Transcript:Benjamin Levy, MD: Let’s move on to just one more immunotherapeutic drug that maybe has been lost in the shuffle but may be reemerging in combination with checkpoint, and that is ipilimumab, a CTLA-4 antibody. There’s been some experience in lung cancer as a single agent—which has not been impressive, at least with tremelimumab, one of the CTLA-4 antibodies—but some perhaps more compelling data in combination with chemotherapy up front and in combination with immunotherapy up front. So, Paul, you want to talk about this and how we make sense of these new agents and whether they will be part of our approach?

Paul K. Paik, MD: Sure. The most mature data we have for the potential role for ipilimumab is a study that was published by Tom Lynch in JCO a few years ago. It randomized patients to getting carboplatin/Taxol as the backbone chemotherapy, and then ipilimumab given either concurrent with the chemotherapy or in a phased approach where [the patients] got a couple of cycles of chemotherapy and then got chemotherapy and ipilimumab. The thought was you needed some kind of priming or you needed an antigen release in order for this immune checkpoint inhibitor to be effective. And that’s what the trial bore out on analysis, that the phased approach had a significant improvement in terms of overall survival and progression-free survival. This is being carried forth now more formally in a randomized phase III trial. Again, some early evidence—this is before PD-L1 inhibition really came to the fore—that CTLA-4 inhibition in connection with chemotherapy in a phased approach might have efficacy. This was also apparent in squamous lung cancers in particular; more so, actually, if you took a look at the subset analysis.

People are in the process of testing combination immune checkpoint inhibition—nivolumab and ipilimumab, MEDI4736 and tremelimumab were testing also. The results are still early on. The number of patients who have been treated are fairly small. The results are promising, if a little bit difficult to interpret. The higher doses do seem to be more effective, but they’re also a lot more toxic in terms of the autoimmune or immune-related adverse events—too toxic, in fact, to move forward—which is why the doses have been trimmed down. It does look like that PD-L1 as a biomarker for nivolumab/ipilimumab, in particular, seems to predict for better response also, but small numbers. Now, this has not been seen for MEDI4736 and tremelimumab, though, where patients who are biomarker-negative seem to have just as good responses, yet even more confusion in terms of the IHC test that’s being performed. But the bottom line is that it’s promising enough to be formally tested now in a larger fashion, and we’ll see exactly what ground we gain. Although it’s important to note that the advances we’ve seen so far, in terms of the data or the promise, is a lot less than we’ve seen in melanoma, which has the approval indication.

Benjamin Levy, MD: It will be interesting to see if these combination strategies move up front and supplant chemotherapy and if it will come down to a sequencing approach. Will a combination be followed by chemotherapy or is it chemotherapy followed by immunotherapy? I’ve come out on the side that we’re not there yet. I don’t know when that will happen or whether we’ll move these drugs up front. But certainly the data that you went over is compelling, showing response rates close to 40% in some of these combinations. We’re getting somewhere. How to sequence these drugs is going to be somewhat of a challenge, and we’ll talk about that at the end. Ed, your thoughts on the combination strategy here and whether it’s going to be meaningful or not for patients.

Edward S. Kim, MD, FACP: We’re mirroring again what’s happening in the immunotherapy field with melanoma and renal cell carcinoma, and they’ve certainly seen the benefits. Some of these drugs—not ipilimumab, but others—are going to fixed doses as opposed to weight-based, and that will change things a little bit. But we’ve seen very interesting data in small-cell lung cancer, glioblastoma, bladder cancer, head and neck cancer, and others. So there is a lot of excitement among the combinations. I do think down the road, whether that is a de-scaled chemotherapy approach plus a checkpoint inhibitor upfront, or a triplet of one chemotherapy and two non-chemotherapies, could definitely happen.

Benjamin Levy, MD: The possibilities are infinite.

Edward S. Kim, MD, FACP: What I don’t want to see is alphabet soup and everyone combining everything under the sun. I think the never-smoker population made us put on the brakes ever since we’re using checkpoint inhibitors; we shouldn’t just test everybody in these combos, and it’s going to work in everyone. There are still prostate data out there that didn’t show benefit, as well. We want to be cautious and thoughtful, but I have no idea how we’re preclinically going to assess these combinations if we can’t do response or these other things. I have no idea how to do that.

Benjamin Levy, MD: It’s getting confusing, even going to ASCO every year now and just the amount of information to keep up with. They’re just throwing darts up on a board in the combination strategies, with perhaps not a lot of rationale of doing so, and trying to keep up with this is challenging, even as a guy who does nothing but lung cancer. We’ve got a lot to learn, but I would encourage trials to be rooted in science and some biological rationale, either clinical or molecular enrichment strategy. Because it’s just a free-for-all right now what’s happening. It’s a total free-for-all.

Transcript Edited for Clarity