AEGEAN Study - FDA Approval of Durvalumab in Resectable Non-Small Cell Lung Cancer

Intro Welcome back to another episode of the Oncology Brothers podcast. I'm Raul Ghosain here with my brother and Co host Rohit Ghosain. Today we have an exciting discussion lined up for you focusing on the recent approval of dirvalumab in the periop and post op settings for non small cell lung cancer based off Asian trial. This trial was also hot topic with FDA ODAC recently Joining us to cover this recent approval, we have Doctor Sandeep Patel, a medical oncologist from UCSD and Doctor Mara Antonov, a thoracic surgeon from MD Anderson. Mara Sandeep, welcome. Speaker 2 Thank you so much for having us. Speaker 3 Sandeep and Mara, thanks so much for joining us. To set the stage, we'll talk about a bit where in adjuvant setting there is modest survival benefit from addition of chemotherapy. To extend that further, different approaches have been tried whether that's with neoadjuvant IO in combination with chemo or adjuvant IO with chemo and the recent talk has been periop. One of those studies is AGENT trial with durvalumab Sundeep. Study Design of AGENT Trial Could you start us off with giving us a bit of an overview of the study design of AGENT trial and how is this exactly any different than KEYNOTE 671 with pembrolizumab? Speaker 4 I think it's a it's a great point. And so to take a step back, these are intended for curative intent patients. So patients when you meet them that they could potentially go for resection. We do not yet know for patients who are borderline resectable what the best approach is though at the current time if they're not resectable, concurrent chemo radiation followed by your durvalumab, the specific approach represents a standard of care. And so for those patients that are deemed resectable both based on host factors, how fit they are for surgery, which Mara can describe in more detail, but also tumor factors, these patients have a couple options in the in the curative intense setting, you can give all the therapy up front. That's a pure neoadjuvant approach that Checkmate 816, that's three cycles of chemo IO with Nibola MAP followed by surgery, no therapy afterwards. You can give the therapy after surgery and you referred to this earlier in the adjuvant setting these that's a tessalizumab for PDL one greater than 1% and with the greatest benefit greater than 50%. That's the I am Power 10 study, the Pearl study with pembrolizumab which showed some interesting PDL 1 strata, but potential benefit even for PDL and negative. And So what about the sandwich approach treatment before and after surgery. That's the perioperative approach and you nicely summarize the KEYNOTE 671 study which looks at chemotherapy and pembrolizumab. There's an overall survival benefit to this approach. It's typically with a cisplatin based regimen and get KEYNOTE 671. The way the study was done was cisplatin pebatrexid for non squamous and cisplatin gemcitabine with pembrolizumab for squamous. Now the Aegean study is a perioperative approach so you get treatment before and after. And I think one of the couple important things, one these patients are acceptable, 2, they do not have an EGFR or alkali arrangement and three is you don't actually need to check PDL one status for any of these approaches. Even patients with PDL 10 could potentially benefit and so in this study patients got 4 cycles of platinum based chemotherapy. Dealer's choice. You could use Carboplat, you can use CIS plat and you can use your preferred doublet. Partner with Durvalivab for four cycles, followed by surgery, followed by a year of Durvalivab afterwards at the primary endpoints being pathologic, complete response rate and event free survival. Speaker 1 So they thank you so much for laying that foundation because as you've mentioned, now we have a few options be a Keynote 671, AGN, Checkmate 816 or even moving forward with surgery and then looking into adjuvant space. However, we're leaning more and more to this periop post op settings, not just in lung cancer, actually breast cancer recently ESMO, we saw a similar paradigm in bladder cancer. And in all these settings often it's our surgery colleagues that see the patients 1st. And it's important for us to rely on multi D approach here. Mara, from surgical perspective, can you touch a little on the importance of disapproval in this evolving space of periopsystemic treatment? The importance of disapproval in this evolving space of periop systemic treatment Yeah, absolutely. You know, I think the importance of this approval is just the recognition that we have another tool in our tool belt, another regimen to add to our armamentarium. I think, you know what we are discovering more and more is certainly that we know that neoadjuvant therapy is extremely beneficial to patients at earlier and earlier stages of disease than we may have previously thought. And you know that that brings to to point that this is just something that we surgeons need to recognize. And I agree with you that in many circumstances, it is the surgeon who's seeing them first. And depending on the healthcare system, there may be situations where there may be some reluctance or some barriers or obstacles