Journal of Clinical Oncology (JCO) Podcast

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors" by Schaffer et al published in the Journal of Clinical Oncology July 17th, 2024.

TRANSCRIPT

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the October 1st issue of JCO titled, “Post-Transplant Cyclophosphamide–Based Graft-Versus-Host Disease Prophylaxis Attenuates Disparity in Outcomes Between Use of Matched or Mismatched Unrelated Donors,” by Shaffer et al.

The CIBMTR registry study set out to compare outcomes of patients undergoing allogeneic stem cell transplantation hematologic malignancies by HLA antigen matching status as well as by the type of GVHD prophylaxis regimen received either calcineurin inhibitor-based prophylaxis or post-transplant cyclophosphamide or PTCy. This study included patients reported to CIBMTR from January 2017 to June 2021 with AML, ALL or MDS, and required that they have undergone allotransplant with either a calcineurin inhibitor based so tacro or cyclosporine, GVHD prophylaxis, or PTCy, which included a calcineurin inhibitor or sirolimus with or without MMF and ATG. Matched unrelated donors were defined as an 8 out of 8 HLA match. And mismatched unrelated donors were defined as HLA mismatched at any single locus or 7 out of 8. The primary objective of the study aimed to compare overall survival or OS and GVHD and relapse-free survival (GRFS) within and between matched unrelated donors versus mismatched unrelated donors separated by calcineurin inhibitor versus PTCy based GVHD prophylaxis.

GRFS was defined as survival without grade 3 to 4 acute GVHD, moderate to severe chronic GVHD requiring systemic therapy or relapse. 10,025 patients were included from 153 centers, with a median follow up of over 36 months. Mismatched unrelated donor recipients were made up of 22% minority ancestry patients as compared to just 8% of patients receiving a matched unrelated donor allo transplant, showing an enrichment for patients of minority ancestry in the mismatched unrelated donor group. Just under 10% of patients were of minority ancestry in the study overall, reflective of challenges in transplant care for these patients, which may include inferior access to care, fewer available and suitably matched donors, among other factors. 54% of all patients were transplanted for AML and 29% for MDS. 45% of patients received myeloablative conditioning, 25% received regimens containing ATG, and 23% overall received PTCy with either a calcineurin inhibitor or sirolimus as well as MMF.

Among patients receiving PTCy, the authors did not find differences in overall survival by degree of HLA matching, whereas among patients receiving calcineurin inhibitor-based prophylaxis, there remained survival differences by HLA matching status. When comparing matched unrelated donor calcineurin inhibitor patients with PTCy matched unrelated donor patients, the PTCy arm had better OS, and the mismatched unrelated donor group who received PTCy had similar OS as well. For GRFS, matched unrelated donor and mismatched unrelated donor PTCy patients had no difference in GRFS, similar to the trend the authors see with overall survival. But these patients also had better GRFS than matched unrelated donor patients receiving calcineurin inhibitor-based prophylaxis. Within each prophylaxis arm, there was no difference in GRFS by HLA matching status. HLA mismatched patients receiving PTCy were less likely to experience GRFS than HLA mismatched patients receiving calcineurin inhibitor-based prophylaxis.

The authors saw similar differences in comparative trends when subgrouping patients based on conditioning intensity and additionally did not find differences in GRFS and OS by ATG exposure. When looking at patients with minority ancestry, those patients who received a match unrelated donor or mismatched unrelated donor with PTCy had comparable outcomes to non-Hispanic white patients. Additionally, among minority ancestry patients, there was a significant benefit in both GRFS and OS in the PTCy groups as compared to calcineurin inhibitor-based prophylaxis. When examining other specific toxicities included in the composite GRFS endpoint, such as GVHD rates among PTCy patients, the authors note that patients receiving a matched unrelated donor had similar rates of grade 3 to 4 acute GVHD but lower rates of moderate to severe chronic GVHD requiring systemic therapy. There appears to be signal that among PTCy patients, HLA matching reduced rates of moderate to severe chronic GVHD compared to mismatched unrelated donor patients receiving PTCy. These same trends also held when the authors looked at non relapse mortality with no significant differences within the PTCy groups by HLA matching status but reduced non relapse mortality compared to both calcineur and inhibitor-based groups.

However, notably, there was a greater risk of relapse among matched unrelated donor PTCy patients than matched unrelated donor calcineurin inhibitor patients, although this risk was comparable between mismatched unrelated donor patients by type of prophylaxis. The authors note that this has also been observed in other retrospective cohorts and may be confounded by differences in conditioning intensity between these cohorts of matched unrelated donor patients, affecting the risk of relapse. Finally, the authors also evaluate whether expansion of donor search criteria to mismatch donors from full HLA matching would increase availability of young donors from minority ancestry patients, and the study noted striking increases for all subgroups examined.

This study fits nicely with the BMT CTN 1703 trial published in the recent past, which has showed the superiority of PTCy with the calcineurin inhibitor and MMF when compared with conventional calcineurin inhibitor based immune prophylaxis for reduced intensity matched related donor and matched unrelated donor allotransplant. Of note, very few patients with one HLA antigen mismatch were enrolled on that study. However, others have shown the feasibility of PTCy in the mismatched unrelated donor setting, which has led to its adoption in practice. Although less than a quarter of patients included in this current study received PTCy overall, the findings clearly are aligned with the BMT CTN 1703 study, which is likely to change clinical practice in the longer term in this field.

As the accompanying editorial in JCO, written by Dr. Chakravarty nicely lays out, the differences between this study and the EBMT registry study, also published in this issue of JCO are subtle but worthy of note. While both studies show that mismatched unrelated donor patients had worse OS and GRFS than those receiving matched unrelated donor transplants, and then among matched unrelated donor patients the addition of PTCy improved GRFS and OS, there is discordance between the studies whether the addition of PTCy abrogates the effect of HLA mismatching on GRFS and OS. As this editorial points out, there are strikingly different rates of T cell depletion with ATG between the US and Europe, which may account for differences in comparator arms that lead to this discordance. There are several very exciting clinical trials ongoing that will aim to answer some of these outstanding questions regarding comparisons of PTCy and T cell depletion, which the field eagerly looks forward to reviewing.

In summary, this registry study of patients receiving allo transplant with matched unrelated donor or mismatched unrelated donor and calcineurin inhibitor or PTCy based GVHD prophylaxis, most notably shows that for patients who may not have a matched unrelated donor available, the addition of PTCy to a mismatched unrelated donor allo transplant allows for improved outcomes after transplant in toxicities and survival. This is most significant for patients of minority ancestries who usually have fewer matched unrelated donors available in registry searches. Improving the transplant options available to these groups of patients is of critical importance in improving equitable access to care for all of our patients. And this study, although retrospective in nature, provides an important understanding of our progress to date and suggests directions for future investigation may indeed be very feasible to continue to close these gaps in care for patients in need of an allo transplant for hematologic malignancies.

This is Alexandra Rojek. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

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. Guest statements on the 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.

Dr. Shannon Westin and her guest, Dr. Brian  Slomovitz discuss the article “Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy For Newly Diagnosed, High-Risk Endometrial Cancer: Results in Mismatch Repair-Deficient Tumors” recently published in the JCO and presented at the 2024 International Gynecologic Cancer Society.

TRANSCRIPT

The guest’s disclosures can be found in the transcript. 

Dr. Shannon Westin: Hello, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts and literature published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist and JCO Social Media Editor by trade. I am thrilled because we are going to be talking about gynecologic cancer today. So, this is my jam. And specifically, we're going to be talking about a manuscript that's a simultaneous publication in the Journal of Clinical Oncology and presented at the Annual Meeting of the International Gynecologic Cancer Society on October 16, 2024. And this is “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer: Results in Mismatch Repair Deficient Tumors.” This is affectionately the KEYNOTE-B21 trial, also known as the GOG-3053 trial and the ENGOT-en11 trial.

And we are joined today by the primary author in this manuscript, Dr. Brian Slomovitz, who is the Director of Gynecologic Oncology at Mount Sinai Medical Center in Miami Beach, Florida, and the clinical trial advisor in uterine cancer for the Gynecologic Oncology Group foundation.

Welcome, Brian.

Dr. Brian Slomovitz: Hey, thanks, Shannon, so much. It's a pleasure to be here. And thanks for giving us the opportunity to discuss this trial.

Dr. Shannon Westin: Yes, it's a great trial and I'm so excited to talk about it. And I think we'll start just because this is a broad group that listens to this podcast, they're not all GYN oncologists, experts like yourself, so can you just level set a little bit and speak a bit about the incidence and mortality of endometrial cancer overall and the recent trends in this disease?

Dr. Brian Slomovitz: Yeah, sure. So, and it is nice to speak about gynecologic cancers, as we know, endometrial cancer was and still is the most common of all gynecologic cancers. The numbers are going up. Right now, there's about 65,000 to 70,000 cases each year in the US diagnosed with endometrial cancer. The numbers are going up. A lot of its obesity related, some other factors, but as the population gets less healthy, those are some of the risk factors for the disease. The thing that, however, is quite surprising is that we're seeing the deaths due to endometrial cancer going up as well, while for other diseases, we're making slow, steady steps to try to decrease the mortality we're actually seeing an increase in mortality. And the most discouraging point, Shannon, as you know is the number of deaths from endometrial cancer is going to outnumber the number of deaths from ovarian cancer if it hasn't done it already. I mean, now's the time. So, we really need to come up with better treatment strategies to everything to decrease the incidence of disease, to help with prevention, but for those poor women who are diagnosed, to come up with better treatment options so we don't have to keep this increasing trend in mortality.

Dr. Shannon Westin: Absolutely. And I think some of that is related and we don't need to get on a soapbox here, but the amount of funding that goes towards research in endometrial cancer, and of course you, you have been leading the way and really trying to get a ton of trials in this space and getting our industry partners and our government partners to really support this. So really just commending you on how much you've worked on, on this area. And to that end, we've had a huge renaissance with immunotherapy and endometrial cancer, a lot of really big trials. Why don't you give the audience a rundown of where, so far, this seems to be best utilized for people with endometrial cancer?

Dr. Brian Slomovitz: Thanks for that. And as you sort of alluded to, it's been a revolution, really, with immunotherapy. We started off at immunotherapy looking at microsatellite instability or the dMMR patients. What we found is similar to other disease sites in the second and third line setting that we saw good activity with the single agent checkpoints, pembrolizumab dostarlimab, that's based on the earlier KEYNOTE data and the GARNET trial. Really, a landmark study in the second line was Vicki Makker and her colleagues put pembrolizumab and lenvatinib combination for those patients with the cold tumors. Not the dMMRs or MSI Highs, but the proficient mismatch repair. And that study in a second line setting found that it was better than chemotherapy for an overall survival advantage. So right there, we know that it works in the second line setting in the dMMR population, and we got an indication in the PMR population saying that immunotherapy works in all women with endometrial cancer at some point, then we really had the groundbreaking trials. And Shannon, thank you. You are the leader on one of the four trials that happened, to DUO-E, AtTEnd, GY018 and RUBY trial, all very similar studies showing that the combination of immunotherapy with chemotherapy in the first line, metastatic or recurrent setting had a better outcome for patients than if given chemotherapy alone.

That actually led to amazing things. We had three of those drugs have FDA approvals, pembrolizumab for all comers, dMMR and PMMR in the first line metastatic setting with chemotherapy; Dostarlimab, PMR, dMMR in the first line or metastatic with chemotherapy. And Shannon, in your study, I think we still have to learn a lot from your study. DUO-E, chemotherapy plus minus dostarlimab. And you also added a PARP inhib, and those patients with a PARP did better. So I'm really looking forward to your data, to the subgroup analysis to figure out which of those patients, depending on the biomarker, do better with PARP therapy. And right now, you have a dMMR FDA indication. But who knows? The future is really exciting to see- to be splitters, not lumpers. And I really want to see how that data pans out. And so that's how it came into the first and second line setting and that led us really to come up with the idea for this trial to put it into the adjuvant setting.

Dr. Shannon Westin: Right. And so, I think this would be really important because we're so ingrained in this. We see this on the day to day. Can you kind of tease out a little bit what's different about those patients that would be treated in that advanced recurrent setting versus the patients that would be potentially treated in this B21 study?

Dr. Brian Slomovitz: Yeah, so the first step, we demonstrated the efficacy in patients that really the treatment options were an unmet need. In the second line setting, we didn't have good treatment options. Those are the patients with measurable disease, with symptomatic disease giving immunotherapy. And not only did we see the efficacy, which was better, but we also were able to give it with limiting the side effects as seen with chemotherapy, which is nice. And then we know that the first line therapy, traditionally for endometrial cancer with carboplatin paclitaxel, response rates about 50%, progression free survival about a year, really something that we needed to improve upon. So, adding immunotherapy to the platinum backbone therapy really demonstrated an advantage. But now what we want to do is we want to see if we could prevent, in the high-risk patients, those without disease, what can we do to help prevent the disease from recurring and help patients live longer without really the need for really lifesaving types of treatments? We want to prevent it from recurring.

Dr. Shannon Westin: Yeah, I think that's essential. We know that if we can sit on that prevention side and kind of invest all the time and effort that we need to upfront, that really does yield the longer survival. So why don't you just walk through the overall design of this trial, please?

Dr. Brian Slomovitz: Yeah. So, this was an all-comers trial, meaning in individuals that had high risk endometrial cancer, high risk for recurrence, that included, in endometrial cancer, we have aggressive histologic subtypes, serous histologies, clear cell histologies, any stage, as long as there was some myometrial invasion. We also, for the first time, included patients looking at the molecular subclassifications. So, if there was a P53 mutation and they were stage 1 with myometrial invasion, they were included. And then in all comers, any patients with stage 3 or up to 4a disease, as long as the surgery was for a curative intent, and they had no residual disease after surgery, then they were allowed to enroll into this trial.

One of the things is that this is the first time we've done an adjuvant trial this large. I think one of the reasons that helped us succeed in doing a trial like this is that we left radiation as investigator’s choice, because a lot of times going into a trial like this, people feel strongly, we know our radiation oncology colleagues, rightfully so, feel that radiation could help prevent disease from coming back. And we also have the camp that says they don't need radiation. We took that question out of this study. We let investigators decide whether or not they're going to get radiation. It was for patients to get chemotherapy, who are going to normally get chemotherapy for their high-risk disease and randomize them to chemotherapy plus placebo or chemotherapy plus pembrolizumab, a PD-1 inhibitor, in order to see if we could prevent the disease from coming back.

Dr. Shannon Westin: And the primary results of this study were just presented at ESMO and published in the Annals of Oncology. Can you give us just a quick overview of what that was, what they found?

Dr. Brian Slomovitz: Yep. So, we enrolled 1100 patients. The primary objective of the study was to look at the ITT population, progression free survival and overall survival. And the overall study was negative. Okay, so the hazard ratio in the ITT population was 1.02, not demonstrating a benefit of adding pembrolizumab in this population. I would say disappointing, but at the same point, something that we could really learn a lot from and somewhere that we know that in the whole population, we need to come up with better strategies to help prevent recurrence of disease, better adjuvant treatment strategies. But there's also information that we learned from this trial and that we're reporting on that we're actually super excited about and we feel may be game changing.

Dr. Shannon Westin: Yeah. So, let's go to that. This is the good news. Your manuscript in the JCO, thank goodness you published it here, was focused on that subset of mismatch repair deficient. So, tell us what you found.

Dr. Brian Slomovitz: So, in this study, we found that the first stratification factor was dMMR versus pMMR. Now, in the pMMR group, those patients had further stratification factors, but dMMR by itself was a stratification factor. Amongst those patients that had dMMR tumors, we found the hazard ratio to be 0.31 benefiting those patients who received pembrolizumab in the adjuvant setting. Really something that when we look at the treatment studies, the GY018s, the RUBYs, the atTEnds, the DUO-Es, in a dMMR setting, we see a similar hazard ratio of 0.3, 0.4. But to get that hazard ratio, which was statistically significant, obviously, is something that we were quite pleased with and something that we felt was worthy of reporting further. I will say it was a pre-specified endpoint. We didn't allocate alpha to it. So, at the beginning, it was a pre-specified endpoint, but at the same time even though we didn't specify alpha towards that outcome, it still, we feel is clinically meaningful and can definitely add to affect the standard of care and the management of these patients.

Dr. Shannon Westin: Yeah. I'm very intrigued to see what kind of people do with this. It makes sense, mechanistically, it makes sense if there was a population that was going to benefit, if not everybody does, this is the group that will. I mean, do you feel like there's enough data? What are you going to do? FDA approval aside, obviously, those kinds of things. But how do you feel about this? Is this something you're going to offer to your patients?

Dr. Brian Slomovitz: The first answer is yes. I think it's something that I would like to offer my patients. As you know, we need one of two things: we either need an FDA approval or for a lot of our payers required to be in the NCCN listings. I don't serve on the committee. I have no influence on NCCN. I'm excited to see how they'll respond to not only the Annals article, but obviously in today's release of the JCO article, I hope that they'll look upon it favorably. It's a drug that we’re used to giving. Pembrolizumab, we have a lot of experience with it. It's interesting. We didn't see any new safety signals, Shannon.

Dr. Shannon Westin: Yeah, I was going to ask - that’s great.

Dr. Brian Slomovitz: There was nothing, nothing additional that we found in this trial. So, I feel that it can definitely improve the outcome of those patients, in my view, with high risk for recurrence, treating pembrolizumab in this setting.

Dr. Shannon Westin: Yeah, I think it's important, of course, to look at the safety. What about quality of life? Any new findings there?

Dr. Brian Slomovitz: Yeah, we did that quality of life as part of the phase 3 trial. No difference between the two arms. No difference between the two arms. When we looked at a couple of the other analyses, we found that the benefit is the same on stage 3, 4 tumors. We saw that the benefit was there as well. So, there were less patients in the stage 1, 2 group. But I think really, for all comers, for the patient population, I would definitely consider giving pembrolizumab, again, for those patients with a deficient mismatch repair.

