Advances in the Treatment of Malignant Melanoma - Episode 5

Neoadjuvant Data Explored for Locally Advanced Melanoma

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Jeffrey S. Weber, MD, PhD: Jason, there are other neoadjuvant trials out there. As I said, there’s been a flood of interest in this. Can you tell us about any of the other trials? I think there’s been one with pembrolizumab alone.

Jason J. Luke, MD, FACP: There are some very interesting results. Going to that question about the pace of the responses, when you start a BRAF inhibitor, you get rapid responses. We know that. The study that you are alluding to by Alex Huang, [MD,] et al, from University of Pennsylvania, it’s very interesting that they gave a single dose of pembrolizumab prior to surgery. They got roughly similar results to giving 3 or 4 doses of nivolumab. A single dose of PD-1 can generate a substantial treatment response. I think that’s really interesting as we think about kinetics of response and a long-term benefit that we can see in some of these patients. As we start thinking about the feasibility of combination regimens, especially, we don’t necessarily need to think about long durations of treatment prior to neoadjuvant approaches. I think that’s exciting.

I also want to note quickly, there are some other intratumoral injection studies that are also starting to come forward. We’ve seen some data for TVEC [talimogene laherparepvec] that look interesting. I’m not sure I would do that, but there are combinations of PD-1 antibodies with other sorts of innate molecules that we’re going to talk about a little bit later that do look quite promising, and again, I think do have the potential to come forward as a strategy in the future.

Jeffrey S. Weber, MD, PhD: OK, I like the TVEC idea. But again, that’s a tough one. What about BRAF-MEK? One would think with the excellent response rate that BRAF-MEK would be the perfect neoadjuvant strategy. What can you tell us about the data? I think there was a presentation probably last year. I don’t think it was updated this year. I believe it was summarized in Alex Menzies, [MD’s,] review that he presented last year.

Sunandana Chandra, MD: Stephanie Blankenstein, [MD,] reported some data. It was a small trial. It was only about 25 patients or so. These patients had either stage III resectable or they could have had stage IV disease, but they had to have somewhere up to 3 lesions that were resectable. The patients underwent 8 weeks of dabrafenib plus trametinib. Out of the 25 patients, 18 patients went through the neoadjuvant regimen, and 17 of them underwent resection. Of the 17 patients, 16 patients had complete R0 resection, which I think is remarkable.

Of course, we don’t have a lot of long-term outcomes yet with these trials. It certainly poses a question of therapy options that we didn’t have before. Then again, it leads to more questions of, for a BRAF-mutated patient, for example, should we think of neoadjuvant immunotherapy versus targeted therapy? I think those questions are still unanswered.

Jeffrey S. Weber, MD, PhD: I would say in Menzies’ article, though, it looked as if the immunotherapy neoadjuvant patients had a better relapse-free survival rate than the BRAF-MEK patients, but again not enough long-term data. Adil, weren’t there more long-term data in that [Elisa] Rozeman, [MD,] presentation at the American Society of Clinical Oncology [annual meeting]? This was the late update on OpACIN-neo, the very latest data. What can you tell us about that?

Adil Daud, MD: I think it’s very interesting. The one editorial, general comment I’d make is that I’m having a hard time disentangling partial responses [PRs], near-complete pathologic CRs [complete responses], pathologic complete CRs, pathologic partial responses, and comparing them…. I feel like all 5 of us could probably look at a scan and say, “OK, this is a CR or a PR.” I have a hard time understanding if in Holland, or in Australia, or at UCSF [University of California, San Francisco], pathologists are going to look at it and come to the same conclusion. I think in the Rozeman article, what you can see is that if you had a pathologic CR, you’re probably going to have a great longer-term outcome. But the one thing to remember with these trials is that there are very few patients in each arm, and I think Su was talking a few minutes ago about the OpACIN trial. It’s interesting that the AEs [adverse events] are seen in the 20% range for different ipilimumab-nivolumab combinations. I simply think that when you’re having 20, 30 patients in each arm, you’re probably not capturing the full range of AEs here as you are, say, in CheckMate 067, where every time patients come in, you’re checking all kinds of laboratory tests, you’re following them for 5 years afterward. With hormone adrenal insufficiency and stuff like that, are you really capturing them in the first few weeks? I apologize for this inconclusive, long-winded answer, which doesn’t help us necessarily.

I think that the pathologic CR issue and path response issue is, it can be gamed in many different ways, as opposed to RECIST [Response Evaluation Criteria in Solid Tumors], which you and I and everybody else can agree on means something. Actually, in one of the trials, I want to say it was the Blankenstein trial, it was interesting that they had a comparison of pathologic CRs and radiologic CRs. It was about 20% lower for the radiologic CRs compared to the pathologic CRs, illustrating that maybe we should minus a certain percentage from the pathologic CRs.

Jeffrey S. Weber, MD, PhD: That seems to be a common scenario, both in my experience in squamous, basal melanoma, and cutaneous cancers. When you treat them up front with immunotherapy, sometimes you’ll get a chance to resect them fully. I think that the radiologic response lags way behind the pathologic response. The nice thing for me about the Rozeman presentation was that even, I think now with 2 and a half, 3 years, of follow-up, if you had a pathologic CR, you stayed in remission something like 88% or 90% of the time. That’s pretty impressive.

Now, you might argue that getting a pathologic CR simply picks out the people who, with adjuvant therapy, would have done well anyway, and the ones who are going to relapse are the ones who didn’t have pathologic CR or a pathologic high-grade PR. But again, only time is going to tell. There is a BMS [Bristol-Myers Squibb] trial, and there’s an ECOG [ECOG-ACRIN Cancer Research Group] trial. In those randomized trials, we’re going to find out, I hope, about the utility of neoadjuvant versus adjuvant therapy.

Transcript Edited for Clarity