to talk about is actually not a new trial. This is probably the fifth or sixth time this trial has been presented at ASCO. It's the CheckMate 067 study, which is a trial. And if you look at the upper right, this is a randomized trial. So patients were randomized to receive in gray ipilimumab, which at the time of this study launch was the standard of care for patients with newly diagnosed, advanced or metastatic melanoma. Patients could have been randomized to nivolumab, which had been shown to be effective in the second line after ipilimumab and was being compared in the front line with ipilimumab. And then the third arm and that-- was sorry, that's in green. And then the third arm in orange is the combination of nivolumab and ipilimumab.

As I said, this trial has been presented many times, but this follow-up presentation was with 6 and a half years of following how patients did on the study. And I don't generally like to show survival curves, certainly not overall survival curves, but I want to show them in this scenario, because what we're seeing, if you look at the lower left, this is progression-free survival. These are patients who started therapy and then their disease hasn't-- when the curve sort of flattens out, that means that whatever that number is, that's probably the number of patients at least with 6 and a half years follow-up, who are likely to remain progression-free over time. We know with ipilimumab, which is the gray line, and it shows 7% of patients who started therapy remain without growth of their disease. We know that those patients, if you're alive and without evidence of disease progression at 5 years, you're probably alive and without disease progression at 10 years. And that may be true for the combination of nivolumab and ipilimumab and nivolumab, which are the green and orange lines. And what's important about that is this is probably the potential cure rate of these therapies. As you can see, the numbers at 60 months and the numbers at 78 months don't look a lot different. And I would anticipate that about 30% of patients treated with nivolumab, which is a PD-1 blocking drug, and more than that, maybe 33 or 34% of patients treated with the combination of nivolumab and ipilimumab, are cured of their melanoma, which was metastatic at the time of starting treatment. And that is really amazing, particularly because this is a disease before these drugs came around that generally led to the death of greater than 90% and closer to 95% of patients who developed it. And that leads me to the second curve, which is the lower right, which shows that at 6 and a half years of follow-up, almost half of the patients treated with ipilimumab and nivolumab are alive and again, compared to probably less than 5% in historical dataset. So this is without a doubt, the most remarkable data when thinking about how patients do with melanoma that's ever been shown, and that's why I wanted to show these pictures.

This sort of picture shows actually the number of patients who are alive and treatment-free. So one of the important concepts of oncology, and I think if patients are polled, generally speaking, they would like a therapy that works, they would like a therapy that's tolerable. And ideally, if that therapy makes your disease go away, they'd like a therapy they can stop. And so on the left where it says nivo-plus-ipi and "n equals 145," what it's saying is that 77% of patients who are alive in and were randomized to that regimen are treatment-free, meaning they never needed another therapy. For the nivolumab, that's 69% of the patients. And for ipilimumab, that's 43% of the patients. And so I think the other point that I wanted to make is that not only does this therapy lead to really remarkable outcomes, but it also leads to one of the key metrics that we want, which are control of disease and not needing to be on therapy.

So to summarize, this study was patients previously untreated with unresectable stage 3 or stage 4 melanoma. It's a 6 and a half year update. And it's a randomized trial of nearly 1,000 patients. This, again, is the longest follow-up data of any anti-PD-1 therapy, with or without an anti CTLA4 antibody like ipilimumab. A durable progression-free survival was seen in about a third of patients with a combination, about 30% of patients with single agent nivolumab, and less than 10% with single agent ipilimumab. And the durable overall survival is close to 50% with the combination, over 40% with single agent nivolumab, and just over 20% for ipilimumab. And then again, importantly, patients alive at this data cutoff, almost 80% with the combination remained off of therapy and never required subsequent therapy.

And then one other important point that was presented by the authors was that in patients who had complete or partial responses, about 80% of those who were treated with a combination, those complete or partial responses were maintained over this time. That was compared to almost 90% of the complete response to the nivolumab, but only a little more than 60% of the partial response with nivolumab were durable. And this is a question that as an oncologist caring for melanoma patients, I'm asked all the time by my patients who have a nice response to therapy, "How long's it going to last, Doc?" And the answer is, in the majority of patients, it seems to last at least 6 and a half years. And again, having additional follow-up data is really important to be able to answer these key questions. So what does this mean for patients? Say the data suggests that a significant minority of patients treated with either the combination of ipilimumab plus nivolumab or single agent nivolumab have durable benefit. I'm not sure if I said it, but it's important that I do say it, that I have been a paid and an unpaid consultant with Bristol Myers Squibb, who is the sponsor of this trial, since 2017.

That goes for this presentation as well. So another really critical presentation that was made at ASCO this year was the so-called RELATIVITY-047 study. So this, again, was a randomized trial. This randomized over 700 patients to either the combination of relatlimab plus nivolumab or to nivolumab by itself. Relatlimab is an anti-LAG-3 antibody. Nivolumab is in the anti-PD-1 monoclonal antibody. Anti-PD-1 antibodies have become the standard of care for a number of different cancers, either in combination or by itself. And they block a key way that the cancer's preventing the immune system from attacking it. Relatlimab is another drug in targeting another one of these important molecules that cancers can use to help prevent immune destruction. And so the idea here is that blocking 2 of these key proteins that the cancer cells may be using to help prevent their destruction by the immune system might be better than just blocking 1.

So this is the progression-free survival. So, again, the number, the percentage of patients over time whose disease hasn't grown since starting the therapy. And what was shown is that the combination was better than just nivolumab by itself at preventing growth of disease. And to say it another way, of preventing disease progression.

And this is busy, and it's not meant to be kind of seen, but essentially that where you see all of those little teal bubbles next to a dotted line, they're all to the left of that dotted line. And that generally means that the combination was better in a lot of different subgroups of patients based on sex, based on age, based on how functional the patients were when they went in, based on BRAF mutation status.

And importantly, they look to see whether or not this was true also for patients who had PD-L1 expression, which is an important, potentially predictive factor of nivolumab treatment, as well as LAG-3 expression, which again was the target of one of the drugs. And the hint here is that there seems to be benefit no matter whether the tumor expresses PD-L1 or not, and whether the tumor expresses LAG-3 or not.

So to summarize, this is another study looking at patients previously untreated, unresectable stage 3 or 4 melanoma, randomized 700 patients, over 700 patients to either a combination of a LAG-3 inhibitor, relatlimab, and a PD-1 inhibitor and nivolumab versus nivolumab by itself. The trial met its primary endpoint. The combination was well-tolerated, although there was some increased toxicity with the combination compared to the single agent. But it doesn't appear that the toxicity is significantly dose limiting, and the majority of patients were able to continue therapy and similarly to those who were treated with nivolumab. And then this subset analysis, it consistently favored the combination. So what does this mean for patients? Well, the data suggests that the combination of relatlimab and nivolumab may be a new standard of care in patients with advanced melanoma. However, there are caveats, including it's contingent on this combination being approved by regulatory authorities. And also important to note that there's no data yet to determine whether this combination would replace or be better than the combination of the ipilimumab and nivolumab, the combination that I talked about in that first presentation that I'm summarizing as part of the CheckMate 067 study. So we really don't know whether this will be replacing frontline therapy for all patients who have unresectable stage 3 or 4 melanoma or just a subset. But it does seem that this data is potentially revolutionary in terms of how we manage this disease.

And finally, I'm going to talk about a clinical trial of a product called lifileucel. This is a trial sponsored by a company called IOVANCE, and I served on a scientific advisory board for the company over a year ago. This is a trial that was looking at the benefit of something called TIL therapy. So TIL stands for tumor infiltrating lymphocytes. So in tumors, we often can identify immune cells that may just be hanging around and watching what's going on or actually may be there with bad intentions, meaning they got there because they can recognize the tumor and are trying to destroy it. And long ago, in the 1990s, a group at the National Cancer Institute began to develop ways of removing these tumor infiltrating lymphocytes, testing whether or not the lymphocytes could recognize a tumor and then would give them back to patients. The cells themselves are unmodified other than they come out, they're grown, expanded, and then given back to patients. The way this works is that a patient will have a tumor removed. So call it the harvest. The lymphocytes or TILs will be removed. They'll be expanded. They'll be tested to see if the TILs actually recognize the cancer. And then a patient will be hospitalized, given chemotherapy to basically prepare their body to receive the TILs. The TILs will be given. And then patients will receive something called interleukin-2, which is a growth factor for the T cells. And then patients remain in the hospital until their blood counts recover from the chemotherapy. And then that's it. That's the only therapy that's given as part of TIL therapy.

So this study was looking at cohort 2, which was patients who had previously been treated for melanoma with a PD-1 blocking drug and then received TILs because the PD-1 blocking drug wasn't working and they needed another therapy. In the bottom left is a curve called a waterfall plot. Down is good. The down can go to 100%, which means that all the tumors that were measurable went away. And in the majority of patients' tumors got smaller. And about 35 to 37% of patients actually had what we call partial response or a complete response. And those responses to the right is shown that they tended to be ongoing and that with a median follow-up of over 30 months, the majority of responders remained in response. So 1 concern is do these responses last, and the answer is they seem to.

So to summarize, this was a trial for patients who had unresectable stage 3 or stage 4 melanoma who were previously treated with an anti-PD-1 antibody. This was an update of a clinical trial for lifileucel. Sixty-six (66) patients were enrolled. The majority had received both ipilimumab and an anti-PD-1 antibody. This it says upfront toxicity. That's why patients are in the hospital. But once patients leave the hospital, there tends to be very few long-term toxicities. Over 35% of patients had a response, and the majority of those responses were maintained with nearly 3 years of follow-up. One additional thing that was presented is that patients who actually had the poorest prognosis factors going in, meaning their disease grew right away when they got immunotherapy before or they had what's called an elevated LDH, those patients actually seem to have the best responses, the best outcomes. So what does this mean? Well, lifileucel's been shown to be effective in a subset of patients with PD-1 resistant disease, the anti-PD-1 resistant disease. And this data suggests that patients with primary refractory disease, anti-PD-1 may benefit the most. And it remains to be seen whether or not this becomes a standard therapy. But if it does, this data supports its use in this setting. I'll stop there. Thanks, Greg.

Greg Guthrie: All right. Thank you, Dr. Sullivan. And now we'll turn to Dr. Dale, who's going to discuss highlights in geriatric oncology research.

Dr. Dale: Well, thank you so much, Greg. And thanks to my fellow panelists, to ASCO, and Cancer.Net for the chance to present this exciting new work in cancer and aging or cancer with older adults. I'm going to present 3 studies, 2 of which are related to each other in that they're both about cognitive loss with the treatment of cancers, and a second one about the pre-existing deficits, which also partners with the others. So I think a really nice, natural follow-up to my colleagues who talked about the risks of balancing toxicities and treatment effects, which is often highlighted for older adults.

So the first study by Schiaffino, et al. is identifying pre-existing dementia in older adults diagnosed with cancer through a national claims database. I'll mention up front that I am a mentor for Dr. Schiaffino, but not of this particular work, which was done independently with another group of providers and mentors. So this study was done in older adults with cancer who were found to have pre-existing dementia of the Alzheimer's type or a related kind of dementia. So the advance of this case is to take a large database, not a clinical trial database, and through the development of a unique algorithm, actually, 2 of them, identify people who have perhaps unknown pre-existing dementia or cognitive impairment. These are all patients over 65 years old in Medicare, combined with a national cancer database called SEER, which is Surveillance, Epidemiology, and End Results study, for about a 10-year period. And it was conducted in people with 6 different kinds of common cancers. And what did we find that was new in this study? It's surprisingly common using this algorithm adapted from clinical diagnostics for people to have pre-existing cognitive impairment concerning for Alzheimer's or another dementia. This is often thought to be quite low, probably because most people with cognitive impairment do not end up enrolled in clinical trials. But if you look at a real-world database like this, 15 to 30% were found to have evidence of pre-existing cognitive losses. So they assessed the prevalence of this pre-existing disease through this algorithm across the cancer types, and it was even more common among certain racial and ethnic subgroups, basically non-white subgroups compared to white subgroups. Again, white individuals are more commonly enrolled to significant degrees in clinical trials.