Dr. Shannon Westin: It's really exciting, and I think you mentioned some of the statistical limitations. Anything else that gives you pause about the study or things you wish you did better? I know we always like to armchair quarterback ourselves after we do these kinds of studies.

Dr. Brian Slomovitz: Yeah, it's interesting. When we designed the study years ago, we used the best information we had at that time to come up with the study design, and we're happy with it, and we really don't think that we could have done it much better. I should say, this was a great partnership that we had here between the GOG, ENGOT and with sponsor Merck, Toon Van Gorp was the lead PI of the global trial. When he gave me the good opportunity to present it at the IGCS and to be the lead author on this, it was really a great partnership. And when we came up with a trial years ago, it was the best trial that we thought at that time. And based on the information now, I think it's really something that we're excited about these results, even though the overall trial was negative.

Dr. Shannon Westin: Yeah, I agree with you. I think it's interesting, it's informative to think about, “Well, what would we do now or then if we knew what we knew now?” But still, you design the trial the best way you can. I think the results are super intriguing. I'm hopeful at the way they'll be reviewed. I agree I don't have any inside information about the NCCN committee, but I do hope that they'll consider the overarching data to support immunotherapy and mismatch repair deficiency and the findings of this study.

And then I guess the last question I would just ask, as you're an expert here, what are you looking forward to seeing coming next in this space? What's the stuff you're intrigued about in endometrial cancer?

Dr. Brian Slomovitz: I think, Shannon, you and I have talked about this for a while. I think we're getting really close to eliminating chemotherapy for some of the patients who suffer from this disease. So, I'm not sure if we'll do a follow up to this trial, but I think a logical type of follow up would be to see: what if we just took away chemotherapy altogether and we did pembro in the adjuvant setting, pembrolizumab versus chemotherapy? We don't have that trial in the adjuvant setting, but actually, we completed accrual of that trial in the recurrent setting and we’re anxiously awaiting those results. That's KEYNOTE-C93, where in the dMMR population we studied pembrolizumab versus carboplatin paclitaxel. How those results may translate into this setting, I'm not sure. Right now, it's exciting what we have, but yeah. And I think future is bright for this. Just to highlight, in the two arms, there's 140 patients approximately in each arm; there were 25 recurrences in those patients who received placebo. Only eight recurrences in those that received pembrolizumab. Really, when we talk about numbers, it's really remarkable and it shows you the benefit it really had on the patients.

Dr. Shannon Westin: Well, this was great. It flew by, as it always does when I'm having conversations with you. I just really want to thank you again for taking the time to share your knowledge with our listeners.

Dr. Brian Slomovitz: Thanks, Shannon.

Dr. Shannon Westin: And listeners. Thank you all for taking the time to hear about endometrial cancer. Again, this was “Pembrolizumab or Placebo, Plus Adjuvant Chemotherapy, With or Without Radiotherapy for Newly Diagnosed High Risk Endometrial Cancer Results in Mismatch Repair Deficient Tumors.”

And this was the JCO After Hours. If you loved what you heard, please check out wherever you get your podcast to see what else we have to offer. Have an awesome day.

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. Guest statements on the 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.

In this JCO Article Insights episode, Subodh Selukar interviews author Dr. Robert Maki on "Combining Response and Toxicity Data to Implement Project Optimus" by Maki, et al published in the Journal of Clinical Oncology September 11, 2024.

TRANSCRIPT

Subodh Selukar: Welcome to this episode of JCO Article Insights. This is Subodh Selukar, JCO's editorial fellow. Today, I am interviewing Dr. Robert Maki on his recent editorial, “Combining Response and Toxicity Data to Implement Project Optimus.”

At the time of this recording, our guest has disclosures that are available in the manuscript and will be linked in the transcript.

Dr. Maki, welcome to our podcast.

Dr. Robert Maki: Hi, Subodh. It's a pleasure to be able to take part.

Subodh Selukar: Yeah, thank you.

So, to start us off, would you give an overview of your article?

Dr. Robert Maki: Yes. Well, it's not my article, but it's just an editorial which is a commentary on an article by authors Cheng and Associates. It's called, “Exposure-Response-Based Multiattribute Clinical Utility Score Framework to Facilitate Optimal Dose Selection for Oncology Drugs.” That's a very technical title and so forth, and yet it's a JCO article because we think that it makes an important point that in oncological trials, we talk a lot about primary endpoints, oftentimes of overall survival or progression free survival, sometimes even just response rates, but most of the time, we don't take into account the toxicity of an agent. So, you can imagine that if a drug is relatively nontoxic, then what you see is what you get. Progression free survival could be associated with what is called some sort of so-called clinical benefit. However, if a drug is really toxic and you're just laid up on the couch all day or bed bound, or need transfusions three days a week, where is that really beneficial for the patient? But, by the same token, there's no quality of life without life itself. You have to have some sort of evidence that someone is going to be around for a longer period of time as an indication of benefit. So, these are ideas that have been played out to some degree for the better part of a quarter of a century.

There's a biostatistician at MD Anderson named Peter Thall, who's one of the first people to think about this idea of combining toxicity data and response data as some sort of a combination primary endpoint for a trial. And where this comes into play for Project Optimus, this FDA initiative to come up with not just necessarily one dose or one dose and schedule, but rather a range or multiple doses and schedules for a drug based on the toxicity that's seen, is that this new paper by Dr. Cheng and colleagues provides one mechanism for doing this, for combining not just traditional clinical outcomes data, but also toxicity data.

Subodh Selukar: So, you mentioned Project Optimus is an important component of all of this. So, can you tell a little bit about what Project Optimus is and maybe a little bit potentially about how Project Optimus has affected you so far?

Dr. Robert Maki: I'd say it's having an effect mostly in the earlier phases of drug development. I'm not certain, but I think it was an outgrowth of some of the toxicity that was seen in some of the studies that were done over the course of the last 10 to 15 years with kinase-targeted drugs. The overall goal from the FDA Project Optimus was to work with companies, with academia, groups like ASCO and regulatory authorities, as well as patients to try and come up with dosing for everyone basically based on patient characteristics that they're focusing not just on those outcomes, such as progression, pre survival, overall survival, but also looking for quality of life and adding that into the mix in terms of how you choose a dose. So that's an effort that's been going on for the last several years now. There's been some nice articles on that from FDA on that and perhaps we could provide some links to those as well for people who are interested in some of the more introductory core information about Project Optimus.

Subodh Selukar: Yeah, for sure. And so, I mean you're on the editorial board at JCO and you've written this editorial, but has Project Optimus affected your clinical research yet?

Dr. Robert Maki: It's just beginning to. So, in phase 1 and 2 clinical trials, especially in phase 1, the goal is not necessarily to look for activity, but just to come up with a recommended phase 2 dose and schedule of a drug. Well, Project Optimus says, “Okay. Well, maybe there's more than one dose and schedule that should arise.” And as I was alluding to earlier, this may have arisen out of what was seen previously where a number of the multi targeted tyrosine kinase inhibitors were developed. But when you got to the phase 3 trial, it was necessary to have dose reductions in 30%, 40%, 50%, 60%, even 70% of patients in some situations. So that to me represents a drug or a development pathway for that drug that was in essence incorrect. Yes, we talk about in traditional chemotherapy of trying to get the maximum dose we can, but is that always the best thing for the patient? And we recognize that there really is a plateau usually for systemic therapies we give, that there is a limit to dose escalation even within an individual patient to try and achieve that same benefit. At some point you're just going to add toxicity. The idea is to bring some element of toxicity into the decision making for a recommended phase 2 dose and schedule or schedules in that case.

Subodh Selukar: And so, building on that, so I think one advantage of these different approaches is that they might identify a single optimal dose, or maybe they'll recommend this range of doses that maximize some maybe clinical utility score combining these different aspects. In the current paradigm, it seems like probably response and toxicity are just these separate concepts that aren't typically linked together. But we typically do have a single recommended dose. But like you said, they might in subsequent trials have a lot of dose reductions and stuff like that.

So how do you think about the process now where this is a single recommended dose of, but there are deviations from that recommended dose in the research process. Like you said, in subsequent trials or within a trial, maybe patients are needing their own dose reductions as well. And then separately once a product is approved, what do you think about deviating from the recommended dose for your standard clinical practice?

Dr. Robert Maki: Oftentimes a work in progress. So even after phase 1, maybe having only treated 30 to 50 patients, they may be relatively homogeneous and that they have to be healthier to qualify for phase 1 trial. Once the drug is released to the whole wide world, then it becomes a different scenario, and you may have patients with poor performance status to start with. Can they still get the same benefit as the patients who got the medication in the context of a clinical trial? And it may not be the case.

And I think this is where Project Optimus and the idea of giving more than one dose or schedule may be useful and say, “Okay. Well, you can give 20% less,” and what's the trade off? Maybe the drug doesn't work as well, but it is less toxic. On average, do you really lose a whole lot as a matter of a few weeks of median progression free survival? Or does the response rate really drop off as you decrease the dose intensity of your drug? One concern about having more than one dose and schedule is could you potentially be underdosing patients by the same token? Since we usually have some amount of time, at least a few weeks, to work out what's tolerable for our patient, at least the parameters of having more than one dose and schedule to choose from can be useful.

Subodh Selukar: So then thinking about potentially maybe we would have a range of doses to recommend, what do you think are going to be challenges once that starts to be incorporated into clinical practice? What kind of complications do you think might happen explaining this to a patient?

Dr. Robert Maki: That's a really, really good question and something that we- I think, just have a difficult time with just the regular consent form. It used to be that maybe you had a couple of information sheets on a standard drug, or if it's a clinical trial, then you'll have a relatively modest consent form that's supposed to be at, whatever, 7th, 8th, 9th grade reading level. But now you start adding this form with complex text to a consent form for a clinical trial. What are people really signing up for? They get a 40-page document, and I don't think they really understand that.

So, the idea that you're trying to relate to them, pushing as hard as you can, but by the same token watching out for that toxicity, I think really does speak to those endpoints of the program, that it really can be a patient-friendly idea. Are we going to necessarily get it right every time? No. As I was mentioning previously there, if you're only treating 30 to 50 patients, you may only have partial information and you come up with some sense of dose and schedule to give. And then you move that into phase 2 and phase 3, and you may have to, you see that maybe one dose and schedule is a lot more effective as you get into a randomized portion of a phase 2 trial before you move to phase 3, for example, or you see that the toxicity is much greater with no better evidence of progression free survival. So those two scenarios could certainly rise. You can't predict them in the early phases of development of a drug, but you have to be able to react or be able to react with a solid clinical trial design that allows you to have that flexibility to make those decisions later. This is where discussion with the regulators, obviously is very important to make sure that what you're doing really still fits these guardrails, as it were, of traditional clinical trial design, or these ideas of adding in the toxicity-based information from Project Optimus.

Subodh Selukar: One of the challenges in early phase trials is, like you said, we might have 30 to 50 patients at the end of the study. I think in the editorial, you mentioned that some of these newer metrics might require more and more patients. Maybe we need 30 to 50 patients on a single dose in order to have reliable understanding of these clinical utility scores. Whereas right now a sample size at a single dose might be six patients, it might even be fewer. What are your thoughts on that aspect of it?

Dr. Robert Maki: That’s an important point, too. When you're doing, let's say, a quick and dirty, as you might say, 3+3 design, which has very large error bars in terms of the confidence intervals around a dose and schedule compared to some of the newer Bayesian-based designs, yes, you can get a phase 1 trial quote done, especially if it's a ‘me too’ sort of drug, so say, another checkpoint inhibitor, you kind of know the characteristics of those over another inhibitor of a specific kinase, you know the toxicities to expect when you block, let's say, EGF receptor. So, if you have some idea, and therefore you're able to more rapidly get to that recommended phase 2 dose from a phase 1 trial, if it ends up being a new drug, then maybe 30 to 50 patients isn't enough. And you really do need to continue that assessment of both response and toxicity as the trials move forward into phase 2 and phase 3.

So, it's kind of one of those ideas of continuous process improvement that if we are going to do this, we really do need to include it, not just in early phase trials, but especially for agents that are acting through a new mechanism of action, that we look at that holistically across the drug development spectrum. And now that trials are kind of being smashed together, phase 1 and 2, now phase 2 and 3, that really increases our need to also add in the assessment of toxicity, and maybe not just on the basis of our own evaluations or lab evaluations of toxicity, but patient reported outcomes, which is something that wasn't addressed in the Cheng article and really hasn't been well addressed in clinical trials in general, I would offer.

There are precious few trials that incorporate patient reported outcome data as a means to determine what's too toxic for a patient, for example. So how do we do that? As you know, we do have patient reported CTCAE clinical toxicity criteria that are based on patient reported outcomes. And wouldn't it be interesting, at the very least, as an academic project, but even more importantly, later on, to use those as the key means to determine whether a dose is too toxic or not in the development of the drug. That, to me, would be really, really interesting and kind of turns the idea of some of the data that we collect on its head. I guess, yes, we do need to collect things like liver function tests and so forth. It is one metric of toxicity of a drug. But patients have a lot of fatigue, we really do a poor job of documenting that as clinicians, and not to mention the elements that go into what that fatigue is. To be able to capture that through PROs would be another noble effort that I think has been underutilized and underappreciated in oncology clinical trials overall.

Subodh Selukar: And so, what do you think are barriers to doing it now?

Dr. Robert Maki: We tend to, for lack of a better term, cut and paste from what we've done before, to develop new, let's say, by patient reported outcome score or metric or worksheet for a given diagnosis. That can be hard, that takes a lot in and of itself, and perhaps has been one of the barriers that we don't have enough disease specific PROs, at least for some diagnoses. For others we do. And the fact that we do have PRO-scored CTCAE sorts of score tables, now, certainly makes it easier to validate and use these tools in clinical trials. So, I would love to see more of that, even if it ends up being secondary tertiary endpoints on phase 1, 2, and 3 trials. It's a pretty easy thing to add, even if you're doing that for the first time. Get some experience with it, and it can only help patients get through a trial or even just assessing it as part of a standard of care that will help our patients in the longer run.

Subodh Selukar: Yeah. And so, thinking about other metrics of success, you mentioned a couple in your article. These aren't necessarily patient reported outcome ones, but like RECIST and RANO. I was curious. I think the Cheng article, maybe I would think about it as a general framework for combining response and toxicity together, whereas some of these other metrics are a lot more disease specific, potentially, or agent and disease specific, maybe even. Do you think that clinical research will end up settling on these metrics that are kind of increasingly specific, or do you think that there's a possibility for general frameworks?

Dr. Robert Maki: Yeah, that's a tough question. I'm just trying to think of some of those patients reported outcomes. They've got kind of the general assessment ones, and then you do have ones that are more disease specific, just like we do have response criteria that are different for, let's say, lymphoma versus brain tumors versus colorectal cancer. We do have different ways of measuring those outcomes, and we all complain that those are imperfect measures. You can always find circumstances where that patient was responding, but it was called progression or vice versa. So even from these more objective tools like RECIST and the like, it’s a challenging field, that's for sure.

We keep going around and trying to find ways of improving those sorts of systems. But let's say, for example, you used - this is part of the reason we moved from two dimensional measurements in WHO criteria versus one dimensional RECIST - if you have two dimensions, well, you have that much more variability in the measurements of the lesion. So, it turned out that we just didn't gain anything by having those bidimensional measurements. Now, since we have the ability to measure tumors better in three dimensions, should we be using volumetric assessments? Part of it depends on the size of the tumor. If you're dealing with a tumor that's 1 cm versus 8 cm, well, then the volumetric changes, you have a lot more variability, the small ones, than the big ones. Not to mention the fact that you have shapes that are not just an ovoid mass in a lot of cancers. There's just so many pitfalls in these sorts of data. What really matters at the end of the day, one thing that's underappreciated, and again is underscored by Project Optimus, is getting back to the patient.

Subodh Selukar: Your editorial made me have this one thought, and so bear with me, it's like a multi-part question. One of the reasons that we're becoming more and more interested in these alternative approaches, these clinical utility scores and everything, is that these new agents are being proposed, where there's a hypothesis that there's more complicated relationships between dose, response and toxicity. And so, 50 years ago, researchers probably didn't hypothesize that these complicated relationships were happening. They probably thought that they were more straightforward. What do you think would have happened if we had had these conversations that we're having today if we'd had them 50 years ago, what do you think would be different? Do you think that maybe we would have different therapies that kind of ended up becoming standard today? Maybe would we interpret or run studies differently today?

Dr. Robert Maki: I like that question as well. Now, if we go back to the Charles Moertel studies back from the 1970s, the whole reason that we have tumor measurements as a criterion are really based on his work, where he got a series of clinicians together and he put these masses underneath a piece of rubber sheeting, and they tried to determine how well they could determine the difference between a mass that they could palpate. And this is when we came up with the idea that a partial response was a 50% decrease in the cross-sectional area of a mass. That came from that very crude but important work from about 50 years ago. And of course, that was also a time when there really wasn't any imaging. Maybe the best you would have would be x-ray tomography to look at a lung nodule or something like that. It was a little bit of a different era. We didn't know how our drugs worked very well. We had at least some biochemical reason to use chemotherapy, and we tried to leverage that. But it was always the idea of more is better, finally disproved later on, in let's say the era of breast cancer, looking at the AC combination or doxorubicin as part of a treatment for breast cancer, that there was a ceiling to the benefit of doxorubicin in the adjuvant setting. Even then, it was clear that we needed to think about dose and schedule. We also didn't have the variety of drugs that we have now, or the different metrics that we have, circulating tumor DNA or something along those lines. Those sorts of things just never existed then either. So, we need metrics that are appropriate for their time, and we have more tools to work with.

