Jeffrey S. Weber, MD, PhD: Let’s turn to refractory disease. We’ve gone through resectable disease, adjuvant, neoadjuvant, frontline, and then comes the tough nut to crack. This is always the biggest challenge. What do you do with a patient who’s been through your frontline therapy, or a frontline and second-line therapy? Now you’re in third-line therapy, or if they fail adjuvant therapy, and then they get, say, combination immunotherapy [IO], then they fail, then what do you do? Adil, let’s come back to you. How do you approach patients who progress on IO if they’re BRAF wild type, or if they progress on IO, then they get BRAF-MEK, if they’re mutated, and now you’re into third-line therapy, then what do you do? What can you tell us about resistance and about how you choose what to do next?

Adil Daud, MD: This is a challenging population, and it’s a hard nut. I have to say that the last couple of years haven’t been super encouraging. From what I can tell looking at the PD-1 refractory tumors, most of those patients don’t have a lot of T cells left. That probably is why we’re seeing disappointing results with additional checkpoint blockade. Once you’ve wrung out PD-1, you’re not going to get much more from other checkpoints, simply because there are not a lot of T cells left in those tumors.

There might be exceptions to that rule. Maybe 10% or 15% of the time, you could restart treatment if you haven’t had it for a while. Your question really goes to the heavy-duty PD-1 refractory field. One encouraging signal we are seeing is getting a new bunch of T cells to come into your tumor. I personally like interleukin-12, but I think you are seeing some encouraging data from these TLR [toll-like receptor] agonists—there was the CheckMate trial that was reported at SITC [the Society for Immunotherapy of Cancer meeting] last year. There are also some intriguing responses, where you’re getting T cells coming into your tumor. You’re turning some lukewarm tumors to a little bit less lukewarm tumors. Then once you add PD-1 to that, you can get responses to it.

With the targeted therapy field, 5 or 6 years ago, there were papers showing that MET, FGF, and secondary NRAS mutation might be responsible. I don’t think they panned out enough in the data that today we can say we really understand what’s happening with BRAF resistance. It’s a challenging field, and you’re probably going to rely on things like the…study where they’re looking at adoptive T cells where, outside of the immune suppressive microenvironment, maybe you can get some fresh T cells to ramp up and then put them back in. You might get some response, although I think the jury is still out on how long term those responses are and whether those are really immune responses, or whether it’s the preparative regimen that’s doing some of the heavy lifting for you in that setting.

Transcript Edited for Clarity