So what does this mean for patients and caregivers if up to 1 in 3 older adults facing cancer treatment have pre-existing dementia, evidence of Alzheimer's, or related dementia? They need to be identified and screened for in advance of being treated for their cancer. Why is this important? Patients with cognitive impairment are at an increased risk for both overtreatment and undertreatment for their cancers. Those with pre-existing cognitive loss are at very high risk for a number of different toxicities and at high risk for mortality when being treated with chemotherapy and other kinds of cancer treatments. And if it's not identified in advance, they could be placed at higher risk and may want to reconsider the therapy choices. If someone is identified with dementia or cognitive impairment, one thing they're at especially high risk for, as we'll see in the next study, is chemotherapy-related, additional cognitive impairment during treatment, which can lead to a number of complications such as delirium and other problems. On the flip side, patients with dementia are often, as we saw with trials, not offered the most aggressive therapies, even when they're not at risk and offered the appropriate support. And so they're at risk of being undertreated based on perhaps an early kind of dementia that would be perfectly appropriate to be treated. So caregivers and family members may need to advocate on behalf of their older relatives or parents or grandparents to get appropriate treatment. So it's important to ask your oncologists and your primary care doctors about the risks when deciding what treatments and in some cases to undergo appropriate screening and testing for cognitive impairment prior to starting treatment.

So the next study is another study of cognitive impairment moving in the direction that the field of cancer and aging is moving, which is identifying effective interventions rather than simply identifying risk factors. So this is a phase II study of 2 combined interventions, exercise and low-dose ibuprofen for cancer-related cognitive impairment, essentially chemobrain, during chemotherapy for patients with cancer led by Dr. Janelsins and their team at the University of Rochester. Who does this study affect? Patients with cancer receiving chemotherapy who are facing cognitive difficulties with the initiation of chemotherapy and testing for 7 different domains of cognition, including memory, attention, concentration, and executive function, among a few others. This was 86 participants reporting cognitive difficulties during chemotherapy. The majority were breast cancer patients, and the vast majority were women. I do note that patients' average age was 54, younger than our usual cutoff of 65, but highlighting the fact that cognitive difficulties can be identified at any age with chemotherapy. I mentioned the 7 cognitive tests. Patients were then randomized into 3 different groups versus placebo for 6 weeks: an exercise alone arm, which included a walking program and a resistance band training program which has been validated in other contexts for cancer patients; daily ibuprofen, 200 milligrams given twice a day by itself; or a combination of exercise and low-dose ibuprofen together. And what did they find, particularly for the issue of attention? So this is the ability to maintain attention on a cognitive task. Exercise alone was the most valuable intervention. People were able to maintain their attention for a significant amount of time, over 20 seconds. Ibuprofen alone also improved significantly compared to placebo at about 10 or 11 seconds. Interestingly, the 2 together had a non-significant improvement in attention of about 8 seconds and raises some questions about why the 2 together would work less well than either alone, perhaps suggesting they use similar mechanisms. Self-reported cognitive function was also found in both of the exercise groups to be improved. So this was the subjective experience of chemobrain was seen to improve in those randomized to the exercise arms.

So what does this mean for patients with cancer receiving chemotherapy? These simple, validated, home-based exercises improved attention and the self-reported or subjective sense of cognitive performance. These are things that could easily be done in the home during chemotherapy and may well improve the situation for those who are experiencing chemobrain. Low-dose ibuprofen, just 200 milligrams, that's 1 over-the-counter pill twice a day, improves the same attention, although not quite as much as exercise. Again, the caveats are noted that these were younger patients. The benefits may be even greater for older patients who are more likely to have cognitive impairment, as we saw, and that it was primarily breast cancer patients and primarily women. There are still questions remaining about why the combination was less effective than either intervention alone.

And the last study I want to talk about is about other kinds of pre-existing conditions for older adults, focusing on those not with earlier stage disease, but with poor prognosis patients. So this was patients over 65 with poor prognosis cancers defined as a median survival expectation of less than 1 year and combined 2 large databases. To understand this, the Health and Retirement Survey, a large nationally representative study, combined with claims information or people's experience utilizing the health care system or on Medicare, and identified over 2,000 older adults with cancer, and just assessed the frequency of these pre-existing conditions, all of which are detected with a geriatric assessment, which is our standard way of assessing older patients with cancer and as part of the ASCO guidelines that were published a couple of years ago. 26% of the patients had lung cancer, 14% had GI cancer, and 60% had other kinds of cancers. What was found? Patients with poor prognosis have high rates of these pre-existing geriatric conditions. Of greatest concern, perhaps, is daily activities difficulties with well over 60% having difficulty climbing stairs, which are in the homes of many people, nearly 50% had trouble standing up from a chair, and a quarter had trouble walking 1 block. This is important as we anticipate giving people chemotherapy to know that the functional losses should be accounted for in advance, if at all possible, and to be prepared for people who may have lived in a house with stairs for many years or who have a low-slung chair that's difficult to get out of, that will become even more of a problem in the future. About a third of people over the year had a significant fall, 12% of which resulted in injuries, again, suggesting that changes in the home or a falls assessment be done or physical therapy to strengthen prior to treatments. And as we noted, just the last couple studies with cognitive impairment, nearly 1 in 10 had trouble managing their finances and another 6% had difficulties with their medications, highlighting additional challenges that come with older adults when they start on chemotherapies and helping anticipate problems that could be addressed or adjusted for. Of note, as people get older, these problems become even more pronounced. In those who are 85 and older who had cancer, over half had falls and even more presented cognitive problems with a fully one-fourth difficulty managing money, 12% difficulty taking their medications. Often, they're on a number of additional medications, just highlighting the challenges for simply getting through their days and anticipating that in the decision-making for starting on therapy or providing the appropriate support prior to starting on therapy. So I don't have conflicts of interest with this study or the prior study of any kind. And that's my last slide.

Oh, I'm sorry, I have 1 more. Let me do the "what this means for patients and families." Advanced cancer is often accompanied by these geriatric conditions that affect health, functional status, cognitive status, falls, and social support is another common one along with the establishing appropriate goals of care. These conditions are detectable with the geriatric assessment. Here I've linked to the ASCO guidelines that came out in 2018. It's now becoming more of a standard of care for older patients. I will point out with the geriatric assessment, it does not require time in clinic to be conducted. It can be done in advance of clinic, and it can be done with nursing support or other staff doing it. Oftentimes online questionnaires can be answered so that these issues can be identified even prior to coming to the clinic or being seen in a video call. Interventions can improve many of these outcomes. We heard earlier from Dr. Markham about chemotherapy toxicities. Geriatric assessment interventions have been shown to decrease toxicities. Polypharmacies, so the reduction in the number of medications that are required that may not be appropriate any longer. Completion of advanced directives goes up with the use of geriatric assessment interventions, and the decision-making choices that need to be made for cancer therapies, whether it's chemotherapy or immunotherapy or others, are enhanced and happen more often with the geriatric assessment being done and help to mitigate the long-term outcomes, especially toxicities and geriatric issues that come up for older adults. I think with my last slide, my timing is just about perfect, Greg, so thanks.

Greg Guthrie: It is perfect, Dr. Dale. So thanks very much for that. And now we can move on to our Q&A session. And we can see what questions we have. Ah, so our first question is for Dr. Sullivan, and it is, is relatlimab a checkpoint inhibitor or is LAG-3 not a checkpoint?

Dr. Sullivan: Excellent question. LAG-3 is an immune checkpoint. Immune checkpoints are molecules that-- I guess the way to step back is to say that to have an active immune response, there needs to be a few things to happen. Typically what the immune response we're talking about against cancer is T-cell immune response. And so the T-cells need to be able to recognize something like a piece of tumor protein that's expressed on the outside of the tumor, like a flag. And then once they've sort of, there's this teaching process or priming process and then that process is involved. So there's a lot of these so-called checkpoints. Some of these checkpoints actually activate the immune system better, and some of these actually block the immune system from working well. And it's this delicate balance. It's almost like our immune systems have to be in the Goldilocks zone so it's not too hot, not too cold, but just right. And so a lot of these drugs, these checkpoint inhibitors, are blocking drugs to either activate cells or once the cells are activated and get into the immune microenvironment of the tumor, then they have to navigate these other potential checkpoints. And so PD-1 and PD-L1 are checkpoints on the immune system that are targeted by drugs like nivolumab, pembrolizumab, atezolizumab. And another checkpoint is LAG-3. So LAG-3 is expressed on what we call exhausted immune cells or T-cells. And so blocking LAG-3 can actually overcome that exhaustion and make those immune cells work better. So LAG-3 is a checkpoint and relatlimab is a checkpoint inhibitor. And that was a long way of saying it.

Greg Guthrie: One of the things that's really interesting about that study is that relatlimab is used in combination, and is that to reach that kind of Goldilocks situation that you were saying?

Dr. Sullivan: It's like the Goldilocks zone. Yeah, not too hot, not too cold.

Greg Guthrie: Just right.

Dr. Sullivan: Well, relatlimab and nivolumab are trying to make the immune system hotter. And so that's a good thing when we're talking about anticancer immunity. The downside, and to Dr. Markham's and Dr. Dale's points about toxicity, the downside of having the immune system too hot is that it can lead to side effects, and those side effects are generally inflammatory. So we worry the more checkpoints we inhibit, that the more side effects we'll see. So the combination in that first study of ipilimumab and nivolumab, when we use that combination, we get a lot of side effects that can be very challenging to get patients through that treatment, which is why we're looking for other combinations that will be more effective than just nivolumab or pembrolizumab by itself, but also will lead to substantial and better antitumor outcomes.

Greg Guthrie: Great. All right. We have another question, this one for Dr. Dale. How often do doctors evaluate patients for ADRD, or if they do not, will they still go ahead and provide chemotherapy?

Dr. Dale: Always risky for me to say what doctors do. I feel like I'm talking about my oncology colleagues like the anthropologist in Mars, I sometimes say where I'm just the geriatrician observing. So I don't know what people do for sure. We do know is that it's still not common for geriatric assessments that include cognitive screening tests to be done in oncology practices for a number of reasons. Resources is a particular challenge. So we already have very busy oncologists, particularly community oncologists, but all of them. And to fit in a cognitive screening test can be a real challenge. And so we have to come up with a different systematic way. Having said that, do they go ahead and treat? I think in most cases when people with dementia are identified, they are less likely to be treated for the concerns people have for cognition. But the way it's identified through family report in patients is known to be inconsistent and not as good as formal testing. So what I would say is we're getting better at creating screening tests that take very little time to do some cognitive assessment. And those who are screened as positive can then be sent for appropriate follow-up with a geriatrician or to a neurologist, whatever is appropriate. But those who are not can then move ahead with chemotherapy and not be excluded. So we're getting there, but there's more work to be done.

Greg Guthrie: Okay, great. And not a follow-up question, but another question for you, Dr. Dale. It seems like we've gotten a couple of questions about ibuprofen. So what is the mechanism by which ibuprofen is thought to improve or affect cognitive function in older adults with cancer?

Dr. Dale: Great. And I'm not an expert in the cognitive impairment directly, more in the health services sense, but my understanding is older adults are especially affected by inflammatory responses. So being frail, for example, is associated with inflammatory markers in our system such as CRPE and other inflammatory markers. And it's thought that ibuprofen as an anti-inflammatory reduces that. And those same markers are associated with this chemobrain cognitive impairment in several different studies. These are still association, so we can't say they're causal relationships. But the hypothesis is if we give ibuprofen and lower the inflammatory profile, that will allow cognition to improve and attention by extension. There is another theory I'll put out there. This is my personal one that I'm a little more sympathetic to, which is the inflammatory response from cancer and cancer treatments is fatigue. And fatigue is by far the most common side effect as Dr. Markham can tell us on the toxicity profile. It's very prevalent. For older adults, being fatigued affects cognition just like it does physical functioning. And it's very difficult to concentrate when you're so tired. And to the extent that we can reduce that inflammatory response and reduce the sense of fatigue, the more people could concentrate. Again, none of this is proven. This is still all at the hypothesis testing stage.

Greg Guthrie: Great. Our next question is for Dr. Markham. Is there any indication from the research that either vaccine, this HPV vaccine, or screening alone made the difference in the lowered incidence rate for cervical cancer? Or was it a combination of vaccination and screening?

Dr. Markham: So I don't think we know the answer to that really, and I have not seen it in studies. We have data that screening is helpful and we have data that the HPV vaccine is helpful. So I suspect that it's the combination, but I don't know how much of each is contributing. I do think that like many things with cancer, it does take a multiple-pronged approach whether to treat it or to diagnose it. So to me, it makes sense that it's some combination of the 2.

Greg Guthrie: So a quick follow-up. For a lot of the squamous cell carcinomas that are included in that HPV study, they conclude by saying that there aren't a lot of screening protocols in place for these types of cancer. Do you think that we have the knowledge to do screening for those cancers and we just don't? Or will further research be needed to find ways to detect and prevent?

