Chapters Transcript Video Early Stage Disease: Adjuvant and Neoadjuvant - Updated Data Thank you, Haas. Um pleasure to be here. I was at Fox Chase uh from 87 to 008, finished my fellowship there, um. So half the oncologists in the room either were my fellows or they're my grandfellows if they've been, uh, uh, trained by HAS or others that I trained, so new term, um, I think I was given 15 minutes but that's OK. I'll try to get it done in 10, uh, so, uh, checkpoint inhibitors and resectable non-small cell. This is a very busy field. Uh, my disclosures the last 10 years historically, uh, cisplatinum-based chemo has been our standard, uh, adjuvant treatment. Um, modest but significant, I'd argue clinically meaningful, 5.4% improvement, five years, uh, um, multiple studies, the lace meta-analysis, nice plateau in the survival curve. The benefit's been largely confined to N1 N2 disease and larger, uh, and zero tumors, 4 centimeters or larger, uh, based on retrospective studies. Here is the landscape, uh. Uh, for, uh, immunotherapy in the resectable setting, and it's, uh, rapidly expanding, uh, obviously the success that we're gonna hear about from Doctor Blaz and Borgay, uh, later in metastatic disease needs to be exported to this setting. So, um, adjuvant approaches where we've seen modest improvements in EFS, no survival benefit. Um, the Empire 110 trial, which, uh, mandated, uh, chemotherapy, uh, upfront and optional chemo in the keynote 091 BR 31, the only pure neoadjuvant trial, uh, checkmate 816, which really led the way, uh, in that area, and then finally the per adjuvant approach neo plus adjuvant, so sort of a sandwich around resection with multiple, uh, trials all reading out virtually all of them, uh, positive. Um, for adjuvant we have two hits and a miss. Um, keynote, uh, Empower 110 was the, uh, lead, uh, trial. It's only 4 years ago that this was presented. It seems like at least a decade, uh, looking at Otezlalizumab for up to a year versus best supportive care and, uh, patients who had undergone resection and got, uh, cisplatinum-based adjuvant chemo. The chemo is mandated, uh, a hierarchical, uh, primary endpoint looking at DFS, uh, in. Uh, first, those who are PDL1 positive of stage, uh, 2 or 3 disease, then all randomized stage 2 or 3 patients, and finally the intent to treat population, and this study was positive but only for that first group which is, uh, really led to the FDA approval just three years ago. Uh, you see a hazard ratio of 0.66, about a 12% absolute improvement. In, uh, progression for your disease-free survival, uh, at 3 years, nice separation of the curves. The other two groups, uh, although the, uh, hazard ratios look pretty good, at least by the statistical standards applied, uh, did not make, uh, uh, that end point. Um, keynote 091, basically the same trial but with Pembroke for up to a year. Chemo in this case was optional though the majority received it. You can see the stratification factors. Uh, primary, they were due primary endpoints. The overall population, those were 50% or higher PDL1 expression, and ironically that group actually had, uh, lesser, uh, benefit that has a ratio in. Uh, the high PDL1 group was 0.82 compared to 0.76 for the entire population. The P value is not significant. We've been very puzzled by this because historically in metastatic disease, Pembrose seems to have its greatest benefit in high PDL1. It's been speculated that the, uh, uh, control group overperformed in, uh, the placebo arm, uh, with high PDL1, but, uh, again that's still not completely clear. And then our miss BR 31, nobody hears about this one. Same study with uh durvalumab, uh, again, uh, uh, 1B through 3A, uh, primary endpoint was disease-free survival. You can see all the stratifications, uh, uh, placebo control, um, nice MRD analysis which we'll talk about shortly. Uh, these are the overall survival curves. You can't shine light. I can't get my laser pointer through any of these curves, and the same applies for EFS. So for whatever reason, Derva failing in this setting. So what about moving it to the front line? So a lot of rationale for neoadjuvant. It's better tolerated pre-op, uh, we have predictive biomarker data can be obtained pre-treatment. Immunotherapy is probably more effective with the tumor in situ rather than post resection, at least our theory. Uh, no time for clonal evolution, so we have more homogeneous, uh, tumors, uh, potential opportunity for lesser lung resections. You can actually have an in vivo assessment of, uh, treatment efficacy. Uh, pathologic data in turn can help, uh, predict both prognosis and potentially guide post-op treatment, which is the mainstay of some ongoing trials and of course the immediate application of systemic treatment in cancer where