CheckMate 9LA: Dual IO Therapy With Chemotherapy in Advanced NSCLC


Shared insight on the CheckMate 9LA trial, which combined dual IO therapy with chemotherapy in the setting of advanced non–small cell lung cancer.


Stephen V. Liu, MD: Another option we have is merging these 2 strategies, looking at dual checkpoint blockade with chemotherapy, and that’s the CheckMate 9LA regimen. It was a regimen that came somewhat quickly for some of us who weren’t aware of it, but this looks at nivolumab and ipilimumab long term with chemotherapy. The difference here is the chemotherapy is only given for 2 cycles, so a very abbreviated course of chemotherapy, and a standard control arm of chemotherapy. This may be the best of both worlds, where you’re getting that initial bump in response rate and progression-free survival, where the chemotherapy maybe gives you a little reassurance in people who have symptomatic disease or high-burden disease, but you don’t continue that chemotherapy. Neal, I don’t know how it is at Duke [Cancer Center], but I know at Georgetown [University], my melanoma colleagues really are not believers in the chemotherapy aspect. They think it’s going to prevent memory T-cell formation, and I think they’re really colored by the biologic, chemotherapy experience in melanoma, where adding chemotherapy to IL-2 [interleukin-2] didn’t really do anything.

Lung cancer is a different disease, and we know from the studies that you went over that chemotherapy can play a role, especially in that PD-L1–negative group, but this strategy allows us to avoid the chemotherapy long term. And what we saw was a clear survival benefit in favor of the nivolumab, ipilimumab, chemotherapy arm, again a limited course of chemotherapy, with an OS [overall survival] benefit, a hazard ratio of 0.74. In that 3-year update also presented 2 weeks ago at ASCO [American Society of Clinical Oncology annual meeting] by Luis Paz-Ares, [MD, PhD,] from Madrid, [Spain], we saw an improvement in progression-free survival, with a hazard ratio of 0.7, and an improvement in response rate, increasing from 25% to 38%. Thus, we get that initial benefit of the chemotherapy and also that long-term survival benefit with the nivolumab and ipilimumab. When we look at the PD-L1–positive group, we see a hazard ratio of 0.74 favoring the nivolumab and ipilimumab combination. In the PD-L1–negative group, there was a hazard ratio of 0.67 favoring that nivolumab, ipilimumab combination. Hence, it’s another chemotherapy, IO [immunotherapy] combination, but sort of bridging those, using dual checkpoint blockade, especially in the maintenance setting, but not continuing that long-term chemotherapy. Neal, I don’t know if this is a regimen that’s found its way into your practice at all?

Neal Ready, MD, PhD: Yes, in patients with low PD-L1 scores and who I think have neoantigens, so smokers, high total mutational burden or other factors that are making me think, oh, they’ve got some sort of a neoantigen that can be recognized, but they have a high tumor burden, and I’m afraid of not giving chemotherapy. That’s the kind of scenario where I would use the 9LA regimen.

Stephen V. Liu, MD: We have a lot of different options, [and] really, it’s tailoring the different options. When I think of a dual checkpoint blockade, there are some different toxicities. I would encourage our audience to submit any questions [you] have. We have another 7 minutes to go before the end of this webinar, so please feel free to submit questions, but here’s one question for you Neal. What adverse events do you notice more commonly in patients receiving dual checkpoint blockade? If we’re looking at adding CTLA-4, does that add any kind of toxicity dimension?

Neal Ready, MD, PhD: I think particularly colitis with the ipilimumab, and then also pituitary inflammation. I think those couple, but then some of the rarer ones will rear up when you add ipilimumab.

Stephen V. Liu, MD: These rare immune adverse effects, I think that if you give enough immunotherapy you start seeing them periodically, and like we said before, I think the key is recognition and a high degree of vigilance so we can intervene early. Colitis is something that we did see with ipilimumab at very high rates in the early studies, I think when we were still figuring out the dose. I know that you were involved in some of those dose-finding studies, and there does seem to be a difference in the dosing for this drug in lung cancer compared to melanoma, right?

Neal Ready, MD, PhD: Yes, in the CheckMate 012 trial, we specifically tried the melanoma regimen in lung cancer…and we proved that you cannot use those regimens in lung cancer. We systematically studied the ipilimumab dose to the point where we felt that we had the sweet spot between giving enough to stimulate the immune system, but to keep it at a tolerable level.

Stephen V. Liu, MD: Agreed. It is important, especially for those of us who treat multiple diseases, we kind of have different doses. I know it seems counterintuitive, but to me it makes a lot of sense because the immune system that allows melanoma to escape is very different from an immune system that allows non–small cell lung cancer to escape, or small cell, or thymic cancers. We know for example in thymoma that checkpoint blockade is much more toxic, that there are far more immune-related adverse events. I don’t think it has to do with the cancer, per se. I think it has to do with the state of the immune system that allows that cancer to slip through, so the dosing in that is important. When we do see colitis, again that is not prohibitive in terms of using those drugs, I think it’s just requiring a lot of vigilance here.

Neal Ready, MD, PhD: I think if you’re using an immune combination and you see a toxicity you think is related to ipilimumab, you can stop it, and often continue with nivolumab alone.

Stephen V. Liu, MD: Exactly right. I think that’s an important point, and we’ve done that. I did that today in the clinic because of some of the toxicities. We got through those, and they were going to resume treatment, but I felt that maybe this was a sign that we should back off from the CTLA-4, using just the nivolumab, and then we’ll see how long that goes.

Transcript edited for clarity.

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