Dr. Markham: So I think like many of these things, we do need more research. The challenge with screening research is that we have to prove, our scientists have to prove that you can screen a lot of people safely and not in a costly manner and actually reduce the incidence of cancer or some other outcome. And those studies are actually really hard to do, and they take a long time. I think the data that has come out on prostate cancer screening and on breast cancer screening with mammograms and at what age do we start and so on and so forth, I think is just a testament to how complicated the screening studies can be. So do we have the ability to screen? I think yes. I know that some dentists, for example, and head and neck doctors, head and neck specialists like ENT physicians, are able to just visually take a look in the mouth, for example, to screen for any abnormalities that look like cancer. Do we as a country or a health system have the ability to do that on a large scale [not] in a costly manner? I don't know the answer to that. And that's where we really do need more research. And same with anal and vulvar cancers, etc.

Greg Guthrie: That's great. Thanks, Dr. Markham. So I think we're going to move on to our final question, and that's for you, Dr. Sullivan, is how similar is TIL therapy to CAR T-cell therapy?

Dr. Sullivan: That's a great question. Both are T cells that are taken from a patient and given back to the same patient. But a CAR T-cell is made by removing a bunch of white blood cells from the blood and then those white blood cells, those T cells, are modified so that they are able to recognize the cancer. And when they do, the immune cell turns it on and they can actually expand. It's really like a living and modifying kind of in real time drug. And so there are a few of those CAR T cells that are approved by the FDA to treat a number of different diseases that express what we call an antigen that the CAR T recognizes. T-I-L therapy, or TIL therapy, are T cells that are removed from the tumor itself. They are not modified in the way, at least, that the standard NIH protocol, which is the protocol that we presented today and was presented at ASCO, which essentially is take the cells from the tumor, expand them, grow them, make sure they recognize the tumor, and then give them back. And so the difference is-- their similarities is they're both T cells and the T cells theoretically can recognize the cancer. The differences are that CAR T cells are taken from the blood and modified, and TILs are taken from tumors and are not modified.

Greg Guthrie: Great. That's very clear, Dr. Sullivan. Thank you, and thank you to all of our panelists for joining us today and sharing this great research and, of course, your expertise. It's been a real pleasure. And to all of you who attended this Research Round Up webinar, thank you to all of you for joining us today. You can find more coverage of the research from the ASCO Annual Meeting and other scientific meetings at the Cancer.Net blog. That's Cancer.Net/blog. If you're interested in more Cancer.Net content, please sign up for our monthly Inside Cancer.Net newsletter or follow us on social media. We're on Facebook, Twitter, and YouTube. And our handle is always @CancerDotNet with dot spelled out. Thank you for everybody for attending, and have a good day. Thanks.

ASCO: Thank you, Dr. Markham, Dr. Sullivan, and Dr. Dale. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, 3 Cancer.Net Associate Editors discuss new research in lung cancer, breast cancer, and sarcomas presented at the 2021 ASCO Annual Meeting, held virtually June 4-8.

First, Dr. Charu Aggarwal discusses new research on targeted therapy and immunotherapy to treat non-small cell lung cancer.

Dr. Aggarwal is a medical oncologist and Leslye M. Heisler Associate Professor for Lung Cancer in the Hematology-Oncology Division at the University of Pennsylvania's Perelman School of Medicine. She is also the Cancer.Net Associate Editor for Lung Cancer.

View Dr. Aggarwal's disclosures at Cancer.Net.

Dr. Charu Aggarwal: Hello, I'm Dr. Charu Aggarwal. I'm a thoracic medical oncologist, and I'm here to talk to you about research that was recently presented at the 2021 ASCO Annual Meeting. I will be discussing 3 studies of interest, and I should say that I do have a relevant disclosure to share. I have served as an adviser and consultant to AstraZeneca, which produces 1 of the compounds called durvalumab, for which I will be discussing research on. So let's start off with what was the most exciting or practice-changing research in thoracic oncology presented this year. We know that lung cancer as a field is changing quite fast and, in fact, is really becoming a poster child for application of targeted therapies. At this year's ASCO Annual Meeting, we heard about sotorasib, which is a first-in-class oral therapy that selectively and irreversibly targets the previously undruggable KRAS G12C mutant protein. KRAS G12C is an oncogene, or a molecular mutation, that occurs in patients with non-small cell lung cancer and accounts for about 13% of all patients with metastatic non-squamous non-small cell lung cancer. In a clinical trial called the CodeBreaK 100 phase 2 trial, patients with metastatic non-small cell lung cancer with this particular mutation in KRAS G12C were enrolled to receive sotorasib, which was administered orally at a dose of 960 milligrams once daily. Patients could have received previous chemotherapy or immunotherapy. And what we found was that out of the 124 patients that received therapy on this single-arm clinical trial, about 37.1% of the patients had objective clinical response, meaning that their tumors shrank when assessed by radiographic imaging.

Patients on this clinical trial had a median overall survival of about 12 and a half months, and patients were [responding] noticeably, with a response as early as 6 weeks, which was the time of the first assessment. Overall, this drug is very well-tolerated and, in fact, welcome news that the FDA approved use of this therapy for second-line and beyond treatment of patients that harbor a KRAS G12C mutation. So this is immediately practice-changing, it applies to a lot of our patients, and I think will serve as a really nice, immediate next therapeutic option in the second-line setting for our patients.

The next study that I want to talk about is the updated analysis of a trial called PACIFIC. We heard a 5-year update on this clinical trial at this year's annual ASCO meeting. For patients that have locally advanced non-small cell lung cancer, the current standard of care involves using combination chemotherapy and radiation, usually with a platinum-based chemotherapy for 6 to 7 weeks, followed by 1 year of immunotherapy with a drug called durvalumab. This standard of care has been based on a clinical trial called PACIFIC, which was first released in 2017, and then updated in 2018, showing a significant advantage to the use of this agent in the consolidation setting. At this year's meeting, we saw a 5-year update of the patients that were enrolled onto this large, phase 3 clinical trial. Patients were randomized to either receive 1 year of durvalumab or placebo following concurrent chemoradiation therapy for stage III non-small cell lung cancer.

At 5 years, we saw a consistent advantage in overall survival compared to placebo for patients that received durvalumab for 1 year following their definitive chemoradiation therapy. While these results are not immediately practice-changing, these are absolutely practice-affirming because looking at these curves at the 5-year time point really enable us to deliver the confidence to our patients that administering this 1 year of immunotherapy will help and improve overall survival and really improving the chances of cure following treatment for locally advanced, metastatic non-small cell lung cancer.

The last study that I would like to discuss is a study of adjuvant immunotherapy that is using immunotherapy after surgical resection for early-stage non-small cell lung cancer. While the study is not immediately practice-changing, I think this does represent a new paradigm. Currently, the standard of care in the post-surgical setting involves chemotherapy in case of involvement of lymph nodes and/or additional radiation therapy depending on which level of lymph nodes may be involved. This study, called the IMpower010 study, asked the question if immunotherapy in this setting following surgical resection and chemotherapy could provide a benefit. They looked at about 1,200 patients that were enrolled following surgical resection and had received 4 cycles of chemotherapy. Patients were then randomized to receive 1 year of immunotherapy with atezolizumab or best supportive care and were followed for survival.

At this year's meeting, we heard that patients who received atezolizumab, especially those patients that had stage II or IIIA non-small cell lung cancer, had a reduced chance of recurrence. Following the use of 1 year of atezolizumab, the chances of reduction in recurrence were about 34%, indicating that this is a positive study. I should add that atezolizumab for this indication has not been currently approved. Therefore, it is not practice-changing. However, I should also add that this is the first study of its kind to show an improvement in recurrence outcomes with the use of immunotherapy in the early-stage non-small cell lung cancer setting, making it a very notable study for this subgroup of patients.

Again, I think this has been a very exciting year for lung cancer research. And that wraps up our brief summary of new research in thoracic oncology from the 2021 ASCO Annual Meeting. Thank you for listening.

ASCO: Next, Dr. Norah Lynn Henry discusses two studies looking at new treatment options for early-stage breast cancer.

Dr. Henry is an Associate Professor in the University of Michigan's Division of Hematology/Oncology in the Department of Internal Medicine and is the Breast Oncology Disease Lead at the Rogel Cancer Center. She is also the Cancer.Net Associate Editor for Breast Cancer.

View Dr. Henry's disclosures at Cancer.Net.

Dr. Norah Lynn Henry: Hi, I'm Dr. Lynn Henry, a breast cancer oncologist from the University of Michigan Rogel Cancer Center. Welcome to this quick summary of updates in breast cancer from the 2021 Virtual ASCO Annual Meeting. I have no conflicts of interest for any of the trials that I will talk about. Today I'm going to focus primarily on treatment of non-metastatic breast cancer, especially that occurs in patients who have inherited mutations in BRCA1 or BRCA2. When these 2 genes have mutations or changes that decrease their function, it increases the risk of someone developing breast cancer as well as other cancers. But it also can give us clues as to which types of treatments these cancers may respond to. I'm also going to talk about a second study that was smaller, that looked at whether allowing patients to keep their ovarian function after chemotherapy is actually a safe thing to do.

One of the biggest stories from at the ASCO Annual Meeting was the results of the OlympiA trial. So in this trial, researchers studied a type of medication known as a PARP inhibitor, which is known to be effective for treating patients with metastatic breast cancer who have inherited mutations in those 2 genes I mentioned, BRCA1 and BRCA2. However, it was not known whether giving PARP inhibitors to patients with non-metastatic breast cancer would actually decrease the likelihood of their cancer returning. Therefore, in the OlympiA trial, researchers tried to answer this question. The OlympiA trial enrolled almost 2,000 patients who had inherited mutations in either BRCA1 or BRCA2. These patients had been diagnosed with either estrogen-positive or negative breast cancer, but HER2-negative breast cancer and were at high risk of having their cancer return. In this trial, patients were randomized like the flip of a coin to treatment with either the PARP inhibitor called olaparib or to a placebo for 1 year. Patients took the study medication in addition to their usual treatments. They had mostly all had chemotherapy already, and they took it at the same time as their anti-hormone therapy. After following patients for 3 years, the researchers found that the patients who got olaparib had more than a 40% decrease in the likelihood of their cancer coming back compared to those who got the placebo. The medication was pretty well tolerated. There was some nausea and vomiting, fatigue, and lowered blood counts, although there were some rare but serious side effects that can occur. So there are some concerns about using the medicine in everybody. The follow-up of the patients has been fairly short so far, only 3 years. So it is not yet known whether taking this medicine will enable patients to live longer after breast cancer. This is a medication that has already been approved by the FDA for treatment of patients with metastatic disease. And based on these data from the OlympiA trial, ASCO guidelines now recommend that olaparib should be considered as part of treatment for patients who have either a BRCA1 or a BRCA2 mutation and who have early-stage breast cancer who are at high risk of having their breast cancer recurrence.

So to switch gears a little bit, I'll talk about the other study I also found interesting. Often very young women who are diagnosed with breast cancer would like to become pregnant after they undergo treatment with chemotherapy. For these patients who want to become pregnant in the future, we often treat them with a medicine to block the function of their ovaries during chemo, sort of to put them to sleep with the hope that it will increase the likelihood that their ovaries will wake up and resume functioning again after chemotherapy is complete. However, we have worried that preserving the function of the ovaries might increase the risk of breast cancer returning, especially for women who have hormone receptor-positive breast cancer. This is because ovaries make estrogen, which is important for those types of cancers to survive. Investigators from Italy conducted a randomized study called PROMISE-GIM6 in which patients were treated either with standard chemotherapy or they got standard chemotherapy plus the ovary-blocking medicine. Now that they followed women on this study for more than 12 years after their diagnosis of breast cancer, they presented their final results. Importantly, they found there was no difference in the likelihood of cancer returning or in survival for patients who did or did not have their ovary function blocked during chemo. So these results should be very reassuring for patients who want to try to preserve their ovary function while they're getting treatment for their breast cancer.

Now, there were a lot of other research findings presented that were related to treatment for breast cancer at the meeting. Importantly, we got glimpses of the many new drugs on the horizon for treatment of breast cancer. And we eagerly await the results of large, randomized trials so that the drugs that work can be used to care for patients with breast cancer. But for now, that's it for this quick summary of important research from the 2021 Virtual ASCO Annual Meeting. Overall, we continue on a fast track with breast cancer with many new and exciting therapies being actively studied, as well as research helping support our patients to do better than ever before. Stay tuned to Cancer.Net for future updates from upcoming breast cancer conferences.

ASCO: Thank you Dr. Henry.

