Molecular Testing for Early-Stage Non-Small Cell Lung Cancer, with Ryan Gentzler, MD; Xiuning Le, MD, PhD; Brendan Stiles, MD; and Vamsidhar Velcheti, MD, FACP, FCCP

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In this podcast, members of the Cancer.Net Editorial Board discuss new research in molecular testing, also known as biomarker testing or tumor marker testing, to help guide treatment for people with early-stage non-small cell lung cancer. This podcast is led by Dr. Ryan Gentzler, Dr. Xiuning Le, Dr. Brendan Stiles, and Dr. Vamsidhar Velcheti. Dr. Gentzler is the director of the Thoracic Oncology Clinical Research Program at the University of Virginia (UVA) and chairs the UVA Cancer Center’s Lung Cancer Translational Research Team.  Dr. Le is an assistant professor in the Department of Thoracic/Head and Neck Medical Oncology in the Division of Internal Medicine at The University of Texas MD Anderson Cancer Center. Dr. Stiles is chief of thoracic surgery and surgical oncology at Montefiore and Albert Einstein College of Medicine. Dr. Velcheti is the director of thoracic medical oncology at New York University Langone’s Perlmutter Cancer Center. View disclosures for Dr. Gentzler, Dr. Le, Dr. Stiles, and Dr. Velcheti on Cancer.Net. Dr. Gentzler: Thank you, everyone, for joining us. We've got a great group here today, and we're really going to focus on talking about molecular testing in lung cancer. This is a very hot topic. My name is Ryan Gentzler from the University of Virginia. I'm a thoracic medical oncologist. We have Drs. Le, Stiles, and Velcheti with us today. I'd like them to go ahead and introduce themselves, starting with Dr. Le. Dr. Le: My name is Xiuning Le. I'm an assistant professor. I'm at the MD Anderson Cancer Center here in Houston, Texas. I'm also a medical oncologist. Thank you, Ryan, for inviting us today. Dr. Stiles: Hey, everybody. I'm Brendan Stiles. I'm a thoracic surgeon. I'm chief of thoracic surgery at Albert Einstein College of Medicine in Montefiore Health System here in the Bronx in New York. Dr. Gentzler: All right, thanks for joining us. And Dr. Velcheti. Dr. Velcheti: Thank you, Ryan. I'm Vamsidhar Velcheti. I'm the director of the thoracic oncology program at NYU. Dr. Gentzler: All right, great. We hear a lot of terms thrown around about molecular testing, genomic testing, biomarkers, oncogenic drivers, and I thought it would be good to just define what exactly is molecular testing, so all of our listeners are aware of what we're talking about. Dr. Le, do you want to take this question? Dr. Le: Yeah. So we have many terms, as you described. In my eyes, there are 2 sets of testing, and then some of them also classify into actionable versus not actionable. So for clinical use, we usually ask the tumor to be tested for both the mutations as well as the immune marker. Usually, the panel of mutational testing is more than a field. Usually, it's depending on the platform we're using, oftentimes in the hundreds of things. And then the immune markers, usually, we refer to PD-L1 and the tumor mutational burden. Those are the 2 commonly used markers now in the clinic. Some of those markers, especially the hundreds in gene testing, not all of them can lead to a clinical decision because we're still in the phase of understanding the interactions of different genes. However, there is a subgroup of those mutations. Nowadays, we have targeted therapy for, we call those actionable mutations. So in the clinic, we push for testing for a panel of mutations as well as immune markers, hoping to look at the tumor comprehensively so that we can recommend a good treatment regimen precise to that particular tumor, precise to that particular patient. Dr. Gentzler: Yeah. Wonderful. This has also been termed precision medicine, where we really match a therapy to a specific genomic abnormality identified on these tests and maybe, Dr. Velcheti, if you could maybe elaborate on some of the different ways that these tests are performed and how we're using these in clinic today? Dr. Velcheti: Yeah, definitely. I think our understanding of the biology of lung cancer has evolved quite dramatically over the past several years and obviously it’s led to a lot of advancements in terms of treatment opportunities for patients. Broadly, the way I look at biomarkers in lung cancer or, for that matter, any cancer, it's like you have biomarkers that actually kind of give us very deep insights into the biology of the cancer and giving us insights into how aggressive somebody's cancer is. Those are called prognostic biomarkers, kind of predicting outcome. And there are predictive biomarkers where there are certain biomarkers. If you do have some of these biomarkers in the tumor, then you could potentially use certain treatments that might work better for patients who have those biomarkers. So now we have a lot of different approaches in terms of how we kind of test for these biomarkers. Especially in lung cancer, now we have a lot of new therapeutics for certain genomically categorized types of lung cancer. And the challenge now is that we have so many different mutations we absolutely need that information to decide on treatment. So how do we test that? Until a few years ago, we've been doing a single gene testing. The problem with those approaches is that we have so many different genes we need to test and we kind of do sequential gene testing, a single gene testing, we won't get all the information we need to make the right decision for our patients. So the standard approach in most oncology