Melanoma: Progression After Immunotherapy

Transcript:

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?

Jeffrey S. Weber, MD, PhD: Is the abscopal effect something that is a significant enough phenomenon that you would want to pursue that?

Hussein A. Tawbi, MD, PhD: I think it’s really interesting. It’s exactly in the realm of clinical trials. I think I should have prefaced most of what I’m saying—what you’re doing in this setting are clinical trials trying to understand which approach may have safety and efficacy. It’s mostly phase I and II clinical trials. We’re starting to see a range of phase III trials in this setting, and I think there’s an absolute dearth of that at this point in time.

A couple of other approaches I’ll just bring up really quickly are to target certain mechanisms of immune resistance. We’ve been hearing about things like LAG3, TIM-3, TIGIT and also potentially using the intratumorals that some of you have discussed. T-VEC [talimogene laherparepvec] is 1 of them, but there’s a bunch of other intratumoral approaches that seem to be capable of inducing an immune response as well. But it’s an open field at this point in time, and again, I would go back to the fact that I don’t have the answer, and neither does anyone at this point.

Jeffrey S. Weber, MD, PhD: Ryan, let me put you on the spot. What clinical trials, of those that are presented here and the trials in progress, do you like and do you think are the most promising? For example, the LAG3-nivolumab or nivolumab-NKTR, pembrolizumab—T-VEC. Which ones do you think have promise?

Ryan J. Sullivan, MD: I think certainly if a patient has an injectable disease, thinking about an intralesional approach plus continuing a checkpoint inhibitor, there are a number of TLR [toll-like receptor] agonists, which are things in our body that actually help stimulate immune response. Injecting those into tumors might help jump-start the immunity in that tumor, with the ideas that inspire some of those tumor-specific cells to spread out of that tumor that’s been injected and go elsewhere. I think there are now more and more trials that are looking at the tumor that’s not just on your hand but in other places.

In a lot of clinical trials intralesional therapy is not just injecting something you can feel but injecting something that can be identified by ultrasound or even CT [computed tomography] guided. Injecting visceral lesions is beginning to happen now. The challenge, of course, is that it’s hard to continually inject visceral lesions or continue to inject multiple visceral lesions. That’s a challenge, of course. But I think that’s 1 avenue, and there are a number of studies with SD-101, with T-VEC, and with CMP-001. These are all TLR agonists or oncolytic viruses that have the potential to jump-start those.

I think from a systemic standpoint, it would be lovely. Because it looks as if the active agents in combinations with a PD-1 inhibitor or a PD-L1 [programmed death-ligand 1] inhibitor have some way of understanding whether the 15% to 20% of patients are the same 15% or 20% of patients or if they’re different patients. For example, for LAG3 expression, are those the patients who have high-LAG3 expression post-PD-1? Is giving that a predictor? If they have expression, will the response rate be 50% instead of 20%? Will that person who doesn’t have LAG3 expression not benefit at all from that? If that’s true, they shouldn’t get LAG3. They should get something different.

There are a number of ways of targeting the tumor microenvironment. You can target cytokines and chemokines. You can target regulatory T-cells. You can target myeloid-derived suppressor cells. And there are multiple ways of tackling these problems, but as Hussein has mentioned, it’s really the realm of clinical trials right now to try to understand this.

Transcript Edited for Clarity