Finally, Dr. Vicki Keedy discusses two studies in metastatic synovial sarcoma.

Dr. Keedy is an Associate Professor of Medicine in the Division of Hematology/Oncology and the Clinical Director of the Sarcoma Program at the Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center. She is also the Cancer.Net Associate Editor for Sarcoma.

View Dr. Keedy's disclosures at Cancer.Net.

Dr. Vicki Keedy: Hello, my name is Vicki Keedy, and I'm a medical oncologist at Vanderbilt University Medical Center, and I specialize in the treatment of patients with sarcomas. Today, I'm going to talk about 2 important studies discussed at the 2021 ASCO Annual Meeting. The first is the SPEARHEAD-1 trial, which is a phase 2 trial for patients with metastatic synovial sarcoma or myxoid/round cell liposarcoma. I'd like to note that my institution participated in and enrolled patients onto this trial, and I have participated as an advisor to this trial. The study evaluated an immunotherapy-based treatment called afami-cel, which targets the MAGE-A4 protein. This protein, also called an antigen, is commonly found in synovial sarcoma and myxoid/round cell liposarcoma cells. Afami-cel is called a T-cell receptor therapy, or a form of cellular immunotherapy. This therapy uses a patient's own immune cells called T cells and engineers them to be able to recognize and eliminate cells that express the MAGE-A4 protein. For this trial, patients could be between 16 and 75 years old but must have had 1 prior anthracycline, such as doxorubicin or ifosfamide-based chemotherapy. For this therapy to be effective, patients' cells must also have a specific group of markers called HLA-A02. HLA-A02 testing is performed on the patient's blood sample, while MAGE-A4 is tested on the patient's tumor tissue. Patients who are eligible for this treatment have their T cells collected through a blood draw called leukapheresis. Patients then receive a short course of chemotherapy, followed by infusion of the T cells. Patients receive no further chemotherapy unless the cancer were to progress. The majority of patients on this trial have synovial sarcoma.

The results show that 39% of patients had a partial response, meaning a decrease in tumor size by more than a third, and 2 patients had a complete response. While the number of responses is exciting, what is most exciting about these data is that these responses seem to last a long time despite the patients not receiving any further treatment for their cancer. Common side effects occurred to the chemotherapy portion of the regimen and were similar to what we would expect for chemotherapy. However, 1 particular side effect of interest for cellular therapies is called cytokine release syndrome. This occurs when inflammation occurs in response to the T-cell infusion. Patients can experience fever and flu-like symptoms or more serious illness. In this trial, 59% of patients experienced cytokine release syndrome, but only 1 patient had a more serious or grade-3 reaction. Patients must be re-monitored closely in the days and weeks following their infusion and are often hospitalized for part of this monitoring. A downside to this technology is that it requires both the correct HLA typing as well as tumor MAGE-A4 expression. In this trial population, only about 1 out of 3 patients were potentially eligible based on these 2 requirements. Having said that, the results of this trial suggest that T-cell receptor therapy against MAGE-A4 expressing synovial sarcoma and myxoid/round cell liposarcomas is a very exciting advancement for patients who are eligible for this type of treatment. Currently, this treatment is only available within a clinical trial, as it is not yet FDA approved.

Another important study reported this year were the results of catequentinib compared to dacarbazine in patients with metastatic synovial sarcoma. My institution also participated and enrolled patients on the study. Catequentinib is an oral therapy called a tyrosine kinase inhibitor. It blocks the signaling of multiple receptors that are responsible for tumor cell growth and invasion. Dacarbazine is a cytotoxic chemotherapy that is commonly used to treat patients with several types of sarcomas. To be eligible for this trial, patients must have had at least 1 prior anthracycline-containing regimen. Patients could've had a prior tyrosine kinase inhibitor, such as pazopanib, which is currently FDA approved for most sarcomas in the United States. This trial met its main endpoint of improving progression-free survival or, in other words, slowing down tumor growth, compared to dacarbazine. Although the improvement was relatively small, from 1.6 months with dacarbazine to 2.9 months with catequentinib, the data showed that there are a portion of patients who experience much longer benefit with nearly a quarter of patients still having stable disease at 1 year on the drug compared to 4% with dacarbazine. Side effects were as expected with this class of drugs, including diarrhea, fatigue, elevated liver enzymes, and high blood pressure. Catequentinib is not yet approved for use outside a clinical trial. And it is not known whether it is superior or equivalent to pazopanib, which is FDA approved for non-liposarcoma sarcomas.

These are only 2 examples of the interesting and important research being done to improve the treatment of patients with sarcoma. And while both happened to include patients with synovial sarcoma, the class of cancers known as sarcoma are actually 50 to 100 different cancers. Although it will not be possible to have a trial for every sarcoma subtype, through collaboration and patient education, we're able to research the individual sarcomas as the distinct entities that they are. Thus, it is important for patients with a metastatic sarcoma to go to centers that have trials for their specific disease when available. With this approach, we'll see even more advancements in the future for patients with sarcoma. Thank you very much for your time, and I hope I have more exciting findings to discuss in 2022.

ASCO: Thank you Dr. Keedy.

You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

Brielle Gregory Collins: Hi, everyone. I'm Brielle Gregory Collins, a member of the Cancer.Net content team, and I'll be your host for today's Cancer.Net podcast. Cancer.Net is the patient information website of ASCO, the American Society of Clinical Oncology. Today we're going to be talking about social determinants of health and how they can impact people with cancer. We'll cover economic stability, neighborhood, community, education, food access, and health systems. Our guest today is Dr. Karen Winkfield. Dr. Winkfield is a board-certified radiation oncologist and Ingram Professor of Cancer Research at the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, and the executive director of the Meharry-Vanderbilt Alliance. She is also the Cancer.Net Associate Editor for Radiation Oncology and Health Equity. Thanks for joining us today, Dr. Winkfield.

Dr. Karen Winkfield: Thank you so much for having me, Brielle. I'm so excited for this podcast.

Brielle Gregory Collins: Yes, so are we. Before we begin, we should mention that Dr. Winkfield does not have any relationships to disclose related to this podcast, but you can find her full disclosure statements on Cancer.Net. Now, to get started, Dr. Winkfield, how would you define a social determinant of health?

Dr. Karen Winkfield: Yeah, it's such a big concept, right? The social determinants of health, the economic and social conditions that impact and influence the way that people, individuals, and groups actually experience their health status. And so 1 of the ways that I like to define it is simply the way that the CDC and others [do]. These are the conditions and the environments where people are born, where they live, learn, play, work, and age. And so it's an entire social context that people find themselves in that really can impact and influence their health and well-being.

Brielle Gregory Collins: Thank you so much for defining that. Now let's talk about some of the specific social determinants of health. So let's start with economic stability. What are some ways financial challenges can affect someone with cancer?

Dr. Karen Winkfield: Money is key, right? I always tell folks that wealth equals health, and certainly, health equals wealth as well. I mean, we certainly feel like, man, we are on top of the world when we're feeling well. But unfortunately, in our society, money oftentimes is 1 of the things that helps us drive well-being and health in this country. So just the simple thing we saw with COVID-19 when people lost their job, for instance. Many people also lost their health insurance. In this country, health insurance is tied to economics, right? But economic stability goes beyond just insurance. It's about what is the budget? Do you have a family budget? There is a recent study that suggested that about 21% of individuals in the United States do not have an emergency fund, right? So that means that if, for instance, they were just living and they were working on a budget, if something happened - their car breaks down; there's a flood in their hometown - they have no financial resources that actually are available to them to help them overcome that emergency.

And so economic stability is important. It's about where you work, if you are employed, what type of employment, are you a salaried employee, or do you only get paid the hours that you work? Which obviously has huge implications for cancer care, right? So if I am a cancer patient and I only get paid for the hours that I work, for instance, if I have a doctor's appointment that's at 10 o'clock in the morning and I have to maybe take 2 buses and a train to get there, or I have to drive 45 minutes, that's more than half the day that I am going to be there for a cancer visit or an appointment with a provider. And that means that I don't get paid for that, that nobody is covering that in terms of the finances. So it's really important to note that, yeah, it's about savings and things, but literally, the day-to-day, the employment that people have is really critical and the type of employment, what expenses people have. We know that cancer care is the number 1 cause of medical bankruptcy in the United States because a lot of the medicines are expensive. And so that economic piece is really critical to understand and for people to understand going into a cancer journey, number 1, where they are financially and what resources might be available to assist them throughout the course of their treatment.

Brielle Gregory Collins: That's helpful to note too in terms of there are places people can turn to, to help with these things. Let's move on to a person's neighborhood, which is another social determinant of health. So how can where a person lives affect their access to cancer care?

Dr. Karen Winkfield: Location, location, location, right? We think about that when we're buying a home, when we are thinking about if we have children, what school are they going to go to? It's about the neighborhood. It's about your ZIP code. And there are tons of evidence that suggests that your ZIP code matters more, frankly, than your DNA in terms of your outcomes, your health status. And so why that matters is you think about, "Well, how close am I to health care in general?" Right? And then you layer on cancer care. So, for instance, if I'm living in a neighborhood that is really close by my primary care team, that's great. But what happens if the cancer center, if I have a cancer diagnosis, is 45 minutes away or 10 miles down the road, but I have to, again, take 2 buses and a train, right? So your neighborhood determines what your access to a lot of things that impact health is going to be.

So it's not just about the health care facilities themselves, but you think about, "Is my neighborhood safe? Are there places that I can walk? Is my neighborhood walkable?" In the homebuyers' market, they'll actually have walkability scores. Is this a place-- where I'm living, is it easy to walk around? Because we know that health and well-being is certainly tied to exercise, the ability to go out and walk around, but to do so safely, right? If you're worried about whether or not there's going to be violence or if there's a lot of pollution or other things that impacting your ability to walk around your neighborhood, that's important. So geography matters because of proximity to health care, but it also matters with respect to proximity to other things that impact your health, including grocery stores, whether or not there are fresh fruits and vegetables that are nearby. These are all the components of health and well-being that are impacted by your physical neighborhood.

Brielle Gregory Collins: Okay. Got it. Thank you so much for explaining that. So community is another social determinant of health. And how does a person's community differ from their neighborhood?

Dr. Karen Winkfield: Wow, that is such a great question. And I had to think about my neighborhood that I lived in in Boston. Love, love, love that neighborhood, fabulous green kind of setting. I was 2 doors down from this amazing pond that I could walk around, so walkability plus, right? Not too far from stores, plus. It was beautiful. But you know what? I never felt part of the community. So neighborhood is the physical location, the geography, if you will, but community is about the people, who's around you, who's supporting you. And so one may actually live in a great neighborhood but not have community in that neighborhood. The community might be elsewhere. So maybe the community is their church family, right, or maybe their community are the families that they connect with that maybe their children are going to school with. So the community is, who are the people that you identify with, whereas neighborhood is the physical structure, if you will, of where a person lives and works.

Brielle Gregory Collins: Okay. Thank you so much for breaking that down. So community is basically a person's social group, the people that they spend time with. Okay. Got it. So how can community affect a person with cancer?

Dr. Karen Winkfield: Yeah. There are lots of influences related to community that people experience. And so the way that I think about a cancer journey is you have to think about the entire cancer continuum, meaning, are there ways to prevent cancer? Are there ways to get screening for cancer? What are the types of treatments that I need to be thoughtful of, right? Those are the entire cancer continuum, from prevention all the way through end-of-life care. That's the continuum. And so you can imagine that there are certain communities, that community influence, that may impact your risk for cancers. For instance, are you a smoker? Many people who are smokers actually smoke because maybe they had a family member who smoked, or their friends smoke, and so they smoke, or they may even just be social smokers, right? They only smoke when they're going out to a bar or after a meal with friends. That's how your community can impact your risk for cancer, because we know that tobacco use is the number 1 modifiable risk factor for cancer.

But here's another one that people don't think about, is obesity. Obesity actually is a very modifiable risk factor for cancer. People don't realize that being overweight or obese is actually a risk factor for cancer. So what happens if you're in a community where you guys like to go out and hike or you're very physically active? That's actually a prevention strategy. And so we know that community can impact one's risk for cancer, but what about the behaviors associated with cancer care? Well, I know that, for instance, in some communities, they don't like talking about the C word. They don't like talking about cancer. And so sometimes if you don't talk about things, you may not have the knowledge that you need to know how to protect yourself better, right, not only from reduction of risk for cancer but maybe also even, "Hey, there's screening that I can do. Let me make sure I get my mammogram," or, "Who am I talking to in my community?" Or, "Hey, you know what? I have a cancer diagnosis. Let me share that with my people, right, so they can learn from my experience." So community, the people that you connect with, the people that you identify with, your social context, that's important because there are ways that you can influence both positively and negatively one's outcomes related to cancer.

