What Did We Learn From IMpower010 in Resectable NSCLC?
At the recent virtual American Society of Clinical Oncology annual meeting, results of the phase III IMpower010 trial demonstrated that adjuvant atezolizumab (Tecentriq) for patients with stage IB to IIIA non-small cell lung cancer (NSCLC) improved disease-free survival in patients with high PD-L1 expression. In this first of four exclusive episodes, MedPage Today brought together three leaders in the field -- moderator Vinay Prasad, MD, of the University of California San Francisco, is joined by Chul Kim, MD, of Georgetown University and MedStar Health in Washington, D.C., and Andrae Vandross, MD, of NEXT Oncology in San Antonio and Austin -- for a roundtable discussion on the goals of adjuvant therapy in the setting of NSCLC, the landscape of treatments, and how the IMpower010 trial might affect their decision-making. Following is a transcript of their remarks:  Prasad: I'm joined back here in the studios at MedPage Today by Dr. Chul Kim from Georgetown University. He is an assistant professor and a specialist in lung cancer. And I'm joined by Andrae Vandross. Dr. Vandross is a hem/onc physician in Texas at NEXT Oncology and he is an expert in solid tumors. Dr. Kim and Dr. Vandross, it's a pleasure to speak with you both. Kim: Thank you. Vandross: Nice to be here. Prasad: I wanted to talk about adjuvant treatment in lung cancer. I wonder if you might get us started, Dr. Kim. Kim: The goal of adjuvant chemotherapy or adjuvant therapy in the setting of resectable or resected non-small cell lung cancer is to increase the cure rate, so that means we should aim for improvement in overall survival in general. That's how the adjuvant chemotherapy in non-small cell lung cancer has been approved based on the studies, including the LACE meta-analysis published now more than 10 years ago showing overall survival benefit if used in a couple of cycles of platinum-based chemotherapy. That is our goal to cure patients. Prasad: That's really well put. When it comes to adjuvant treatments in lung cancer, we've surgically removed the tumor, we see no evidence on any scan of any cancer, but we know it's going to recur in a large fraction, and our goal is to increase the curative fraction. Vandross: It's really important. It's individualized. Each patient is going to come to me with different ideas about what to expect when they are getting a treatment. I know one expectation is, especially if their cancer is surgically removed, that they want sort of an insurance policy that the cancer will not come back and that they are going to be living longer. One of the things that I ask them to consider is obviously the data that supports offering the adjuvant chemotherapy to begin with and then whatever their personal preferences are, because there are certain scenarios in which adjuvant therapy is actually a large part important for the patient to weigh in on whether they desire it or not. I present all the information that is relevant to their particular case. I ask them to think a lot about how they want to spend their time. Those are things that I can easily talk about with a patient when helping them decide whether adjuvant therapy is right for them, specifically in the context in which it's not clear that the adjuvant therapy has a distinctive benefit. Prasad: Dr. Kim, I'm working my way to the study we're going to talk about today, IMpower010. But if you were to think about the landscape of adjuvant treatments in lung cancer over the last 15 years, you look over at our colleagues in breast oncology and it seems like every year they got a new drug. They got another one, another one, another one. Adjuvant treatment is always changing. You've got to find the newest guidelines. Kim: That is true. In lung cancer -- I think each field is different in how they view disease-free survival or other surrogate endpoints -- in lung cancer, traditionally when we look at the adjuvant chemotherapy trials and the time analysis, our focus was on overall survival. That has been the most valid endpoint for patients. But nowadays we have newer drugs, targeted therapy and immunotherapy that are being assessed in different clinical trials. The landscape has changed quite a bit and is evolving rapidly in this field. Prasad: Yeah, that's well put. Before we jump into this study, maybe one last question for you, Dr. Vandross. I wonder if you might talk about disease-free survival. If a patient says, "Dr. Vandross, what is disease-free survival?" Vandross: Well, part of it is that it's in the name. And letting them know that the disease-free survival is something along the lines of the fact that they are going to be living their lives normally and being able to do the things that they like doing, and that's going to be done without the cancer being present in their body -- which you can get more nuanced than that, but that's simply how I try to lay it out, at least at the beginning. Prasad: Yeah, that's really well put. I think that's something that we have to remind ourselves in oncology all the time, disease-free survival at the time until something bad happens. One of those things is the cancer comes back. The other thing is that the patient passes away. God forbid that happens. Cancer coming back in these studies is typically measured by we find it on a radiograph, we biopsy, and we prove that it's cancer. Sometimes a patient feels that site of metastasis, but not always in these studies. Then I think Dr. Kim makes the excellent point that the goal in lung cancer is we've never taken our sight off the prize, which is we need to increase overall survival. That is really the goal. When you see overall survival curves plateau and the treatment sort of reaches a higher plateau, the difference in the plateau, that's the increased cure to fraction. It isn't just a median increase in overall survival. We want to see that plateau be higher as well. We are really aspiring for cure. Dr. Kim: Yes. This is a study that assessed the role of adjuvant atezolizumab, which is anti-PD-L1 antibody therapy. The treatment was given to patients who had surgical resection and they had disease stage between IB and IIIA. All of them received cisplatin-based chemotherapy, various regimens depending on your histology, and then the patient