HER3-DXd in EGFR-Mutated NSCLC: HERTHENA-Lung01

Dr. Shannon Westin and her guest, Dr. Helena Yu discuss the paper "HERTHENA-Lung01, a Phase 2 Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-Mutated NSCLC Following EGFR TKI Therapy and Platinum-Based Chemotherapy" published in the JCO during the World Conference on Lung Cancer in Singapore.  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 on manuscripts that are published in the Journal of Clinical Oncology. I am your host, Dr. Shannon Westin, GYN Oncologist and Social Media Editor of the JCO. And as always, it's my pleasure to review an incredibly exciting manuscript.  Today, we're going to be talking about “HERTHENA-Lung01: A Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in EGFR-mutated NSCLC Following EGFR TKI Therapy and Platinum-based Chemotherapy.” And this is exciting. This is a simultaneous publication in the JCO on September 10th, 2023 at the same time it's being presented at the World Conference on Lung Cancer in Singapore.  I am joined today by the first author and overall outstanding physician, Helena Yu. She's an Associate Attending Physician, Thoracic Oncologist, and Early Drug Development Specialist at Memorial Sloan Kettering Cancer Center in New York, New York.  Welcome, Dr. Yu.  Dr. Helena Yu: Thank you. I'm glad to be here, and thanks for having me.  Dr. Shannon Westin: So we're so excited to have you, and we love doing these simultaneous podcasts because I think not everyone can go to Singapore and be with you today. So it's awesome that we'll be able to give people the data that they want to see as soon as possible.  So first, let's just level set. Coming from the GYN Oncology standpoint, I always like to get down to the basics of the cancer. So, can you speak just a little bit about the incidence and mortality of lung cancer overall and what have been some recent trends in the treatment of this disease?  Dr. Helena Yu: Everyone knows somebody that has been touched by lung cancer. It's the second most common cancer that is diagnosed in men and women in the US today. It is the leading cause of cancer-related deaths, with 25% of cancer deaths really being attributable to lung cancer. Historically, prognosis with lung cancer has been poor, with five-year survivals around 10%. What's really interesting is over the last couple of years, there have been some improvements in survival with lung cancer. And I think that that can largely be attributed to the advent of immunotherapies as standard of care, as well as targeted therapies for driver mutation-positive lung cancer.  Dr. Shannon Westin: So that leads right into the next question: What is the role of the EGFR pathway in lung cancer? How common are these aberrations and how successful have prior treatments targeting this pathway been?  Dr. Helena Yu: Yes. So we, in lung cancer, have this mutation pie, which really describes the different oncogenes that we see in lung cancer. And probably now two-thirds of patients actually have a detectable driver mutation when their tumors undergo next generation sequencing. EGFR is probably one of the first mutations that was identified. About 15% to 20% of patients diagnosed with lung cancer in the US have mutations in EGFR. It is both activating and sensitizing. So, obviously mutations in EGFR cause cancer and they are sensitizing to different EGFR targeted therapies we have.   Right now, the standard of care for first-line treatment for EGFR mutant lung cancer are EGFR tyrosine kinase inhibitors. And those are oral therapies that actually are very successful at managing EGFR mutant lung cancer. They're not curative, but they do kind of control disease for a long period of time. But unfortunately for all patients, at some point their cancer does progress on these targeted therapies. And the most common one we use today is one called osimertinib, which is a third-generation EGFR TKI. And we do not have any approved targeted therapies after osimertinib. And so that kind of is the setting for this new drug, patritumab-deruxtecan.  Dr. Shannon Westin: So tell us a little bit about HER3-DXd and why you prioritize targeting this particular part of the EGFR pathway in this population.  Dr. Helena Yu: Yes. So HER3 is actually part of the HER EGFR family, and it is a protein that, when expressed, really portends a poor prognosis. It kind of tells us cancers that are more likely to recur and cancers where overall survival is shorter. So HER3-DXd is an antibody drug conjugate. There are a slew of new medicines in lung cancer that are ADCs. Historically, we looked at HER3 monoclonal antibodies in EGFR mutant lung cancer and they actually were not successful, not efficacious. And so it's really interesting that using these antibodies as part of an ADC construct has led to better efficacy.  The HER3-DXd has that HER3 monoclonal antibody, there is a linker and then there is a chemotherapy payload. So for the deruxtecan family of which there are a few ADCs has a topoisomerase 1 chemotherapy, and in part, we know that HER3 is sort of more significantly expressed in these EGFR mutant lung cancers. And because HER3 is part of the EGFR family and heterodimerizes with EGFR, it was sort of a natural initial population to study this drug.  