the risk of systemic recurrence is quite high, metastatic disease by and large governs, uh, survival here. So the first study was the Nadeem effort from the Iberian. Peninsula, uh, Provencio has really led the way. This was a nested trial in resectable 3A. Nevo plus Pat Carbo, note 3 cycles, uh, 91% resection rate, uh, nearly unbelievable, uh, major pathologic response, 74%, over 50% with PA CR. A lot of us were quite skeptical. Could it ever be this good? Well, it was good but not that good. So this led to, uh, two. Um, uh, neoadjuvant trials. Nadeem 2 is actually peradjuvant because he gave, uh, Nevo out back for six, months, uh, after neoadjuvant, uh, uh, Nadeem 1 Nevo Pat Carbo, um, checkmate 816 is the only pure neoadjuvant trial and looking at Nevo, uh, with, uh, histology appropriate chemo versus chemo alone again, three cycles followed by surgery. Uh, you can see the eligibility criteria very similar to the adjuvant trials on every major endpoint. The, the, uh, these trials were positive. So if we look at, um, major pathologic response, pathologic complete response, event free survival, major advantages, hazard ratios of, uh, 0.63 for the, uh, checkmate 816 when it comes to EFS, and a nice trend at least for, uh, survival in these, uh, trials. Uh, here are the, uh, path response data for 816 again, profound responses, a fair number that, uh, uh, actually showed, uh, PCRs in the primary tumor. You have the PCR rate rising from 2% in the control to 24% on the interventional arm and the MPR rate going from 9% to 37%. Um, more complete resections, fewer pneumonectomies in that arm, so theoretically more tumor kill, greater, uh, resection rates, more lung sparing resections. I don't know if this is, uh, translated for Doctor Sue and others, uh, but, uh, at least, uh, fewer pneumonectomies. When we look at event-free survival now with somewhat more, um, mature data, um, we can see about, uh, 11 month, uh, difference, and the benefits are particularly pronounced in those with higher PDL1 levels, so 50% or higher. Uh, uh, uh, has a ratio down to 0.24. The greatest benefits in those with, uh, higher stage disease 3A disease and also higher PDL1. So, uh, the 1% or higher group, uh, about a 26% advantage of two years for those that, uh, don't have, uh. Uh, PDL one expression, you can argue perhaps that this is not really beneficial. Uh, Pat Ford has, uh, updated the data from, uh, 816, uh, just this year in New England Journal, and we now have OS data with a 10% absolute advantage again has a ratio of 0.72 and a P value that just squeaks by under 0.05. Once more, greater benefit, uh, relatively speaking, particularly in the high PDL1 population. Well, that's neoadjuvant. The vast majority of these, uh, studies have really been. Periadjuvant, uh, the Aegean trials phase 3 effort looking at DUV, uh, and chemo followed by adjuvant Derva presented just 2.5 years ago at AACR by John Haymmack. So the study design is shown here, um, demonstrated again a statistically significant. I'd argue clinically meaningful improvement in path CR and event-free survival here again of this PPCR and MPR figures, uh, you see a tripling in MPR, about a 4-fold improvement in path CR rates. And that is translated into an EFS advantage of an 11% increase, uh, with a hazard ratio of 0.68 and, uh, lots of zeros in that uh P value with nice separation of the curves I call those fishtail survival curves. You don't want a banana shaped survival curve. You wanna see more separation over time and again this has been updated by John at Worldlung just last year. EFS and EFS advantages persisting. Uh, OS doesn't quite make it, at least not yet. Uh, some separation beyond 4 to 5 years has a ratio of hovers 0.89. Lung cancer specific survival does. I question that because that does not include the potential latent toxicities that perhaps the combined modality is improved, but at least if you just look at lung cancer as a cause of death, it's a benefit. Keynote 671, uh, a bit different. Uh, this is Pembro with chemo. But cisplatinum-based chemo confined to stage 2 and 3, so no 1B's here. Same design though, neoadjuvant and then Pembroke out back with placebo control. Again, uh, majority of patients here were actually 3A, some 3B's squeaking in about 70%, even distribution of PDL1 status, 50% or higher, 1 to 49 and less than 1. Same pattern, major benefit for both NPR and PCR. You see the, um, uh, PCR rates settling in between sort of 17% and 25% in these trials. This is striking 22% absolute uh improvement in EFS at 2 years, and this is, uh, now been updated again. The uh higher PDL1 level seemed to, uh, garner greater benefit with the hazard ratio of 0.42. Uh, Heather, uh, presented this, uh, I believe just a couple weeks ago at ESMO. We now have 5 