First-Line Treatment Armamentarium for Patients With Unresectable or Metastatic Melanoma


A comprehensive review of how the first-line treatment armamentarium in unresectable or metastatic melanoma has evolved over time.


Sajeve S. Thomas, MD: I think the last decade has been exciting for folks who are dealing with metastatic melanoma. Prior to 2011, we didn’t really have anything other than IL-2 and dacarbazine chemotherapy. Chemotherapy doesn’t really do much, but if you’re young, healthy, fit, and you had IL-2, we did see folks who had responses with IL-2. There’s a 1 in 20 chance, but if you’re that lucky 1 in 20, you look like you didn’t have cancer come back. It was a disease that was well maintained and controlled for decades. In 2011¼ipilimumab was approved as a CTLA4 inhibitor that ultimately works in a way of reactivating exhausted T-cells, as well as some suppression against the regulatory T-cells. Ultimately, when you give this drug, it improved the response rate to 1 in 5, so we went from 1 in 20 with IL-2 to 1 in 5 with ipilimumab. I have folks who are more than 10 years out without having seen cancer come back, just with the 2 to 4 doses of ipilimumab. In 2013-2014, roughly speaking, that’s when pembrolizumab and nivolumab, which are PD-1 inhibitors, were approved, and that moved the bar to about 1 in 3, which is amazing. We see responses at 30% to 40%, and it didn’t come with the many adverse effects that we have seen with the ipilimumab. So, 1 in 20, 1 in 5, to 1 in 3, and again I have folks who have had only pembro, nivo, back in 2013 to 2014, and here they are very many years later off all therapy without seeing cancer come back. Also, I didn’t have the significant adverse effects issues that we’ve seen with some of the combinations or with ipi. Ipi/nivo was assessed in a CHECKMATE study, the CHECKMATE-067 (NCT01844505). It was nivo with or without ipi, compared with ipi alone. That showed the response rate of 50% to 55%, which is basically every other patient we treat. So, 1 in 20, 1 in 5, 1 in 3, to now every other patient we treat where we give immune therapy to shrink tumors down, and the majority of those patients kept it. It came at a bit of a price, because you saw that much grade 3 or grade 4 adverse events. Also¼we see responses to intracranial metastases that we really haven’t seen as high of a response with any other prior therapies. Most often with brain metastases, we think about surgery and radiation therapy. This relatively showed that nivo with relatlimab, comparedwith nivo alone, had a response rate of 40%, and it didn’t come as much with the adverse effects that we’ve seen with ipi/novo, for example. Ultimately, relatlimab works as an antibody against LAG-3. It’s another inhibitory checkpoint, and at the end of the day, the Holy Grail of what we’re trying to do is [to] get those exhausted T-cells turned on. If you can target LAG-3 and PD-1 and take the brakes off or reactivate these T-cells, you can get responses that are better than just the PD-1 therapy by itself.

All these regimens don’t really require any biomarker assessment. Certainly you can check PD-1 expression, and if they’re high, they may just do well with PD-1 monotherapy, but it’s not required. I do find that more clinical factors are more important in my decision-making when I talk to patients about what are the options and the goals of therapies. Is it response, is it disease control, is it to minimize adverse effects issues, and a lot of that is not dependent on biomarker assessment. Certainly, if this were a perfect world, I would love to have PD-1 and LAG-3expression and a variety of other things that we look at as we have more options to give our patients. At this point, I find that more clinical factors influence my decisions to offer one therapy versus another. The exception to the rule, if we’re going to talk about targeted therapy, for example with BRAF MEK, we’d need to know that they have an exon V600 alteration that’s sensitive ortargetable to BRAF and MEK inhibitors. In addition to BRAF, we also assess for ... NTRK, and NRAS, which has some options for oral therapy as well as clinical trial options.

Transcript edited for clarity.

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