Dr. Shannon Westin: Why don't you briefly highlight the design of the trial and your key eligibility for our listeners? Dr. Helena Yu: So this phase II study came off the heels of an initial phase I study that helped us identify the appropriate dose of HER3-DXd for patients with EGFR mutant lung cancer. And so this study enrolled patients with metastatic EGFR mutant lung cancer. All patients had to have received EGFR TKI, most of them received osimertinib and that's first line standard of care globally. And then also patients had to receive platinum doublet chemotherapy, which is really our second line standard of care treatment. The initial study randomized patients to two cohorts. One, which was all patients received 5.6 milligrams per kilogram every three weeks intravenous. The other cohort was an uptitration cohort, where they actually started with lower doses and then kind of sequentially over cycles increased the dose to see if that mitigated toxicity based on emerging phase I data that really showed that the 5.6 milligram per kilogram had the better efficacy as well as better toxicity profile. Pretty soon after the study started, all patients received that 5.6 mg per kilogram.  And I think the other important thing to say is that patients with asymptomatic brain metastases were allowed. Lung cancer, in general, has a very high incidence or frequency of brain metastases. But in EGFR mutant lung cancer that number is north of 50%. So having a therapy that is effective in the CNS is especially important for this population. Dr. Shannon Westin: So let's talk a little bit more about this population. The group that you enrolled and treated, is it representative of the general population that we might see in the community?  Dr. Helena Yu: Yes, I think so. I think that one thing to highlight are these patients were pretty heavily pretreated. The median prior lines of therapy were three lines prior to study enrollment, but I think that went up to eleven for certain patients. And so that is one thing that I think is unique about this population, where they're able to sort of receive several sequential therapies. I think it was unique in allowing those asymptomatic brain metastases and then EGFR mutant lung cancer has certain demographic tendencies. And so we see women, Asian, never smokers, which may not kind of represent the typical demographic for lung cancer, but certainly is the typical demographic for EGFR mutant lung cancer. Dr. Shannon Westin: Got it. And let's hear about your primary results. What did you discover? Dr. Helena Yu: To set the stage, this is really an unmet need where post EGFR TKI and post chemotherapy, we really don't have exciting efficacious therapies. When you look at real world studies, the response rate to third line and beyond treatments are less than 10% PFS less than three months. And so really searching for something in this treatment landscape. And so for the study, the primary endpoint was confirmed overall response which was 30% for this patient population. Duration of response was 7.4 months and the median progression free survival was 5.5 months. Looking at sort of prespecified subgroups, there really did not seem to be a particular subgroup that had enhanced benefit.  Dr. Shannon Westin: So that is a really impressive improvement in the expected standard of care results. So I congratulate you and I'm so excited.  I was also really excited to see that you included patients with the asymptomatic brain meds for the recent ASCO-Friends guidelines. Can you speak a little bit about the efficacy in this population specifically? Dr. Helena Yu: Absolutely. As I mentioned before, for these novel targeted therapies, we really do need to look specifically at CNS efficacy because that is absolutely an area where we often see disease progression. And so having studies that allow those patients really is more representative, of course, of the clinical practice that we actually treat. And so when you look at the subgroup that had a history of brain metastases, which in this group was actually, I believe, 51%, so the majority of patients, the response rate was really similar to the patients that did not have brain metastases. I believe it was 29% response rate for patients with brain metastases and 30% for patients without.  And I think what is especially useful that we did was we had specific neuroradiologist look for measurable target lesions within the CNS that had not received prior radiation or prior local therapy to look at intracranial response rate. And so there were a subgroup of patients, 30 patients that had measurable target lesions within the CNS and the confirmed intracranial response rate was 33.3% in those patients with measurable target lesions in the CNS and disease control rate was 77%. So, I think, it's really exciting to see that the response rate in the CNS was really comparable to what we see with systemic disease. Dr. Shannon Westin: That is awesome. I don't think I've ever seen anything quite like that. So really, you and your co-authors are to be congratulated for including this really important population.  