practices, especially larger cancer centers and academic medical centers, is do comprehensive genomic profiling, and that's being widely accepted as a standard approach right now. Dr. Gentzler: Wonderful. And this has really been something that has fallen on the laps of thoracic medical oncologists as we've treated patients with advanced stage or stage 4 disease. And this is starting to become more and more important and relevant for surgeons. And Dr. Stiles, I just wanted to bring you into the conversation and see if this is something that, prior to some of the more recent data, which we'll discuss in a minute, is this something that as a surgeon, you've kept up with and think it's important in a surgical practice? Dr. Stiles: Yeah, definitely, Ryan. And I think now is probably the most exciting time for that, right? We used to just be sort of in the prognostic side, like Vamsi said, but now we really are in the predictive side in the early-stage disease. And I think that's why everybody is so excited. But that's why there's now this pressure about the timing of biomarker testing. What do you get? Do you get a whole panel? As we'll talk about some of the trials that have made their way into earlier stage disease, but it becomes inherent upon surgeons to really think about this and understand this, from the first time that they meet the patient I think, as we increasingly get better therapies in earlier stage disease. Dr. Gentzler: So as this has moved into earlier stage disease, a lot of this has been driven by some new data from clinical trials, and Dr. Velcheti, I thought maybe you could comment on the IMpower010 trial and its relevance and why molecular testing is important in the context of that trial. Dr. Velcheti: Yes, absolutely. I think the IMpower010 Trial is certainly a new shift in our approach to treating stage I, II curable non-small cell lung cancers. So we haven't had an approval in the adjuvant setting in a while. I mean, of course, we had approval with the osimertinib result of the ADAURA trial, but that's only for EGFR patients. Now we have approval for using immunotherapy in the postoperative adjuvant setting for patients with any level of PD-L1 expression. So this is a large randomized study looking at the role of adjuvant atezolizumab, which is a PD-L1 inhibitor in patients who have PD-L1 expression greater than 1%. Patients were randomized getting platinum doublet alone, which is a standard-of-care adjuvant assistant therapy for patients at stage I, II lung cancer. It is atezolizumab at a dose of 1,200 milligrams given every 3 weeks. Patients who received atezolizumab had significantly improved outcomes in disease-free survival. And the benefit was actually really striking for patients who had high PD-L1, patients with PD-L1 testing TPS score of greater than 50%. They had a really remarkable increase in terms of disease-free survival for those patients. So this is certainly very encouraging. And of course, we know it's now approved. We are still awaiting some overall survival results to mature. But given the extent of the benefits we're seeing with the disease-free survival, I think it's a very promising approach. Dr. Gentzler: Yeah, so obviously, immune therapy has had a tremendous benefit in the adjuvant setting from this trial and still some longer-term follow-up that's needed. But I think the important point here is that molecular testing may identify certain mutations that may make patients less likely to benefit or respond, or perhaps there's more appropriate treatments than immunotherapy within this group. And that brings us to the next trial that I think really shifted this discussion stage with the ADAURA trial. Maybe Dr. Le, if you could summarize this trial and give us your thoughts on why molecular testing is so important in the era of ADAURA. Dr. Le: Yeah. So ADAURA trial is also an adjuvant trial, meaning that the patient received additional treatment after the completion of surgery. So ADAURA trial looked at patients who have EGFR mutations. So it's a different biomarker. It's a gene biomarker, not the immune biomarker. So this is a large international trial, enrolled almost 700 patients and then randomized the patients after surgery, after standard chemo, the patient can go on to either receive 3 years of osimertinib, which is the standard-of-care therapy for EGFR mutant patients for metastatic setting, or the control group if the patient just received standard of care, which is to continue the monitoring. The trial actually showed that for people who had osimertinib before that prolonged time of 3 years, the risk of the disease coming back is almost 5 times lower than the patient who did not receive therapy. So based on that really striking benefit of after surgery, after chemotherapy, continue osimertinib in EGFR patients, FDA approved after the surgical resection and all the standard care patient can go on for osimertinib for a prolonged time, which we think currently the data is saying the disease is more likely not to come back. And hopefully, in the future, that result will translate into overall survival benefit. Dr. Gentzler: Okay, wonderful. And I think both of these trials, both the ADAURA and the IMpower010, are adjuvant trials. So these are trials that allow us adequate time to do molecular testing on a large surgical specimen, formulate our plans, and implement those plans up to a month or longer after surgery. Obviously, there's some new data that we've seen in a press release from the CheckMate 816 trial. This is a neoadjuvant trial of chemotherapy plus