to the patients getting seen for the needed neoadjuvant therapy. And ultimately, I think really that the burden and the onus is on us, the surgical community, to educate our peers to make sure that patients are getting the multidisciplinary care that they need. This approval of of the Aegean regimen is obviously incredibly important, but as you said, it adds to a number of other regimens that we already have in place and things that we've already seen through other trials. And now we have options involving pembrolizumab or nivolumab or dirvalumab. And I think our use of adjuvant alone using a tizelizumab, I think we're tending these that only more in situations where patients are upstage at the time of surgery. Perhaps we think it's someone where surgery alone might be curative and they may not need any systemic therapy. And then we have occult nodal disease or something, an satellite lesion that changes the two status, something that results in an upstaging and end up meeting it afterwards. But in terms of getting patients appropriate preoperative evaluation to ensure that they get helpful neoadjuvant therapy upfront as well as making sure that they get appropriate molecular profiling and our candidates, it's for adjuvant therapy as it may be appropriate. Again, I do think the burden is on us as as surgeons and I, I think it's time for surgeons to step up and start taking responsibility for that. I'm incredibly privileged to work in a place where I get to be a super specialized oncologic thoracic surgeon and take care of lung cancer patients 100% of the time. But there are certainly plenty of folks who are in practices where they do need to take care of a wider range of patients. And it is on us as surgeons to educate our peers to make sure they understand the importance of the multidisciplinary discussion, of making sure patients get their full molecular profiling, staging, evaluation, everything that they need to do. And, you know, it wasn't that many years ago that we were having to convince people, don't take people to surgery until you stage the mediastinum. Now it's just adding to that list that people need to have molecular profiling, they need to have multidisciplinary discussion. And I think part of that is emphasizing the importance, but also highlighting the data that we have. And I don't know if we're going to discuss it, but on trials such as AGN that, that tell us that the patients don't get to surgery less frequently when they receive immunotherapy. We see in the in the arms of the study that the patients who receive chemotherapy are actually often times those who receive chemo and and placebo are less likely to make it to surgery than those who receive the the chemo with with the immunotherapy. So obviously we know we lose some patients to surgery for any new adjuvant therapy and that's kind of the nature of the beast. But ultimately it's, it's weighing that the long term oncologic risks with the short term perioperative risks and and trying to to do right for our patients. Speaker 3 Cannot emphasize the importance of multidisciplinary approach. Multidisciplinary approach Yes, as you stated Maura that you're lucky to be practicing in a in a specialized setting and same thing for Sundeep and same thing for Rahul and I. However, there is good amount of population which still practices in rural settings as a community oncologist where they do send these patients out to surgery colleagues. But it is important for these surgery colleagues to circle back and move ahead with just further evaluation of where perioperative or neoadjuvant approach will benefit these patients. On our end, before committing this to anyone to this strategy, it is important to ensure that there are no targetable mutations where they would in fact qualify for any adjuvant approach there where immunotherapy should not be utilized. OK, so the So what did the exactly study show Sir? What did the study show? So we we saw a benefit to invent free survival. The overall survival is still immature for patients that receive the durveilumab both pre op as well as post op compared to those who received chemotherapy alone. And I think the Rothel's point, this is actually something we've seen in other tumor types Melanoma probably most famously that having some of the immunotherapy given while the tumor is still in the body has a pseudo vaccination like effect. And so that's why we're seeing some of the the differences. I think there's still a question on neoadjuvant versus perioperative. There was a recent data for more lung a patient level analysis that suggested patients who are PDL 1 less than 1%, for example, may benefit more from a full perioperative approach. But I think we're not going to have any trials that that really make these comparisons anytime soon. And so that analysis I think is important. I think here we see that patients get a benefit in terms of event free survival and we're looking forward with a hazard ratio of 0.68, which is quite robust. I think one point to consider is this is curative intent treatment, right? The goal of the use of the immunotherapy here is to cure patients and it's to maximize that that curative intent window. And so we see a clinically significant P value