year overall survival, uh, with 11% absolute advantage. This was the first study to actually show an OS advantage in the neo or peradjuvant setting with a hazard ratio of 0.74, and this is seen in every subgroup. Uh, of course, EFS is also an advantage has doubled, uh, from 26% to nearly 50% with every subgroup benefiting. Note that the control arm does at least cross over to PD1 based treatments about 50% of the time at progression, only about 21% in the Pembroke group so uh just two years ago. This was approved. It feels like it was five years ago, but it's a, uh, relatively recent. And finally, uh, 770 phase three study comparing neoadjuvant Nevo plus chemo with, uh, additional adjuvant Nemo outback. So basically it's the, um, Aegean or uh 671 version of 816. So we're adding the Nevo onto, uh 816. Um, difference here, uh, 4 cycles instead of the three cycles that were used in 816 again, placebo control here EFS, uh, by Bicker, uh, was the primary endpoint. Uh, no surprise it was positive, has a ratio of 0.61, and 18% improvement, a year and a half, 2.5 years again, the high PDL1 group garnering a relatively greater benefit. Stage three patients also garnering a relative benefit. OS not quite there. Same pattern we've seen before. Hazard ratios overlap unity. The, uh, hazard ratio, uh, the confidence intervals overlap unity. The hazard ratio is 0.85. Lung cancer specific survival, though again, uh, greater separation with has a ratio of 0.6. Um, do we need four cycles? My argument is no. If you look at 816 and 77, basically the same drugs, the only difference is the, uh. Uh, use of, uh, um, the Nuvo Outback, so same induction regimen, the PCR rates here identical at 25%. A lot of open questions. I have only 3 minutes left, so I'll address some of these, but not all. Uh, which approach is preferable, adjuvant or neoadjuvant? I think that while there are studies that are looking at this, we have clearly moved into the neo and peradjuvant realm. Uh, survival differences are quite pronounced. If you look at EFS hazard ratios for adjuvant, it's about 0.8. For the neo or peradjuvant trials, generally 0.63 or less, and the survival differences when they're documented or confined to the neo and peradjuvant overall survival in keynote 091 and in power at 110 or 010, uh, were not significant. Here are the curves for those two absolutely no difference in long terms. So you could have really argued you. In the absence of an OS benefit with modest PFS or EFS benefit, should we be using these drugs in the adjunct, and perhaps we'll discuss that during the, uh, um, uh, moderated session. 816, you see a separation in survival, uh, it was significant. Keynote 671 again significant nice separation at about 3 years. A trial I didn't talk about from China, Neotorch with topalimab in a largely squamous population also showing a positive trend. Are there patients in the adjuvant setting who can benefit? Well, um, the high PDL1 group certainly does seem to garner, a potential, uh, uh, both DFS and OS benefit. You see about 25% improvement in DFS at 3 years, has a ratio of 0.43, and that is the one group where I think we see a, uh, potential survival advantage, about 17% absolute improvement at 5 years. Um, this is the, uh, what I call the diamond in the rough, uh, BR 31, remember, was a negative trial for DUV, but they did look at MRD. This was a tumor informed whole exome sequencing of resection samples, uh, to look at variants for circulating tumor DNA, and then. Uh, that was re-assayed prospectively over the course of the, uh, the trial. Uh, it was prognostic. Certainly those with MRD, uh, with the circulating tumor DNA do poorly, as you'd expect. Major separation curves for, uh, all comers and particularly for those with PDL1 positivity. But what we didn't expect, this is about 10% of the population, they actually benefited from DEA. If you look at the, uh, hazard ratio for 1%, PDL1 or higher. The hazard ratio is 0.49 for those 25% or higher, it was down to 0.30, although the, um, if you look at all comers it wasn't significant. Can we enhance outcome in the adjuvant setting? Well, this is in a deem adjuvant setting again just presented at uh uh ESO, uh, looking at not just adjuvant after platinum but concurrent Nevo with, uh, chemotherapy. So, uh, versus, uh, just chemotherapy alone. An underpowered trial you see about a 14% improvement in uh disease uh free survival with a hazard ratio of 0.65, pretty impressive, but unfortunately the P value is 0.085. You need more patience to actually prove this. Um, we are currently looking at this in the alchemist, uh, trial, uh, chemo IO concurrently Pembro with platinum followed by Pembro versus just Pembro, uh, adjuvant. And uh there's the InterPath 002 trial looking at um mRNA vaccine plus