I suspect that we'll have more specialization in oncology along disease lines, or even molecularly characterized subsets of diagnoses as well. All the detailed classification that we now need for a lymphoma, for example, or different flavors of triple negative breast cancer, all of those things are impacting how we even put a person on a trial. Similarly, since these patients are also going to get different classes of drugs that are relatively unique to them, there are a lot of drugs now that are available that really are only approved for one diagnosis. Then you really have to drill down pretty deeply in order to be able to focus on that clinical scenario. But I think we have the means to do so. Nonetheless, the general idea of these frameworks, again, the idea of combining response and toxicity data that can apply across essentially any cancer or neoplasm that we want to study.

Subodh Selukar: Okay. So, I want to move a little bit to aspirational, like where we want to move forward now. And so I think you've talked a little bit about this so far already, but would you tell me a little bit about when you're seeing a patient, interpreting results that have been given in clinical trials, are there results, metrics, summaries of trials that you wish you could communicate to them, metrics that actually already exist but don't really get implemented? You already mentioned quality of life is something that doesn't seem to be there but are there other things that maybe quality of life might not just be collected enough yet. But are there metrics on data that we have and we just don't really report them at all?

Dr. Robert Maki: That may be the case, or maybe the data end up in a secondary and tertiary publication, so they don't really become part of the lingua franca of the oncologist. I think it really speaks to just having the experience as an oncologist that you try the FDA-approved dose for medication for somebody and you run into trouble if they're, let's say, in their 80s, whereas the study population was in their 40s and their 50s with better bone marrows or better renal function on average, and things like that. So, another untested waters are geriatric oncology. What are the maximum tolerated doses when they're 80 versus when they’re 40 or 50? It's a real challenge. Probably they had the most experience of that with things like prostate cancer, where we do treat largely an older population of men compared to other diagnoses, potentially.

I suspect we're going to see just more specialization, just like we do with the medications. We do need more specialized assessments for those adverse events and or quality of life that will be diagnosis specific. If you have GI cancer, abdominal pain is going to be a bigger issue or obstruction sorts of questions. And the symptoms that you may have from having a tumor within the abdomen versus, let's say, another diagnosis, which may tend to give you more, let's say, lung metastases. So those little subtleties can't come out. And the toxicities of the drugs that we use in those diagnoses are also going to differ as well. So those should be kept in mind as we come up with, let's say, disease specific toxicity metrics that we want to combine with those outcome data. So, I think we're going to see more and more specialization of that over time.

You have to create the tool and you've got to validate it. So, all these things will take some time. But again, people have been interested in this for a long, long time. There are any number of careers that are built around quality of life and cancer, or for example, long term survivorship in pediatric cancer patients. And all of these things can be very useful and just require our attention, both as clinical investigators as well as clinicians, when we face our patient’s day to day.

Subodh Selukar: And so just one last question before we close. Is there anything that we haven't had a chance to talk about that you like to share with our listeners?

Dr. Robert Maki: If it's anything it’s that I'm really heartened as I get older with this very large influx of new clinicians and new investigators. Oncology continues to get more interesting and more sophisticated. We need more people- we still don't have enough oncologists, even for our population here in the United States. We'll have plenty to do for a very, very long time. So, I'm excited to see a new generation of young oncologists such as yourself and the trainees that I see here, the new fellows, junior faculty who are all beginning to answer these questions, thinking about them. And as me and some of my more senior friends can help promote this kind of idea and help together to answer some of these questions. We're still trying to figure it out and there are just so many variables and clinical scenarios that we need to chase down in terms of clinical research. It is going to be an ongoing discussion and hopefully this article is just one example towards the goal again of finding the right dose for our given patient.

Subodh Selukar: Thank you so much for sharing and yeah, I'm very excited to be a part of this as well.

This has been Subodh Selukar interviewing Dr. Robert Maki on his recent editorial, “Combining Response and Toxicity Data to Implement Project Optimus.” Thank you for listening and stay tuned for the next episode of JCO Article Insights.

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. Guest statements on the 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.

 Dr. Robert Maki Disclosures:

Consulting or Advisory Role: Deciphera, PEEL Therapeutics, Eisai, GlaxoSmithKline, Medtronic, Boehringer Ingelheim Speakers' Bureau: MJH Life Sciences  Research Funding: Amgen, Astex Pharmaceuticals, Boehringer Ingelheim, BioAtla, C4 Therapeutics, InhibRx, Regeneron, SARC: Sarcoma Alliance for Research though Collaboration, TRACON Pharma Patents, Royalties, Other Intellectual Property, Uptodate Travel, Accommodations, Expenses Company name: Stand up to Cancer, Fondazione Enrico Pallazzo

Host Dr. Davide Soldato and Dr. Shelia Garland discuss the JCO article "Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors."

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato. I am a Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today we are joined by JCO author Dr. Sheila Garland. She's a Professor of Psychology and Oncology at Memorial University, and she's the director at the Sleep, Health, and Wellness Lab and Senior Scientist at the Beatrice Hunter Cancer Research Institute. Dr. Garland will be discussing the article titled, “Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors.” Thank you for speaking with us, Dr. Garland. 

Dr. Sheila Garland: Thank you so much for having me.

Dr. Davide Soldato: So, Dr. Garland, you designed a study that relied on cognitive behavioral therapy to treat insomnia, and then you assessed whether improvement in insomnia would be associated with an improvement in cancer related cognitive impairment. So I wanted to ask if you could give us a little bit of context and explain the rationale between these studies. So how common are these symptoms among cancer survivors, and why do we think that improving insomnia would also improve cognitive function? 

Dr. Sheila Garland: Yeah, thank you very much. That's a really, really good question. And so cognitive behavior therapy for insomnia has been used to successfully treat insomnia in cancer survivors for quite some time. I think JCO was one of the first publishers to really demonstrate the potency of this intervention to improve insomnia. But as we know, patients will often present not just with insomnia, but insomnia comorbid with pain, fatigue, and very commonly cognitive impairment. If we take a look at the experimental research in sleep, we know that sleep quality and quantity is associated with very important cognitive functions. And so we've had clear sleep deprivation studies where if you're not able to successfully get sufficient quality or quantity of sleep, you're going to have impairments in attention and concentration and memory. So it really makes sense that if we're able to improve sleep in cancer survivors, that we're also able to address maybe some of the other concerns that they would have related to sleep. So this is an important clinical question for the patient's quality of life, but I also think it has important system implications where if we're looking at like resources and efficiency of allocating those resources, if we have an intervention that can treat multiple problems, that means that we can more effectively address lots of symptoms and use fewer resources in doing so. So that was the thought in designing this trial.

Dr. Davide Soldato: Thank you very much. That was very, very clear. So you spoke about the intervention that you implemented in the clinical trial. So I was wondering if you could give us a little bit of context. How long was the intervention? What were the main points addressed? Because you said that, in the end, we already have some data regarding cognitive behavioral therapy for treating insomnia. So I was wondering, did you personalize in any way, the program or the intervention to fit more to the cancer survivors population? 

Dr. Sheila Garland: Yeah. So it is based on a protocol that has been well researched and has a great deal of evidence of efficacy. But we delivered this intervention over a course of seven weeks. So individuals had individual sessions with a trained therapist, and those sessions lasted about an hour and were over roughly about two months or so. Seven sessions over two months. And because they were delivered individually, there was some adaptation based on the clients’ presenting problems. So while there's sort of a standard protocol, if the client is also presented with levels of fatigue or pain or anxiety or depression, the therapist was able to integrate those concepts into the therapy as well. There was nothing for cognitive impairment. So there was no additional intervention for cognitive impairment at all. We weren't doing any memory training or anything like that. So it was strictly the sleep and other symptoms looking at the impact of improving that on not only your perception of your cognitive abilities, but also on performance on a number of neuropsychological test measures.

Dr. Davide Soldato: So thank you very much for the detail. And I think that it's very interesting what you said, that the personalization of the intervention would also allow to treat some other symptoms that are distressing for cancer survivors. Like, for example, you mentioned fatigue or anxiety or depression. And I think that this goes back to the first point that you made about the intervention. So being able to treat different symptoms all at one in one single intervention, I think that that is a very intelligent use of resources and also to promote and implement, potentially some interventions that are beneficial for survivors of cancer on different domains and potentially different symptoms. So, going to the results a little bit, what did you observe regarding specifically insomnia with the intervention that you delivered?

Dr. Sheila Garland: Yeah, so, of course, we wanted to make sure that we were effective in targeting the primary outcome of what the trial was supposed to do, which was we were supposed to treat effectively, treat insomnia, and then determine whether treating that insomnia was related to improvements in cognition. So we were expecting that the intervention itself was going to be successful at improving insomnia, and we were. So we were able to not only demonstrate a statistically, but also a clinically meaningful improvement in insomnia severity. Usually that's measured by a change of about 8.4 on a measure called the insomnia severity index. And the change that we were able to produce was over 11 points. So it was clearly over the clinically meaningful change threshold.

Dr. Davide Soldato: Going back a little bit to the design of the study, this was a randomized clinical trial. And how did you allocate the participants of the study into which arms? And can you guide us a little bit in the study design? 

Dr. Sheila Garland: Yes. A lot of thought went into the study design. We ultimately decided on having a waitlist randomized controlled trial, and this was because there is no other intervention for insomnia that has comparable efficacy. And we felt it would be unethical to not give people the standard treatment that we know works to treat insomnia. So that's where having them wait for a period of time and then receive the treatment was ultimately what we decided on. Overall, we were able to recruit 132 participants, and those were randomized into either receiving treatment immediately or receiving treatment after a two month waiting period.

Dr. Davide Soldato: So you mentioned that the intervention was actually very effective for treating insomnia. You reported an improvement in the insomnia severity index of almost 11 points. And as you mentioned, this is both clinically meaningful and it was also statistically significant. Did you see any improvement also on cognitive function, and how did you measure this outcome? Was it self reported, or did you also have some objective measure to see, for example, working memory or some other type of cognitive function?

Dr. Sheila Garland: Yeah. Also, a lot of thought went into choosing the primary outcome for this. And there's people who have argued compellingly that self reported cognitive function should be the primary target because we know, based on past research, that objective and subjective ratings of cognitive performance do not always correlate well with each other. And taking a very patient oriented approach, we wanted to make sure that we prioritized the patient's perception of their own function. We used one of the subscales of the functional assessment of cancer treatment cognition scale. So it was the Perceived Cognitive Impairment subscale that was what we used as our primary, but we also reported the two other subscales, which was the Perceived Cognitive Abilities and the Impact of Cognition on Quality of Life. We were able to not only discover that there were clinically significant improvements on all three of those subscales, but actually translated into, again, the clinically meaningful change threshold that's been established for the perceived cognitive impairment subscale is, I think it's around, like 5.9 points. So, using that cutoff, 75% of the participants in the trial reported clinically meaningful improvements in their perceived cognitive impairments, compared to just 43% of those participants in the wait list group. And we looked not only at the immediate intervention effects, but also on whether they were durable. So we had follow up assessments of both three months and six months after completing treatment, and the effects on insomnia, as well as the cognitive dimensions, they were maintained. 

Dr. Davide Soldato: Thank you very much for this last remark, because I think that one of the worries I would say that we have when implementing this type of behavioral intervention is that in the end, the change that we produce and the behavioral change that we produce might be effective in the immediate time after completing the intervention. But frequently we sort of see the loss of this benefit that we produce with the intervention at later time points. And I think that this is very important that you also looked at the benefit that was maintained over time for the three and six months after the end of the intervention. And it's true that before we add some data regarding other types of behavioral intervention, for example, for weight loss or some other symptoms and other toxicity that we frequently target with this type of intervention, I was wondering, do you think that it's something specific to cognitive behavioral therapy and the specific symptoms that you were treating, so insomnia, that in the end, produced a durable and meaningful benefit over time? 

Dr. Sheila Garland: So I do think that there's something really specific about this type of intervention. With insomnia, you're really changing the person's fear of not sleeping, and you're giving them tools to be able to both prevent the reocurrence of insomnia and also if the reocurrence should happen, they know what to do then to address it themselves. I was very curious about the impact that it might have long term. I actually wasn't sure whether it would have an effect immediately, considering that people do accumulate kind of a sleep debt after having insufficient sleep for a period of time. So I didn't know whether we would see anything immediately. I thought maybe we would need the long term follow ups to see some of the effect. But I guess maybe not surprisingly, at the end of the trial, thinking about when somebody has a good night's sleep, they're feeling the effects even the next day.

Dr. Davide Soldato: Thank you. That was very insightful. Regarding the duration of the intervention, because in the end, this was very short, because it was just seven sessions weekly, and usually also when we design or implement this kind of behavioral intervention, we frequently go for a longer period of time where the patient is subjected to this type of behavioral intervention. Frequently, we see around three, six months of intervention. And so I think it's really amazing the effect that you had on this specific symptom with such a short intervention. So I think that that is also something that speaks to the possibility of further implementing this type of intervention and this type of program for symptom control.  

And going back a little bit to what was one of the main questions of the trial that you designed and the results of the article that you published, did you observe a mediating effect of the improvement of insomnia on the cognitive function? So, you said that insomnia improved, and so improved also your primary outcome, which was the scale of the FACT-Cog questionnaire. But did you see whether this improvement in cognitive function was really related and associated to the improvement that you observed in insomnia?

Dr. Sheila Garland: Yeah. So that was a very, very important question. We needed to first demonstrate that there was a relationship between the intervention and insomnia, and then there was a relationship between insomnia and cognition. And then we did some mediation analyses subsequent to determining both of those, and we found that the change in insomnia was a full mediator of the change in cognition. So we were able to say that it's not just time or it wasn't related to something else, that improving sleep did have this direct effect on the improvement that patients reported in their cognitive impairment. 

Dr. Davide Soldato: We spoke a lot about the subjective improvement in cognitive performance. But you said that you also evaluated some specific and objective scale with, for example, I imagine some neuropsychological tests. Did you also observe some improvement for those specific tests, and did you observe the same amount of benefit or the same improvement, we could say, between the subjective and the objective weight of measuring cognitive function? 

Dr. Sheila Garland: I think that's where the outcomes become a little less clear. So, we did measure performance based cognition at all of the time points, and we were very careful in selecting these measures. So we followed the guidance provided by the International Task Force on Cognition and Cancer. They had some very specific recommendations about how and what measures we use. So we made sure to use measures that were able to be repeated, so that had multiple forms, that had very identifiable ways to indicate improvements. So we used the Hopkins Verbal Learning Test to measure word recall, both immediately and delayed. We used measures to look at verbal fluency and working memory. Overall, we had six different specific aspects of cognition that we were looking at, immediate word recall, delayed word recall, word retention, verbal fluency, word recognition, and working memory. Some of those presented with a different pattern of change overall. So a little bit trickier to interpret than the person's perception of their own cognition.

Dr. Davide Soldato: That's very interesting because it's important to have this kind of objective assessment. But in the end, what we are really trying to target is a symptom that is distressing for cancer survivors. I'm not even sure that sometimes we need all of this detail, or at least that even if these outcomes that are more objectively measured, we do not observe the same amount of benefits. Still, if we are able to produce an improvement in the symptoms and the perception that the survivor or the individual or the patient, whoever we are trying to help in that specific moment and for those specific symptoms, reports an improvement, I think that is already very important. And I totally share the patient oriented approach that you followed in the study. 

Going back a little bit to the population, because I think that this speaks a little bit also to potential avenues for further research. You included a population of cancer survivors who completed treatment at least six months before being enrolled in the trial. And relating to the population, I had two questions. So the first one is, do you think that you would have the same kind of results, so the same benefit, also among a population of patients who's in active treatment? And then the second one is a little bit more speculation, but do you think that we will arrive, or do you envision research where we kind of deliver this type of intervention in sort of a preventative way? So if we would be able to identify those patients who might later develop these types of symptoms, could we use this type of intervention sooner? So can we prevent these symptoms even before they appear? And could this be potentially associated also in a less symptoms developed over time and less need to treat these symptoms when they become more severe? 

Dr. Sheila Garland: Those are two very, very good questions. The first one is regarding the population. You're right. These people were at least six months out of treatment, and we wanted to make sure that if there was any temporary disruption, that would have maybe been stabilized over that. But most of the people in this trial, and I will mention that we didn't focus on any specific cancer type or site. So this was really a heterogeneous group of cancer survivors, both male and female. The most prevalent diagnosis that we had was breast. But some of these people who were enrolled in the trial had advanced cancer, and as long as their cancer treatment, their regimen was stable, they were eligible to participate in the trial. So I think that's a very important point. If somebody is on a very intensive round of chemotherapy, it can be tricky to implement some of the more aggressive behavioral changes that can come with some of these insomnia treatments, because their level of wellness just isn't there. So during active treatment it can be challenging, but it is definitely not impossible. We would just tweak things a little bit to accommodate their physical well being at that time. 

To your next question, though, this is where I think we really need to be going. Just like they've done in the area of, like, physical activity, trying to really strengthen people prior to treatment is the way to go. Because some of my other research looked at symptoms prospectively from the time of diagnosis over the first year, and it's roughly about half of people, at least, this was in my work with women with breast cancer, about half of women with breast cancer come into treatment with clinically significant sleep problems. So, a proportion of those people just continue to have sleep problems or even get worse after it. So there's definitely a role for that, sort of like rehabilitation, not only for maybe physical fitness to try and ward off fatigue, but also getting their sleep on track. I think people are really focused, especially in that early time, about like, “I want to eat right, I want to exercise,” but I say it as many times as I possibly can, that you're not going to make healthy food choices, and you're not going to be getting out there and working out if you're not getting sufficient sleep. So we really need to have sleep there as the foundation and what supports all of those other healthy lifestyle behaviors that people are trying to change.

Dr. Davide Soldato: So sort of comprehensive intervention for people undergoing treatment where we kind of identify symptoms that are already there at the beginning, and we deliver some sort of intervention that can target a lot of those symptoms, maybe not all of them, but maybe improving also the way that treatment is perceived or the toxicity that they might develop over treatment.

