Melanoma: Progression After Immunotherapy

Source: OncLive, September 2019

Jeffrey S. Weber, MD, PhD: Let’s transition to the elephant in the room. We’ve heard great things about single-agent PD-1 [programmed cell death protein 1] blockade, ipilimumab-nivolumab, BRAF/MEK—multiple combinations, all frontline therapy. What do you do when somebody progresses right after their initial immunotherapy, or their BRAF/MEK therapy? Obviously, if you’re BRAF mutated, you can flip from 1 to the other. That’s easy; not a problem. But what if you’re BRAF wild type? What do you do if you fail ipilimumab-nivolumab? Hussein, what do you think is either coming down the pike? Do you think you have the solution to what to do in second line if someone fails immunotherapy and, say, they’re BRAF wild type?

Hussein A. Tawbi, MD, PhD: I don’t have the solution. Neither does anyone, as far as I can tell at this point. It’s a really difficult problem because, as we come up with effective therapies, we’re defining new phenotypes of melanoma. And this new phenotype of PD-1, CTLA-4 [cytotoxic T-lymphocyte–associated antigen 4]–resistant phenotype is actually heterogeneous because there are multiple reasons why the immune response might have not actually happened in the first place, which we call primary resistance. Or patients who have had a response or stability of disease and then progressed, which would be considered secondary resistance. There are multiple different mechanisms that have been described to a certain degree that tell you that this may be the reason these patients are not responding.

But in general, we don’t really know how to classify those patients at this point. There’s been a lot of interest in this field, a lot of drug development that’s happening, and the whole idea in the situation is how to reinvigorate the immune response. If it had already started and then waned off, can you reinvigorate it with, say, adding radiation therapy to certain parts of the body, the so-called abscopal effect? Or do you need to have a completely different approach and come in with drugs that target some of these mechanisms of resistance?