Brielle Gregory Collins: Okay. That makes a lot of sense. And we also want to talk about education, which is another really important social determinant of health. So how can a person's access to education have an impact on their cancer experience?

Dr. Karen Winkfield: Just like we were talking about neighborhood and location, I use that example of people moving into a particular neighborhood if they have children because they want to make sure the school systems are great, right? Why is that? Because we know that getting educated, having a good education-- even if it's just a high school education, having a good education opens doors, right? It opens opportunities. And similarly, having education status actually opens up doors related to health and well-being. So what's fascinating is we don't oftentimes think about how much of our health and well-being is tied into our ability to read, right? In our society nowadays, everything is text or is on online or you've got to Google it. You go to the doctor's office, and they hand you a stack of papers that's 5, 10 sheets long, and you have to fill it out. What happens if you can't read, right? So there are people in this country-- probably 20% to 25% of the United States is functionally illiterate. And so that impacts one's access to care and also can impact one's access to information around their care, around their health care, around their well-being. So information is key, and that oftentimes is related to our education level or our literacy because, unfortunately, there are some places in the United States that one could actually go all the way from kindergarten through high school and graduate and still not be literate. Sounds ridiculous, but that's what happens. And unfortunately, it's 1 of these things where this is why school districts and schools matter.

So the education is also related to language. And so as our community becomes more and more diverse - we have a lot more immigrant populations coming in - it's really important to think about language and how that impacts access to care. I was very surprised when I was the associate director of the Wake Forest Comprehensive Cancer Center that the number 2 most common language from an interpreter standpoint was Arabic. Who knew? In North Carolina. So Spanish was the first requested language, the top requested language from the interpreter services. But Arabic was number 2. And that was because we had a large number of Somalian refugees that were coming in who spoke Arabic as their primary language. So you can imagine being in a brand new-country, don't speak the language, and how do you even know how the country runs? Forget it if you have an issue that comes up where you need medical care. And that resonates for me because I remember I was on my honeymoon with my husband, and we were in Spain, and he got sick, and I didn't speak Spanish. And so we had to go to the emergency room not speaking that language. Language matters, and so that's why educational status matters. Whether or not you've had good early childhood education is key, what your literacy rate is, and certainly, having higher education oftentimes makes one more available-- and make themselves more available to the information that's out there on the web or other forms of printed materials that may actually impact one's ability to navigate the healthcare system better.

Brielle Gregory Collins: What about a person's access to food and how a lack of access to good nutrition can impact someone with cancer?

Dr. Karen Winkfield: Oh, Brielle, you are talking about something that has recently become more resonant for me. It was something I actually hadn't thought about, was this concept of food and food insecurity, until I heard a recent discussion at an annual conference that about 33% of individuals with cancer show up with some form of food insecurity. Now, what is food insecurity? Well, that may mean that you might not necessarily know where all 3 of your meals are coming from in the day, if you eat 3 meals a day, or it may be that you don't have fresh fruits and vegetables or access to that. Everything is canned because there's not a place where you can go and get fresh fruits and vegetables. There are places in this country that are considered food deserts, which means there might not even be a grocery store that's within a 10-mile radius, or even sometimes it's even much, much wider than that.

And food is important. Remember, we just talked about obesity being a modifiable risk factor for cancer. So what is the cause of the obesity epidemic that we're seeing in the country? It's not necessarily that people are overeating, although that's 1 thing. But we eat so much processed food, right? We eat so much stuff in cans that has sodium content out the wazoo, or we don't know where our food is coming from or how it's been engineered. And there may be things in the food that we don't control that may actually be causing some of the obesity epidemic. You think about how many calories are in some of the fast food products that are out there. You get a meal, for instance, a bundled meal. That meal can have 1,200, sometimes up to 2,000 calories that a person is consuming in a single meal. But you know why they're doing it? Because it's cheap. If I can go and I can eat for $4 for a meal versus having to kind of go and find food and cook it and all that kind of stuff, sometimes it's cheaper for people to eat food that's been heavily processed and that may have things that are low nutritional value, but it satisfies them. And so they're kind of forced, if you will, to eat that because they may be living in an actual food desert where they don't have access to fresh fruits and vegetables at a reasonable price. And so that's important. So from a prevention standpoint, thinking about food is critical, but so is not being hungry while you're going through cancer care, right? We need protein. We need nutrition to help our body repair. Cancer therapy is stressful, right? Cancer therapy impacts normal cells, and so we need to make sure patients have the access to the foods they need to help their body to recover during their cancer journey so that they can really not only just survive cancer but to survive it well during the process.

Brielle Gregory Collins: So it's not just about how much a person's eating. It's about what specifically they're eating and how what they're eating can help them through the cancer process.

Dr. Karen Winkfield: Absolutely.

Brielle Gregory Collins: Another social determinant of health is health systems. So what are some of the challenges health care systems can create for people with cancer?

Dr. Karen Winkfield: Yeah. This is a very complex issue, right? So health care systems have grown and developed over the last couple of decades to become more and more complex. A lot of it is also driven by the insurance and by the payers, right, meaning what your insurance companies will cover, what Medicaid and Medicare will cover. This is a huge issue for patients because there's oftentimes lack of transparency, frankly, in terms of what insurance will cover related to cancer care along the entire continuum. So let me give you 1 example, for instance, of colorectal cancer. We know that the Task Force just recently reduced the age of colorectal cancer screening from 50 down to 45. And the reason why is there are more and more younger people who are showing up with colorectal cancer, and so important to make sure that we have a screening available to younger people. Well, that's all good and well, but what happens when you don't have availability of a doctor who can actually do a colonoscopy, right? So colonoscopy is the gold standard, if you will, for getting colorectal cancer screening. But there are other things, right? So this is where information is important. So people can get a stool-based card, right, where it's looking for DNA or looking for blood. And that test can be done as well. But there's so many different complexities that it oftentimes is a challenge for people to kind of think through what's going to work best for them.

Now, here's 1 of the things around the health care system in colorectal cancer that is a challenge for those of us who are in this space. So if a person goes for a colonoscopy and they're just going for a straight screening, it is covered by their insurance company, right? That screening is. Now, what a colonoscopy does, it takes a camera and looks inside the lining of the colon to see if there might be any polyps or any kind of abnormal growths that are inside the lining of the colon. So what happens if a doctor sees a polyp or something that's abnormal? Well, they go in, and they biopsy it or they remove it. What has just happened when the doctor does that, the provider does that, that has turned from a screening exam to now a diagnostic exam, and the insurance might not cover that. So what's the challenge is that you're going and you're encouraging people to go for screening, but the test itself is wonderful because, look, if a polyp was found and a doctor removes that polyp, that has just now prevented cancer. We know that for colorectal cancer, any polyp will eventually become a cancer, so you need to remove it, and that's why this colon screening is beautiful, because it's both screening and prevention. But our health care system is built in such a way that is complicated, where if you go in for a screening procedure and someone does a procedure that is potentially life-saving that now becomes diagnostic, it might not be covered. I mean, that's a complexity that most people aren't going to understand, and it's hard to explain.

So that's just 1 example of how health care systems are messed up with respect to insurance, but we also have to think about the individual institutions. How welcoming are institutions to individuals, right? Is it scary to walk into your cancer center? Is it overwhelming? How is your signage, right? Who's sitting at the front desk? Are the people who are welcoming people, do they look like the community that you're serving? These are all systems-based things that can be done or that can really complicate, if you will, cancer care if it's not done in the right way. And so these are just a few examples. Even we can talk about the fact that there are some cancer centers that don't accept Medicaid. I mean, what is that? That means you're excluding a whole host of individuals because they may have lower income than other people. Does that mean that people who have lower income are not as important as people with more money or have the ability to have private insurance? Shouldn't be that way. But again, health systems issues that can cause barriers and create issues-- especially when we talk about clinical trials, which are part of cancer care. We want people to be enrolled and participate in clinical trials because that's what changes the way that cancer care is delivered in this country. The reason why we are curing some breast cancers, the reason why we are curing other cancers is because there have been clinical trials that have led to discoveries that have allowed us to say, "Wow, this is a new standard of care. We're saving lives." But that means that if you don't have access to certain cancer centers where the clinical trials are happening, you are not able to participate. And so these are the barriers, the systemic barriers, the health system barriers, just a few of them that actually can really complicate care and make it such that individuals who might want to participate in treatments that can potentially change the face of cancer care-- they're not able to do it right now. So we have some work to do in trying to figure out how to open up the access and remove those barriers.

Brielle Gregory Collins: Right. Thank you so much for outlining that and for outlining all of these social determinants of health. So now that we've kind of talked through all of these different social determinants of health, how can addressing these social determinants of health help improve cancer outcomes?

Dr. Karen Winkfield: The biggest thing that we could do is prevent cancer. That's the way to have the best outcome, right? So if we are to think about location, where people live, their ZIP code as being a driver of health and health status, then that means that we need to start thinking about the context that people are living and saying, "What is it that can be done both from an individual, family, community, and a systems standpoint to help improve health status of different ZIP codes?" You may have seen the maps where people have mapped out a lifespan on a map based on a distance, right, whether it be along a highway or on the subway system, in Washington, DC, looking at the Metro system. And so there's people who are living, like, in the middle of DC, and they have a lifespan of 83 years. But literally, you go up on the yellow line, and you go up to northeast DC, and that drops by 10 years.

Where you live should not matter in terms of your health status, but it does. And so, again, by thinking about these social determinants of health, we can say, alright, what are the factors that are impacting access to care, that are impacting one's ability to prevent cancer or to reduce risk for cancers, meaning reduction of tobacco use, reduction of food insecurities, improving how you can walk around in a community or get exercise? What are people's employment status? Do people have to work 2 or 3 jobs just to make ends meet? If so, that means they're going to pay attention less to their health and well-being, right? Those are the sorts of things that we can think through to really help improve health status.

Now, the other thing that's really important in terms of thinking about from a cancer perspective is one's ability to get access to screening. So, again, social determinants of health, what insurance product do people have, making sure that people have access to the screenings. And like I said, this colorectal cancer example that I gave you is 1 where, what the heck, you go from screening to a diagnostic just because there's a procedure that's done that really can help prevent cancer. These are the sorts of things that are really vital to make sure that we're addressing. And also kind of thinking about, again, location, how do we get people to and from the places where cancer care is is really an important consideration as well because if people can't get to where the cancer care is happening, then obviously, they're not going to get access to the treatments that they need, or it may delay their care. And we know that delays in care can oftentimes lead to worse outcomes as well.

Brielle Gregory Collins: Right. Okay. And finally, where can people with cancer find resources to help them cope with the challenges of these social determinants of health?

Dr. Karen Winkfield: So anyone who has a cancer diagnosis is obviously thrust into this massive system, right? It doesn't matter if you're in a local community center where you might meet with a surgeon and then have to travel 30 minutes in the other direction to go and meet with a medical oncologist, and maybe you drive another 100 miles to go to radiation, right? There's that. Or you can go to a big giant cancer center where everything is put into 1 single building. You're popping up and down floors, or maybe everything's on the same floor. Doesn't matter what system you're in. My first recommendation would be let people know what your concerns are, right? Let 1 of your providers know, for instance, "Hey, listen, I'm struggling with transportation," or, "I'm worried about my job," or, "I'm worried about X." Really important to feel comfortable with your care team, right? So that first step in terms of overcoming barriers is, do I feel comfortable with the people who are helping me through this cancer journey? And it's the entire team, not just the doctor. It's the nurse. It's the therapist. It's the entire team that, hopefully, you feel comfortable with so you can say, "You know what? I just need to be open, and I need to share what my concerns are related to X," right? Doesn't matter if it's finances or food or whatever; just talk to your team.

And so 1 of the things that I'm trying to do is encourage providers also to ask people, right? So this is bidirectional. So, yes, we're talking right now directly to individuals who may experience cancer, or maybe the family member has experienced cancer. So, yes, please bring it up if you have concerns. But the other piece is providers need to do a better job asking kind of what people's concerns are as well. So that would be the first thing. Many centers will have social workers or other people who can help to navigate people through the system and be able to reduce some of those barriers. The other thing is I oftentimes will point people to wonderful resources online. So, again, not everyone has access to online kind of services. So this is why asking and having conversations with your care team is important because we don't want anyone to say, "Well, I don't have access to the internet," or, "I don't know how to Google," or, "I can't read." So please, please, please don't think that this is just comprehensive. I want to say please talk, right, opening your mouth and having conversations first, but certainly, online, there's some great resources. The American Cancer Society has wonderful resources. They've been providing a lot of transportation services for individuals with cancer for decades. I know that with COVID, some of that kind of was reduced, but it's a wonderful opportunity for volunteers even to say, "I'm going to give back. I want to be there to provide transportation services for individuals going through cancer journey." So the American Cancer Society has lots of resources.