Dr. Sheila Garland: And that's what I think. I think that if you're taking people who are already coming into treatment, that are looking after their health in ways that they can, they may be able to tolerate more aggressive treatments, they might be able to complete more rounds of chemotherapy, just getting them strong, going into treatment that way. 

Dr. Davide Soldato: Also still focusing on that very patient oriented perspective that I think it's very important in general for oncologists and also for patients. I think that you were very wise in choosing an intervention that could be also delivered virtually, and this was one of the bases of the intervention. And regarding also the way the intervention was delivered, I had a question regarding the fact that this was actually an intervention that was delivered by professionals. But we also have some, maybe initial evidence, that suggests that some of this cognitive behavioral therapy can also be experienced, or at least the benefits can be obtained by the patients, even when it's self directed. So programs where patients are not actually interacting with a professional, but they are just following these types of programs. So do you think that there is room for both of those? And maybe should we suggest this type of self directed programs for all patients or all survivors and then just refer only those with a more significant or important symptom severity for the intervention with professionals? And this, I think, also goes to the discussion that we had at the very beginning about allocation of resources and ability also to tailor these types of interventions to the needs of different individuals.

Dr. Sheila Garland: I think that's really important to consider when looking at what's available for patients. They did a survey in the US of NCI Cancer Centers where they looked at the availability of CBT-I, and it was very low. I think around 20% or so of NCI Comprehensive Cancer Centers had the ability to refer to in-house CBT-I. If we had sort of a stepped care model like you're talking about, we may be able to more appropriately allocate people to the level of care that they need. A line of my research now is going into a specific app delivered cognitive behavior therapy for insomnia tailored to cancer survivors. And so looking at that very point, not everybody needs a provider, but I think that a self help manual or an app is also not going to work for everybody. So you're not going to completely take out the person. And depending on the complexity of the situation that the patient finds themselves in, they may really need that provider to consider all of the other factors. They might need it to encourage adherence or address maybe some of the barriers that would be getting in the way. So having different levels of care and being able to match people not only to the level of care, but also maybe by their preference. So, “I'd like to use an app.” Great, we've got an app for you. Or “I'd like to see somebody.” And I think matching it to people's preferences automatically encourages or enhances their engagement and their motivation to complete because they're getting what their preference would be.

Dr. Davide Soldato: And I think that at least if we could use a little bit more of these types of apps or tools or whatever we have out there, maybe we could increase at least that 20%. For example, if only 20% of NCI Cancer Centers, which are already places where care is delivered, probably with a higher attention to these types of symptoms for survivors compared, for example, to community hospitals or to smaller private clinics. So if we could at least have sort of a base and then refer only those that maybe have a higher need for a provider directed therapy or intervention, that maybe would also improve outcomes for a larger part of the population of survivors.  

And one other thing that I wanted to ask you is, do you think, in your experience, because this was not really in the trial that you designed, but do you think that we also need cultural adaptation of these types of programs? Meaning, do we need to diversify based, for example, on ethnicity or level of education or, I don't know, just the background that the patient is experiencing?

Dr. Sheila Garland: Yeah, very, very good points. There are some studies currently being conducted out of the United States that have looked at cultural adaptations of CBT-I specifically. So there was a trial looking at CBT-I for African American women survivors of breast cancer, and also the Latinx population as well. From the results of those trials, it didn't necessarily improve the effects of intervention, but it improved the engagement, so people were less likely to drop out. So it wasn't always the content. It was how the content was presented. So people were able to visually see themselves more, they were able to relate more to the content in just the way it was presented, which made them go, “Oh, okay. This is why I should be here.” And I think that that's part of the argument that I used for sort of adapting the cognitive behavior therapy for insomnia treatment that's being used in the general population, specifically to people who have had cancer, because people want to know, “All right. You know what? Is this safe for me to do? Will this work for me to do? How do I also do this when I have cancer related fatigue, or how do I do this when I also have pain?” So they want to know that, “Alright. This is right for me.” That's probably, again, relating more to getting people and keeping people engaged with the treatment, maybe even convincing them to do it to begin with, talking about getting buy-in from important leaders in their community to say, “This is something that I would recommend or I would endorse.” And those sort of community level endorsements maybe are just breaking down barriers to get people willing to engage with an evidence based treatment. 

Dr. Davide Soldato: And I think especially with cognitive behavioral therapy, because I think that when we propose drugs for treating symptoms or, I don't know, intervention for losing weight or to be more physically engaged, well, the latter that I mentioned might be also a little bit more complicated, depending on the cultural context. But drugs are very easy to accept for the patients in most cases. But I think that cognitive behavioral therapy also has some type of cultural resistance, maybe among some of our patients and cancer survivors. 

Dr. Sheila Garland: And I would also include oncologists in there as well. So, some of the treatment providers are not even exactly sure why would talking about this help. So I think separating it out, it's not just I'm going to talk about my sleep, it's that I'm going to engage with my sleep differently and breaking down maybe some of the stigma that, just because we're referring you to cognitive behavior therapy doesn't mean your problems are all in your head, but it means that there's ways that you can think about your sleep and ways that you can behave differently, which will reduce the things that are getting in the way of your sleep functioning the way that it should normally. I think when I talk to patients, and also when I do training with providers, I talk about how we can condition our bed to be associated with things other than sleep. So if we repeatedly snack in front of the tv, even though we've just had supper maybe a half an hour before, if we go and sit down in that chair that we always snack in, we're not hungry, but we find ourselves reaching for something to eat. The same thing can happen at night, where if you repeatedly pair your bed with things other than sleep, if you're thinking in bed, if you're planning, if you're worrying, if you're ruminating, if you know you're doing anything, if you're on your screen or you're watching tv or you're doing anything that's arousal producing, people can find that they're so tired, they're nodding off on the couch. They go up to bed, and all of a sudden, bang, they're wide awake and their mind is turning and they're thinking and they're like, “Why is this happening to me? I was just tired. I was so tired.” People with insomnia can relate to that very easily. That, “Oh, okay. So there's this conditioned association between my bed and wakefulness. How do I get rid of that?” That's where what we think and what we do around our sleep, we can change to be able to make our bed someplace that is strongly associated with sleep and not all of those other activities. 

Dr. Davide Soldato: Thank you for the remarks on oncologists and sometimes our resistance to accept this type of intervention. I think that this also speaks to the merit of the Journal of Clinical Oncology, which publishes high level evidence also on symptom management, and these types of interventions that are, in the end, effective for our patients. 

So I think that this concludes our interview for today. Thank you again, Dr. Garland for joining us. 

Dr. Sheila Garland: Thank you Dr. Soldato.

Dr. Davide Soldato: Dr. Garland, we appreciate you sharing more on your JCO article titled, “Randomized Controlled Trial of Virtually Delivered Cognitive Behavioral Therapy for Insomnia to Address Perceived Cancer-Related Cognitive Impairment in Cancer Survivors.”

If you enjoy our show, please leave us a rating and review and be sure to come back for another episode. You can find all ASCO shows at asco.org/podcast.

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. Guest statements on the 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.

In this episode of JCO Article Insights, Dr. Giselle de Souza Carvalho interviews Dr. Hatem Azim and Dr. Ann partridge on their JCO article “Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy,”

TRANSCRIPT

Giselle Carvalho: Welcome to the JCO Article Insights episode for the August issue of the Journal of Clinical Oncology. This is Giselle Carvalho, your host. I'm a Medical Oncologist in Brazil focusing on breast cancer and melanoma skin cancers, and one of the ASCO editorial fellows at JCO this year. Today, I will have the opportunity to interview Dr. Hatem Azim and Dr. Ann Partridge, two of the authors of the POSITIVE trial. We will be discussing their trial on “Fertility Preservation and Assisted Reproduction in Patients With Breast Cancer Interrupting Adjuvant Endocrine Therapy to Attempt Pregnancy,” which was published in May this year. 

Hello, Dr. Azim and Dr. Partridge. Welcome to our podcast.

Dr. Ann Partridge: Hi. Thanks.

Dr. Hatem Azim: Hello.

Giselle Carvalho: So, beginning with our interview for breast cancer survivors, in addition to the treatment itself, aging is one of the major contributors to infertility. The optimal duration of adjuvant endocrine therapy in patients with hormone positive early breast cancer ranges from five to ten years, depending on patient and tumor characteristics. This time interval can be critical for women who wish to attempt pregnancy. One of the main concerns in daily breast cancer oncology practice is whether breast cancer recurrence rates are increased either by temporary interruption of endocrine therapy for pregnancy or by the use of assisted reproductive technologies.

Dr. Azim, what about assisted reproductive technology is worrisome regarding breast cancer outcomes? And how do the POSITIVE study results address the concern about worsening breast cancer outcomes either with assisted reproductive technology or endocrine therapy interruption?

Dr. Hatem Azim: So, in the primary analysis of the POSITIVE trial, we tried to address one of these questions, whether temporary interruption with endocrine therapy affects breast cancer outcome. And what we found was that interruption did not appear to have a detrimental impact at the median follow up of 41 months. So in the current manuscript, we addressed the second question, whether assisted production of fertility preservation has an impact as well on breast cancer outcome. And we did not find any worsening of outcomes in patients who underwent these procedures compared to those who had a spontaneous pregnancy. Of course, we have relatively short follow up, but at least the outcomes at the median follow up of around 3 to 4 years appears to be reassuring.

Giselle Carvalho: I see. Thank you. These are really important outcomes regarding premenopausal patients.

So, moving on, results from your study show that after 24 months, 80% of women under 35 years old had at least one successful pregnancy, while the same was true for 50% of women aged 40 to 42. These results are particularly impressive considering that over 60% of women over 35 had undergone chemotherapy. 

Dr. Partridge, other than age, what factors did you find were associated with a successful pregnancy? 

Dr. Ann Partridge: Yeah. The biggest factor, other than age, that was associated with successful live birth pregnancy was use of assisted reproductive technologies. So either having gone through IVF prior to diagnosis and banking eggs or embryos prior to diagnosis and then using them during the study, for undergoing stimulation of the ovaries during the study and then using it during the study. And that's what we also looked at in this most recent analysis of the initial POSITIVE data. 

Giselle Carvalho: I see. Thank you. The group of patients who underwent embryo oocyte cryopreservation at diagnosis were more likely to be nulliparous and treated with chemotherapy. Presumably these represent the patient group most afraid they will be infertile, as they would be receiving chemotherapy, and most desirous of pregnancy, as they had not yet had any children. Fertility preservation techniques are expensive and not easily available for all patients, particularly in less wealthy countries. Is there any group of your breast cancer patients with a high enough likelihood of pregnancy without assisted reproductive technology that you would not recommend this? 

Dr. Ann Partridge: Sure. So we are so glad to have assisted reproductive technologies available in many places, but as you know, they're not available everywhere. And even where they're available for some people, it's either inaccessible for a number of reasons or it doesn't feel right emotionally or ethically. And then finally, sometimes people need fairly quick treatment and they just don't have the time, even though we don't think there are long delays. And so we do and are able to know who can get pregnant after standard chemotherapy. Not perfectly, but we can give estimates. And the gestalt is, the younger a woman is, the less likely she is to become amenorrheic and the associated infertile, although it's not a perfect match in terms of amenorrhea being a surrogate. And then there are particular chemotherapy regimens that are more gonadotoxic than others. The more cyclophosphamide, for example, or alkylating agent, the more anthracycline, the higher the likelihood generally of causing at least amenorrhea and likely infertility. The huge caveat there is that for some of our newer therapies, we have no good information about how they might impact on menstrual status, let alone the actual rates of fertility. So we need to collect those data. But certainly, if someone's very young, they're going to get four cycles of TC or they have inflammatory breast cancer, we often take kind of a let the chips fall where they may approach, because they just aren't able to access it and we'll often do something like ovarian suppression through the chemotherapy to help support them and hope that it improves their menstrual functioning in the long run and/or fertility.

Giselle Carvalho: Thank you for your insight. So you found that pregnancy incidence over time differed by age group, although incidence of menstrual recovery over time was similar across all age groups, which I conclude that menstrual recovery does not translate into fertility. The addition of gonadotropin releasing hormone analogs to chemotherapy was not associated with time to pregnancy. However, of course, such use was not randomized. 

Dr. Azim, if assisted reproductive technology is not available to patients for reasons such as socioeconomic factors, would you recommend using GnRH analogs with chemotherapy for the purpose of fertility preservation? 

Dr. Hatem Azim: Yes. The short answer is yes. Of course, POSITIVE study was not designed to address the question around GnRH analogs, but we do have several randomized studies and meta analyses that have shown clearly that the use of GnRH analogs with chemotherapy reduce the risk of premature ovarian insufficiency. And subgroup analysis of some of these studies have shown a trend towards higher pregnancy rates as well. So, of course, if a patient does not have access to assist reproductive technology, GnRH analogs in combination with chemotherapy represent a very good alternative. 

Giselle Carvalho: I see. Thank you. Thank you for your response. At enrollment, 93.2% of women on POSITIVE trial had stage 1 or 2 disease and 66% had no negative disease. Therefore, one possible bias is that investigators might have been more comfortable with temporarily interrupting endocrine therapy if the risk of relapse was low.

Dr. Partridge, what recommendations would you have for women with stage three hormone receptor positive breast cancer who desire to attempt pregnancy?

Dr. Ann Partridge: Yeah, thank you. That's a really good question. It comes up in our tumor boards and discussions about patient care all the time, and I think, as you know, only a small proportion, about 6%, had stage 3 disease. Those patients are at higher risk of recurrence by nature of their stage. Not that all stage 3 are created equal, because, of course, if someone had a complete pathologic response to preoperative therapy and their stage 3 disease at diagnosis went to a PCR, then that person may have even better outcomes in the long run than someone who had postoperative treatment, and we don't know their likelihood even with stage 1 or 2 disease. But someone that you're concerned about their risk of recurrence, they still remain at risk of recurrence. And while we do not think, based on the POSITIVE data and all the data that we've had from retrospective studies and other data sets collected for other reasons, that a pregnancy would worsen their outcome, we certainly don't believe that a pregnancy at this point in time will dramatically improve their outcome or as a treatment for breast cancer. That's when I have a heart to heart conversation with the patient, really acknowledging they still remain at high risk. And most of my colleagues tend to want the patient to get more endocrine therapy into their system before they take a break. We've kind of discussed this, and we want someone to get more like at least three to five years. That may be a little bit paternalistic, because, as we know, taking the break for people with a little lower risk didn't seem to worsen outcomes. Maybe it's fine. I don't know that a break at five years is any better than a break at two years. I don't know. Hatem, how do you handle this in your practice?

Dr. Hatem Azim: Well, I completely agree with you, Ann. I mean, it's very much decided on a patient by patient basis. The level of uncertainty that some patients accept to take is not necessarily like others. And sometimes we as physicians, we adopt this. I agree with this paternalistic approach. Nevertheless, it's very important for the patient who is 32, is not necessarily counseled like the patient who’s 39, and her acceptance and the feasibility of waiting a bit longer as well in order to attempt pregnancy - the success of pregnancy afterwards is not necessarily the same. So I'm not sure we could adapt a one size fits all approach here. And I do not necessarily tend to factor much the elements around the stage. I think my point to patients is usually, well, you do have give and take this amount of risk of relapse, for example, and whether we accept to take such, what we could refer to as relatively unconventional approach of temporary interrupting endocrine therapy, and when we are comfortable to go ahead with this journey, depending on the feasibility of getting pregnant afterwards as well. So, yeah, I completely agree. It's very customized, based on and tailored according to the patients’ situation.

Giselle Carvalho: Thank you. I really appreciate your response to this. So, moving forward, tamoxifen alone was the most commonly prescribed endocrine therapy, followed by tamoxifen plus ovarian function suppression. The latter was preferred over aromatase inhibitors ovarian function suppression in the selected population. Endocrine therapy prescription changed in the second half of the recruitment period after July 2017 across all continents, likely due to the results of the SOFT and TEXT trials. It demonstrated absolute improvements in all disease outcomes by escalating endocrine therapy, which was more clinically meaningful in patients with high risk disease. Dr. Azim, how do you imagine this change could impact positive outcomes?

Dr. Hatem Azim: Honestly, I'm not necessarily sure that it impacts significantly the way you interpret the data and the way we counsel our patients. So, in our study, some 50% of patients received GnRH analogs and around 15% received AI. And most of the patients, I would say, were recruited in the second half of the study after we had the results from, for example, SOFT and TEXT. Furthermore, as we alluded to earlier, we had 60% of patients who received chemo. So most of our patients had a stage 1 and 2 disease in which you would argue that the absolute difference between the different hormonal therapy options is not necessarily massive. Whether or not this would impact much, I'm not sure. I think the main counseling recommendations would apply, that patients who receive endocrine therapy would be asked to interrupt it for at least three months and then they attempt pregnancy afterwards.

I don't know what you think, Anne, but I'm not sure that if we have more patients, and this is pretty much the case now, we have more patients treated with AI. I tend to do this a lot, especially if I'm thinking of interrupting, so I think I'm giving them maybe the best option first. I'm not sure this is necessarily, I mean, affecting me much, while interpreting that it does not appear that temporary interruption on the short term has an impact.

Dr. Ann Partridge: I completely agree with your strategy. Depending on the patient and their tolerance, if they have enough risk to warrant ovarian suppression with AI or tamoxifen, of course I recommend that. And yet, at the same time, I agree with you in this group that was in POSITIVE, I think the groups are relatively low enough risk. Although 40% had no positive disease, the majority got chemo, so they weren't that low risk. And so I think over time, these kinds of patients are more and more going to get ovarian suppression. I'm doing that more in my practice as tolerated. And I hope that all that means is that their breast cancer outcomes will be better independent of a pregnancy.

Giselle Carvalho: And on the topic of women with higher risk disease, CDK4/6 inhibitors are now used in the high risk adjuvant setting. How do you envision this impacting fertility?

