Combination Therapy Is the Future for Metastatic Melanoma Treatment


An expert discusses recent exciting advances in the treatment landscape of metastatic melanoma.

The treatment landscape for patients with metastatic melanoma is quickly evolving, with combination regimens growing in their use and future potential, explained Allison Betof Warner, MD, PhD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

Warner recently discussed these changes, as well as exciting findings from the COMBI-i trial, examining the PD-1 inhibitor spartalizumab plus dabrafenib (Tafinlar) and trametinib (Mekinist) in previously untreated patients with advanced BRAF V600—mutant melanoma.

Oncology Nursing News®: What are the current immunotherapeutic options for these patients?

Warner: In the metastatic setting, we obviously think first about whether or not a patient has a BRAF mutation. In the BRAF-mutated melanoma, those patients certainly can receive targeted therapy or immunotherapy. I think we still don't have clear data on if one of those is better to start with than the other. Those data hopefully will someday be available, although I'm not sure. We're seeing more combinations of those coming forward.

In the BRAF-wildtype space, it's certainly an immunotherapy-dominated field. PD-1 monotherapy, I think, is getting more and more common as we see people in the community getting increasingly comfortable prescribing immunotherapy and managing the toxicities. Combination immunotherapy is still being widely used, particularly in the more academic settings where people are more comfortable with the toxicities.

We're seeing an increasing balance of people using ipilimumab (Yervoy) 1 mg, nivolumab (Opdivo) 3 mg, versus ipilimumab 3 mg, nivolumab 1 mg. I think that's really promising in terms of a toxicity with the data that have emerged within the last year or so. Efficacy at least seems to be similar. That's the general lay of the land for standard of care.

In the trial space, we're seeing combinations upon combinations, which are really exciting. There are combinations of almost every type of other therapy that hopefully we can finally bring to the melanoma space.

Can you talk more about the combination of immunotherapy and targeted agents?

There are great rationales, in addition to the flat efficacy of both of those approaches. I, personally, am really interested in tumor micro-environment. That's how I was trained as a scientist. If we look at environmental changes that happen as a result of immunotherapy, we know that may be a cytoreductive situation, which targeted therapy may be really beneficial. Additionally, with the data that MEK inhibition may, in fact, increase antigen presentation, it's really promising.

Of course, we're waiting on final analysis, but the data that came out [from the COMBI-i trial], at ASCO were really promising and really exciting. We're all waiting with unbated breath to see the final analyses. But I think there are numerous other combinations that are coming, of targeted therapy, and not just BRAF/MEK targeted therapy. I think that's exciting.

The axitinib (Inlyta)/nivolumab combination that was published in the Journal of Clinical Oncology this year for mucosal melanoma, we've been increasingly using in patients with [the disease]. That’s a whole new type of target to bring to melanoma. It's really exciting. I'm treating a few patients with it now.

Why are results from the COMBI-i trial so exciting?

COMBI-i, I think, is one of the more exciting trials of combinations to come out recently. The trial combined dabrafenib, trametinib, and spartalizumab. One of the really exciting findings from that trial, from what we've seen so far, is a confirmed complete response rate of 40%, which is a number we haven't seen yet in our field. And they're largely durable responses, which I think was the big question. With targeted therapy, we see these great responses, but they tend not to be lasting.

One of the ideas behind the combination is to get that upfront, really beautiful response from combination therapy. But then the question really was: can immunotherapy make that a durable response? From what we've seen so far, the answer may be yes, and that's really exciting.

The other big question going into COMBI-i was about the toxicity of the combination, knowing that there could be overlapping toxicities. Overall, while toxicity continues to be an issue with combination therapy and targeted therapy, there wasn't a huge safety signal. It seems to be that most patients can tolerate this combination. We're really looking forward to seeing the final data, but I think it's really promising. We're going to see more and more of these combinations coming.

How do you see this landscape evolving in the future?

Right now, we're talking about triplet therapy. BRAF/MEK plus a PD-1 or a CTLA-4. I think soon we're going to be talking about quadruple therapy. Are we talking about CTLA-4 plus PD-1 in some dosing scheme, plus targeted therapy? Or run in with one and finish with another. Those are coming.

But [we're looking forward to] truly novel combinations as well. The combination of axitinib plus PD-1 really opens the door to these other targets that we haven't been seeing in melanoma for a long time. I think we're going to see more of that as well, not just in the VEGF or TKI space, but a variety of targets. We're seeing HDAC inhibitors and things like that in trials as well.

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