The other thing is Cancer Support Community is another online venue. You can pick up the phone and call them. But Cancer Support Community is another opportunity to kind of really have-- these are some resources that are available. And I must say probably 1 of the number 1 resources I tell people to go to is Cancer.Net. And you know why? It's because they actually have a full-on resource page, right? So you can go to Cancer.Net and actually look at the resources page, and they list some of these, including Cancer Support Community, right? So there are lots of different resources that can be available to individuals. It's just a matter of looking, and it's a matter of kind of knowing where to go. So, again, I point people to Cancer.Net because it oftentimes has lots of different places that people can go to, some of which are related to a specific cancer diagnosis, right? So Komen for Breast Cancer is 1, but many of them generic, like the American Cancer Society or Livestrong or Cancer Support Community. So I just recommend people go to Cancer.Net or 1 of those other online resources to help them find what might work for them.

Brielle Gregory Collins: Thank you so much, Dr. Winkfield, especially for sharing your time and your expertise today. It was so great having you.

Dr. Karen Winkfield: Well, thank you, Brielle. I'm so grateful for this opportunity. I'm so thankful that we're able to talk a little bit about social determinants of health and things that people can do to help reduce some of those barriers to cancer care.

Brielle Gregory Collins: Yes, absolutely. And for our listeners, you can find more information on this topic at www.cancer.net/disparities.

ASCO: If this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world's leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's podcast, 4 Cancer.Net Specialty Editors discuss new research in prostate, bladder, kidney, and testicular cancers presented at the 2021 Genitourinary Cancers Symposium, and 2021 ASCO Annual Meeting.

This episode has been adapted from the recording of a live Cancer.Net webinar, held June 16th, 2021, and led by Dr. Neeraj Agarwal, Dr. Tian Zhang, Dr. Petros Grivas, and Dr. Timothy Gilligan.

Dr. Agarwal directs the Genitourinary Oncology Program at the Huntsman Cancer Institute at the University of Utah.

Dr. Grivas is the clinical director of the Genitourinary Cancers Program at University of Washington Medicine. He is also an associate member of the clinical research division at the Fred Hutchinson Cancer Research Center.

Dr. Zhang is an associate professor of medicine at Duke University School of Medicine and is a medical oncologist at Duke Cancer Institute.

Dr. Gilligan is an Associate Professor and Medical Oncologist at the Cleveland Clinic Taussig Cancer Institute.

Full disclosures for Dr. Agarwal, Dr. Grivas, Dr. Zhang, and Dr. Gilligan are available at Cancer.Net.

Greg Guthrie: So today, let's introduce our participants. First we have Dr. Neeraj Agarwal of Huntsman Cancer Institute and University of Utah and the Cancer.Net Specialty Editor for Prostate Cancer. Next we have Dr. Petros Grivas from Fred Hutchinson Cancer Research Center and University of Washington. He is the Specialty Editor for Cancer.Net for Bladder Cancer.

Next we have Dr. Tian Zhang of Duke Cancer Institute. And she's our Cancer.Net Specialty Editor for Kidney Cancer. And last, we have Dr. Timothy Gilligan. He is with the Cleveland Clinical Taussig Cancer Institute and the Specialty Editor for Testicular Cancer. So to start off, we'll have Dr. Agarwal talking about prostate cancer.

Dr. Agarwal: Thank you, Greg. It's such a privilege and honor to be here discussing these studies. So I would like to start with the first study, which was led by Dr. Stephen Freedland, a urologist at the Cedars-Sinai Medical Center in Los Angeles and was co-authored by me, Dr. Dan George, and many others. And here in this study, we present the utilization of therapies, which are associated and known to be associated with very significant, in fact, I would say dramatic improvement in overall survival, as shown by multiple randomized control trials over the period of the last 5 to 6 years. Just to take a step back for the audience, until 2014, standard treatment for metastatic castration-sensitive prostate cancer or newly diagnosed metastatic castration-sensitive prostate cancer used to be androgen deprivation therapy. And combining androgen deprivation therapy with those medications which were approved in the castration-resistant metastatic prostate cancer setting. So basically, using those drugs upfront led to dramatic improvement in overall survival with 33% to 35% reduction in risk of death across those clinical trials. So we actually wanted to look at the real-world utilization, so look at the real-world users of these medications in these patients who are being diagnosed with -- newly diagnosed metastatic prostate cancer in the United States. We also wanted to see how patients who belong to minority populations or racial minority populations, how they are being treated with these medications, which are backed by level 1 evidence. So this was a retrospective analysis of a Medicare database, more than 35,000 patients were included from 2009 to 2018. And we can see here a very representative patient population, predominantly white patients, 11.8% were African American, and 5% were Hispanic.

And here are the results. From 2010 to 2014, the use of standard androgen deprivation therapy with bicalutamide, was used in 97% of patients. We did not have trials reporting by that. Let's go to 2015 to 2016. Docetaxel was already approved in this setting now, and we can see some patients received docetaxel, but a small minority of patients received docetaxel. And then let's move to 2018, which is 4 or 5 years after docetaxel data had been presented by Dr. Sweeney in the ASCO plenary session. And abirateron was approved in 2017, and we are still seeing even like almost 2 years after -- we are still seeing the vast majority of patients being treated with standard androgen deprivation therapy or standard deprivation therapy with bicalutamide. So 62% plus 19%, we are talking about almost 80% of patients still not being treated with standard of care treatment, which is androgen deprivation therapy plus docetaxel, or androgen deprivation therapy plus abiraterone at this point of time, and now we have 2 more drugs available, which include enzalutamide and apalutamide in this study.

Another interesting thing was if you look at the patients who belong to minority populations, so let's look at African American patients compared to Caucasian patients. The use of intensified therapy was numerically lower. So in Caucasian patients, we are seeing higher use of intensified, as we call them, intensified therapy, or therapies which are considered standard of care, compared to African American men. So overall, the use was lower across the board, but if you look at African American men, the usage was even lower. So this is definitely concerning. I call it alarming, underutilization of life-prolonging therapy in patients who are being diagnosed with newly -- or new diagnosis of metastatic prostate cancer, and we definitely can improve this. We can definitely offer better care to our patients. It is not acceptable in my view to have 30% or less patients receiving standard of care therapies. So with that, I'll go to the next study.

Greg Guthrie: Great, thanks. And this study is, "Health-related quality of life and patient-reported outcomes at final analysis of the TITAN study of apalutamide versus placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen-deprivation therapy." And you were the presenting author of this, Dr. Agarwal?

Dr. Agarwal: Yes, Greg, thank you for giving the opportunity to present this study. And this is basically the continuation of the previous trial. I will not delve into in-depth analysis of these data. I just wanted to show that quality of life is not being impacted adversely by using intensified androgen deprivation therapy, so if you are using these drugs, which improves survival in a very significant fashion, and they are not being used in our patients, as we just saw in the previous study, what could be the reason? Is it the concerns about quality of life or adverse impact on quality of life? If that is the concern, this study, I think, helps refute those concerns. And in this study, which was a large study known as the TITAN trial, which led to approval of apalutamide for patients with hormone-sensitive or castration-sensitive metastatic prostate cancer and showed improved survival and radiographic progression-free and overall survival. We looked at quality of life data as reported by these patients, and these quality-of-life data were assessed by very standardized, validated scales known as FACT-P, or Functional Assessment of Cancer Therapy Prostate scale, or Brief Pain Inventory tool. And there are many other tools. So I will show you the results. And we can see here consistently there was no difference in quality of life as reported by the patients, or I would say any adverse impact on quality of life for these patients in any of these questions. As they were taking these questionnaires. So whether it was physical wellness, emotional wellness, functional well-being, social, or family, we go in and look at fatigue and there was no adverse impact on quality of life. At least from this perspective, we should not be concerned about using these drugs up front in our patients who have newly diagnosed metastatic prostate cancer.

Greg Guthrie: Great. And so what does this mean for patients?

Dr. Agarwal: From patient perspective, we can see here very clearly that using standardized tools, very validated tools, which have been used in multiple trials in the past, patients are not reporting any adverse impact on their quality of life when being treated with intensified androgen deprivation therapy. In this context, apalutamide.

Greg Guthrie: Great. Alright. So let's move on to our next study, which is, "Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer." The VISION trial.

Dr. Agarwal: Thank you. In my view, this is 1 of the most important studies presented in the 2021 ASCO Annual Meeting. This study was a phase 3 study where 7,000 patients were recruited, and they had metastatic castration-resistant prostate cancer and had disease progression on a prior novel hormonal therapy such as enzalutamide or abiraterone and the patients had received a taxane chemotherapy. So at least 1 taxane chemotherapy was required before the trial, and the patient had to have disease progression on a novel hormone therapy. These patients were randomized in 2 to 1 fashion to a novel drug, which is a type of radiation, intravenous radiation, as I would explain to my patients, and this is known as beta radiation. And this is a novel radiotherapy where radiation particle, which is delivering beta radiation particle to the cancer cells, is tagged to a molecule, which binds with the prostate cancer cells. So I'm simplifying it for the sake of our patients. And this particle or this compound was added to standard of care therapy and patients were randomized to standard of care therapy versus standard of care therapy plus this new compound. And standard of care therapy was a novel hormonal therapy or anything which did not include chemotherapy or radium 223, which is another type of radiation particle, but a different kind of particle known as alpha particle. So in this study, radiographic progression-free survival and overall survival were primary endpoints. We can see here that the study met both primary endpoints. There was a significant improvement in radiographic progression-free survival with an almost 5 month, 5.4 months, to be precise, improvement in radiographic progression-free survival, with a 60% reduction in risk of disease progression or death. If you look at overall survival, it was also improved in a significant fashion in patients who received the new compound known as lutetium-PSMA-617, and the median survival was improved by 4 months with an approximately 40% reduction in risk of death. This was a well-tolerated drug overall, and if you look at hybrid side effects, treatment, and emergent side effects, there were 52.7% of patients in the experimental arm, and 38% in the control arm had those treatment-related side effects. So overall, Wwell-tolerated regimen with improved overall survival and radiographic progression. Thank you very much.

Greg Guthrie: Thank you, Dr. Agarwal. This is really interesting, and it will be interesting to see if this treatment does change standard of care based on this research. Let's move on to Dr. Grivas and bladder cancer research. Let's see, so Dr. Grivas, your first study is, "Avelumab first-line maintenance for advanced urothelial carcinoma: analysis of clinical and genomic subgroups from the JAVELIN Bladder 100 trial." And Dr. Grivas was a co-principal investigator in this trial and is senior author of the New England Journal of Medicine publication and co-author of this abstract. Go ahead, Dr. Grivas.

Dr. Grivas: Thank you so much, Greg, and thank you to Cancer.Net for the opportunity, and thanks to the audience. We welcome questions. I would like to update the audience today about the data we saw at the ASCO meeting, and I would like to place this data in context, and I would remind the audience the JAVELIN Bladder 100 trial that changed clinical practice was initially presented last year at the ASCO Virtual Meeting 2020 by Professor Powles. And this particular trial tried to answer the following question: does the immunotherapy, especially the PD-L1 inhibitor avelumab, add value in patients who completed chemotherapy in the first-line setting of metastatic urothelial cancer compared to just best supportive care in terms of longer life, in terms of overall survival, and time until the cancer grows or death, progression-free survival? This is important because until this study came about last year, the practice was, in the setting of spread metastatic urothelial cancer, when the chemotherapy stops, was we cannot give it for a long time because of potential side effects. Usually you used to wait until the cancer grows back, it progresses, or grows. So this trial compared this approach, the best supportive care, versus the immunotherapy with avelumab and the best supportive care. This particular trial, so the significant improvement of life expectancy and overall survival as well as progression-free survival, time until progression of the cancer or death, in the patients that received this immunotherapy drug avelumab as a way to maintain or sustain the benefit that is seen with chemotherapy. So we call this a maintenance therapy approach because we tried to maintain or sustain the benefit with chemotherapy. I want to highlight that this was published in the New England Journal of Medicine and the audience can retrieve that from PubMed if one wants to read the manuscript. The bottom line is this trial changed practice, and we can go now to updates. We saw this in this particular meeting, ASCO 2021, and I think the main question was, are there any particular subsets of patients, different categories of patients, who benefit more from the avelumab maintenance approach, or does this benefit all the patients? And we saw at the ASCO meeting, we saw that the benefit with this immunotherapy appears consistent across the board, across different subcategories of groups of patients. And I think that it's important to point out that we looked at patients who had what we call local disease around the bladder, that was invading this area, and the pelvic side wall that was not amenable to surgical rejection and also patients with spread of the cancer in distant sites, what we call metastasis. And we look at patients who had a primary origin in the bladder or higher up in the urinary tract, what we call kidney pelvis, or ureter, and we call this upper urinary tract, versus the lower tract, which is the bladder, and we also look at patients who had metastatic spread in the lymph nodes only or other parts of the body. And with the bottom line, we saw that the benefit with the immunotherapy was consistent across the different groups of patients. So many patients benefit from this treatment, again, with variable degrees, variable magnitude of benefit, but overall, the bottom line is, take home message is if you have clinical factors or other molecular factors, we do not have a reliable, accurate tool to select which patients should go with avelumab, so we offer it nowadays in every patient who has no contraindication to get immunotherapy and has received some disease control. Meaning a response of the cancer or stabilization of the cancer with the chemotherapy phase. So that has real clinical implications, and I encourage the audience to discuss with their oncologist about the optimal roles of immunotherapy with this maintenance setting after chemotherapy when this is controlled with chemotherapy.