Dr. Hatem Azim: Well, this is a very good question. Of course, this is something, this is an area of research that we have to address. Some analysis from some of the adjuvant studies, for example, the PENELOPE-B, I think they reported on some of the results of their study in which they were evaluating palbociclib in the adjuvant setting and did not appear that there was significant differences in terms of the level of estradiol levels and FSH and anti-Müllerian hormone, for example. I think these were the parameters that were evaluated in this study. So, of course, more information. Of course, palb is not the CDK4/6 inhibitor approved in the adjuvant setting. So we need more information as well about the other CDK4/6 inhibitors and longer follow-up. 

In my view from a counseling perspective, I think maybe you would have a certain level of uncertainty regarding whether or not this could have a mental impact on fertility. But the concept as well of possibly proposing a temporary interruption as we adopted in POSITIVE, would still apply. These patients would be treated as well, often, because if they are receiving CDK4/6 inhibitors in the adjuvant setting, it means that they have a high stage disease, so often they will be treated as well with GnRH analogs. I would counsel them pretty much the same, acknowledging a certain level of uncertainty regarding the data we have today on CDK4/6 inhibitors.

Dr. Ann Partridge: Yeah, if they got a full course, they would generally be further out than many people on POSITIVE, because we treat with, for example, the abemaciclib for two years and then you want to wash out and things like that. In POSITIVE, the average was two years. And so you'd expect people of higher risk to be a little further out, which I think would make everybody a little more comfortable too, because someone who's very high risk, you'd worry about very early bad recurrence, too.

Giselle Carvalho: Yeah. Thank you.

So, Dr. Partridge, regarding adherence to endocrine therapy resumption after the two year break, what was the percentage of patients who resumed treatment and which strategies would you suggest to increase adherence in this case?

Dr. Ann Partridge: That's a really great question. In the study, it was well over 70%, which is actually higher than you see in the general population of breast cancer survivors, especially young women. So in some cases, and I can tell you anecdotally, I experienced in my clinic that patients were more likely to start and take their endocrine therapy when they had the promise of the POSITIVE trial, to take a break to have a baby, because some of them don't want to start it, let alone stay on it, if they're told they have to take a full five to ten years. So it actually promoted adherence, ironically. And then for the people who got back on in the real world, the data suggests that by four years, somewhere close to half to 30% to half are no longer taking it. And so in POSITIVE it was, I think, 74% got back on, and that was only at the time point cut off when we did the initial primary data report. And of course more people will have gone back on because some people were still having babies and in the middle of things. And so I think that it's not as much of an issue with POSITIVE. In part, these are very compliant people, right? They're participating in a clinical trial to share the data with the rest of the world. They could have gotten pregnant on their own and they want to do it with their doctors. And so I think this is a little bit of a different group, but it was very reassuring to see that most people got on hormonal therapy after their interruption.

Giselle Carvalho: And recurrence of hormone receptor positive breast cancer may occur late. How long do you plan to follow patients enrolled in the POSITIVE trial?

Dr. Ann Partridge: So our plan is to follow them for at least 10 years. And it's interesting because we're starting to get close to that. We started enrollment in 2015, so I saw someone earlier this week who will have her 10 year mark next year because she got on in 2015. And that's very exciting. Obviously, it would be great to follow them even longer because ER positive breast cancer can recur many years later. But I do think that we feel as though at least 10 years will give us a good, very evidence-based feeling about the safety.

Giselle Carvalho: Thank you. Thanks for sharing. With enrollment occurring at 116 institutions in 20 countries across four continents, this representation of different races and ethnicities provides strength to support this recommendation for this group of patients worldwide.

Dr. Azim, what are your hopes for future analysis from this study and what future research in the area are you planning or would like to see performed? 

Dr. Hatem Azim: So Ann mentioned, of course, it would be crucial to conduct the long term follow up of these patients, and provide more reassuring evidence on the safety of this approach of adjuvant endocrine therapy. So this is something we're really looking forward to. Other analysis that we are working on is the breastfeeding analysis. So looking at patients who underwent breastfeeding and how far the feasibility of this approach, obviously, but how far as well this had an impact on their breast cancer outcome. So this is something that hopefully we are going to report on soon, expected end of this year. As well, we are working on evaluating, we had a large translation research program within POSITIVE, addressing several questions, including the evolution of ovarian function parameters over time and the ovarian reserve. Also, we are working on reporting on this information. We hope that this could happen maybe in the coming year.

Giselle Carvalho: Great. And finally, what advice do you give young women in your clinic who have been diagnosed with early stage hormone positive breast cancer and who are hoping to attempt pregnancy.

Dr. Hatem Azim: We address these kinds of questions relatively early in their treatments and often they are very much concerned about their chance of future fertility. Usually early on, for example, before going for chemo and so on, I just share the information that this is something that we certainly could discuss and certainly there are the possibility that we could consider in the future that it's not a ‘no go’ at least. And definitely it's something that we could work on once treatment is completed and recover from the adverse events of therapy. And because throughout the journey of treatments as well, women's wishes evolve over time and their perception of their pregnancy project as well evolve and change over time. So I think it's important to acknowledge, in my view, it's very important to acknowledge that this is feasible, this is possible, and because this as well provides an important psychological boost for them. And then as the patient comes over for their follow up after therapy and so on, start understanding, getting a little bit deeper into these kind of questions regarding feasibility, timing. If they are ER positive, then if it's okay to interrupt, not to interrupt, to explain a bit better and to consider a bit better regarding what kind of risk we're talking about. Articulating better, what do we mean by risk? So that sometimes you have a patient that is willing to accept a 10% risk, although others 1% risk for them represent a major threat. Also, it matters nulliparous versus a patient who already has two or three kids. So I think I tend to go a bit more granular in this kind of information as patients are out of chemo and on hormonal therapy and start addressing these matters. But I think it's important early on to share the information that nowadays we do have sufficient information not to discourage women who would like to have a pregnancy in the future.

Giselle Carvalho: Thank you. Thank you. Dr. Partridge, would you like to add some final comments on this?

Dr. Ann Partridge: Yeah, I think this is just such an important issue for our young breast cancer survivors and cancer survivors diagnosed at a young age, regardless of the type of cancer. So I think paying attention to this at diagnosis and through their survivorship is critical, both for their thriving in survivorship as well as for their long term health and cancer outcomes. Getting back to that adherence issue, people, if they're unhappy, won't do all the right things for themselves, sometimes medically and emotionally. And we know that infertility can be associated with long term distress for patients with and without cancer. So we need to pay attention to this and I'm really happy that ASCO is doing a podcast on this and I'm really happy that JCO is doing a podcast on this. 

Giselle Carvalho: Thank you. I really would like to thank you both, Dr. Azim and Dr. Partridge for attending this interview.

This is Giselle Carvalho. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows asco.org/podcast.

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. Guest statements on the 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.

 Dr. Azim Employment Company name: Pierre Fabre, EMERGENCE THERAPEUTICS Stock and Other Ownership Interests Company name: Innate Pharma, Diaacurate Travel, Accommodations, Expenses Company name: Novartis Dr. Partridge Research Funding Company name: Novartis Patents, Royalties, Other Intellectual Property Company name: UpToDate

Host Dr. Davide Soldato interviews Dr. Sana Raoof to discuss the JCO article Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.

TRANSCRIPT

Dr. Davide Soldato: Hello, and welcome to JCO After Hours, the podcast where we sit down with others from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, Medical Oncologist at Ospedale San Martino in Genoa, Italy. Today, we are joined by JCO author Dr. Sana Raoof, Physician at Memorial Sloan Kettering, to talk about her article, “Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.”  

Thank you for joining us today, Dr. Raoof.

Dr. Sana Raoof: Thank you so much. It's lovely to be here.

Dr. Davide Soldato: So, Dr. Raoof, I just wanted to start a little bit about the theme of your article, which is really centered around multi-cancer early detection tests. And this comes from the results of several studies that showed their reliability and efficacy in identifying cancer in the average risk population. But I just wanted to ask you if you could give us and our readers a brief overview of how these tests work and how they were designed for this specific population.

Dr. Sana Raoof: Of course. Well, there's an interesting story. The origin of multi-cancer early detection tests actually begins with insights that come from the field of obstetrics and gynecology. So about six or seven years ago, in the peripheral blood of pregnant women, we discovered that you can actually find fetal DNA floating around. And that was an early discovery of cell free DNA coming from the baby into the mother's bloodstream. But in some of those young, otherwise healthy women, we also discovered that there's another clonal signal, unfortunately not coming from the fetus, but coming from an undiagnosed tumor. And that led to the entire field of circulating tumor DNA and all of its applications. 

Of course, scientists in the last six or seven years have harnessed the fact that DNA and the methylation patterns on the circulating tumor DNA, as well as other analytes like glycosaminoglycans, proteins, and other analytes, are secreted by tumors into the peripheral blood in order to try and screen for tumors, hopefully at early stages, when there are still curative, definitive interventions that are available. There's several different tests now that are providing the ability to detect cancers at many stages, including early stages. They're in different phases of preclinical to clinical development, and one is even commercialized and available by prescription in the United States.

Dr. Davide Soldato: Okay. So I think that in most of these tests, they really look at the tumor DNA, so they identify mutations or, for example, methylation patterns. But do we also have some tests that integrate some other type of biomarkers that we can identify in the blood? Like, are they integrated all with the others, or are we just relying on circulating tumor DNA?

Dr. Sana Raoof: It's a great question. There's a lot of really fascinating biology that different companies predominantly are using in order to find signs of early cancer. One of the analytes that I find really interesting, other than looking for small variants in circulating tumor DNA and looking at methylation patterns, as you mentioned, is looking at fragment length. So, for example, the company DELFI looks at the different patterns of the length of DNA fragments that are floating around in the peripheral blood. And not only is fragment length tissue specific, so in theory, a fragmentomics based multi-cancer early detection test could tell us what is the tissue that this aberrant signal is coming from, but they can also tell you if there's likely a cancer present, because there's a difference in fragment length patterns in cancer versus non cancer. 

There are also other analytes. I mentioned glycosaminoglycan. There's another company that doesn't yet have prospective data, to my knowledge, that is making a test that looks at these analytes instead. There are other companies, again, without prospective data yet, that are looking at circulating tumor cells. And I'm sure that in the next few years, we're going to start getting prospective data from all of these players and also hear about other analytes that scientists have found can predict cancer from non cancer and maybe even protect tissue of origin based on artificial intelligence.

Dr. Davide Soldato: So you mentioned artificial intelligence. So, basically what you're suggesting, but correct me if I'm wrong, is that when we use this test, we are actually measuring something in the bloodstream, but at the same time, we are actually applying some type of artificial intelligence to actually interpret these results and then give us the definitive results, or what we would call like a positive and a negative of the tests, is that right?

Dr. Sana Raoof: Yeah, absolutely. And it's an important distinction that you're making, we are measuring something in the blood, but we're not just measuring it. We're using machine learning algorithms that have been trained on thousands and thousands of patients with cancer and thousands and thousands of patients without cancer, and have measured various analytes and analyzed the patterns, for example, of DNA sequence, or bisulfite sequencing of methylation patterns of patients with and without cancer, and have been trained to look for the differences between them. And so the analyte that we're looking for is not a specific mutation per se, but is a pattern that looks like patterns that you typically find more so in cancer patients.  

There's many different companies, they are trained on different types of cancer. So some companies, like GRAIL, have a test that looks for a very expanded list of over 50 cancer types. Other tests have a narrower focus and were trained and validated on a smaller list of cancer types. So there's just a great diversity in this space. These tests are trained to look for different types of cancer. They're trained and validated on different populations of interest. So, for example, some of the populations that these tests were trained on are predominantly white, and that will have impacts, potentially on how these tests perform in non-white populations. And that's a really interesting area of future research. These tests may or may not have included cancer survivors in their populations, and that could ultimately impact how these tests perform in those populations. 

So there's just so much to learn, so much data that's going to be coming out in the next few years from all of these different key players in the multi-cancer early detection space. But one thing that I'm sure of is between all of the different analytes, all of the different training and validation studies, and all of the different prospective studies, we're going to learn a tremendous amount about the potential clinical utility of using multi-cancer early detection tests to complement the few standard of care surveillance cancer screening tests that we have recommended today.

Dr. Davide Soldato: So just taking a step back and going back to the fact that we actually use machine learning algorithms to identify a pattern that can give us an idea of whether cancer is present or not, I believe that there is also some room for calibration of these types of tests. And I think that this is one of the key arguments that you make in your paper where you say that we can actually personalize a little bit more these types of tests to understand and then to decide what we are looking for. Is that correct and can you expand a little bit on that?

Dr.Sana Raoof: Yeah, absolutely. This is the central concept of the paper that we're discussing. Because these tests are machine learning based, as I said, they're trained to say cancer versus not cancer, and some of them are further trained to say, coming from this organ or coming from that organ. But what does it mean to say cancer or not cancer? There are specific thresholds that are defined to say, above this threshold of signal detection, we're going to say this is a positive cancer signal detected, and below it we're going to say negative. And so right now, these tests are kind of designed to have this binary output, and the concept that I wanted to put forth in the paper is it doesn't necessarily have to be binary, and the thresholds don't have to be static. So, for example, you can imagine that in an average risk population where the pretest probability of cancer in your lifetime for Americans, it's pretty high, roughly 40% for lifetime. But at any given moment in time when you're getting a test, it's lower. For example, in Americans, 50 to 80, the chance of having cancer at any given moment is just under 3%. So you don't necessarily want a test that is very nonspecific, you don't necessarily want to tell a lot of perfectly healthy people that are asymptomatic screening populations that they have cancer if they don't. And so these tests were designed to have very high specificity, predominantly across the board, across the different companies making them at the cost of, in some cases, having lower or moderate sensitivity in early stages.  

And it's important to keep in the back of your mind that we cannot ever expect the types of early stage sensitivities from multi-cancer early detection tests that we're used to thinking about for single cancer screens that are just optimized for one single organ. They work in a completely different way. So I don't expect a future where the sensitivity of a mammogram, which is only for breast cancer, is going to be analogous to the sensitivity of a blood-based test that's looking for all cancers in your entire body. I don't think it's fair to expect that. But I do think it's possible to imagine a future where we do change the thresholding of these tests that were trained and validated in average risk screening populations, and say, “Let's turn the knob on the dial and let's take the sensitivity a little bit higher, even if it means the specificity drops from 99%, for example, which is the very high number of the gallery test, down to 98%, down to 97%. Let's see how this affects the positive predictive value and the negative predictive value of the test.” And how having a higher negative predictive value by having a higher sensitivity may or may not make it more clinically useful for higher risk populations that have higher pretest probabilities, in which case we are kind of more interested in being sure that we're ruling out cancer. 

Another concept that I talk about in the paper, aside from just turning the knobs, is to make it a continuous variable rather than a binary report. Rather than saying signal detected or not signal detected, I can also imagine a future where we personalize the output of multi-cancer early detection tests to return a score, for example, from 1 to 100 or 1 to 10, and give physicians the ability to use that continuous variable in addition with other clinical findings, physical exam findings, other labs, symptoms, patient’s past medical history, family history, all of that together to make decisions about should we pursue further workup, should we do an invasive biopsy. This is kind of the way that we use other scoring tests in oncology, like the oncotype tests for breast cancer, decipher test in prostate cancer. And I think physicians like having continuous variables to work with and to help them make very personal decisions for patients' diagnostic workups.

Dr. Davide Soldato: To summarize a little bit, what you're arguing in the paper is that we could potentially modify a little bit these tests as they fit the type of population that we are looking for. For example, if we are looking at the average risk person in America, there we just want to be sure that we are just doing additional workout and additional follow ups and additional invasive procedure, for example, biopsy, when we have a very high probability of finding that cancer. At the same time, if we have someone who has a baseline risk which is higher, like cancer survivors, in that case, we are more interested in seeing if there is really cancer at that point, and so we can increase the sensitivity and go down on specificity, but still looking at the overall outcome that we want to have for that specific patient. 

One thing that I was wondering is, do you also see a future where we personalize a little bit more also including additional information that comes from risk factors, environmental or behavioral patterns, type of diet, or these types of risk factors that we already know from epidemiology are associated with a higher risk? So could we potentially customize this test even more, saying, this patient has a higher risk of developing colorectal cancer, so could we look more specifically to that specific cancer type and that specific risk compared to tobacco associated cancers, that for that specific patient, they are not so relevant? 

Dr. Sana Raoof: What you're saying is actually a fascinating and really compelling idea, and it reminds me of the way that noninvasive prenatal testing works. So, again, back to the world of obstetrics and gynecology, you have a woman at the end of her first trimester having fetal DNA testing to look for chromosomal abnormalities. And when you order that test, you actually do put in various features about the woman to help you understand her baseline risk for carrying a fetus that has chromosomal abnormalities, including her age, the status of her other children, and other things in order to help you calculate a pretest probability. And so after that, the non invasive prenatal test takes that into consideration and returns a probability of carrying a fetus that might have those aberrations, and it's not a binary risk. It's, as I said, a continuous variable.

So I think what you're proposing actually goes beyond what I wrote about in the article. I think it's a fabulous idea. And I think that in the near future, I can imagine that as natural language processing is exploding, and in general, large language models and the ability to extract features about a patient from the EMR are exploding, we might have a better stratification in general of patients into average risk, low risk, high risk, and really high risk, using EMR data, using real world data that could help us feed a really accurate picture of a patient's pre-test probability into this test, so that these tests could be further refined and further trained and validated on patients, taking into consideration more factors and help us improve the predictive power of the tests as they're returned in a report to the physician. So I think maybe you should even write an article about the idea just proposed. It's a great idea.