here. I think overall survival, which is the gold standard end point in curative intent studies, is something we're eagerly waiting data to see. Speaker 1 Absolutely. These results are promising. This whole idea of sandwich approach looks good. We still continue to question how much is the post op immunotherapy buying us, but again, hopefully we'll have longer and more data to appreciate that. But coming back to itching, we saw that the event free survival or PCR, we saw this benefit in early Stage 2A, but even also in Stage 3B. So Mara, coming back from the surgical perspective, you touched on this, we're not compromising the number of patients that are going for surgery with us. Post-op surgery Can you touch a little more from that surgery perspective when you're talking to your patients or at that tumor board? What does this really look like when we're talking about be it dirvalumab or this periop post op approach? Speaker 2 I would be remiss to tell you that the operations are the same when patients are are operated on in a virgin chest compared to a patient who has had any type of systemic therapy. I will also be 100% transparent with my extreme bias, which is that I happen to have a specific niche in operating on patients who have stage 4 disease and have received extensive therapy. And so this is a place where I feel comfortable and I think this is a difficult conversation. But ultimately it is, is my belief based on data that we have even in the era where most patients got cytotoxic chemotherapy that the extent of response to systemic therapy regardless of the drug impacts the extent of hylar fibrosis. I firmly believe that to be the case and that when a patient responds extremely well to the treatment they've received, regardless of whether that is chemotherapy, whether it's pembrolizumab, nivolumab, whether it's osumertinib, whatever the drug is that a patient who's had a phenomenal response that they are going to have greater scarring, fibrosis, sclerotic lymph nodes, it becomes technically challenging. Lymph nodes that are previously positive and shrink down dramatically will bring the outer layers of the very fragile vessels with them into that scar. And that requires a greater level of precision, a greater level of awareness of the structures, envisioning planes that are no longer there. It's challenging and it's tricky and it's hard and I would be inaccurate to tell you that these operations don't require a different level of technical complexity. But in terms of the safety Ness and whether or not they can be done and getting the patients through them is a whole separate thing. I think we need to stop thinking about surgical complexity in terms of what is the operative duration and what is the blood loss because an experienced talented team who can do right by the patient can get a very challenging case done in a reasonable amount of time with minimal blood loss. But if we're looking at the nuances of the operation and the extent of hylar fibrosis, how challenging it is, yes, it may be harder. But this is my plea to surgeons. If the reason that it is harder is because the patient has had an outstanding response to the systemic therapy that they received, that translates into longer event free survival and longer overall survival and better quality of life and everything better for the patient. Speaker 3 Well, thanks so much for summarizing that, Maura Sundeep, with regards to from the community standpoint or even from academic standpoint. Choosing the right chemotherapy regimen for your patient Now we have 3 options available in this sandwich approach or rather neoadjuvant versus adjuvant. Checkmate 816 with Nivola Mab and neoadjuvant. Keynote 671 with pembrolism agent with Durvala Mab and a tisolismab In adjuvant setting. How are you deciding which approach to go with? Any particular nuances for us to keep in mind, whether one should consider one over the other PDL, one expression or CDCTDNA positivity or anything like that? Speaker 4 Yeah, and it's a great question. So the honest answer is there is no exact answer. We're all kind of flying blind. And and you know, it's the paradox of choice. Sometimes when you have too many good options, it feels like you don't have any. But in fact, we're getting the best outcomes in the curative intense setting, like Mara, nicely summarized. And so the surgical difficulty is on another level. The regimen picking difficulty really is a discussion with the patient. I have some patients, they live 2 hours away. They have APDL 1 score at 80%. Their TMB is in the 99th percentile, their lymph node negative, right, or maybe N1 lymph node. I'm very confident with three cycles of chemo nivo, right, based on that and based on what they want to do and you know based on their goals, other patients maybe N 2 positive, maybe close to bulky, maybe a large primary as well. PDL one 1% zero right, low TMB. That's a patient. I maybe think about perioperative approach and at least based on the individual level data from 816 and 77 T that is presented by Pat forward. It's not a randomized comparison, but it's the only data that we have. It also depends on the patients. Some patients, you know, listen doc, I'm going to go through surgery. You're