Just for context here, I want to highlight the options the patients have in clinical practice. And when someone is diagnosed with spread urothelial cancer, they can be offered nowadays avelumab as a maintenance strategy to maintain the benefit of chemotherapy, and the other options include immunotherapy up front, like drugs like pembrolizumab or atezolizumab, and I will come back to that question how to select your treatment in my last slide. And I want to point out these are the options, and obviously clinical trials are always a great option for patients, and they should ask their oncologist about those options. So since I talked about immunotherapy, I want to point out that the ideal chemotherapy is cisplatin-based chemotherapy. Not everybody has enough fitness of the body to tolerate cisplatin. For those patients, we think cisplatin may be too much, we use carboplatin/gemcitabine, and we use avelumab maintenance in that scenario. What about immunotherapy after that? Is there data supporting that use? And the answer is yes. There is some data suggesting that immunotherapy can be an option for some of the patients, and in this particular slide, we update the data from another clinical trial. And I will let Greg, you can read the title of that.

Greg Guthrie: Sure, so this study is, "First-line pembrolizumab in cisplatin-ineligible patients with advanced urothelial cancers response and survival results up to 5 years from the KEYNOTE-052 phase 2 study." Dr. Grivas, you're a co-author on this study.

Dr. Grivas: That's right, thank you, Greg. This trial presented longer follow up to see what happened in patients who received the immune checkpoint inhibitor anti-PD called pembrolizumab because they were not fit enough to get cisplatin chemotherapy. Keep in mind this was designed before the previous study I showed you presented the results and included patients who were not fit for cisplatin, but some of them could have been fit for carboplatin. There was no comparison here, everybody received pembrolizumab as a single agent, alone, and in this particular study, we would try to see the degree of shrinkage of the cancer and the overall response rate as well as how long people lived over time. So with longer follow-up, by the way, we published this study in the Lancet Oncology years ago, and we have longer follow-up, and what you see here is a degree of shrinkage of the cancer, what we call overall response rate, was about 29% in what we call all comers, and it was higher size of tumor shrinkage in patients with high PD-L1 expression. PD-L1 is this brake of the immune system, the checkpoint of the immune system and highly expressive measured by particular assay that pembrolizumab works better in those patients. However, some patients even with low PD-L1 measured by this CPS score I put in the slide still might have benefits, so the take-home message here is there is a particular proportion of patients who can benefit from the checkpoint inhibitor pembrolizumab. PD-L1 can be used in that setting to help decide between chemotherapy and immunotherapy. However, we have not compared directly the chemotherapy followed by the available maintenance with immunotherapy up front, so this question is still lingering. However, if the patient has a response shrinkage to pembrolizumab, many of those patients may have a long-lasting response. We tried to figure out with research how can we predict who is going to benefit more from this treatment as a matter of ongoing research.

Greg Guthrie: Dr. Grivas, can you really quickly define CPS for our audience?

Dr. Grivas: Absolutely. Great question. CPS is a tool we use in the pathology labs to measure the PD-L1 expression. It can be measured by different assessing antibodies, and the pathologists use a score to define if the PD-L1 is high or low. In this particular study, CPS of 10 or higher defines PD-L1 high expression, CPS below 10 defines PD-L1 low expression, and this appears to have some association with a chance of the tumor shrinking with immunotherapy with pembrolizumab.

Greg Guthrie: Great. Thanks, Dr. Grivas. So our last study is, "Pembrolizumab versus investigator's choice of paclitaxel, docetaxel, or vinflunine in recurrent, advanced urothelial cancer: 5-year follow-up from the phase 3 KEYNOTE-045 trial."

Dr. Grivas Very quickly, this study compared immunotherapy, pembrolizumab, the anti-PDL1, compared to chemotherapy with paclitaxel, docetaxel, or vinflunine, the latter one is in Europe, after progression of cancer growth on platinum-based chemotherapy. This was published in the New England Journal of Medicine a few years ago, and pembrolizumab prolonged survival, people lived longer compared to the chemotherapy. And this longer follow-up presented by Dr. Bellmunt and colleagues, showed the sustained results with follow-up, this population of patients had already received cisplatin-based chemotherapy and the cancer progressed, growth, despite that chemo, and in those patients, pembrolizumab appears to produce better results compared to this salvage chemotherapy shown in that slide. And this has implications because immunotherapy can be used in those patients after progression on platinum-based chemotherapy.

And just to wrap up here the discussion, I just want to give the options to the patients, see if someone has a new urothelial cancer, options include cisplatin/gemcitabine, or if someone is not fit enough for cisplatin, carboplatin/gemcitabine, and both of those scenarios can be followed by avelumab, and those with shrinking or stable disease, patients who have progression on platinum-based chemotherapy can get pembrolizumab and of course other options available. We can go into another podcast, and I encourage the audience to look and discuss with their oncologist about those options, and the take home message, the clinical trials is what got us here, and I recommend clinical trials to be discussed with your oncologist. Thank you so much, and I'll be happy to take questions.

Greg Guthrie: Thanks, Dr. Grivas. So we're going to move on to Dr. Zhang, who is going to talk about kidney cancer. So our first study today is, "Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: a randomized, double-blind, phase III KEYNOTE-564 study."

Dr. Zhang: Thanks, Greg. I'm really excited to be here today and thanks, everyone, for joining. KEYNOTE-564 was presented at the ASCO plenary by our colleague Dr. Toni K. Choueiri, and this is a highly anticipated study in the adjuvant space for kidney cancer and enrolled patients with high-risk clear cell kidney cancer who had undergone either nephrectomy or a metastastectomy, removing their few sites of metastatic disease and treating those patients with either pembrolizumab for up to a year or placebo. And the endpoint was disease-free survival, and enough events had occurred by this ASCO for us to see the primary results. So the overall -- the study was positive. For the primary endpoint, disease-free survival improvement was met with a hazard ratio of 0.68 and the estimated disease-free survival rate at 2 years was 77% for patients treated with pembrolizumab versus 68% for patients treated with placebo. The overall survival favored pembrolizumab, but it was not yet statistically significant, and follow-up will be needed. Overall, we see an improvement in disease-free survival delaying time until recurrence for patients treated with pembrolizumab, and this was the first study in this adjuvant space showing checkpoint inhibition has a role in adjuvant treatment of renal cell carcinoma.

Greg Guthrie: Thanks, Dr. Zhang. Our next study is, "Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: results from 42-month follow-up of KEYNOTE-426."

Dr. Zhang: This study, KEYNOTE-426, we are all very familiar with. Pembrolizumab and axitinib has been used for the last 2 years in the first-line treatment of clear cell metastatic kidney cell cancer, and it's a longer-term follow-up, more events and more understanding of what happens to these patients once they're treated in a longer term, so primary endpoints of course of this phase 3 study were progression-free survival and overall survival. When we're looking at this medium duration of follow-up at 42 months, so about 3 and a half years, pembrolizumab and axitinib improved both median overall survival as well as median progression-free survival. We'd point out that the -- at the 3 and a half year mark, the overall survival rate for patients treated with the combination was about 57.5%. And the progression-free survival rate was about 25%, so about a third of patients had not had progression of disease at 3 and a half years. Which is quite meaningful if they can stay on their first-line treatment for that long. The objective response was 60%, and of note, the complete response rate had been updated to about 10%. So there are some patients that do have delayed complete responses. And no new safety signals were observed. So overall, certainly still provides a lot of evidence to treat with pembrolizumab and axitinib for patients in the front-line setting.

Greg Guthrie: Great. And our last study here is, "Health-related quality of life analysis from the phase 3 CLEAR trial of lenvatinib plus pembrolizumab or everolimus versus sunitinib for patients with advanced renal cell carcinoma."

Dr. Zhang: This was the phase III trial in first-line treatment of metastatic clear cell kidney cancer that was reported at GU ASCO in February of 2020, and it was a 3-arm randomization to lenvatinib with everolimus in the standard study, and lenvatinib with pembrolizumab or sunitinib alone, and we saw the efficacy data in February, and here we're seeing the quality of life outcomes, and looking at how patients are doing, patient-reported outcomes on these treatments. And so with multiple quality of life measures, we're seeing improvements in patients that had better disease-related scores of symptoms when treated with lenvatinib and pembrolizumab versus sunitinib. We're seeing pain scores improve and patients having less diarrhea, appetite loss, when we're comparing against sunitinib. Of note, it's hard to specifically tie a particular symptom, if that's improved, because they've had better disease control or if it's more from the treatment side effect itself. So still hard to tease out a causality in these quality of life measures, but overall, improvement in patients' quality of life when treated with lenvatinib and pembrolizumab. And certainly provides some more data for patients receiving this combination.

And so I just wanted to highlight our ongoing phase 3 combination trials and first-line metastatic kidney cancer. PIVOT-09 with bempegaldesleukin has completed accrual in the first triplet of COSMIC-313 with ipilimumab, nivolumab and cabozantinib has completed accrual, so the actively enrolling studies currently are PEDIGREE and PROBE. These are studies that are being carried out in the cancer cooperative groups, as well as a triplet belzutifan lenvatinib with pembrolizumab, a study that Merck is running and all 3 very important studies we will continue to learn from and answer some important, clinically relevant sequencing treatment discontinuation, nephrectomy side effect questions. Thanks to everybody.

Greg Guthrie: We have 1 more. So, "Clinical activity of durvalumab and savolitinib in MET-driven, metastatic papillary renal cancer."

Dr. Zhang: Dr. Rodriguez from Spain presented this of papillary renal cell carcinoma treated with savolitinib and durvalumab, and specifically looked at the MET-driven subset of 14 patients out of these 42 patients. The efficacy primary end point was objective response rate. And of note, and median progression-free survival for the 42 patients who were all treated, it was 4.9 months and in MET-driven disease, so savolitinib targets MET, so MET-driven disease was 10.5 months and the median overall survival in everyone was 14 months, versus MET-driven was 27 months, and also higher response rates for patients with MET-driven disease. So I think personally, hypothesis generating, we will likely be seeing more trials with durvalumab and savolitinib in MET-driven papillary renal cell carcinoma.

Greg Guthrie: Thank you, again, Dr. Zhang. And Dr. Gilligan, we're going to talk about some testicular cancer research now, and the first study is, "Testicular cancer in the cisplatin era: causes of death and mortality rates in a population-based cohort."