Dr. Davide Soldato: So another aspect that I was really interested in is I've looked at one of the papers that you cited, and I wanted to discuss this with you as you are an expert on the topic. In one of the articles that you cited that used this type of test, they identified some of the cancers that we also normally identified with standard screening procedures, like breast or lung or colorectal. So for those cancers, we add a certain proportion, or like, for example, for breast cancer, a higher proportion identified with conventional screening. But still we had some other cancer that eluded those types of screening and were identified using liquid biopsy tools. So do you envision a strategy where we would use the screening methods that we already add as a complement to those liquid biopsies, or do you think that someday liquid biopsy could potentially completely substitute standard screening procedures? 

Dr. Sana Raoof: I think we're too far from a day where liquid biopsies are going to replace standard of care screens. The scope scans and smears that the United States Preventive Services Task Force has recommended are gold standard screening interventions because, number one, for all of them, except for cervical cancer screening, we have randomized data with definitive endpoints that tell us that there are mortality benefits from doing those screens. We don't have that type of data yet from the world of multi-cancer early detection. And as we talked about earlier in this podcast, those tests are kind of designed with a different approach where they have higher sensitivity and much lower specificity than multi-cancer early detection tests. 

So I think that the molecular cancer screening companies have done a very careful job of creating tests that are really more optimized to be complementary tests rather than a standalone catch all test, to have higher specificity at the cost of lower sensitivity. So I don't imagine a near future, at least not in my career, where we're going to stop doing colonoscopies and mammograms and pap smears. I don't think that that's going to happen. But I do think that whereas right now 75% of cancers that Americans die from, we lack cancer screening mechanisms for them, I think that that number has the potential to really drop. If in the next few years, one of these multi-cancer early detection tests is ultimately approved and covered, then I think that a lot more cancers could be detected by screening rather than by symptoms, and we might ultimately see a big stage shift. 

Dr. Davide Soldato: Yeah, I think you're absolutely right. In the same article that I was mentioning before, there were several of those cancers which can be lethal if diagnosed at an advanced stage, that were diagnosed at an early stage, for example, ovarian cancer, bladder cancer. So I really think that we really have potentially the way to screen, or at least have a signal for cancer that currently we just diagnosed when symptoms associated with higher stage appear. 

But moving on to turning the knobs on this type of test, and so going to the higher risk population, for example, cancer survivors, which is something that you speak a lot about in the manuscript. So you also discuss a little bit the question of whether we should use multi-cancer testing versus single cancer testing. So are we looking at a specific recurrence from that specific tumor, or are we looking at a general risk of cancer in a population that has a common risk factor, like tobacco? And so I was wondering if you think, and this is probably just your perception or just your opinion, that that is another way that the physician should turn the knob. Should we evaluate the risk of those cancer survivors and say, in this specific patient right now, the risk of recurrence is higher so I should use or I should be more in favor of a test that is more centered on the risk of recurrence versus I have a general risk of several cancers that could appear, and so should I use something that is more multi-cancer? This, of course, is merely speculative because we still don't have definitive data regarding the efficacy of this test. But it is just your perspective on this type of approach in the near future or not so near future. 

Dr. Sana Raoof: Well, I think if we're speculating, then I think that the fantasy situation for any oncologist is that you have two types of liquid biopsies. One is a multi-cancer early detection liquid biopsy. And it would be great if you could select whether you want it to be optimized for highest NPV, negative predictive value, or highest PPV, positive predictive value. And then you also have a host of single cancer screening liquid biopsies that can help you specifically figure out if there's a recurrence of a single cancer type that you're suspicious about.  

So, for example, in the article, I talk about how there will be clinical gray areas, and it's not always going to be obvious which test you should reach for. But one example that I think we can all relate to in the oncology community is you have some indeterminate imaging finding, and you don't know what to do about it. So, for example, you have a woman that has a history of breast cancer, has had no evidence of disease for a few years, now, has back pain. You do a spine MRI, you see a lesion. Maybe it's an atypical hemangioma that's causing pain, maybe it's a breast cancer metastasis. You're not sure. What should you do? Should you do a biopsy of that lesion in the spine? Should you wait and see if it grows and do another MRI in two or three months? What are your options? And so in this situation, I think we can all agree that if you had a liquid biopsy that was optimized for really high sensitivity, specifically for breast cancer, and had a very high negative predictive value, and if it came back negative, then in that setting, it might help you avoid an invasive test, like a biopsy in the spine, and give you a little bit more comfort as a physician to say, “You know what? I'm going to come back in two or three months and do another spine MRI. I'm going to see how this woman is feeling, and I don't need to biopsy this right now. Maybe it really is just hemangioma.” 

Dr. Davide Soldato: And in this specific setting, let's take the same patient. So it's a female patient, she had a previous diagnosis of breast cancer. Do you think that there is a difference between tumor-informed tests, really based on the molecular aberration that the primary tumor had for these women, versus just a standard test that gives us information regarding the presence of breast cancer cells or not? And if you think that there is a difference, what would you think would be the advantage of one? And the disadvantages, for example, is a tumor informed essay more complex to obtain? Do we need more time? Is it more expensive versus a commercial test that is already available or something like this? This is my understanding as someone who's not so much in the topic, but I think that this is a point that many oncologists probably wonder about, and probably we should speak a little bit more about with someone who is an expert on the topic. 

Dr. Sana Raoof: Absolutely. And I think that you've actually hit all of the major points on the head. So comparing a tumor informed versus a tumor agnostic test is like really comparing apples and oranges. A tumor informed test where you're starting with a patient's pathology and you are looking specifically for mutations and other molecular features that you know the patient has in their tumor, is going to, of course, result in a test that is, number one, more expensive and harder to make, but also, number two, more sensitive, more specific, more predictive, and in every way probably just more powerful than a test that is, in general, optimized for a single cancer type, but is almost certainly going to be trained and validated on people with a mix of histologies, a mix of molecular features, and will not be as sensitive or specific as a test that is actually informed by that single individual's tumor. One of the things that matters a lot to me is health equity in oncology. There are just huge disparities in outcomes in patients that are advantaged and disadvantaged. And it stems from lots of different things. In no small part, it stems from later stages of diagnosis in disadvantaged patients, and then even once you have a diagnosis, delays to confirmatory workup, delays to starting treatment, disparities in the treatments offered. 

I don't imagine a world where everyone on earth is going to have access to tumor-informed liquid biopsies. I do imagine a future where tumor agnostic liquid biopsies, both for single and multi-cancer screening, should be a lot more economical than they are now, and should be more available for multiple cancer types, and should be more available to patients that aren't at just the Memorial Sloan Ketterings and the Dana-Farbers of the world. And so I do think that those types of off the shelf tests have the potential to really revolutionize the way that we work up suspicion of cancer, not just in advantaged patients, but also in patients that are diverse, in patients that are not at academic cancer centers, but at other cancer centers around the world. And I think it's a really exciting prospect.  

Thinking about the chance of recurrence in the breast cancer patient is a perfect example of when you want to test that is optimized just for breast cancer, because you see something in the spine, you know her history, and you're less worried about a new primary and a new MET from that primary. But there are other situations that are also interesting to consider. For example, patients that have had lung cancer and have a history of smoking, because they've had a history of smoking, they're actually at risk for a dozen different cancers, not just lung cancer. And when you think about what we do to follow lung cancer survivors, we're just doing CTs of their chest and of course, physical exams. But the vast majority of cancers that people with lung cancer history will get may not be present in the field of view of a CT of the chest. They may also get renal cancer, bladder cancer, they might get leukemias, they might get pancreatic cancer. So there are a lot of things that you're not going to catch in a CT of the chest. And so in that situation, you care not only about recurrences, which in thoracic oncology, it's kind of a gaussian probability distribution, where the tail is almost close to 0 after five years, but also a uniform distribution of roughly 3% per year of a second cancer, a new primary cancer that goes on for the rest of their life. And so in that clinical setting, you can imagine that having an off the shelf multi-cancer early detection test may be dialed up for higher negative predictive value, would be extremely useful.

Dr. Davide Soldato: Yeah, I totally agree, but thank you for clarifying these points, because I think that there is a little bit of confusion also in the oncology community, as this type of tests, they're also based on very complicated molecular biology, sometimes could be potentially integrated, and we could potentially integrate them in the clinic. 

And so I wanted to close up with kind of a personal question. I was wondering how you came to be so interested in this field of molecular screening or early diagnosis and prevention associated with molecular data. 

Dr. Sana Raoof: Well, it's an interesting story. I did my MD PhD at Harvard Medical School, and my PhD was in the opposite world from molecular cancer screening. I was designing drug combinations that could be used in advanced oncogene mutant lung cancers. And I thought I would become a medical oncologist and spend my life designing new systemic therapies for advanced malignancies. And what I saw every day in the lab during my PhD is drug resistance emerges and it's a process of evolution by natural selection happening on a cellular level. And although we have some really great slam dunk drugs that come to mind, for example EGFR inhibitors in certain lung cancers, immunotherapy in melanoma, on average, the median overall survival gain from all of the FDA approved drugs in the last 10 years is roughly two months.  

By the end of my PhD, I really started feeling like, is the best use of my life to continue fighting a battle against natural selection in cancer cells, or is it a better strategy, to me, it seemed like a more sensical strategy to just try and find cancers in these patients earlier, when you don't have to engage with the complex signaling mechanisms of a cancer cells biology, and instead can just provide a definitive local intervention, like surgery or radiation, which already is curing many patients with non metastatic cancers. And as I looked around the world, I just didn't see that many people investing heavily in early detection research at the time. It was the very early days of multi-cancer early detection. And so I became involved with all of the groups, the companies, the organizations that were developing these tests, and really fell in love with, number one, just the concept of the tests, the concept of multi-cancer early detection, rather than single cancer screening alone, because no one knows what cancer they're ultimately going to get. But I also really fell in love with methylation biology, fragmentomics. I fell in love with the types of clinical trials that were being designed and the new types of endpoints that we have to think about when we're designing clinical trials for a multiverse of single cancer screening. And it's just such an exciting time in that community, it's the early days. So that's how I came to this space, and it's just the perfect time to be in this space, because everything is exploding. 

Dr. Davide Soldato: Thank you very much. And thank you also for sharing the personal side of the story.

Dr. Sana Raoof: Thank you so much. I'd like to thank Razelle Kurzrock, who's an amazing medical oncologist who's worked with me on two really fun papers so far, one on real world data, and this one on turning the knobs on liquid biopsies. It's always great to bounce ideas around about multi-cancer early detection with friends and collaborators, and Razelle did an absolutely amazing job helping write this piece. 

Dr. Davide Soldato: So this brings us to the end of the episode. Thank you Dr. Raoof, for joining us and sharing more on your JCO article titled, ”Turning the Knobs on Screening Liquid Biopsies for High-Risk Populations: Potential for Dialing Down Invasive Procedures.”  

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In this episode of JCO Article Insights, Rohit Singh interviews Dr. Ticiana Leal on the editorial, "Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade."

TRANSCRIPT

The guests' disclosures can be found in the transcript.

Dr. Rohit Singh: Hello and welcome to JCO’s Article Insights. I am your host Rohit Singh and today we will be discussing the JCO article, “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade.” And we are joined by the senior author of the article, Dr. Ticiana Leal. Dr. Leal is an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, and she serves as director of Thoracic Medical Thoracic Oncology Medical Program and Multidisciplinary Thoracic Oncology Leader at the Winship Cancer Institute. She also served as a member of the Board of Directors at the Georgia Society of Clinical Oncology. 

Dr. Leal, welcome to our podcast and thank you for joining us.

Dr. Ticiana Leal: Thank you, Rohit. Thank you for this interesting opportunity to discuss our editorial. My co-authors and I are very glad to be here today. So, Dr. Jennifer Carlisle and Dr. Liu were co-authors with me on this editorial.

Dr. Rohit Singh: It's a really good article. And just for our audiences, the article again, titled “Back to the Drawing Board: Overcoming Resistance to PD-1 Blockade,” it discusses the challenges and the potential strategies for overcoming resistance to immune checkbox inhibitors in patients with non-small cell lung cancer. In this article, Dr. Leal and colleagues talk about the second line of drug when the patient developed disease progression while immunotherapy and they develop resistance and their definitions and what to do. 

So, to Dr. Leal, can you please explain the mechanisms of primary and acquired resistance to immune check prohibitors in non-small cell lung cancer? I also saw in your article you proposed the definition of immunotherapy resistance in solid tumors, distinguishing between primary resistance and acquired resistance. So, if you can please share your thoughts and explain their mechanism.

Dr. Ticiana Leal: So primary resistance and acquired resistance are related to tumor intrinsic and tumor extrinsic factors. And this is mainly clinically defined as of now according to previous response patterns and timing of occurrence, and these definitions can be heterogeneous, and we certainly think that biologically they can be very different. And it can be different according to prior therapy, whether patients got immunotherapy as PD-1, PD-L1 inhibitor alone or combination strategy with CTLA-4, or the combination with chemotherapy. But the patterns of resistance can be very different and can be based on defects and antigen presentation. It can also be due to tumor microenvironment immunosuppressive effects, and there are also additional inhibitory checkpoints that can be involved. 

The definition in terms of when to call it primary or acquired resistance at this point has really been based on consensus guidelines by SITC, by Esmo, as well as our group Lung-MAP has developed clinical trials in this space. Specifically, through Lung-MAP, we've defined and incorporated the definition of acquired resistance as patients who have had prior exposure of 84 days or greater and then have had progression of their disease. 

Dr. Rohit Singh: I can see why it is so challenging to come up with a standard definition for immune checkpoint resistance and I think incorporating these definitions and predictive biomarkers for clinical trial design is going to be more important going forward. Your article talks about CONTACT-01 study, so can you please discuss the CONTACT-01 study and how the shifting treatment paradigm in the first-time study impacted it and at the same time also discuss the potential implication of the differential outcome observed between the men and women in the CONTACT-01 study.

Dr. Ticiana Leal: CONTACT-01 was a much-awaited study. The authors, Dr. Neal et al, looked at a very important question in the area of immunotherapy resistance. So, CONTACT-01 was a randomized phase three global study that investigated the combination of cabozantinib plus atezolizumab versus docetaxel in patients previously treated with chemotherapy and immunotherapy. And as background, cabozantinib is an inhibitor of multiple receptor tyrosine kinases including VEGFR-2, MET, RET and TAM family kinases. Preclinically, cabozantinib could lead to immuno permissive tumor microenvironment and so it was rational to combine it with a PD-1 inhibitor. In early results of a phase 1B expanded cohort of COSMIC-021 showed really promising results of this combination which led to the rationale of CONTACT-01. In this study, however, patients that were included had different prior treatment sequences. They could have had prior immunotherapy alone followed by chemo or the opposite, or they could have had prior immunotherapy and then upon progression gotten a combination of immunotherapy plus chemotherapy. That to say that immunotherapy rechallenge is something that people are doing in clinical practice given the unmet need and the desire to overcome immunotherapy resistance. But perhaps that also includes a more resistant population of patients, and these patients certainly could have had heterogeneous mechanisms of resistance which could have impacted these results.  

The study did not meet the primary endpoint of overall survival. We saw a median overall survival of 10.7 months with the combination of atezo plus cabo and 10.5 months with docetaxel alone. In terms of the differences between sex that we saw in the CONTACT-01 study, just to go back in terms of the preclinical studies that have been done, there have been some preclinical studies that demonstrated that perhaps there may be some biological differences in models of different genders in mice. However, in the clinical setting, there have been, I think, contradicting results. A meta-analysis showed that perhaps women derive less benefit than men. Other studies have shown that perhaps women have more adverse events to immunotherapy. In this study specifically, only about 20% of the patients enrolled were women and the majority actually had non squamous histology. And we saw here less benefit for immunotherapy in women. But again, I think the numbers here are quite small. This is an exploratory analysis and I do think it highlights though the importance of making sure that we include populations and have higher rates of accrual, not only in women, but in other representative populations. In this study, only about 1% of the patients were black.

Dr. Rohit Singh: Yeah. Thank you so much for highlighting those disparities. I think it's very important to make sure that we have proper representation of all the groups in our trials. I think based on just coming off the VEGF inhibitors, I think the Lung-MAP trial S1800A, showed a significant improvement in median OS with the combination of pembrolizumab and ramucirumab compared to standard of care. Do you envision any future commission therapies targeting the VEGF pathway with immune prohibitors in non-small cell lung cancer? 

Dr. Ticiana Leal: I definitely think that targeting VEGF with multikinase TKIs based on the studies that we have seen, several now randomized phase 3 studies showing that this strategy is ineffective. So, this has been quite disappointing. But we've now seen the results of CONTACT-01, that we're just discussing here, but also other studies, including SAPPHIRE, which was also a randomized phase 3 that investigated nivolumab plus another VEGF multikinase TKI, sitravatinib. And then we also saw LEAP-008, which was a negative study investigating lenvatinib plus pembrolizumab. There still is a question though, whether you can target the VEGF pathway inhibition with a monoclonal antibody, so that's ramucirumab targeting VEGFR-2 plus ICI, and whether that can actually be an effective strategy. In our Lung-MAP trial, the S1800A, this study was a randomized phase 2. Here we used the definition of acquired resistance of patients receiving prior immune checkpoint inhibitor for a minimum of 84 days, and they were randomized to the combination of pembrolizumab plus ramucirumab versus investigator’s choice of standard of care, which did include docetaxel, ramucirumab, docetaxel gemcitabine and methotrexate. This was a positive study. It led to significant improvement in median overall survival and there weren't any significant safety signals here. And we're waiting for another confirmatory study called the Pragmatica-Lung study. 

Dr. Rohit Singh: Yeah, I did have one patient who raced through pembro, and I utilized this combination and was able to get some responses. 

You mentioned Pragmatica-Lung trial. Can you provide more information about the ongoing Pragmatica-Lung trial and its potential impact on the treatment paradigm?

