Jeffrey S. Weber, MD, PhD: There’s a whole raft of phase III trials that will come to mature—SD-101, CMP-001, the MASTERKEY-265—and then there’s the NKTR-nivolumab trial. Jason, a lot of buzz about these IL-2—like compounds. There’s ALKS 4230, which is a genetically modified IL-2. There’s NKTR-214 which is a pegylated IL-2. And the idea was it would not bind to the alpha receptor of IL-2, so it wouldn’t promote T-regs [regulatory T-cells] and it would activate T-cells. What’s your read on the NKTR-214–nivolumab trial? That’s a phase III trial.

Jason J. Luke, MD, FACP: The predicate here being that before we had all these drugs we’ve just been discussing, a high-dose IL-2 was the therapy that was available to some patients and was associated with a long-term benefit. That’s really fallen away because of the toxicity, but we still all acknowledge the fact that some patients were cured. As you’re suggesting, these are novel approaches to harness IL-2 biology and then bring it into the checkpoint inhibitor space. NKTR-214 is a pegylated molecule that tries to sort of take the parts of the IL-2 molecule that we think are the important ones, then tries to use that in combination with checkpoint blockade to enhance that.

I think that the early data set are very interesting in that regard. The clinical data have showed that in some patients with advanced melanoma in the frontline setting, there were complete responders in patients who were PD-L1 [programmed death-ligand 1] negative, and that was thought to be pretty unlikely. There were changes on the translational level, in terms of number of immune cells going into tumors, and the immune changes in a tumor that you would think would associate with immune response. All that trended in the direction that you would expect, enough that this phase III trial has been launched.

I think it’s worth noting, in the context of our prior conversation about refractory disease, that the trial was launched in a frontline setting. And so it won’t necessarily help us with that second-line question. And we’ll have to see. And so really the question sort of becomes, can you add gas to the fire? I think that’s what people are thinking about with this. Can you supercharge PD-1 [programmed cell death protein 1] so that it works even better? And I think we all are hopeful. I think we all have to be cautious, however, given our overexuberance perhaps about our most recent phase III trial, which failed in this space. And did we learn adequately the lessons regarding how much data we really need to generate, to feel confident about our phase III result? I think that’s still an open question. This is a trial that I very much hope is positive, but I think we’re going to have to wait and see.

Jeffrey S. Weber, MD, PhD: I hope at the next ASCO [American Society of Clinical Oncology Annual Meeting] or next ESMO [European Society for Medical Oncology Congress], we’re going to get some answers. I just hope we’re going to see positive studies. The other interesting phase III trial is with ipilimumab, and I was a bit surprised to see that, Vern. There was an ipilimumab, versus ipilimumab plus tilsotolimod, which is yet another TLR [toll-like receptor]—type agonist. That’s already gone to phase III. Were you surprised to see that it went to phase III never having stopped at phase II in the middle?

Vernon K. Sondak, MD: There’s still a lot we don’t know about how to best develop these drugs. We have so many combinations, so many choices. I personally would love to see us develop some of these compounds in the neoadjuvant setting because we can really understand, from before-and-after tumor samples, whether the drugs are achieving the desired effect, rather than wait for a 700-patient, phase III trial to tell us it had no effect. But the pressure is on.

There are so many different compounds and so many different companies, that yes, there’s a push to push a lot of these directly into phase III trials. And for all the focus that has been on combining with anti—PD-1, I do think it’s important to recognize that ipilimumab with its toxicity and its disadvantages, we need to do better with that 1 too. It’s still a very important part of treatment. There’s nothing inherent about any of these immunologic combinations. They will only help an anti–PD-1 agent be more effective. It won’t help an anti-CTLA4 agent be more effective.

Jeffrey S. Weber, MD, PhD: Are you implying that ipilimumab is a victim of the Rodney Dangerfield effect. I mean, it doesn’t get any respect?

Vernon K. Sondak, MD: It doesn’t get much respect.

Jeffrey S. Weber, MD, PhD: Is that what you’re trying to say?

Vernon K. Sondak, MD: That may be the case, yes. It doesn’t get a lot of respect.

Hussein A. Tawbi, MD, PhD: I like the fact that this study has a control arm as ipilimumab in this setting, in the second-line setting. Because ipilimumab, we know, is a drug that can still cure 21%, 22% of our patients, and is the appropriate comparator from my perspective in the second-line setting.

Transcript Edited for Clarity