Novel Trials of Immunotherapy Combinations for NSCLC
Panelists: Mark A. Socinski, MD, Florida Hospital Cancer Institute; Mark Kris, MD, Memorial Sloan-Kettering; Jared Weiss, MD, UNC Lineberger Comprehensive Cancer Center; Ross Camidge, MD, PhD, University of Colorado Cancer Center; David R. Spigel, MD, Sarah Cannon Research Institute
Mark A. Socinski, MD: Our focus now has been on combining the PD-1 and PD-L1 inhibitors with CTLA-4 inhibitors. Is there another combination that people are excited about in this immunotherapy combination space?
Jared Weiss, MD: Well, we have so few combination trials.
David R. Spigel, MD: It’s interesting, what has been in the news lately is the IDO story—the IDO inhibitors, without naming one specifically, in combinations with PD-1 inhibitors. What I’ve been impressed by is at least 4 large randomized phase III studies getting off the ground with that combination based on a small number of patients from a phase II study, which is not unusual in the immunotherapy world. So, there are a lot of folks banking on that strategy working. Obviously, there are a number of combinations with other immunotherapy checkpoints—LAG-3 and the TIM-3 combinations. I think the vaccines are interesting, but those are still a bit off.
Mark A. Socinski, MD: Well, you haven’t mentioned one. I want to go back to Dr. Kris, because he’s the advocate for bevacizumab. Is there a role for adding antiangiogenic therapy like bevacizumab to the immunotherapy?
Mark G. Kris, MD: Yes. There’s clearly an additive role, because they probably have complimentary mechanisms of action. I’m sure they’ll add toxicity to each other. And I think the jury is still out about the laboratory data and the clinical data about how much benefit you’re going to get beyond additivity. So, again, I think if you had a patient who really needs a response and these were 2 safe drugs, it would make some sense to add them, just like you’d add any chemotherapy drug. Whether or not there are preclinical data and clinical data that say it’s more than additive, the jury’s out.
Mark A. Socinski, MD: Let’s talk about what I think is a very exciting area. I’ve said for 2 or 3 years that the trial I’m waiting for that I think is most important is the PACIFIC trial. And we have a press release.
Mark G. Kris, MD: It was May 12th.
Mark A. Socinski, MD: So, regarding the PACIFIC trial, we haven’t really moved the bar to the chemoradiotherapy arena in a while. Mark G. Kris, MD: Oh, decades. It’s worse than that, but we tried to increase the dose of radiation, and we sadly, sadly harmed people.
Ross Camidge, MD, PhD: And don’t forget, adding bevacizumab didn’t do much good either.
Jared Weiss, MD: The harshest editorial I think I’ve ever seen.
Mark G. Kris, MD: Yes, but it’s true. This makes sense. Obviously, we’ve been talking about how helpful these drugs can be, and it is really going to be a game changer. Just improving PFS is going to be enough. Whether or not survival is going to be improved, time will tell that.
Mark A. Socinski, MD: Yes, we don’t know the magnitude of the PFS benefit yet.
Mark G. Kris, MD: Yes, but I’ve been trying to get my hands on the trial so that number is findable. I don’t know if somebody here knows that, but it’s surely going to take over. At ASCO, there’s going to be a presentation about giving pembrolizumab after the current chemoradiation therapy. So, I think people had some safety issues, and obviously those are gone. Given the fact that it didn’t happen in the PACIFIC trial, where nearly 500 patients per hour were compared to people who got a placebo and they didn’t have any horrible pulmonary toxicity, I think that question has been answered—there’s not a huge amount of horrible pulmonary toxicity. So, I think it’s just going to take over and it’s really good news.
David R. Spigel, MD: The other thing is that it was just a simple design. It didn’t really mandate the chemoradiation therapy that you got and there was no use of consolidation therapy, which I think many of us stopped using a while ago, but it’s still relatively popular in the community.
Mark G. Kris, MD: And academic centers.
Mark A. Socinski, MD: You’ve got to give 4 cycles.
David R. Spigel, MD: Right. So, that trial tells you that you don’t need that if you subscribe to the results, which we haven’t seen, but it is a major step forward.
Mark G. Kris, MD: Well, we have seen.
David R. Spigel, MD: We’ve seen a press release.
Mark G. Kris, MD: Yes, but let’s go back to that pembrolizumab press release last June. They told us exactly what we needed to know about that pembrolizumab versus chemotherapy trial. I’m sorry that that has been combed over. It’s a 1000-patient, worldwide trial. I think the data are in the bank.
David R. Spigel, MD: No, no, I’m not doubting the data. We just don’t know the numbers. We haven’t seen the magnitude of them.
Mark A. Socinski, MD: And we don’t know overall survival.
Mark G. Kris, MD: But we do know the numbers. Anybody who has the protocol in front of them knows what it had to be to be cream of the crop.
David R. Spigel, MD: You know the lower limit of that.
Mark G. Kris, MD: Yes, but for 1000 patients who were put on that trial, their doctors agreed that that was a reasonable thing to go after, whatever it was. I assume it was many months of improvement.
Jared Weiss, MD: It also gives us hope for other efforts, right? So, there are good scientific reasons why what happens after chemoradiation may not be the same thing that happens after surgery. But we do have a much greater number of patients treated with surgery for the goal of cure than chemotherapy radiotherapeutics because of the staged layout of non–small cell lung cancer. We have multiple trials looking at adjuvant PD-1 inhibitors. I’ll make a plug for the ALCHEMIST trial Cooperative Group effort. It gives us at least some hint of hope that we might have a positive effort there, where we’re not just adding months to survival or durable control for a small percentage of patients, but we’re also given the hope that for the first time in a very long time we might move the needle on cure.
Mark A. Socinski, MD: Raise the tail of the curve, right?
Mark G. Kris, MD: We haven’t mentioned that about all of the drugs we’re talking about, but to me that’s the most amazing thing that they do. You look at the curves. I think many of you saw the report from Hellmann last year at ASCO that when you biopsy these patients, the residual disease didn’t have cancer in it. These are people with stage 4 disease, and you never see that with chemotherapy, you never see that with a TKI, and you never see that even with bevacizumab. You see it with these drugs. So, it’s different. Sadly, it’s a minority of patients, but for those people, it’s really profound.
Mark A. Socinski, MD: I was involved in the START trial, and the START trial was an immunologic manipulation after chemoradiation in stage 3 disease. It was a very large trial, and there was clearly a signal by administering an L-BLP25 vaccine, or MUC1 vaccine, that in patients who had received concurrent chemoradiation, there was about a year difference in median overall survival and respectable Kaplan-Meier curves. That drug was discontinued in its development for other reasons, but I was hoping we would see another trial where an immunologic manipulation was done after chemoradiation. As Jared pointed out, we don’t really know the immune system issues that are ongoing after chemoradiation. It may be a perfect setup for that. This PACIFIC press release was reassuring in that finally, after decades of not moving the bar, we’ll have an option for patients. As you were telling us before, patients will say, “What now?” Right?
Mark G. Kris, MD: Yes, absolutely. It’s crazy when we give adjuvant therapy after surgery—for people with a comparable or even greater degree of risk after chemoradiation, we give nothing.