Dr. Ticiana Leal: Yeah, the Pragmatica-Lung trial is an ongoing study, S2302. This is an effort that is ongoing. Dr. Karen Reckamp is the chair of this study. And this is a study that actually has a very, I think, modern study design. The term Pragmatica, this is an effort that is supported by the NCI to really propose a clinical trial design that is pragmatic to promote diversity and inclusion in clinical trials. The aim of this trial specifically is to validate what we saw in terms of overall survival in S1800A. So, in this study, patients with previously treated advanced non-small cell lung cancer are randomized 1:1 to the combination of pembrolizumab plus ramucirumab versus standard of care for patients previously treated with immunotherapy and chemotherapy for stage 4 recurrent non-small cell lung cancer. Primary endpoint here is overall survival. And I think this kind of highlights what we were talking about in terms of empowering investigators to treat patients in a clinical trial more so like a real-world setting. And I think this can be paradigm changing and decrease barriers to enrollment and also include now the real-world population that we see in clinical practice.

Dr. Rohit Singh: Yeah, changing gears a little bit. I think your article also mentioned other agents that have been tested in ICI resistance settings, like lenvatinib-sitra. However, those trials results have been disappointing. What are the possible reasons behind those dose point results with multikinase inhibitors? 

Dr. Ticiana Leal: We saw some really interesting, promising overall survival results with these combinations in phase two setting. In the phase 1B expansion with CONTACT-01, we saw prolonged overall survival that we thought would be promising enough to investigate in a phase 3. Ultimately, I don't know because there weren't any biomarkers that we could really tease out what was going on. Again, to highlight that both in LEAP-008 as well as CONTACT-01, there was no definition of immunotherapy resistance, which could have impacted, and we did choose the definition for SAPPHIRE, that patients had to have acquired resistance and immunotherapy had to be the most recent prior therapy. Ultimately, one potential reason for why these are not effective could be that this targeting with a multikinase TKI with multiple targets is ineffective, and you really have to target VEGF more precisely, which is the case here of ramucirumab, which targets VEGFR-2, and whether there are differences between a TKI and a monoclonal antibody may also impact the outcomes here. 

Dr. Rohit Singh: You mentioned biomarkers. Do you think, are there any other potential biomarkers beyond PDL-1 or human mutation burden expression that can help us predict the response image checkpoint, especially in non-small cell lung cancer?

Dr. Ticiana Leal: I think that's a great question. I definitely think that more effort needs to be dedicated, and of course, there are multiple efforts in this direction. One of the challenges, obviously, has been to obtain tissue to do this biomarker testing in clinical trials. When you look at CONTACT-01, they did PDL-1 expression, but this was all based on archival tissue and it was all based on standard of care, local testing. So, a lot of heterogeneity there, and certainly using PDL-1 at baseline from initial diagnosis for a second line trial may have significant flaws there. Ultimately, right now, for clinical practice, there isn't anything that's ready for prime time. But certainly, it sounds like, based on what we're seeing, that combining biomarkers is more likely to improve the accuracy. And I think a single biomarker alone is probably going to have insufficient predictive capacity. It'd be great to be able to better comprehensively characterize an individual's tumor, to individualize immunotherapy strategies in this relapse setting. 

Dr. Rohit Singh: Yeah, definitely. We need more, better biomarkers. Coming to your point of heterogeneity, PD-L1. I myself had a patient, when we got PDL expressions from one site, they gave us one to 49%. However, for the testing, I sent the patient to a further lab at outset and PDL turned out to be 80%. But that was from a different site because of the bio sets only. Yeah, to your point, it's very heterogeneous and definitely we need to be more cautious interpreting those. 

In that trial, in CONTACT-01, we have, through the patient who have oncogenetic lung cancer. Are there any plans to explore the role of immune checkpoint in oncogenetic lung cancer, especially like non-EGFR, non ALK? I know those are the ones that we have seen in multiple studies that don't respond but are other oncogenetic lung cancer is getting more and more target treatments coming out for non-small lung cancer?

Dr. Ticiana Leal: Yeah. So, for patients with driver mutations, the paradigm has been well established that if there is a driver mutation, the patient should receive the appropriate targeted therapy. Immunotherapy as monotherapy has been ineffective in a lot of the patients with driver mutations beyond EGFR and ALK, certainly RET and HER2, ROS1, or other driver mutations that we believe that immunotherapy alone is ineffective. However, we are seeing some interesting ongoing clinical trials, or completed clinical trials investigating immunotherapy in patients with driver mutations. Going back to the EGFR population, we recently saw the results of HARMONi-A, which investigated ivonescimab, which is a bispecific antibody hitting PD-1, and VEGF, that in combination with chemotherapy, improved progression free survival in patients with EGFR mutated, non-squamous, non-small cell lung cancer with progression on prior TKI treatment. So, I think it is still an area of active investigation, and I do think that ongoing trials, perhaps with different PD-1, PD-L1 combination strategies such as bispecifics may be interesting but does require investigation.

Dr. Rohit Singh: Yeah, definitely. It looks like combination therapy is going to be the most likely answer coming forward with more research, we're able to figure out the best possible treatment in this subgroup of patients. Considering the current challenges and ongoing research efforts, how do you see the field of non-small cell treatment evolving in coming years?

Dr. Ticiana Leal: This is an interesting and important question. I think it's been really exciting to be working in thoracic oncology research. We have seen that these research efforts have led to advancement in the field. I think we need to continue to partner and collaborate with institutions, partner with industry, and also with patients and patient advocates to design clinical trials that are really going to focus on the needs of our patients in clinical trials. The gap in the second line and beyond after immunotherapy failure is a significant one. So, I do think that the challenges are to continue to develop biomarkers, to really understand who will benefit from immunotherapy strategies, who benefits from combinations, and most importantly, who does nothing. I think biomarkers are going to be something that we need to continue to incorporate in clinical trials, and I do think that there's a lot of room for hope and promise in the field. We've seen some interesting results with antibody drug conjugates and the combinations there may also be of interest. And then other important strategies, we're looking at T Cell engagers and different drugs with different mechanism of actions, including CAR T and vaccines. So beyond immune checkpoint inhibitors, I think we have different classes of drugs that may lead to different treatment strategies for patients in second line and beyond. 

Dr. Rohit Singh: Yeah, certainly we have seen such extensive development in lung cancer. However, there's still a lot to be done as you just mentioned. 

Thank you so much Dr. Leal for your time and great insights discussing your article with us.

Dr. Ticiana Leal: Thank you.

Dr. Rohit Singh: Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You'll find all ASCO shows at asco.org/podcast.

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. Guest statements on the 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.

Dr. Leal Disclosures

Consulting or Advisory Role Company name: Novocure Company name: Amgen Company name: Roche Company name: AstraZeneca Company name: Regeneron Company name: Novocure Company name: Takeda Company name: Jazz Pharmaceuticals Company name: Catalyst Pharmaceuticals Company name: Pfizer Company name: Janssen Company name: Genentech Company name: Novartis Company name: Sanofi Company name: BMS GmbH & Co. KG Company name: Abbvie Company name: OncoC4

Research Funding Company name: Pfizer Company name: Daiichi Sankyo/Astra Zeneca

Travel, Accommodations, Expenses Company name: Regeneron Company name: Sanofi

Dr. Shannon Westin and her guest, Dr. Chao Cao, discuss the paper "Prevalence and Cancer-Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022" recently published in the JCO.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare. 

Dr. Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth with authors and manuscripts that have been published in the Journal of Clinical Oncology. I'm your host, Shannon Westin, gynecologic oncologist by trade and Social Media Editor for the JCO. And it is my pleasure to welcome Dr. Cao, a research fellow in medicine, Department of Medical Oncology, Dana Farber, Cancer Institute, Boston, Massachusetts. Welcome.

Dr. Cao: Thanks for having me.

Dr. Shannon Westin: Of course. And we're going to be discussing your very important work, “The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022,” which was published in the Journal of Clinical Oncology on April 4, 2024. And Dr. Cao has no conflicts of interest in regards to this podcast. 

So let's get right into it. I'd love to level set. Can you speak a little bit about the definition of cancer survivorship and the number of cancer survivors currently in the United States? 

Dr. Cao: I think this is an important question because everyone somewhat has confusion about the definition of cancer survivorship. So based on the definition by the National Cancer Institute, cancer survivorship refers to the phase of life following the diagnosed cancer. And nowadays, it's estimated about 80 million American individuals are living after being diagnosed with cancer. And this number is projected to rise to 26 million by 2040.

Dr. Shannon Westin: Wow. So obviously, any research that we can do in this population is going to be so important as that number absolutely continues to grow. 

And before we get into the specifics of your work, I'd love for you to speak a little bit about the importance of functional disability, which is what we studied in this work and why it might be observed in cancer survivors. 

Dr. Cao: Yeah, sure. So, maintaining physical function is fundamental to perform life tasks and engage in fruitful jobs. In terms of cancer survivors, many cancer survivors experience side effects from cancer and its treatment. These side effects, include the pain, fatigue, and musculoskeletal dysfunction, which can induce physical limitation and eventually physical disability. And specifically, this is such a burden for the US, social, societal and economic burden. Here I have the specific number: so in 2019, an estimate of over 100,000 people living with and beyond cancer were unable to work and they received a Social Security Administration disability benefit with the resulting cost of US$1.8 billion in disability claims.

Dr. Shannon Westin: Wow. We always think about the impact on the survivor, on their family, but I think it's also really important to look at those other objective data about the impact on society as a whole. Thank you, that was great detail.  

Do we know anything about who might be proportionately more affected by cancer induced physical impairments and disabilities?

Dr. Cao: Actually, this is our key question for our manuscript, but before we developed our hypothesis, we also looked at the data from the general population. So we observed that visual minorities and underserved populations, such as people with lower socioeconomic status and living in the rural area, and also those with unhealthy types of behavior, for example, smoking, obesity, and physical inactivity, are more likely to have physical limitations and disabilities. And also the comorbidity in cancer survival, such as diabetes, cardiovascular disease, also increase the likelihood of physical disability. We also have cancer survivors, particularly for cancer patients who are currently receiving cancer treatment, for example, chemotherapy and radiation therapy, they also are more likely to report side effects from the treatment, also have the reduced physical function. So we also think the cancer patients during the treatment also have a higher likely chance to have physical disability.

Dr. Shannon Westin: Absolutely. That makes sense, and that really dovetails nicely into the objective of your study. We'd love for you to briefly summarize your objective and the methods you employed to achieve that goal. 

Dr. Cao: Yeah, sure. We used the six-year data, 2017 to 2022 from the Behavioral Risk Factor Surveillance System to investigate problems and factors of functional disability in over 47,000 cancer survivors and 2.4 million adults without cancer diagnosis aged 80 years and older. And we specifically focused on two types of functional disability. The first one is mobility disability, which is defined as self reported severe difficulty walking or climbing stairs. And also another one is self care disability, which is defined as self reported difficulty dressing or bathing. And also we examined the factors, for example, social demographic characteristics, lapse of behavior, and health related factors, and some cancer related factors, how these factors related to the functional disability.

Dr. Shannon Westin: Okay, great. So before we get into your findings, I'd love to hear just a little bit more about the BRFSS, the Behavioral Risk Factor Surveillance System. Why did you choose data from this survey for your study? 

Dr. Cao: This is a very key question, because nowadays there are no specific cohort studies for cancer survivors. And also actually, in the population based study, there is no field data specifically for the cancer survivor. But fortunately, in the United States, the CDC conducted several nationally representative surveys to examine the health status of the people living in the United States. So we used the data from the Behavioral Risk Factor Survival System, we also called BRFSS. So BRFSS is a nationwide telephone based survey conducted by the CDC and it collects information on health related risk factors and chronic micro conditions among the US adults aged 80 years or older. And specifically for our papers, because recently, the BRFSS also added a section on the cancer survivorship, which included a lot of the variables on cancer, diagnosed cancer type, and also cancer related factor symptoms, for example, the cancer or cancer treatment related pain. So we used this data to realize our idea. 

Dr. Shannon Westin: Okay, great. So let's start with what you found in regards to the first aspect with mobility disability. 

Dr. Cao: First, we observed the problems of mobility stability are much higher in cancer survivors than non-cancer adults. And also among cancer survivors, more than 25% of cancer survivors reported mobility disability. We also observe the prevalence of mobility disability is much higher in racial minority groups and underserved populations and those with unhealthy behavior and medical conditions.

Dr. Shannon Westin: In addition to the underrepresented minorities, were there any other kind of socioeconomic, demographic factors associated with high prevalence of mobility disability?

Dr. Cao: Yes, the factors like lower level of education, income, being unmarried, and living in non metropolitan areas were associated with higher prevalence of mobility disability. And also, I forgot to mention another factor is cancer related factors. We're also including several cancer related factors such as cancer and cancer related pain. So we also observed a higher prevalence of the mobility disability in people, in cancer survivors with cancer and cancer related pain. We also see the prevalence of the mobility disability is much higher in the patients who are currently receiving the cancer treatment than those who already completed the cancer treatment.

Dr. Shannon Westin: Yeah, that makes a lot of sense. And to that end, with regards to treatment, were there any cancer specific patterns of mobility disability?

Dr. Cao: Yeah, and also, I think this is another strength of our study, because the BRFSS high sample size, which clearly evaluates the mobility disability in over 47,000 cancer survivors,  which allowed us to do the cancer specific part of mobility disability. We observed that the survivors of lung cancer and brain cancer and bone cancer have the highest prevalence of mobility disability. And interestingly, we also observed that the women with cancers also had, for example, ovary, cervical cancer survivors also have higher problems of mobility disability. Probably you know, better than me, and I just tell the data.

Dr. Shannon Westin: Well, it’s interesting, I was thinking, it seems like we have a lot, but I have no, obviously, frame of reference with other cancer types. So it's intriguing to me that that's definitely what we see in our clinic. So I'm intrigued to understand more about this. 

But before we get into the next steps and that type of thing, I do want to make sure we touch on that other aspect that you looked at, the self care disability and give the listeners a little bit of an idea of what you found there? 

Dr. Cao: The self care disability is kind of the more severe of the functional disability, which means, we say candidates, lower prevalence compared to the mobility disability, but still the patterns or factors associated with self care disability are much similar with mobility disability. An interesting finding is that in terms of the mobility disability, we find that older survivors are more likely to report mobility disability than younger survivors. In contrast, in terms of the self care disability, younger survivors are more likely to report than the older cancer survivors. 

Dr. Shannon Westin: You've touched a little bit on some of the socioeconomic and demographic factors that were different with self care disability. Was there anything else that really caught your eye? Cancer specific factors or anything else like that?

Dr. Cao: Yeah, besides this, I think also we observe that women are more likely to report self care disability. I think also this is driven by the cancer specific, particularly the woman cancers have a higher prevalence of the self care disability.

Dr. Shannon Westin: Well, it's definitely something for me to take back to my clinic. Now that you've covered all these results, how are your data compared to existing literature in this area? 

Dr. Cao: Yeah, we have tended to do comprehensive literature reviews. When we discuss our results and compare it with existing literature, our result is quite aligned with previous literature and particularly we clearly see the racial ethnic minority have a higher prevalence of physical limitation and physical function decline. But our paper focused on the physical disability which is much more severe than the physical function. And also we also looked at another study conducted in Australia, we quite find very similar results even for cancer specific patterns of the functional disability. 

Dr. Shannon Westin: I guess the next question I have is was there anything that surprised you about your results? 

Dr. Cao: I just mentioned that what surprised me the most is that the older people are more likely to report the mobility disability, but the younger people are more likely to report self care disability. Our data don't support or explore why this happened and what's the etiology behind this. But our hypothesis is that the younger cancer survivor, younger cancer patients are more likely to receive the aggressive treatment that can play a significant role in the functional outcome. 

Dr. Shannon Westin: Yeah, it sounds like that's definitely an area of unmet need for more research. But I like your hypothesis. I do wonder if that's somewhat related.  

And I guess that leads us to our final question. What are your next steps and how can I potentially use this in practice? How can our listeners employ these findings in their practice? What do you recommend?

Dr. Cao: I think our findings highlight the importance of screening for functional limitations at the baseline and throughout the cancer treatment and even the cancer survivorship. Oncology providers also should encourage patients to be physically active. And also American Society of Clinical Oncology and also American College of Sports Medicine recommend that regular exercise during the treatment can help cancer patients preserve their fitness and reduce the incidence and the severity of the cancer related disability. And also providers can provide referral to rehabilitation services and support groups for additional care. 

For the next step, our finding highlights the importance of developing ways to limit the long term side effects of cancer treatment both during and after treatment to preserve fixed function and prevent disability. Particularly, target intervention should in particular address special needs in vulnerable populations, including the racial ethnic minorities and those living in the rural areas to improve their quality of life during a long term survivorship. And also due to the advance in the technologies, now we want to see whether wearable sensors, wearable devices can be a novel tool to monitor their physical functions during the treatment because better monitors can lead into their better treatment and their prevention.

Dr. Shannon Westin: That's great. Yeah, what a great way to end. I think that exercise clearly is key not only for preventing these issues, but also we know that it potentially can even improve response to therapy and recurrence free survival. So I think lots of reasons to be focusing on physical activity in our clinics and ensuring our patients and our cancer survivors are really participating in those types of activities. 

Well, Dr. Cao, it was such a pleasure. I cannot believe you are only a research fellow. I can't wait to see where your career takes you. Congratulations on this great work.

Dr. Cao: Thank you. Thank you for this great opportunity to share my work and I look forward for my future work in the field.

Dr. Shannon Westin: Oh, yeah. So you guys, if you're looking for somebody to come and push the boundaries of functional disability and activity, you know where to look. 

And again, thank you all our listeners for tuning in to another episode of JCO After Hours. Again, we were discussing, “The Prevalence and Cancer Specific Patterns of Functional Disability Among US Cancer Survivors, 2017-2022.” Original research published in the JCO, April 4th, 2024. So if you're looking for more podcast offerings, check out other JCO After Hours offerings wherever you get your podcasts. Have an awesome day.

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. Guest statements on the 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.

