PD-1 Inhibitor Use in Melanoma

Transcript:Mark A. Socinski, MD: Of course, you know where these agents really got their start was in the immunogenic tumor, the melanoma patients. So, tell us how this changed melanoma with regard to the PD-1 agents.

Howard L. Kaufman, MD: I think they’ve increasingly become the standard of care for melanoma, and I think because they started there, we probably have the longest follow-up data available. One of the important stories that’s coming out now is that it does appear that the patients that are alive at 3 years are still alive at 5 years. And so we’ve seen that now, with both ipilimumab and now with the PD-1 inhibitors in melanoma. If you get a good response with these drugs, it really does translate to real durability and response.

The other thing that we’ve been learning is that it does appear that you can re-induce patients. So, if you have a patient who’s had a response and then progresses later, going back on therapy, Steve Hodi recently reported an update with nivolumab at the AACR meeting that there was a 38% objective response rate again in patients who needed to go back on therapy at the time of progression. It suggests that if patients come off this therapy, you may be able to use it again at the time of progression. I think we solved some unanswered questions in melanoma. We still don’t know exactly how long to treat patients. These data are encouraging, that you may be able to re-induce them. And I think the issue of whether or not patients might develop resistance to these agents is an open question that we don’t really understand.

The future is going to be understanding how best to sequence them. The combination of ipilimumab-nivolumab is really taking over as the new standard in melanoma, based on high response rates. But there’s also higher toxicity with those agents, and it’s unclear whether or not you can get those kind of responses with a sequential regimen compared to doing these concurrently.

John V. Heymach, MD, PhD: Howard, melanoma is so interesting because even just a decade ago, it was something where we just had really inactive drugs, obviously like dacarbazine or DTIC. But now you’ve got BRAF inhibitors, as well. And you know that they are spectacularly active. So, two major breakthroughs. What are your thoughts about the state of combining those and sequencing, and how do you deal with having two really active therapeutic approaches now?

Howard L. Kaufman, MD: Yes, it’s interesting because nobody wanted to work in melanoma a decade ago, and now we’ve become the poster child for both precision medicine and immunotherapy.

John V. Heymach, MD, PhD: Same for lung here, yes. What goes around comes around.

Howard L. Kaufman, MD: It’s a good problem to have. One of the very interesting findings is that there have been a few studies that have shown that in patients who get exposed to BRAF inhibitors, there is an influx of lymphocytes at the tumor site. And so that, of course, would suggest that this might be a good thing to combine. And so many trials are underway. A lot of the studies haven’t matured yet, so I think we have to wait and see the data.

Again, in terms of what are we doing in the clinic, it’s nice to have these options available to us. I’m an immunotherapy person, so we tend to go with immunotherapy first. Interestingly, we’ve looked at BRAF status in the studies and it does not seem to make a difference in terms of outcome. So, most of the patients prefer to go on an immunotherapy first, if they can. That tail of the curve is, of course, really appealing to both the physicians and the patients. But patients who may have rapidly progressive disease, patients who get into serious autoimmune-kind of side effects with the agents, having the targeted therapy as a backup is how we’re using it right now.

Mark A. Socinski, MD: I want to come back to Dean in a second because recently in bladder cancer, we had the approval of atezolizumab, the first PD-L1. But before we do that, I want to ask John: PD-1, PD-L1, does it make a difference?

John V. Heymach, MD, PhD: Yes, it’s a great question. PD-1 is on the T lymphocytes, but there’s also PD-2, which is very similar. And you’ve got two ligands—you’ve got PD-L1 and PD-L2—and there are other potential interactions that are out there, as well. So, they’re not exactly the same, and there are theoretical reasons there may be differences. It’s thought, for example, that PD-L blockade—PD-L1 blockade, especially—might have a different incidence of pneumonitis, and there are other theoretical reasons the toxicities might be different.

Looking at the data as a whole, there haven’t been dramatic differences between PD-1 blockade and PD-L1 blockade. Both approaches so far look effective, and both of them look to be far better tolerated than docetaxel, as Jared was saying before. Now, the jury is out. Maybe, as we learn more, there might be subgroups that benefit more from one or the other. But so far, they’re looking pretty similar. And the correlations we see with PD-L1 status seem to be holding for both PD-L1 inhibitors and PD-1 inhibitors.

Transcript Edited for Clarity

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