Pembro versus placebo again in the uh uh adjuvant setting. Are there patients uh who received uh neoadjuvant chemo checkpoint inhibitors uh for whom we don't really need to continue the checkpoint inhibitor, for instance those with past CR as well. Um, this is a, uh, highly, uh, controversial, uh, exploratory analysis of checkmate 772 and 816. Remember, the only difference here was Nevo Outback versus just Neoadjuvant. Uh, and this compared outcomes, uh, for those who got, uh, at least one dose of Nvo, uh, in the, uh, 770 trial suggests a benefit for the perioperative approach as opposed to neoadjuvant approach that really should have looked at all comers, not just those who received it. Um, nevertheless, the adopt lung ETO study is directly comparing this in all comers, uh, Derva plus chemo up front followed by surgery and then randomization. To Derva Outback versus observation with stratifications based on past CR, uh, uh, stage and PDL1 status, probably the group that we really need to focus on are those with past CRs. You look at outcome here, uh, from the Nadeem trial, for instance, 96% 5 year survival. It's very hard to improve on that. And then Check made 816 very similar data. In fact, amongst those who had a past CR with Nevo chemo, uh, none of the deaths that occurred were due to disease, so. Uh, the swab trial, it's an intergroup trial. It's open now. It's available to all of us, is directly looking at DERV versus surveillance after, uh, PACR. Can we enhance outcomes in those who don't have PACR MPR? Again, um, the more, uh, residual tumor you have in this path specimen, the more likely you're gonna have a poorer outcome, and this is proportionate based on, uh, tumor viability. Uh, the AGan trial looked at circulating tumor DNA and the absence of PCR, and you can see they had the worst prognosis of the group. So can we do trials that will enhance the outcome? This is an InterPath 009 that's looking again at mRNA, uh, vaccine in combination with Pembroke versus Pembro alone in the, uh, 671 setting. And then, uh, TRU 019 looking at a, uh, ADC cecetuzumab terriotecan again in the same, uh, setting. Uh, Neocoast is moving those drugs up front. Basically this is PC 9, but in the neoadjuvant setting, so monolizumab, lectumab, probably the drug that looks most promising is the Dato DXD. Uh, here are the data for each of those arms. Uh, this has actually been the randomized phase two, and, uh, you see a benefit potentially for, uh, Dato DXD regardless of PDL1 status across the board. Uh, Doctor Kumar has already covered this, and I think Doctor Sue will cover this as well, aspirational patients, uh, just one, comment. This is a retrospective selected cohort study by Doctor Rudi looking at patients who are borderline resectable, unresectable, so folks with T4 disease, N2 or N3 involvement. Remarkably, after neoadjuvant chemo IO, the resection rate in this group was 75%, the PCR rate 29%, the MPR rate 42%. Uh, needless to say, those with high TMB or high PDL1 seem to benefit the most. Uh, Doctor Kumar covered MTB Bridge. Finally, what happens to those who do not make it to surgery? This is not a small group. Across the board, a consistent theme, about, uh, 18 to 27%. Do not go to surgery, a variety of reasons progression AEs. The other includes patient decision, physician decision, consent withdrawal. I suspect some of these folks were aspirationally resectable but didn't make it. We need to really figure that out. Uh, they don't do well, so without definitive surgery, uh, unfortunately all, all those curves lead to the bottom. Uh, so, uh, these are not the same patients necessarily as the Pack one, crowd. So, um. Well, I think receptibility is best determined prior to starting treatment by the operating surgeon and most importantly as part of the multidisciplinary team. So we'll end here. Adjuvant Otezo confers a clear PFS advantage in stage 2 and 3A PDL1 positive post resection, and those with a PDL 150% or higher may actually have an OS advantage. Pembro, uh, yields similar benefits. It's approved across the board regarding, regardless of PDL1 or stage status. Durva in the same setting has failed. We have neoadjuvant peradjuvant trials with a variety of drugs Nvo, Otezo, Pembro, torapalimab, uh, all of which have, uh, conferred clear PCR, MPR, and EFS advantages, and now survival advantages. Can we escalate in those who have less than PCR? Those trials are ongoing, and can we de-escalate in those with past CRs? And finally, do we really need a phase 3 trial comparing new adjuvant to, uh, uh, adjuvant, uh, MRD biocarlas will be the secret to figuring all of this out. Thank you. Created by Related Presenters Corey Langer, MD Professor of Medicine (Hematology-Oncology), Penn Medicine's Abramson Cancer Center
