Chapters Transcript Video Early Stage Disease: Adjuvant and Neoadjuvant in Driver Positive Disease Thank you, everyone. Uh, I must confess actually, many of my prior colleagues masterfully covered many of the slides that I'm about to show here. So in the interest of time, I'm just gonna forewarn you, I'm gonna go fairly quickly. All right, so I'll be talking about early-stage driver-positive disease, uh, neoadjuvant and adjuvant approaches, my disclosures. So, again, as we've discussed, perioperative therapies with checkpoint inhibitors in particular have really kind of become, um, largely the standard of care. However, there's also certain target agents we also use, um, largely in the adjuvant setting. In particular, EJF Row. These are all listed in NCCN guidelines. The thing I wanna highlight just at the very top and something I think we've already kind of discussed, but I wanna kinda re-emphasize is, you know, we always think about in this context of metastatic or stage 4 disease, the importance of molecular testing. But now more than ever, it's really important that we get the exact, that same molecular testing for patients with early stage disease, not only to assess PDL1 status, but in particular to look for particular oncogenes. That we think might not respond well to chemo immunotherapy, in particular, things like EGFR, uh, and ALC. And so again, the importance of molecular testing, efficient molecular testing is also an important thing because certainly we don't want to delay the time to potentially get to definitive treatments running all of our, uh, tests. And there, there's a nice figure here that I actually borrowed from some of our colleagues, um, from Penn. They recently had. A nice review publication about this exact same topic and made this very nice figure and they talk about in particular the importance of molecular testing up front and they kind of make these two flow diagrams and what I wanna emphasize here again is that if there is an EGFRALK mutation that's something we need to confirm whether or not the tumor in fact does have that you do not wanna be giving perioperative kind of immuno chemotherapy type approaches to those patients. Is there a role for liquid biopsy? Certainly, liquid biopsy has a significant role in the stage 4 setting as far as a complement to kind of our tissue-based testing. I know it's come up in the past where people have said, oh well, can't you send a liquid biopsy if there's not enough tissue based off of the, uh, the original biopsy? Uh, that is not exactly true when, especially when it comes with early stage disease, there's probably less circulating tumor DNA. I certainly would not hang my hat on a negative liquid biopsy result as a way of determining. That there is no EGFR or ALCA mutation in early stage disease. So again, the importance of tissue-based testing, especially in early stage disease, is of utmost importance. We've already talked about at least twice, if not 3 times, the Dora trial, so I won't go too much into that. Uh, the significant disease-free survival benefit, also an OS benefit. Certainly we all recognize that there is controversy in regards to the control arm, which many of those patients didn't necessarily have access to osimerib at the time of progression, which may have kind of skewed the results a bit. Alina study, also something that we've kind of already discussed. In brief, this was a similar type of study looking at the targeted therapy ectinib in the adjuvant setting. However, something I do kinda wanna uh show that is a difference, unlike the Odura study where most patients they get chemotherapy first and then went on either to osciertinib versus placebo, this was a randomization 1 to 1 to either alectinib. Versus chemotherapy and rather than the 3 years that was mandated with ossamerib and the Alina trial, it's 2 years with electinib and also I wanna say is there's nothing magic about these numbers of 3 years versus 2 years. I mean, these are what were selected for clinical trials and as we know there's other clinical trials that are forthcoming looking at longer durations of treatment. Um, in regards to the Alino study, as was previous, previously. discussed significant disease-free survival benefit. Again, I wanna highlight the CNS benefit, which I think is a critical component because certainly we all know with these driver uh mutated cancers, there is that greater propensity for CNS, uh, metastases, and I think that's really one of the key benefits of doing these targeted therapies in the adjuvant setting is the fact that it does gain better CNS control for these patients. This was a recent update at ESO. Again, kind of showing more mature, longer-term follow-up, showing that significant disease-free survival benefit. They started to show some uh OS data as well. And as you can see, there's not much splitting of the curves here, at least thus far. I mean, it's still relatively early data. I mean, if anything, what this really shows is that our targeted therapies, especially in the AK-driven space, seem to work really. Well, even among those patients who just got chemotherapy in the adjuvant setting, had relapse, and then went on to a drug like alectinib. Unlike the Adura study, a significant percentage of patients did in fact get alectinib. It was like 60, 65% did get alectinib. They're in the post-progression setting. The vast majority of the other patients did get uh TKI as well at progression. Um, and then just a couple of questions that remain. I know many of these we've kind of already touched on, but the duration of TKI, I think that's a bit of an unknown at this point. There are studies forthcoming looking at longer durations of TKI in this context. Me personally, I know this is a point of controversy, but whether or not we're actually curing these patients, I think this is something very distinct and different from patients who get chemo immunotherapy. I think a lot of those patients, especially those with PTCRs. are in fact uh cured of their disease, but in the context of driver-driven disease like EGFR and ALC, I'm not necessarily convinced that we're curing these patients with the additional adjuvant therapy. So certainly more work in this space uh needs to be done. And then another thing that I think, uh, is a point that I think we discussed a fair amount is the role of adjuvant chemotherapy for patients with the EGFR and ALC-driven disease. Do they actually need it? I know within my own practice. I do still give the adjuvant chemotherapy, especially those with EGFR disease and also AC disease. I do tend to also favor giving the chemotherapy unless there's a really good reason why a patient cannot receive it, um, largely because we do have, you know, long-term, it's been kind of the tried and true established OS benefit, albeit modest, but OS benefit nonetheless of giving adjuvant chemotherapy, um, at post resection. And then as far as neoadjuvant approaches, I know we've discussed this, the NeoDora trial again. Um, you, the primary, uh, endpoint was major pathological response. So that's not the same thing as you guys know, as, as complete response. You know, we saw about 24, 25% in the awesome metum containing arms as compared to chemotherapy alone. Very, very small percentage, 5, 6% actually had a complete response. And whether or not this actually translates into a meaningful disease-free survival benefit or subsequent OS benefit is, is, is yet to be seen. Other trials for other driver, uh, driven cancers, uh, these, I've, uh, we've also kind of touched on. This is for the ALC rearranged disease trials that were just, uh, very recently, uh, um, uh, presented. You know, the data here actually looks a little bit better than as compared to EJFR. You can see, um, uh, a higher, um, major pathological response, uh, of, of 60% in the Nautica A1 trial. These were just, but the caveat is, it's a small number of patients, just 330. Three patients with ALC rearranged disease, uh, 60%, uh, MPR rate, and then as far as PT CR it was 25%. Again, the big caveat is this is a small number of patients, uh, um, uh, 26% had, uh, nodal downstaging. And then another trial, uh, a NIO trial, this was done, uh, in Italy, phase two study also looking at a small number of 33 patients with stage 3 alkyre arranged disease, um, uh, 42% with major pathological response, about 12% with, uh, path CR. And then as this slide, uh, again is, um, uh, uh, that uh shows tables that were, uh, borrowed from our colleagues at, at Penn's review, uh, article which was very nicely done. I highly recommend it. It was just published just to. Earlier this year, um, in the ASCO Education book and just really kind of represents the flurry of activity in this space, not only in EGFR and ALC but also driver mutations including things that we see more in smokers like KRRSG12C but as well as other kind of oncogenes that we see more in the never to light smokers like RET mutations or RET rearrangements, uh, trials in that space as well. All right, well, thank you very much. Created by Related Presenters J. Nicholas Bodor, MD, PhD, MPH Assistant Professor, Department of Hematology/Oncology, Fox Chase Cancer Center