Dr. Gilligan: So this study was looking at what happens with testicular cancer patients who are cured of their cancer, are they at risk of dying of other causes? They looked at over 5,000 men treated between 1980 and 2009, so it's important to recognize that some of the treatments given back then are a little different than the way they're given now. And it looked at the risk of death from causes other than testis cancer compared to men without testicular cancer in the general population, and the concerning finding from this study, and it's not the first study to report this, was that the risk of non-testicular cancer death, that is, death from other causes, was increased by about 28% in men who had been treated with radiation therapy and about 23% in men treated with chemotherapy. There's a risk of non-testicular cancer death, the risk, excuse me, was doubled in those whose treatment included both. So it was higher with either radiation or chemo and it was actually 100% higher or double than both those who had chemotherapy and radiation. As you got more chemotherapy, the risk went up. There was no trend towards the increase with just 1 or 2 cycles. We started to see the increase with 3 cycles, and it became statistically significant with 4 cycles. But there wasn't much difference between 3 and 4 in terms of the absolute number that was seen. In terms of death from other cancers, so why is this happening? Other cancers are a major issue after chemotherapy or radiation. Again, the risk was increased 60% after radiation therapy and 43% after chemotherapy, and those who got both, the risk of cancer was 3 times higher than the general population. So that's in men who had chemotherapy plus radiation therapy. Fortunately, there are not a lot of men who get both of those treatments anymore. Non-cancer deaths increased 17% after chemo and 55% of treatment included both. So the risk for non-cancer deaths was not as high as the risk for death from secondary malignancies. Interestingly, the risk of suicide increased 63% in men treated with chemotherapy. That's not affecting as many men as those other numbers, even though 63% number looks high, but it is a concern. Those treated only with surgery did not have an increased risk of non-testicular cancer death. What does this mean for patients? It really means when we can use surgical treatments instead of chemotherapy or radiation as an additional incentive to try do that, and what that may mean is there should be a larger role for retroperitoneal lymph node dissection as an alternative to chemotherapy or radiation therapy. Secondly, for patients getting chemotherapy, it's important to minimize the number of cycles of chemo as long as we're not sacrificing long-term cure rates, because the biggest risk of death is dying from the cancer, but that means limiting to the 3 cycles instead of 4 cycles is probably a good idea, and I think it's an argument to use 3 cycles of BPE instead of 4 cycles of EP because it's really the etoposide and the cisplatin that is linked to the secondary cancer risk, not the bleomycin, as far as we know. And then lastly, we need to pay attention to the mental health needs of men treated with chemotherapy. That there is more emotional distress and we're seeing here a higher risk of suicide.

Greg Guthrie: So our second trial is the, "SEMS trial: result of a prospective multi-institutional phase 2 clinical trial of surgery in early metastatic seminoma."

Dr. Gilligan: So if we're going to use more retroperitoneal dissection and less chemotherapy or radiation, 1 place to do that is in stage 1 and stage 2 seminoma, and many centers around the country have started doing that, and this was a trial that looked at that approach. So these are men who normally would be treated with chemotherapy, 3 cycles of BEP, or radiation therapy to the back of the abdomen and part of the pelvis potentially. This study looked at the small number of patients, 55 men, low volume, stage 2 seminoma up to 3 centimeters of size and maximum dimension. And what they reported of those men undergoing retroperitoneal lymph node dissection, 10 relapsed, so 18% relapsed after median follow-up of 24 months, they were all alive at the end of the study. No deaths. 8 of 10 relapses were treated with chemotherapy, and 2 were treated with additional [surgery]. Out of the 55 men, 8 ended up getting chemotherapy. Normally, all of them would have gotten either chemo or radiation. Relapse-free survival was 87%, overall survival was 100%.

Seven (7) patients developed complications after RPLND and 5 of them were mild. Two (2) were more severe. So it's a well-tolerated treatment, if it's done at a large volume center, it's worth noting that the centers participating in the study were large volume centers. Again, if not treated with RPLND, all of these men would have gotten chemo or radiation. The relapse rate after chemotherapy or radiation is about 5%. So the relapse risk is higher after surgery, but in the sense, if we take 100 men with early stage 2 seminoma and do an RPLND instead of chemo or radiation, we can spare 80% of them the long-term effects of chemotherapy or radiation. Alternatively, if the priority is simply to prevent a relapse, radiation therapy and chemotherapy are more effective at that, the relapse risk being 5% but at the cost of long-term side effects from chemotherapy or radiation. Bottom line there is an additional treatment option for low volume stage 2 seminoma for men who prioritize avoiding the complications of chemotherapy or radiation therapy. Both of which are associated with an increased risk of death from other causes. The price we pay for that is the relapse risk is higher with RPLND compared to the other approaches. Not all centers are going to be offering this, but major centers that do a lot of testicular cancer, this is becoming a new treatment option. With the caveat that we have less experience with this approach. This is a relatively small study. And we have a lot more experience with chemotherapy or radiation. I don't think there's a one size fits all here, but I think patients should talk about it with their doctor. If they have early-stage seminoma, they should talk about surgery as an alternative to radiation or chemo.

Greg Guthrie: Here we go. "Surveillance after complete response in patients with metastatic non-seminomatous germ-cell tumor."

Dr. Gilligan: So this study is looking at the question, if you take a man who has retroperitoneal lymph nodes that are enlarged and metastatic non-seminomatous testis cancer with lymphadenopathy in the back of the abdomen and you put them through chemotherapy and at the end, all retroperitoneal nodes are now within normal limits, normal size nodes, and no bigger than 10 millimeters or 1 centimeter, do we need to do a retroperitoneal lymph node dissection on those patients? Some centers recommend it and some don't. This looked at 388 men in that situation. They were put on surveillance. These men did not undergo the post-chemo RPLND. Two years survival, overall survival was 97.8%. Two-year progression-free survival was at 90%, 34 patients relapsed, and 10 of the men died. Men who did relapse had surgery, chemotherapy, or both as subsequent treatment. There's a prior similar study that was multicenter that had longer follow-up of 5 years, and they reported of ;161 men who had a complete response to the first-line chemo, 10 relapsed (that's 6%) and none died. If we combine these 2 studies together, the bottom line is you would have to perform a post-chemotherapy retroperitoneal dissection, which is a big operation, on about 550 men to prevent potentially at most 44 relapses and 10 deaths. We don't know if we would prevent or how many of those relapses and deaths we would prevent. But there's a lot of operations with a relatively low yield. In the future, we hope to have blood tests that will tell us which men need surgery. And even right now, we're close to the point that we have blood tests that will detect residual cancer. And the chance is we worry about residual cancer in these patients and we don't have the blood test to pick it up. But the bottom line is in the meantime, the preferred management strategy is surveillance rather than surgery for most men. There's some men for whom RPLND may make sense in the center in this setting and some centers that will probably continue to recommend it for most men. I think this data really casts doubt on whether we ought to be doing this operation in these men as a routine practice as opposed to an exceptional practice for men who have particular characteristics. Thank you.

Greg Guthrie: Thank you, Dr. Gilligan. And now we can move on to answering some questions.

What is the average time expected to see a decline in PSA in patients treated with lutetium-177 PSMA?

Dr. Agarwal: I think this a great question and I think we're waiting for the manuscript published to go through the nuances of those data. Right now, what Dr. Michael Morris from Memorial Sloane-Kettering presented were the high-level data on pre-survival and overall survival and some secondary endpoints. We are anxiously waiting the full data in the form of a manuscript. And until then, I will not be able to answer that question. I would like to add that usually the median time, if you look at how -- for how long patients were receiving lutetium, it was 5 to 6 months. If I -- if my recollection is correct.

Greg Guthrie: Is radiation required prior to initiating chemo if there's tumor presence? And Dr. Gilligan, you responded. "We rarely use radiation therapy for testicular cancer at this time. Sometimes it is used for stage 1 or stage 2 seminoma as primary treatment instead of chemotherapy."

And I'll just read these aloud for our viewers here. If a patient has both prostate and bladder cancer, how do you decide which therapy should take priority, also, is the CPS typically included on the biopsy report? And Dr. Grivas, you responded, which I'll read here. "This is a bit of a complicated scenario that requires detailed discussion with a urologist and medical oncologist. Regarding CPS, the possible role is only in the first-line setting of metastatic disease to help somewhat decide between chemotherapy followed by avelumab maintenance and immunotherapy. However, it's not a perfect biomarker and not part of the pathology report, it's a special test that requires specific ordering." I have a question for you, Dr. Zhang. Why do combination treatments seem to work better in kidney cancer? Wouldn't you have more side effects because you're taking 2 drugs at the same time?

Dr. Zhang: It's an interesting question. You know, our immunotherapy backbones seem to have good treatment benefit for these immune responsive diseases. The VEGF inhibitors that blocked blood vessel formation for many of our patients with clear cell kidney cancer, they tend to have an immunomodulatory role, so if we normalize blood vessels in the tumor microenvironment, the thought is that the T cells and immune cells can actually get into that space more readily. And so many of these blood vessel blockers are hypothesized to have increased immunomodulatory times of behaviors and the combination actually can be more effective than either agent alone, and we've certainly seen that in practice and really excited to see these combination strategies thrive and be standard of care for our patients now and first-line treatment. For the side effect question, you know, I do think that sometimes we do have to tease out which of the side effects is related to the oral treatment, the blood vessel blocker versus the immune therapy. But it's often experienced oncologists who are able to manage these side effects. We can try to tailor and see which of the side effects is due to which treatment and how to reduce or hold treatments when necessary.

Greg Guthrie: Great. I just got a follow-up question for you, Dr. Zhang. Are there any studies for papillary type kidney cancer with sarcoma?

Dr. Zhang: I would assume you're asking about sarcomatoid renal cell carcinoma within papillary, so for papillary type of kidney cancers, there are ongoing studies. For example, with FH mutations and FMH loss. For sarcomatoid disease, this is a special type of histology that can occur with any of our actual histologies of kidney cancer. And we know from our phase 3 trials in clear cell sarcomatoid renal cells that these tend to respond to the immunotherapy combinations. And so I would urge using an immune therapy combination in patients who had sarcomatoid renal cell carcinoma.

Greg Guthrie: Dr. Agarwal, here is a question for you. There were several studies in here that showed many patients did not receive combination ADT with other novel therapies, which you describe as the standard of care, including the one you discussed. Is this something that patients should proactively bring up with their doctors?

Dr. Agarwal: Fantastic question. I'm so glad you asked. The answer is yes: It is our responsibility as physicians and providers, but it doesn't hurt if our patients are educated and challenge us in our decision-making. It is a shared decision-making, it is not the doctor's decision. In my view, it's the patient's decision with help from the doctors. So, yes, please go do it. Doctors usually welcome that.

Greg Guthrie: Great.

Dr. Grivas: I see one for Dr. Gilligan about surveillance imaging that just popped up. [Is there any data on the benefits vs. risks for imaging based surveillance (CT, MRI, none) for longer-term follow-up periods (e.g. 2+ years)?]

Dr. Gilligan: Yeah, they're asking whether there's data on benefit versus risk for imaging-based surveillance and it's actually a very timely question in the sense that we're starting to get data that MRI is very accurate for this. And may likely become a substitute for CT scans at some point in the future. This is something we talk about a lot in terms of surveillance for testicular cancer patients, can we switch to MRI from CT because CT has ionization that can cause other cancers, and MRI does not. The good news is it looks like with current CT scanning, which is lower dose than older CT scanning, the risk of cancer from the CT scan seems really miniscule. Ultimately, it would be great to get it down to 0 and not do them, but we're still doing them. The switch to MRI is being held up by the fact that when you go in and get an imaging study for surveillance, your scans get looked at by a radiologist and also by the oncologist and all of us who do a lot of testicular cancer have multiple stories of catching stuff that the radiologist missed, and they also catch stuff that we miss. It goes both directions, and we're having 2 different people read the films to get a more accurate read. With MRI, most oncologists are not competent to read an MRI well and some radiologists are not great, and the centers where they have excellence have shown that MRIs are just as good as CT scans if read by fully qualified people. And the concern is: are they going to be skillfully read? So the switch to MRI will happen in the future, and I have spoken with people very recently about this that are practicing around the country and the people I talked to were not ready to make the switch because of the concern that stuff might get missed. And I think we can be reassured with the modern lower-dose CT scans, the risk seems to be quite small, and I look forward in the future to making that switch at some point.

Greg Guthrie: And I think that's going to be our last question this afternoon. Thank you to all our participants for sharing this great research with us, as well as your expertise, it's been a real pleasure on this live webinar here. ASCO: Thank you Dr. Agarwal, Dr. Grivas, Dr. Zhang, and Dr. Gilligan. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

This Cancer.Net podcast is part of the ASCO Podcast Network. This collection of 9 programs offers insight into the world of cancer care, covering a range of educational, inspirational, and scientific content. You can find all 9 shows, including this one, at podcast.asco.org.

Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/donate.

This presentation is provided solely for informational purposes. The ideas and opinions expressed in this presentation do not necessarily reflect the views of the American Society of Clinical Oncology (ASCO) or its affiliates. The mention of any product, service, or therapy in this presentation should not be construed as an endorsement of any product, service, or therapy mentioned. The information herein does not constitute medical or legal advice, and is not intended for use in the diagnosis or treatment of individual conditions or as a substitute for consultation with a licensed medical professional. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the presentation or any errors or omissions. © ASCO 2021, all rights reserved.