went on to receive atezolizumab for about a year. There are a couple of different endpoints in this study. The primary endpoint was disease-free survival, the endpoint we just discussed, and the secondary endpoint was overall survival. They used this hierarchical sort of testing and that overall survival is sort of the last endpoint they're going to assess. The data is premature, but what the study has shown was that the use of adjuvant atezolizumab after you're done with the surgery in adjuvant chemotherapy, that increased the ... there was benefit in terms of disease-free survival. That was the main point of the trial. There are different subgroups. They looked at PD-L1-positive. They also looked at all patients who received the treatment and also focusing on stage I, II, through to IIIA and also looking at IB to IIIA. There are different endpoints. The study design was a little complex in terms of how they assessed the statistical endpoints, but that was the main takeaway point of the study conclusion. Prasad: That's a great summary. It seems like the breast oncologists have rubbed off on us a little bit because we're using disease-free survival [DFS] now in lung cancer and that's going to create some of the dialogue around this trial. But you did a great job, I think, summarizing what was really complex, which is a lot of nested and adjacent subgroups that you're going to see a lot of data on. You're going to see does it work in [stages] II to IIIA. You're going to see a lot of these sort of analyses. Some are significant. Some are on the verge of significance, dare we say. I don't doubt that will be as significant. There is a lot to unpack there, so we'll get into it in a second. You see lung cancer among other cancers. You've gotten comfortable with checkpoint inhibitors. Now they're moving the checkpoint inhibitor way upfront and they are telling you that it looks like we're getting a DFS signal. Vandross: Well, there are a couple of ways that I can think about it, and in fact I do think about it. One is that, as you noted, there are times in which, or at least you alluded to, sometimes you want more options. Well, not sometimes -- you definitely need more options with people with cancer. Then there are certain cancer types obviously that have more need than others at a particular point in time. It's always nice to see that there is some information that we can glean from a clinical trial, especially in the phase III setting. The other thing that came to mind is, especially for patients when they are trying to evaluate whether they should do something like adjuvant therapy -- again, it's this issue with the disease-free survival and what it really means in that context. Because, again, I keep focusing on the fact that when a patient comes to me, or comes to us, the thing that is either said or it's implied is that we're going to be helping them live longer. This surrogate endpoint doesn't signal that. If I'm going to be able to talk to a patient about what this new information means, I'm not going to be able to say that it helps them live longer. Plus, I don't know if I'm jumping the gun, but the other thing I think about is some of the adverse events that may be associated with adjuvant therapy and whether that would be right for the patient, especially given that we're administering this medication in the hopes that the cancer won't come back. Prasad: Yeah, that's a great point. That although we become familiar with and comfortable with managing the immune-related adverse events, this is a treatment that necessarily you're going to give to some people who are not going to relapse either way. That's the truth of adjuvant therapy. Kim: Yes. I totally agree with Dr. Vandross. There are certain toxicities you need to worry about because some patients might have been cured and then we know that immunotherapy-related side effects can happen even after you stop the treatments. So it's important to follow the patient long-term to make sure there are no untoward side effects that will reduce their chances or impair their well-being, or impair their survival. Overall survival data from IMpower010 is immature at this time, but it is a very important endpoint to follow, although there was a secondary endpoint in the clinical trial. Prasad: All right now, gentlemen, I'm going to get into my beef with this study. I'll get into my beef. This is a beef I have with a lot of these studies. So many of these studies irritate me in this way, which is here's how they present their analyses. They say, "Let's look at everyone with a PD-L1 over 50." And if you look at those people with PD-L1 standing over 50, you know that they tend to be exquisitely sensitive to checkpoint inhibitors and their hazard ratio is exquisite. It's 0.43 for DFS. It's really, really good. To be honest, within over 50, there is still a dichotomization that could happen. There is 50 to 79. Then there is 80 to 100 or 90 to 100. I bet 90 to 100 it's really looking good. We're talking maybe ADAURA-like hazard ratios in 90 to 100. But you lump all those together, fine. That's fair. Fine. You lump over 50. Then the next thing you tell me is over 1. But over 1 includes over 50, so over 1 is 0.66 hazard ratio, a little less impressive than over 50. They don't give it to you that way. Then, of course, under 1 they do give you and that's a 0.97 hazard ratio. It looks quite null in that group. I put all these numbers together and I calculate under 50, and under 50 I get a hazard ratio of 0.93, which I suspect would probably be null. I don't know that to be true because I don't have access to the dataset. I guess my question here is, what we see with this study, what we see with KEYNOTE-048, what we would see with a number of studies with checkpoint inhibitors, is what I call a nested subgroup. They take the first subgroup of the people you really think benefit. Then they add that subgroup to the second subgroup and they add it to the third subgroup. They are using the group with the greatest benefit to potentially drive the whole trial. But as the doctor, who is interested in the right drug for the right patient at the right time, you want to know the outcome for a patient with your PD-L1. Kim: Right. It is relevant to look at these subgroups and see whether the overall