The New Frontier in NSCLC: Immuno-Oncology Combinations - Episode 13
Mark A. Socinski, MD: Ben, we’ve recently seen some exciting data on a small number of patients, but these are some interesting data. Could you summarize that for us?
Benjamin P. Levy, MD: Yes. There’s been some nice work looking at the role of single-agent nivolumab in surgically resectable patients—stage 1, 2, and 3. This trial looked at small numbers—20 patients. Every patient got just 2 doses of nivolumab followed by surgery. Importantly, there were no new safety signals in this early-stage setting, and it didn’t delay surgery.
They looked at an endpoint that is, perhaps, underrepresented in the literature, which is major pathological response. This is defined as less than 10% viable tumor cells on the specimen. And in the trial, 9 of the 20 patients had a major pathological response. There have been some data that suggest that major pathological response correlates with overall survival.
Not surprisingly, patients who had major pathological response were more likely to have a higher mutation burden when they were treated. Also, those patients who achieved a major pathological response were more likely to have T-cell clonal elaboration in both the blood and tissue. I think this is thought-provoking. Again, this looked at a very small number of patients. It’s interesting to see. It will be interesting to see, compared with chemotherapy, what the difference in major pathological response would be. Nevertheless, I think it needs to lead to further trials to better understand, in a larger patient population, if this is really meaningful. I think the translational aspects of the trial are interesting, in looking at T-cell clonal expansion elicited by these drugs and how that was found more commonly in these patients who achieved major pathological response. But clearly, this is a small number. I’m stating the obvious. We need larger data sets to better validate what we’re seeing here.
Mark A. Socinski, MD: Including safety in the set.
Benjamin P. Levy, MD: Including safety, yes. Overall, we didn’t see anything new. But nevertheless, I think we need to see a larger group of patients get studied.
Mark A. Socinski, MD: Yes, and there are a number of perioperative, particularly adjuvant trials ongoing now. Does anyone have any thoughts or predictions? Dr. Langer, what are your predictions?
Corey J. Langer, MD, FACP: I want to make a comment about this induction nivolumab trial. It’s tantalizing. This is not unique. Back 10, 20, 30 years ago, we were looking at chemotherapy in the same setting as induction when some of these chemotherapy regimens were new. We observed major pathologic responses. It certainly didn’t make it to the New England Journal of Medicine.
I think it’s important, exploratory. It’s important from a scientific standpoint, particularly to look at how T cells aggregate and perhaps predict who might benefit, post operatively, in the context of the adjuvant setting. But I would certainly emphasize the need to properly enroll on these adjuvant trials. The one that’s currently available in North America is the ALCHEMIST/ANVIL trial. Patients had their tumor sent for central testing. If they had an EGFR mutation, they go on to, at least for now, erlotinib versus observation—originally, placebo. ALK—they go on to crizotinib versus observation. Those arms, unfortunately, haven’t been accruing all that well.
Karen Kelly, MD: They are getting better.
Corey J. Langer, MD, FACP: But the amended trial, the ANVIL trial, which specifically looks at nivolumab in the much larger group of unselected patients who don’t have oncogenic drivers, is accruing quite well. It will probably finish ahead of schedule. It’s analogous to the PACIFIC Trial. It’s really the same basic concept. We take patients who have been definitively treated for cure and test the role of checkpoint inhibition, immunotherapy, in the setting. After PACIFIC, I predict that 1 or more of these trials will be positive.
Benjamin P. Levy, MD: It’s going to take some time.
Corey J. Langer, MD, FACP: I’m hoping that I’ll still be practicing when these trials finish. But given how quickly PACIFIC read out, it may just be a few years until we really know the data. And there, too, it’ll open up the doors for looking at chemotherapy in combination with immunotherapy and looking at immunotherapy doublets. It’s been very frustrating.
You can look at our meta-analyses for our standard chemotherapy in this setting, which is still the standard—4 cycles of a platinum-based doublet post resection. For anybody with nodal involvement, anyone with a 4-sonometer or larger tumor, that’s not going to be displaced. But can we graft it onto the chemotherapy? Can we perhaps replace that regimen at some point? That’s 2 or 3 trial designs ahead of us. But here, too, for the last 10 to 20 years, we’ve been stagnant.
Karen Kelly, MD: The bar is higher, though. The bar is higher in earlier-stage disease than it would be in PACIFIC. I think there is a lot of enthusiasm. There are many phase III trials in addition to ALCHEMIST that will be giving us a consistent readout, I think, in a consistent time frame.
Corey J. Langer, MD, FACP: So, you feel that if 1 trial’s positive, all of the rest will be positive?
Karen Kelly, MD: Well, I think we’re going to see all of the results come forward in a very short period of time.
Corey J. Langer, MD, FACP: When they are reported out?
Karen Kelly, MD: Yes.
Corey J. Langer, MD, FACP: It’s going to be a few years yet.
Karen Kelly, MD: It’s going to be a few years, yes. On the other hand, there’s also enthusiasm to do neoadjuvant trials. Hypothetically, it makes a little bit more sense. You’ve got a tumor there for the immune response, and so it makes more sense to do it in the neoadjuvant setting. But we need to figure that piece out, as well, and a lot of trials are going on—randomized phase III trials. The Lung Cancer Mutation Consortium has a trial. Again, I think we’re going to at least be seeing more data coming in, in bits and pieces. The definitive trials in the neoadjuvant setting just started, so those are far away. I think it’s, again, an exciting time across the whole spectrum of non—small cell lung cancer, to really look at neoadjuvant and adjuvant modalities.
Transcript Edited for Clarity