So I'm gonna talk about peri operative as well as adjuvant treatment of early stage lung cancer. And certainly this is uh uh this uh treatment area has changed rapidly over the past couple of years. These are my disclosures. This is the current FDA approved uh regimens in this space. Uh We have neoadjuvant therapy, adjuvant therapy as well as perioperative therapy and just this past week, nivolumab plus chemotherapy um followed by surgery and then adjuvant novo was approved. So again, I've never seen something change so rapidly and this is great to see, but it's like holy cow, what do we do? So for advent uh immunotherapy trials, we have two regimens that are approved for use. One is a tab for patients with stage two and three, a disease after resection. Who whose disease is PDL one positive uh based on the Empire 010 Study. Now, pembrolizumab is approved in this space as well uh for patients regardless of PDL one status. Um and we'll get into the differences of these two trials and the differences in the approval. These are the two trials uh side by side. As you can see here, the primary endpoints were slightly different on how they were designed. But disease free survival was the primary endpoint. One trial required cis platinum containing chemotherapy with uh uh power uh 0 10 study. And then in the keynote 091 study, uh chemotherapy was recommended um and carboplatinum was allowed. So a little bit more real world uh in our clinic. So disease free survival um was positive for these trials. Um uh particularly for the patient, for this trial, for the Empower or Talum trial, particularly for those patients with stage two and three A disease that um their disease was PDL one positive. And and certainly you can see here, the curves were significantly different for the keynote 091 study or pembrolizumab. The disease free survival curve was also significantly better if these patients receive pembrolizumab. But this was regardless of PDL one status. Now, overall survival while um uh not exactly the primary endpoint. But you can see here uh for the Empire 010 study and the keynote study, if you took all the patients, uh there was really no significant difference in overall survival. But you can see here in those patients with PDL one positive disease, the overall survival was uh significantly improved with the TESI. Uh And uh then, interestingly, this year, Doctor Philippe um presented a five year update on the Talab uh trial. And you can see here definitely the benefit was improved if you had uh the disease had a higher PDL one status. You can see here the differences between the two groups PDL one positive and then the PDL one greater than 50%. And you can see here the risk of recurrence was significantly less if you received a Talab compared to those patients who did not. And that again, that trend improved if your um disease was PDL one high. So what about neoadjuvant or perative studies? I'm gonna focus on the Perative studies because later on, I get to debate neoadjuvant therapy versus advent. Um but we have now three regimens that are approved for use. Both the uh pembrolizumab plus chemotherapy followed by surgery and then advent pembrolizumab, we have derval nab plus chemotherapy followed by surgery and then advent Valium. A and then the newest kid on the block, the nivolumab plus chemotherapy followed by surgery and then adjuvant nivolumab. And the differences in the diff the trials were some uh the primary endpoint was event free survival. Some of the trials uh also looked at complete pathologic response, which I'll show you some data uh as well. And again, these are some of the differences between the trials. I think I'd look at the bottom. Um uh row. The concern is when you're adding immunotherapy before or after surgery. What about increased toxicity compared to chemotherapy? And really, there wasn't that much difference in the percentage of patients who actually had grade three or higher uh toxicities and the, also the concern was if you give this type of therapy before surgery versus a, as well as after surgery, what about long term risk of, of death? And they really didn't see significant differences. The only trial that you saw a slight increase in grade three was the, uh, the keynote trial off to the far, right at the bottom, there was a slight increase of grade three through four toxicities compared to just chemotherapy or the other arm. Um But um not really that significant. What about just looking at the patient trials? It's like how do you decide which, which combination to use? You can see here the uh checkmate trials with Novo AAB really this uh they had a high percentage of patients with uh stage three disease and about 5050 of patients who had PDL one positive disease. Now, the Aegean trial with Valium A or the keynote trial with pembrolizumab, these patients were more likely to be have PDL one positive disease, uh 60% or greater. Um And uh in this trial, maybe these trials may be a little bit higher percentage of patients with stage three disease. Now, what about the outcomes? Again? This is a little small but you can see the check uh checkmate trials with nivolumab, the event free survival at two years was very similar. Um And in the neoadjuvant trial, you can see here that was just three cycles or nine weeks of neoadjuvant where the other trials had uh four cycles or 12 weeks of Neo Avent. Again, you can see the differences here. But really the twoyear event free survival was very similar across all of these regiments. So again, it's great to see consistency. But based on this data, I can't really tell which uh combination to use over, over another just to drill down a little bit. So the keynote uh study with pembrolizumab in the Per op op setting, this was the only trial that was designed to look at overall survival as well. And this was the only trial that had showed so far in overall survival uh difference. And obviously, this was one of the primary end points. But again, you're seeing consistent improvements in pathologic complete response improvements in event free survival. And in this particular trial is a significant improvement in overall survival. So what about using pathologic complete response? Do all these people need adjuvant therapy? I think that's some of the biggest questions right now out there. And certainly the FDA wants to know as well. What about the contributions of the adjuvant component? You know, that's the question, do all of these patients? And if you just look at the neoadjuvant study, checkmate 816 with which had nine weeks of neoadjuvant therapy. Again, we have about 20 to 25% of patients achieving a pathologic complete response across these trials. And in