Advances in the Treatment of Malignant Melanoma - Episode 10

Novel Therapies for Metastatic Melanoma

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Jeffrey S. Weber, MD, PhD: Let’s talk about the data. Let’s turn to Su. There have been some relatively long-term follow-up studies of at least ipilimumab plus nivolumab-pembrolizumab, eventually nivolumab alone, and BRAF-MEK. The longest would be the dabrafenib-trametinib story. What can you tell us? Do you feel there are enough data to drive you in metastatic first-line disease in a BRAF-mutated patient to want to choose 1 or the other? Sorry to put you on the spot, but those are the data.

Sunandana Chandra, MD: Absolutely. That’s an excellent question. First, I have to point out that the options we have in front of us today have really blown the field wide open for melanoma, right? The response rate we see with anti–PD-1 alone is somewhere around 40%. The response rate we see with combination anti–PD-1 and CTLA4, is probably somewhere between 55% and 60%. There’s certainly a survival benefit, which I’m happy to get into. Then the response rates with targeted therapy are probably somewhere over 70%, potentially with less of a durable response.

It’s important to note that we have so many choices in front of us in terms of anti–PD-1 alone, combination, targeted therapy for those who have a BRAF mutation. I do use a lot of I/O [immuno-oncology], even in the first-line setting. That is certainly a little a bias. The COMBI-d and COMBI-v trials have now 5 years of data. The 5-year overall survival is 34%, which is not insignificant by any means. Compared with that, for example, the CheckMate 067 data, where over 900 patients were randomized 1:1:1 to ipilimumab plus nivolumab, nivolumab alone, and ipilimumab alone with matched placebos. The response rate was almost 60%. I believe it was 58%, albeit the grade 3/4 adverse-event rate was also almost 60%. The overall survival at 5 years was 52%, meaning 1 of 2 people are still alive at 5 years.

The data are really exciting. I had alluded to the fact that I do use a lot of I/O in the first-line setting for the BRAF-metastatic population. Part of it is because I have seen in my practice that if I use targeted therapy in the first-line setting—and once they become resistant, I barely have time to get them onto an I/O regimen, because their disease seems to just be accelerating—the performance status declines. There are just a lot of factors that prohibit me from then trying a second-line therapy. Now I know it’s doable. I’ve certainly been able to do it in some patients. That is a worry that I always have.

Jeffrey S. Weber, MD, PhD: I wonder, do your colleagues agree with that? Jason, do you agree that if someone fails frontline targeted therapy, then the immunotherapy becomes a difficult scenario?

Jason J. Luke, MD, FACP: My bias is to say yes. I also think that patients who fail any therapy in the frontline are also harder to manage. I look for the high upside, and because of that, those ipilimumab-nivolumab data look quite impressive. It’s worth noting that we certainly have not figured out the optimal regimen in terms of immunotherapy in the front line, or even combinations with targeted therapy. All this is evolving.

In the last couple of years, we’ve had some discrepancy around the most appropriate dose of ipilimumab become an issue in the field, with CheckMate 511 showing potentially no difference in the benefit between nivolumab 1 mg/kg–ipilimumab 3 mg/kg and nivolumab 3 mg/kg–ipilimumab 1 mg/kg, but that’s in contrast to previous randomized studies. There are data for ipilimumab plus pembrolizumab with a lower dose of ipilimumab. All this is to say that we have a lot more to do. When I think about which treatment to use in the front line, I am somewhat biased toward immunotherapy as well, going into long-term overall survival with PD-1 around the low 40s and doublet I/O in the low 50s. I like those data. That is usually what drives my perspective.

I’ll also note that you have the BRAFinhibition in the back pocket, so if you don’t get the kind of long-term sustained benefit you want, you can get disease stability, which allows you to regroup and think about future options. All those are ways I think about it. I will note, just for the record, that the best patient with BRAF-mutant disease to treat with a BRAF inhibitor, though, is the patient with low-volume disease who is almost always going to be the person in the front line. On some level, we are putting ourselves behind the book when it comes to using targeted therapy if we do it that way. Probably everyone here is going to, generally speaking, agree with that sentiment.

Jeffrey S. Weber, MD, PhD: Yeah, I would agree with you.

Transcript Edited for Clarity