survival really pans out in each subgroup. I mean, roughly it's a really continuous variable when we talk of PD-L1, but we think about greater than 50% or 1-49% and less than 1%. In the advanced non-small cell lung cancer setting, we have a couple of trials as you mentioned, Dr. Prasad. For example, there is a KEYNOTE-042 where they assessed pembrolizumab in patients with PD-L1 expression of at least 1% and metastatic non-small cell lung cancer. The benefit was driven by those who had a PD-L1 expression that was 50%. When you looked at the 1% to 49% subgroup, there was no overall survival benefit when you use pembrolizumab over chemotherapy. I think there are similar analyses we need to do in this sort of adjuvant atezolizumab setting and to know which group or subgroups would benefit from this treatment. I think that's an important point. Prasad: Yeah, that's a great point. I even think over 50 is still more categories in there. There is a nice paper by Aguilar and colleagues in Annals of Oncology where they look at response rate in the 90 to 100% versus 90 to 50%, and it is different. Vandross: I mean, I can't disagree with what you're saying, because especially in the context of wanting to actually have a personalized approach to this because it's something that can actually ... if we can tease out those types of things. If there are three different subsets and we know the likelihood of response-based on those three subsets, or four subsets, or whatever they are going to be, we are in fact going to be able to specifically speak to an individual patient, go through the trial data, and show them a graph, show them what category that their lung cancer fits in. Then we're going to look at their results and we're going to say, "You have a high likelihood of responding to this therapy; therefore I am in favor of recommending it to you," and let them digest that information. It will be that collaborative effort that we can all feel more comfortable about making these recommendations. Prasad: That's well put. Then the next thing I want to know about this study, that maybe we'll get with the manuscript, is the rate of PD-L1 therapy upon metastatic presentation of disease. We know right now the standard of care in all our practice is that we use these drugs quite liberally in non-small cell lung cancer. There are people with exquisitely high PD-L1 stains that we might use pembrolizumab only. We use a lot of pembrolizumab chemotherapy. I think the question here is, disease-free survival, that first endpoint, that's not going to be affected by subsequent lines of therapy. That's really only affected by what happens on protocol. But subsequent endpoints like the time to the second progression or overall survival, those are affected by subsequent lines of therapy. What you really want to see is that giving this drug upfront to all these people improves overall survival, as Dr. Kim put it, compared with what we're doing right now, which is if you have de novo metastatic disease, you're going to get pembrolizumab. I hope that this trial reports the rate of administration of IO [immuno-oncology] among people who present with relapse disease. I think that will be telling. Kim: Yeah, I agree. I mean, this, I believe, was a global trial. The access to PD-L1 therapy may not be universal in this study. I have to look into the manuscript once it's out. Yeah, I agree with you fully that the evaluation of post-progression therapy and how they might have affected the clinical trial results is another consideration we need to all think about. Prasad: I think one of the challenges with global trials is that unfortunately some places around the globe don't have the same resources to commit to cancer care as we do in the United States. I don't fault them for that. That's a reality of their situation. But the challenge with the trial is that if the trial is positive, it doesn't help those nations because they can't afford the drug, because they couldn't afford it at the outset in the control arm for people who progress. If the trial is positive, it doesn't really inform the U.S. because they're not using post-protocol therapy consistent with U.S. standard of care. Well, it seems to inform pocketbooks, is what it looks like to me. We hear a lot of buzz this last year about medicine by press release. You're getting fed these little bits, these factoids of information. Vandross: In general, I would say that it doesn't change practice tomorrow, my practice. I'll speak for myself. It doesn't change my practice for tomorrow. We have already learned a recent lesson with regards to accelerated approval, that things can change as more patients are put on study, longer-term evaluation, we get the answer that we are supposed to be looking for. We want to be able to recommend to our patients therapies that are extending their lives and helping them to maintain or improve their quality of life based on the impact that the cancer has. Therefore, I would feel more comfortable making recommendations with a little bit more mature data. Kim: If atezolizumab were to be approved by FDA ... I'm not sure, of course. It's possible based on the data. I am using the accelerated approval pathway. Then I will discuss the treatment with the patients. However, I will tell them, "This is the data. This is the benefit in terms of disease-free survival." I have to explain to them what that means. "But yet we don't know whether that will improve how long you're going to live or whether that will positively impact your quality of life because we don't have data yet." However, I will discuss with the patients the treatment options and then also look at their individual characteristics. In those subsets of patients, it's less likely that the immunotherapy will sort of cure the disease. Based on the data we know in adjuvant setting, their immunotherapy in EGFR or ALK is a pretty low objective response rate. I will take into account all those considerations and patient goals. Some patients really don't want to get therapy. I mean, some patients even like chemotherapy. Some patients will like surgery, although we recommend it. I think it comes down to individual patient-doctor discussions at the end of the day. Prasad: That's well put. Dr. Kim and Dr. Vandross, thank you so much for doing this.