this trial, it was almost 25% and you can see those patients who actually had achieved a pathologic complete response at the time of surgery did extremely well, both in event free survival and overall survival. Compared to those patients whose disease did not achieve a pathologic complete response. Now, that group of patients were lumping together 100% residual uh viable tumor versus is 10% residual viable tumor. So I think we need more research in this area as well to be able to parse out, you know how much is enough uh killing. And we know that some of the the these effects of the immunotherapy do take some time as well. But I think those patients who actually have a pathologic complete response, I question, do we really need adjuvant therapy? So do look, look at this a little bit differently. Again, for pathologic complete response, the three year event free survival is greater than 90%. And over 95% of these patients are alive at three years without adjuvant therapy. So what about perioperative? It does seem to be more effective than IO at least based on the hazard ratios. Again, you can't uh completely compare this uh because we're uh discussing two different disease free survival versus an event free survival. Um But if you just look at uh just a time at the on the curve, they're very similar. So what about Pertti versus neoadjuvant therapy? Again, that question about advent therapy. And again, if you look at the hazard ratio here there. Uh It does seem that Pertti might be a little bit better but very similar. But we really need the anvil study, which we're waiting for these results of just adjuvant Nevo. So it would be great to be able to look at these different um uh curves as well as these patient populations in order to really drill down. What do you need neoadjuvant per op or adjuvant. So, but uh my colleague, Dr Ford did try to do this in trying to pull this uh two studies, the checkmate 816 as well as the checkmate uh 77 T studies. Again, the perry in the checkmate 77 T versus the neoadjuvant therapy. And this analysis did get a lot of uh uh flack back. But I think it gives us a window of uh what might be working in the adjuvant setting. So this analysis only took those patients who made it to surgery, ok. And then uh looked at event free survival. And it did seem that those patients who receive per op therapy seem to do better. You can see here the hazard ratio compared to those patients who only received neoadjuvant therapy. But if you look at the patients who received pathologic complete response, who achieved that versus those patients who did not, it didn't seem there was that much difference bet between those patients who uh achieved that pathologic complete response. They had a very good event, free survival. And maybe they don't need adjuvant therapy. But for those patients who did not achieve a pathologic response, these patients seem to benefit from the addition of that per op or adjuvant therapy compared to those patients who only uh had neoadjuvant NovoLIN plus chemotherapy. So this kind of in my mind gives me an idea when I'm sitting in front of a patient. If, if they have achieved a pathologic complete response, I'm much less likely to push, push a adjuvant therapy. I mean, yes, you could ar argue, hey, those patients, you know, it worked. And so maybe they do need just kind of a a boost uh after surgery with the adjuvant therapy. But I don't think so. But again, time will tell. But for those patients whose disease does not achieve a patho pathologic response, I'm much more likely to push them into adjuvant therapy. Um But um again, we still don't know what about those patients who absolutely had no response, 100% viable tumor at the time uh of surgery. That's where, where we really need um money to figure out what is that best treatment afterwards. So I'm not sure if I've helped to push you one way versus another. So I feel like I'm a kid in the candy store. You know, there are a lot of different options. Now in the early stage setting, I used to just use the slide for metastatic setting but now I get to use it in early stage and there's so many choices. But I think obviously the easy things when we're sitting in front of the patient to decide Neo Advent therapy per therapy, adjuvant therapy. First is looking at all these trials did exclude most of these, most of these trials did exclude patients with EGFR and ALC the Advent Therapy uh did not uh for the keynote study. But uh again, based on a lot of metastatic uh studies where these patients do not benefit from uh immunotherapy. I think knowing that uh upfront and excluding those patients from neo avent or adjuvant immunotherapy would be important. Again, the question, those patients who are in front of us with stage one disease, obviously, they're going to go to surgery. I would not offer them uh neoadjuvant therapy. Uh Sometimes obviously, like we just talked about some of these patients. Uh at the time of surgery, we we find occult uh un unknown uh nodal disease and then we would uh recommend adjuvant therapy there. Um And certainly if they have lymph node of involvement before, when you're seeing them before surgery, I do believe having uh giving them neoadjuvant therapy is of of benefit. And then obviously, if a patient uh in my mind, if they have achieved a pathologic complete response in the neoadjuvant setting at the time of surgery, I don't tend to push them into adjuvant therapy. Uh But certainly those patients who do not. We have a serious conversation. And it's been interesting to me, even in the adjuvant setting, I've had more patients refuse immunotherapy than chemotherapy. Which is weird to me. But I do think some of these longer term toxicities with adjuvant therapy or, or immunotherapy in general is, does make these patients pause um about this. So, and I've had some patients who have developed long term toxicities that are life altering. they're manageable, but they certainly are. Uh yeah, do may require treatment long term. So and then then lastly even uh just the patient preference like I just talked about and then the overall health, um obviously, immunotherapy is very in general easy to tolerate. But certainly we uh some of the patients who have borderline performance status, they may not be going to surgery anyway. But those patients who just get into surgery, we do have to think about how well are they to uh receive this type of therapy. So, thank you so much. And I hope I made it a little bit clearer, but we have so many options um to pick from in the in the early stage disease. Now that I truly feel that this field has moved a one step forward. Thank you.
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