Role of Neoadjuvant Therapy in Resectable NSCLC

Dr. Zofia Piotrowska: I think the elephant in the room still is, what is- what do we do with neoadjuvant therapy? Is there a role here? And so, if you imagine, I think we've all started to have these discussions in the tumor board. You meet your patient, you send the testing appropriately on the initial biopsy. And so, before you even get to a decision about surgery, you know that the patient has an eGFR mutation. I think it's a really tough question as to what to do with those patients. But again, this year at ASCO, we actually did see a little bit of, I think, intriguing and thought-provoking data about the use of neoadjuvant Osimertinib. And maybe Luda, you can walk us through some of that.

Dr. Lyudmila Bazhenova: In neoadjuvant eGFR inhibition trials, we're just barely starting to scratch the surface. We have small studies. So, the one that was presented by Dr. Aredo was 20 plus patients neoadjuvant Osimertinib. And they were looking for pathological response rate. And the major pathological response rate was only 15%. And there are actually two other studies that were done prior to was NEOS trial as well as the emerging trial, which also looked at neoadjuvant Osimertinib and other TKIs. And I think what we learned from those three studies, again, all of them were small numbers. Number one, patients do respond to target therapy. Number two is, in some patients, we see notal clearance. Number three is, the major pathologic response and major- and complete pathologic response are nowhere near what we see in chemoimmunotherapy. So, the major pathologic response in those studies was in the order of 20, 15%. Many of the studies did not have a complete pathologic response. So, in my practice, outside of the clinical trial, I am not giving neoadjuvant tyrosine kinase inhibitors for any oncogenic-driven tumors. I think the way I kind of think about it, why are you giving it? If I'm giving it because the surgeon tells me that, if you don't give it, it's going to be a pneumonectomy. And what if now we can maybe do a lumpectomy? That's one question. For the second question, I'll be trying to improve the cure by giving neoadjuvant tyrosine kinase inhibitors. And we don't have the answer. We don't know. But certainly, one thing I know is, I'm not going to give them neoadjuvant chemo IO. And I think what I took from Dr. Aredo’s presentation is not mainly the efficacy data, but the tremendous ability to learn about resistance to target therapy. And they found two potential biomarkers. Again, for a small number of patients, we need more studies. But they found that at the time of completion of neoadjuvant Osimertinib, they saw patients who had increased expression in YAP, and patients who had an increased expression in RBM10 tended to cluster in the population of patients who didn't respond. So, I think this is what we gain from those studies. We can learn more about why other patients became resistant, and what's the persistent cells. And then, using that information, try to design studies on the neoadjuvant Osimertinib. But I think the NeoADAURA study is very important. So NeoADAURA study is ongoing, it's randomized phase III. You can give neoadjuvant osi for one arm, osi plus chemo for a second arm, and chemotherapy by itself. And they have endpoints of major pathologic response, pathologic complete response, DFS, and OS. And I think the study we'll learn a little bit more than we have known now from the small neoadjuvant trials.

Dr. Zofia Piotrowska: I think it was thought-provoking data, but I agree, small numbers and still so much to learn. Jay, I'm curious, because I think this is often a conversation between the oncologist and the surgeon to try to figure out what is the best approach. So, I'd be curious to hear your thoughts.

Dr. Jay Moon Lee: So, I think at the current time, it's not standard of care to give neoadjuvant Osimertinib, although we need to. We need that. We need that data, particularly stage three patients, and stage two patients where you're thinking about neoadjuvant therapies. And it's complicated by the fact that the FDA approvals for CheckMate 816 don’t necessarily mandate that you're eGFR ALK-negative. In Asia, it was required to be tested, but in the rest of the world, it wasn't tested in 816. When KEYNOTE-671 was performed, there was no standard of care for these perioperative trials where eGFR now- There was no ADUARA data. So, they were included in 671- in KEYNOTE-671. And then in GN with the perioperative IO trials, it was excluded both eGFR and ALK. So, it isn't because there's necessarily efficacy in the eGFR ALK population from the vast majority of data that we know from the late-stage setting, it's just we didn't have that man- that mandate to exclude them. So, it creates confusion in this field. But we do need that regimen and management setting mainly so that we can get patients as an alternative to the chemo IO. And we just fall back on what we- what we've already been doing, which is neoadjuvant chemotherapy alone. Which is what we've been practicing for many years. We want more than just chemo alone. The other thing I'll say is that the path regression data is more complicated amongst TKIs. It's not the same meaning as in chemo or IO. And we have to remember that the trials like NeoADAURA, yes, the adjuvant portion is standard of care, but the standard of care for eGFR mutated patients is three years of osi. So, in NeoADAURA, all of those arms are getting adjuvant osi. So, for the path regression data, we shouldn't expect that the path regression data is going to have a one-to-one relationship to the EFS or DFS, or OS data because it's a combination of both. So, the relevance of the- of the preoperative path regression data is less meaningful in the path- in the perioperative trials.

Dr. Zofia Piotrowska: Such an important point. We have to think about these therapies differently. I completely agree.

Dr. Gustavo Cumbo-Nacheli: And if I may add, the importance of providing them with the patient in order to do the trials you need for neoadjuvant is to capture data upfront whenever you do the first biopsy. Unfortunately, on a large scale in the country, the pulmonologist or the radiologists mostly send for non-small cell. But it's very important to have some sort of reflexive testing, at least at the biopsy. The first point where there is a thoracentesis and EBUS, lung biopsy by any means to same eGFR, to PD-L1, to save more multi-genes or expansive genetic foundation once for the time of resection has been the practice of my colleagues. So, it's very important that we as a community, whether it's a diagnostician or whether it's the surgeon or the oncologist, understand that we have to think harder about capturing more patients that could be tested, optimizing the diagnostic that we are going to do, improve the therapeutics and accelerate recovery. That's the only way we are going to be able to get to DFS and OS. Otherwise, if we don't start at the very beginning getting this information, by the time the oncologist sees a two or a three, he already passed a month to two. And we may already have moved from one stage to the other. So, let's think about this upfront, provide them with what they need, and let's see about that OS.

Dr. Zofia Piotrowska: Such an important point. Absolutely.