nivolumab. We've seen previous data from this trial showing some results, but this moves the conversation into the neoadjuvant space, and Dr. Stiles, I wonder if you could give us a summary of your thoughts on the CheckMate 816 and the relevance for molecular testing in that context of neoadjuvant therapy. Dr. Stiles: Yeah. Thanks, Ryan. I think, first of all, those are incredibly important adjuvant trials. I saw 2 patients each this week on adjuvant osimertinib and adjuvant atezo [atezolizumab], so it's real-life practice. Every day, it's going to benefit patients. But I think that's easy, like you said, these are big specimens that are taken out. You've got time to decide while the patient gets better. Now, we have to shift all this even earlier because CheckMate 816 really has some pretty impressive results. We, unfortunately, don't have the paper yet. I'm told it's going to be coming out soon, but the primary endpoint pathologic complete response 24% versus 2.2%. That's with chemo-nivo versus chemo alone. Obviously, people are questioning, does pathologic complete response correlate with outcomes? Certainly, we got a signal on a press release that the event-free survival is going to be the hazard ratio is 0.63, so it sounds like it does, and I think we'll see more data on that in the next couple of months. A difference in median event-free survival of 32 months versus 21 months in the report. So everybody is excited to see this. And I think it has some advantages over the adjuvant strategy. First of all, more patients are able to tolerate it. It's just 3 cycles, and so it's not given indeterminately for a year. And it worked across different subgroups. And we can talk about some of the nuances, but as where atezo [atezolizumab] was only looking good in the PD-L1-high. This sort of worked across different groups. The caveat to that is we don't really know what happens with these EGFR patients who are eligible and sort of, how do we then move that test? And all of a sudden, we've got to make a decision on neoadjuvant therapy. Now we need to know. It helps to know the PD-L1 maybe preoperatively, with the high PD-L1, maybe you could wait until adjuvant therapy, with the low to sort of medium PD-L1, maybe you want to give them their shot in the neoadjuvant space. But if they have an EGFR mutation, it's probably not the right thing. We don't really know the data on that and CheckMate 816 yet, but certainly, I'd be sort of hesitant to give them neoadjuvant chemoimmunotherapy. So then you have to teach surgeons all this too, and teach them to think about this and teach them to hold their horses on taking patients to the operating room while they wait for molecular testing. But that probably means we need to speed up the process somewhat either with sort of more rapid turnaround test, with consideration of liquid tests in some instances. It's just an incredibly fast-changing place that here we are speaking about a trial that hasn't even been published yet, so that tells you how fast things are happening. Dr. Gentzler: One last question. How can the results of these tests guide therapy after surgery? Do we incorporate a full NGS [next-generation sequencing] panel at the time of surgery? And we don't have data on adjuvant therapy for ALK or ROS1, or RET. Do we factor that into how we think about adjuvant chemotherapy, adjuvant immunotherapy, do we employ targeted therapies for some of these mutations? Any thoughts on that? Dr. Le: Ryan, I think you bring an important point in that EGFR is 1 of the 8 actionable mutations we have nowadays based on FDA and NCCN. The tumor biology between EGFR and ALK-fusion oncogenesis and potential response and benefits probably share some similarities. So we look forward to seeing trials reporting out the adjuvant setting with ALK inhibitors with ROS1. And the smaller target might require a multi-institutional or co-op group effort to really achieve the sample size for us to see. But as of now, we don't have the approval. We try to enroll patients to the oncogene trials, but I think currently we're practicing based on EGFR and PD-L1. Dr. Stiles: Yes, and I agree. I'm excited to see what comes out of some of those trials. They're slow to grow, but we'll eventually get some readouts. I think an interesting question sometimes is PD-L1. And we had an example recently where in the pre-op biopsy, the patient had a low PD-L1, and so not particularly enthusiastic. And the question sometimes arises, do you test that whole tumor to consider them as kind of an adjuvant to atezo [atezolizumab]and then the fully resected tumor, the PD-L1 was greater than 50%. And so I would sort of sound a caution that the small biopsy sample, they're incredibly helpful for many things, incredibly helpful for moleculars. It may not always be totally representative of the PD-L1 staining. Dr. Gentzler: And I think that's a good point. Even for molecular testing, sometimes if you have smaller biopsies, you may get a result that's negative, but it could be low levels of DNA and not sufficient to complete the full panel with high quality. So you really have to pay attention to the report and make sure that there's some confidence in the amount of DNA in some of these results. Well, I think that's all the time we have here, so I appreciate everyone's participation, and hopefully we're able to learn a little bit about genomic testing today. ASCO: Thank you, Dr. Gentzler, Dr. Le, Dr. Stiles, and Dr. Velcheti. Learn more about treating lung cancer at www.cancer.net/lung.  Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.