Advances in the Treatment of Malignant Melanoma - Episode 6

Adjuvant Data Explored for Locally Advanced Melanoma

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Jeffrey S. Weber, MD, PhD: Speaking of adjuvant, let’s go back to Ryan. I think at ASCO [the American Society of Clinical Oncology annual meeting], there were 2 presentations, both of which were updates. They were not new trials. One was COMBI-AD, and that was excellent. The other was the readout of Lex [Alexander] Eggermont, [MD, PhD,] for KEYNOTE-054. What can you tell us about updated data? Does that change your mind about using one versus the other at all?

Ryan J. Sullivan, MD: I think the way to set the context is for so long, we had interferon, and there were people who would use interferon. There were people who wouldn’t use interferon. They would draw sabers at conferences and fight each other about this. Then thankfully, we had more effective therapy in the metastatic setting that was able to be brought forward into the adjuvant setting.

You know full well, Jeff, that the CheckMate 238 trial, which is nivolumab versus ipilimumab, but even before that, there was the EORTC study comparing ipilimumab versus placebo. That was a positive trial with regard to relapse-free survival [RFS] and overall survival, really resetting the template, if you will, for adjuvant therapy. Interestingly, what was presented last year, ipilimumab versus interferon, is not a slam dunk for ipilimumab. We would have anticipated that ipilimumab would have been way better than interferon. Interestingly, there were 2 doses of ipilimumab looked at, 3 mg/kg, 10 mg/kg. If you had to choose one of those from a toxicity standpoint, you would choose 3 mg/kg because it’s much less toxic. Remarkably, against interferon, the difference with 3 mg/kg versus interferon was better than the difference with 10 mg/kg, suggesting that the toxicity may actually be influencing the ultimate benefit because of presumably the immunosuppression utilized to counteract that toxicity.

Then bringing forward the more contemporary, even though that was probably the most recently first presented adjuvant trial, the CheckMate 238, that is nivolumab versus ipilimumab, showing clear improvement in relapse-free survival. I believe you presented the 3-year data last year showing about a 60% relapse-free survival for nivolumab.

This year, Lex presented the KEYNOTE-054 3-year update, again showing about a 60%, I think the number was 58%, 3-year relapse-free survival for pembrolizumab, comparing that to placebo, which was in the mid-40% range. I’m not sure those data help us to distinguish between those 2 drugs, but it’s comforting that the relapse-free survival is pretty solidly above 50% at 3 years.

The COMBI-AD study, which is now for something completely different, BRAF-MEK inhibitor therapy versus double placebo, so dabrafenib/trametinib versus double placebo. I think the most remarkable part about these data is they continue to show, really for the first time in an adjuvant study with a molecularly targeted therapy, continued improvement in relapse-free survival of the treatment arm versus the placebo arm. Most of those studies look like this, where there’s an initial benefit and then it comes back together….

Suggesting that you haven’t actually cured patients, you’ve just delayed when their disease is going to come back. The data with COMBI-AD, 5 years down the road now, suggest that they’re probably curing patients with BRAF-targeted therapy, or if you’re not, you’re delaying those relapses by 5 or 10 years. Interestingly, the 3-year data look almost identical to the nivolumab and pembrolizumab data, 59% relapse-free survival, the 5-year data, 52%. There’s a little bit of decay in the relapse-free survival curve. It’s not a complete plateau, and we’ll have to see in the future whether we see complete plateaus with nivolumab and pembrolizumab in those respective studies. I think the bottom line is if you were somebody who would think about targeted therapy for patients with stage III melanoma, you’re still going to offer that. If you were somebody who wanted to go up-front PD-1 inhibitor therapy for patients with a BRAF mutation, you’re still going to offer that. The data from KEYNOTE-054 and COMBI-AD reinforce what you’re previously thinking of doing. Then if patients are BRAF wild type, the data from KEYNOTE-054 and most recently last year, CheckMate 238, again support the use of nivolumab or pembrolizumab in patients with high-risk stage III disease.

Jeffrey S. Weber, MD, PhD: Yes, certainly it looks like the KEYNOTE-054 and the CheckMate 238 curves are very close at 3 years. I was absolutely fascinated by the fact that COMBI-AD looks like it’s coming to a plateau. The urban legend was that the targeted therapies would have an early high RFS, and then it would dip down below immunotherapy, but that hasn’t really happened. Actually, they have the longest follow-up of any of the current adjuvant trials. I was actually quite impressed that the patients on COMBI-AD who got treated with dabrafenib/trametinib did very well in the long term.

Transcript Edited for Clarity