I guess the next natural question is, how was HER3 expression? Did you look at that? How was it associated with response to therapy? And did you find any other intriguing genomic alterations associated with benefit from the HER3-DXd?  Dr. Helena Yu: That is a super interesting topic because I think in lung cancer we are well familiar with these driver mutations that really are the biomarker for targeted therapy. It is less clear what the appropriate biomarkers are for some of these antibody drug conjugates. We absolutely looked at HER3 expression, pretreatment tissue was required for this point specifically. And actually within EGFR mutant lung cancer, almost all patients have some degree of HER3 expression. And so we're already looking at a population that is enriched for potential response.  But we actually looked at H-scores, looking at membrane HER3 expression and really did not find differences in the degree of HER3 expression when you compare patients with response versus stable disease versus progressive disease. So I don't think the degree of HER3 expression really is an appropriate biomarker. And I think we're still figuring out with ADCs, I think you actually might need very little of the surface protein for these ADCs to be internalized and be effective. So, right now, the disease population of interest is EGFR mutant lung cancer, where we think there's reasonable efficacy. Dr. Shannon Westin: And that makes sense. And with this particular drug, is there a bit of bystander effect as well, like we've seen with some of the other ADCs?  Dr. Helena Yu: There absolutely is a little bit. And I think what is interesting for this drug too is there are a few ADCs that are in development. So there is trastuzumab-deruxtecan, which is already approved for HER2 positive lung cancer; and then there is also datopotamab-deruxtecan, which is a TROP2 ADC. And so I think there really will be a wave of these different ADCs which are studied in slightly different populations. But I think understanding what the biomarker is for these and then, will there be cross resistance because of the similar chemo backbone, is something that we will need to find out in the future.  Dr. Shannon Westin: Yeah, these are definitely unmet needs in this space.   I guess one other question just around safety signals, anything unique for this particular agent? Kind of take us through the dose interruptions and dose reductions?  Dr. Helena Yu: Absolutely. So I think that it is important to remember, and I do remind all of my patients that have consented to this study, that ADCs are a hybrid chemotherapy agent. So they will have some of the typical chemotherapy adverse events like cytopenias. We did see a little bit of alopecia with this as well. So I think there's thrombocytopenia and neutropenia that actually is more front-loaded and actually weren't necessarily associated with significant clinical sequelae like bleeding or neutropenic fever.  The rate of treatment discontinuation from adverse events was actually pretty low at 7%; but about 20% of patients did require a dose reduction, and many of the side effects do appear to be dose-dependent. So I think those dose reductions are helpful. And then a really important side effect of this class of drugs is ILD or interstitial lung disease or pneumonitis. And we've seen kind of varying ranges of pneumonitis with these drugs. So far it really looks to be the highest with trastuzumab-deruxtecan with an ILD rate north of 15%; but with this drug, the independently adjudicated rate of ILD was 5%. So present, but maybe not as high as some of the other drugs in this class.   Dr. Shannon Westin: Well, that's great news. Well, congratulations on these exciting results and your presentation and your paper.  The last question I have for you is what's next for this agent? What do you see? Where do you see it going? Dr. Helena Yu: Absolutely. So I hope that with these promising results in an area of unmet need, that we will get approval for this drug so that we can get access to our patients. The other interesting thing that we are looking at is combining HER3-DXd with osimertinib, which is the standard of care EGFR inhibitor. So the idea of combining this novel therapy with the standard targeted therapy for this type of cancer, I think, is really interesting to see if we'll get even sort of greater efficacy and in particular greater CNS efficacy by combining two CNS active agents. So those are results that I'm looking forward to seeing, too. Dr. Shannon Westin: That's great. Well, thank you so much for being here, Dr. Yu. And congratulations again on these incredible results and your incredible success in the lung cancer space.   And thank you all of you for listening in to JCO After Hours, again, discussing the “HERTHENA-Lung01: Phase II Trial of of HER3-DXd in EGFR Mutated Non-Squamous Cell Lung Cancer.” We are always excited to have you. Please check out our other podcasts, reach out and let us know how we did. And until then, we'll see you next time.   The purpose of this podcast is to educate and to inform. 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