going to ask me to do a year of therapy after doing months of therapy before. That's just not for me. And, and, and I think if they get a Pat CR, that's actually a very reasonable point, right? If they get complete eradication of the tumor, some will say, listen, I'm going to do everything possible to keep this cancer at Bay. I don't care about the side effects. They may both biologically and socially want a perioperative approach. And if you want to, you know, buy the book, use carboplatin. Aegean is one way of doing that right? Cisplatin plus pemotrexin system side to be very reasonable regimens, but maybe you don't want to use that, though the FDA label does give you some complexity. I think many of us are purists in how we interpret the trials. And so I, I, I think it's good to have these options. It gives patients the flexibility we may eventually write for patients in non pat CR in great radiation, right? And folks are familiar, right, with Pacific and drvalumab, right? And so I think these are the building blocks for what the future curative intent care would be. But I think 2 points that I'd like to make is I think amongst, you know, three medical oncologists and a surgeon here having these discussions is hugely important. But we won't get these patients if the primary care doctors aren't ordering low dose CT to screen for patients to find localized cancer. And then secondarily, our colleagues, often in pulmonary, interventional pulmonary who are doing the mediastinal assessment, right, because if someone has multi station positive disease, they're not resectable after discussion with your surgical colleague, then they need to see your friendly neighborhood radiation oncologist, right? For, for a different approach. And so getting all the this information, it really is, it really is a Sprint now, right? It used to be much easier. You got the nodes, you're good. Now you got to understand resectability, understand the host factors, understand the tumor factors and you got to get them to the right specialist and, and the cancer's not taking a time out while we're doing this. And so it really just goes to the point that these kinds of discussions that are multidisciplinary, picking up the phone, calling your your specialist is so important. Speaker 1 A few things to reiterate, Cindy, you brought up SYS versus CARBO and leaning towards CARBO if you're going to use AGN. Historically in the community settings for good or for worse, we have relied more on CARBA. We know that specially in curative settings, the data is stronger with CIS, but our community oncologist continue to be more find comfort with carboplatin. So in that scenario maybe Checkmate 816 or Agen. But coming back to what you reiterated, lung screening continues to diagnose these patients early and early and that's very critical. And with these approaches, our goal is our patients are living longer and longer. So this is very exciting. Mara, just before we close, any thought for you, for our community oncologist surgeons or community surgeons that are seeing these patients day in, day out? Community Oncology Yeah. You know, I, I just think we can't over emphasize the importance of multidisciplinary discussion, but also having humility and seeking perspectives from colleagues as well as we're learning to implement all of these different regimens and figuring out, you know, can we use three cycles of something that was studied with four cycles? Can we add a, add an adjuvant regimen to something that was only studied in the neo adjuvant realm? There are a lot of questions and we aren't going to be able to answer them all with the data that we have. But the importance of being able to talk to colleagues and to trust one another and to really put the the best interests of the patient in terms of understanding, you know, what the wealth of information and knowledge that our community has. So I think putting the patient perspectives, their quality of life metrics, and our own own humility all in check, all of those elements will really hopefully get us to the right endpoint. Speaker 1 Sandeep Mara, thank you both for these invaluable insights. For our listeners, let's go over a quick recap. Conclusion In today's discussion with doctor Sandeep Patel, a medical oncologist and Dr. Mara Antonov, a thoracic surgeon, we had a chance to focus on the recent approval of their valumab in periop and post op settings for resectable non small cell lung cancer based off HN trial. This study showed improved pathological complete response and event free survival. However, it remains unclear which patient is deriving the most amount of benefit from additional immunotherapy in the post sub settings. Speaker 3 As we shift towards more perioperative and post operative treatments for resectable non small cell lung cancer, a multidisciplinary approach becomes essential. Early referral to medical oncology by our surgical oncology colleagues prior to surgical intervention is in fact the key. Additionally, selecting the right patients and ensuring upfront NGS testing for actionable mutations is critical. Thank you for joining us. Stay tuned for more discussions on recent approvals and practice changing data. We are the oncology brothers.