In this JCO Article Insights episode, Alexandra Rojek provides a summary on "Anti-CD19 Chimeric Antigen Receptor T-cell therapy for Richter’s Transformation: An International, Multicenter, Retrospective Study by Kittai, et al published in the Journal of Clinical Oncology March 29th, 2024. 

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Alexandra Rojek: Hello and welcome to JCO Article Insights. I'm your host, Alexandra Rojek, and today we will be discussing an original report published in the June 10th issue of JCO titled, “Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study,” by Kittai et al. This report addresses the real world efficacy of CAR T-cell therapy for patients with Richter transformation of CLL to large B cell lymphoma, which represents a high risk group of patients with an unmet need for novel and more effective therapeutic agents than are currently available. Richter's represents the transformation of chronic lymphocytic leukemia, or CLL, to an aggressive lymphoma, most often a large B cell lymphoma, most similar to diffuse large B cell lymphoma or DLBCL. Treatment for Richters is often modeled after treatment practices for DLBCL. However, there's no clear standard of care and outcomes for these patients lag behind those of large B cell lymphoma patients otherwise.

An important advance in recent years in the DLBCL field is the approval of anti CD19 CAR T-cell therapy in the second and third line settings. However, patients with Richter transformation were largely excluded from these pivotal trials. This study in JCO thus set out to address what the real world outcomes were for patients with Richters who were treated with CAR T-cell therapy across 12 centers internationally. The study included 69 patients across these twelve sites, with a median age of 63 years at diagnosis of Richters and a median of six years after initial CLL diagnosis. Included patients received a median of four prior lines of therapy for either CLL or Richters, with a median of two prior lines of therapy for Richters, although two patients had not received any prior therapy for their Richter transformation.

The most recent prior treatments included chemoimmunotherapy in 29% of patients, followed by BTK inhibitors in 19%, as well as combinations of BTK inhibitors and BCL2 inhibitors in 12%. 17% of patients had not received prior therapy for their CLL before their diagnosis with Richters, 58% of cases had known TP53 mutations at time of transformation, and 41% exhibited deletion 17p by FISH. Prior to receiving CAR T-cell therapy, 86% of patients required additional bridging therapy, most commonly with a BTK inhibitor or chemoimmunotherapy. A diverse set of commercial CAR T-cell products were represented in this study, with the majority of patients at 64% receiving axi-cel, 25% receiving tisa-cel, 10% receiving liso-cel, and one patient received brexu-cel in an investigational setting. Median time from apheresis to CAR T infusion was 34 days, and 59% of patients continued on a BTK inhibitor throughout CAR T-cell therapy.

When we move on to look at responses, 66 out of 69 patients were available for response. Three patients died related to adverse events after infusion and before response assessment, with the best overall response of complete response or CR in 46% of patients and partial response or PR in 17% for an overall response rate of 63%. With a median follow up time of 24 months, the median PFS in the study was 4.7 months and the median OS was 8.5 months. For those who achieved a CR, the median duration of response was an impressive 27 months, and for those achieving PR, the median duration of response was only two months. The two year PFS rate was thus 28%, and the two year OS rate was 38%. Four patients who achieved a CR went on to receive an allogeneic stem cell transplant. Among those whose disease progressed, 8% had relapse involving the CNS, compared to 10% of patients having CNS involvement prior to CAR T in this study population. The authors were also able to look at minimal residual disease, or MRD testing for CLL in a subset of 27 patients in this study. MRD was undetectable by PCR or flow in either blood or bone marrow in 81% of these 27 patients. However, not all of these patients had paired pre and post CAR T samples available for comparison, thus limiting more detailed interpretation.

In an analysis of risk factors linked to adverse outcomes, the study authors found in a multivariable analysis for overall survival that a greater number of prior lines of therapy for Richters, a higher Ki-67 proliferation index, and a higher baseline LDH and CRP were all associated with shorter OS. They did not find an association between patterns of BTK inhibitor use, whether prior to apheresis, as a part of bridging, or concurrent with CAR T-cell therapy, to be associated with either PFS or OS. In evaluating rates of toxicities for patients with Richters treated with CAR T, the authors find that grade 3 or higher cytokine release syndrome or CRS occurred in 16% of patients and grade 3 or higher neurotoxicity or ICANS occurred in 37%. They did not find any baseline features associated with higher risk of severe CRS, however, did find that prior venetoclax exposure was associated with severe ICANS.

Overall, the authors find that CAR T-cell therapy is a feasible and effective therapy for Richter transformation of CLL to large B cell lymphoma, thus contributing data to support this additional therapeutic option in a high risk patient population with unmet therapeutic needs. While the PFS and OS rates are lower than those of their large B cell lymphoma counterparts, overall response rate of 63% and particularly the CR rate of 46% with a duration of response of 27 months for this group is quite promising. Those who achieved less than a CR had a much shorter duration of response and progressed quickly, and overall, the median overall survival of the whole study population is only over eight months, which reflects the high risk and poor outcome nature of treatment for Richters with currently available therapies. As the authors discuss, it is likely that the efficacy of CAR T-cell therapy is somewhat overstated in their results by virtue of not being able to include patients who were intended for CAR T-cell therapy but could not receive it in this retrospective study. This represents one of the many real world challenges patients and clinicians treating Richters face. However, the promising results for those who were able to receive CAR T-cell therapy represent a path forward for future investigations for Richters patients.

One of the avenues of future pursuit is the addition of BTK inhibitors to CAR T-cell therapy. A subset of patients included in this study received BTK inhibitors for CLL before, during, and after CAR T-cell therapy, and although limited by subgroup analysis and statistical power constraints, this study's authors did not find a difference in outcomes for those who received BTK inhibitors in these settings. Toxicities with severe CRS and ICANS were higher than rates reported in large B cell lymphoma CAR T trials. However, as the authors note, these were comparable to the study of liso-cel toxicity in CLL patients. Higher rates of infection related deaths were also noted compared to large B cell lymphoma patient counterparts, however, in line with comparable CLL patient studies and thus likely related to the unique biology of Richters arising from CLL rather than de novo large B cell lymphoma.

In summary, this important work evaluating the outcomes of patients with Richter's transformation treated with anti CD19 CAR T-cell therapy in the commercial setting provides important evidence as to the efficacy of this therapy among patients with an unmet need for efficacious and novel therapies to improve outcomes. As this group of patients is often excluded from clinical trials, this data is particularly important and should drive forward future studies focusing on and or including patients with Richters, given the benefits seen for a subset of patients who achieve a response in the study. While the antecedent CLL distinguishes Richters from de novo large B cell lymphoma biologically along with differences in prior treatment regimens, this study in JCO suggests that future strategies targeting improving baseline disease factors prior to CAR T-cell therapy, including successfully bridging patients to CAR T, reducing risk of CRS and ICANS with treatment, and improving long term efficacy after CAR T with novel constructs, and CAR design, may all be promising next steps in the advancement of CAR T-cell therapy for patients with Richter transformation.

This is Alexandra Rojek. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts.

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. Guest statements on the 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.

Dr. Shannon Westin and her guest, Dr. Bryan Schneider discuss the article “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer” recently published in the JCO and presented at the 2024 ASCO Annual Meeting.

TRANSCRIPT 

The guest on this podcast episode has no disclosures to declare.

Shannon Westin: Hello, everyone, and welcome to another episode of JCO After Hours, the podcast where we get in depth on manuscripts published in the Journal of Clinical Oncology. I am your host, Shannon Westin, GYN Oncology Extraordinaire and also the Social Media Editor of the Journal of Clinical Oncology. And it is my great pleasure to present some really incredible work today that is going to be a dual publication in the Journal Clinical Oncology and a presentation at the American Society of Clinical Oncology Annual Meeting on Monday, June 3. And this is the “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer.”

And I am joined today by the senior author on the presentation and the primary author on the manuscript, Dr. Bryan Schneider. He is the Vera Bradley Professor of Oncology, the Professor of Medicine and Medical Molecular Genetics at the Indiana University Melvin and Bren Simon Comprehensive Cancer Center in Indianapolis.

Welcome, Dr. Schneider.

Dr. Bryan Schneider: Dr. Westin, thank you for having me on today.

Shannon Westin: We're so excited and we're really excited to really summarize this incredible work that's being presented today. So, first, let's just levelset. Can you speak a little bit about peripheral neuropathy and the most common causes in patients with cancer?

Dr. Bryan Schneider: Yeah, I mean, I think for those of us who treat patients using the taxanes, we recognize probably one of the most important and common side effects that we deal with is peripheral neuropathy, and one that can, I think, impact both quality of life, but also impacts the ability to maintain dose intensity. When we think about risk factors for neuropathy, historically, I think obesity has been reported as a potential risk factor, as has diabetes and other conditions which put people at risk for neuropathy.

Shannon Westin: And prior to your work that you'll discuss with us today, what do we know about the incidence of peripheral neuropathy in patients that identify as black?

Dr. Bryan Schneider: Yeah. So, interestingly, I think we've recognized that patients who self identify as black have disparate outcomes in terms of inferior survival and more aggressive subtypes of breast cancer, like triple negative breast cancer. But I think the idea of toxicity being a disparate factor as well is probably a more recent one. Interestingly, as we set out to identify biomarkers to predict outcomes in the large adjuvant trial E5103, we weren't really setting out to look at this by race. We were using at that time, genome-wide approaches to identify biomarkers for toxicity and also efficacy. But what was interesting as we did that one of the most important predictors, as we looked across a number of important toxicities, was ancestry. And really the science spoke to us, it was very clear that patients of African ancestry had higher rates of bev-induced hypertension, anthracycline-induced cardiomyopathies and also peripheral neuropathy.

Shannon Westin: That's so interesting. We have so much overlap in gynecologic oncology and breast cancer. And I don't know that I've ever seen work like this. And now it's making me very intrigued and making me want to move forward to that.

Can you talk a little bit more about this ECOG-ACRIN E5103, like briefly about the study and what it demonstrated specifically?

Dr. Bryan Schneider: Yeah. So E5103 was an adjuvant breast cancer trial that really set out to look at the impact of bevacizumab in the curative setting. This was a 5000 patient trial that randomized patients the standard backbone of chemotherapy. So everyone received four cycles of doxorubicin and cyclophosphamide, followed by weekly paclitaxel, and then with or without the addition of bevacizumab. So the parent clinical trial showed, as we know now, bevacizumab didn't add benefit, but certainly this was a fertile ground for us to use genomic markers to try to identify a number of other important factors and predictors.

Shannon Westin: And what did you find genomically in that study that led to kind of where we are now?

Dr. Bryan Schneider: Initially, what we found is that ancestry was a major predictor of neuropathy. And in that trial we saw essentially a doubling of the risk of grade 2 and above and a doubling of the risk of grade 3 and above neuropathy. When we then looked comprehensively across the genome for common variants that might put patients at risk for neuropathy, we had enough patients in the black population to identify some markers that seemed to differentially predict the risk of neuropathy in the patients of African ancestry. So there we found a variant in the gene FCAMR, which appeared to be protected from neuropathy, and FCAMR is known to have an immune modulatory effect. But importantly, we also found that rare variants, so we did this using an exome wide approach in a gene called SPF2, predicted an increased risk of neuropathy. Now, interestingly, that gene SPF2 is also thought to contribute to a hereditary form of neuropathy, Charcot-Marie-Tooth. Here, what we found, obviously, is that if you inherit two of these variants, you probably have a hereditary neuropathy, but if you inherit one, you may not have neuropathy at baseline, but if exposed to a neurotoxin, much more predisposed to that event.

Shannon Westin: That is so intriguing and makes so much physiologic sense. So, can you talk a little bit about how that led to the development of the current study, the objectives design, that type of thing?

Dr. Bryan Schneider: Yeah. I think, overarching question and concern is, and we see this with all clinical trials in the United States, is that we're seeing disparate outcomes in a population that are largely underrepresented in our clinical trials. And so one of the first things we wanted to do was really focus on the population that was being disparately affected. So EAZ171 was set out to accrue patients, and in fact, only accrue patients who were self described as a Bck race or African American. So the goal of this trial then was to see if, number one, we could further predict which patients were going to get neuropathy based on our germline genotyping, and then also to better personalize the type of taxane based, again on genomics, but also on the risk of dose reductions, risk of neuropathy, impact on financial toxicity, quality of life, and a number of other, what we felt to be, important clinical variables.

Shannon Westin: So let's get into the details. What did you find regarding the incidence of neuropathy in the study, and how was it impacted by the type of chemotherapy the patient received?

Dr. Bryan Schneider: Yeah. So the starting point, the primary objective of that study, was to try to validate a high and low risk composite score for neuropathy. And the trial was negative, meaning our genotypes did not predict significantly differences based on the germline genotyping. Now, interestingly, the genotyping did numerically separate, meaning those in the high risk category had about a 12% higher risk of neuropathy, but this did not meet statistical significance. Another major or key secondary endpoint, though, was to look at the type of taxane and its impact in this population. And indeed, what we found is that patients who received paclitaxel had a markedly and statistically significantly higher risk of both grade 2 and above and grade 3 and above peripheral neuropathy. And in addition, we saw more dose reductions, both because of TIPN and all causes in the paclitaxel arm.

Shannon Westin: So why do you think you were unable to validate the genomic predictors in the current study?

Dr. Bryan Schneider: This is an incredibly important question. So, number one, I mean, we were happy to see the directionality of our preliminary data be correct. But I do think that neuropathy is a very complicated toxicity, and it's probably a multigenic effect, and it probably is also impacted a lot by a variety of clinical factors. So some of the future work we'll be doing is looking at polygenic risk scores and other known genes that may be impactful, and also melding that with a number of really important clinical variables, because I still think we have the potential to predict this ahead of time.

Shannon Westin: I know that this was such a patient driven topic, really focused on the patient experience and how to improve not only survival outcomes, but also toxicities and quality of life. Can you speak a little bit about the role of patients in the design of this trial, and maybe with helping it be as successful as it was with accrual?

Dr. Bryan Schneider: Yeah. This has truly been one of the most exciting projects I've ever embarked on, and largely because of the incredible team atmosphere and contributions by so many people. Real thanks to the late Worta McCaskill-Stevens and also the late Edith Mitchell, who were two really fundamental disparities experts who really helped motor this trial to where it was. And also our patient advocates and the community at large really were part of the design and part of this from the very beginning, all the way through the publication, I think, have made it a clinically relevant study, and one that I think we're all very proud of.

Shannon Westin: Is paclitaxel typically, what is the go-to? Or are more people using, let's say, docetaxel?

Dr. Bryan Schneider: I think it depends a little bit on the disease setting and type. And again, is a function of historical clinical trials. One of the pivotal trials, E1199, actually compared a number of these. So it compared weekly paclitaxel to every three week paclitaxel to weekly docetaxel to every three week docetaxel in a two by two design. And essentially the conclusion there is that weekly paclitaxel and every three week docetaxel both outperformed what at the time was a standard of care, every three week paclitaxel. Now, weekly paclitaxel, at least through ECOG-ACRIN, has been adopted as kind of the standard reference therapy and schedule of choice, but largely because of the side effect profile. And again, this is based predominantly on white patients, where the tolerability is much better.

Shannon Westin: Well, I mean, I think that this leads to really great information around how we're designing these trials and how we're potentially making those differences. What are your next steps here?

Dr. Bryan Schneider: So I think one of the things this clinical trial did was first validate that we do see high rates of peripheral neuropathy in Black patients with breast cancer. This was a prospective study using both physician and patient adjudicated variables. So I think this is a really nice validation that this is a problem in this population. I think it also shows us that docetaxel is probably a more tolerable drug for black patients with breast cancer.

The goal, though, I think in our future work, is really going to try to bring equity in terms of outcome and side effects. So we're working with ECOG-ACRIN now on our second trial, where really the primary endpoint is going to be to nullify the disparities and try to bring equity in terms of toxicity. One of the other pieces of work we're really excited about is we're doing some ex vivo work. So from patients in EAZ171, we have a blood stick where we're taking white blood cells and differentiating those into peripheral neurons. And here we're hoping to look at really important changes in both gene expression and epigenetics that might lead us to a little bit deeper understanding of the mechanism of the disparities in neuropathy, maybe what's causing some of the neuropathy. And we hope ultimately, these may lead to nice drug targets to help prevent or treat neuropathy down the road.

Shannon Westin: Those are some really great ideas. The other thing that really caught my eye around your findings was what you all found regarding the physician reported and patient reported toxicity. I'd love for you to summarize that, because I think that's always a concern as well.

Dr. Bryan Schneider: Historically, I think we recognize that physicians probably underreport side effects. And so we felt, and our team felt, that having patient reported outcomes would be a really critical piece to this study. What was fairly astonishing to me, if you look at the CTCAE, both patient and physician reported outcomes, they were actually pretty similar. And I think what this is a testament to is if physicians are actually thinking about the side effect, they do a pretty good job of predicting it. Now, one thing we're looking very forward to is that we have a long term follow up out to three years. So it'll be interesting to see if physicians continue to pay close attention to neuropathy, because I know the patients will be. So we'll be looking at the discordance at these longer term follow up time points as well.

Shannon Westin: Well, great. This is such incredible work, and I’m like literally taking notes to get in touch with people I know that do this type of work and gynecological malignancies because I think that this is going to have far reaching consequences. So just thank you so much for taking the time to review this and congratulations on the JCO publication and ASCO presentation. It's very well deserved.

Dr. Bryan Schneider: Thank you Dr. Westin.

Shannon Westin: And thank you to all of our listeners. Again, we have been discussing the “ECOG-ACRIN EAZ171: Prospective Validation Trial of Germline Predictors of Taxane-induced Peripheral Neuropathy in Black Women with Early Stage Breast Cancer.” We're so grateful you joined us, and please do check out our other offerings wherever you get your podcasts. Have an awesome day.

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Disclosures

Research Funding

Company name: Genentech/Roche

Company name: Pfizer

Company name: Foundation Medicine