Promising Late-Stage Trials in Melanoma

Jeffrey S. Weber, MD, PhD: Let’s turn to Su. Can you tell us what you think are the more promising phase 3 strategies? We acknowledge they’re not going to be mature. What do you like? I hear there’s at least a half a dozen studies going on.

Sunandana Chandra, MD: Absolutely. Most of these studies haven’t given us real mature data that we can hang our hat on. There are certain approaches that are being looked at that look fairly promising. One thing that’s being looked at is targeting the toll-like receptor 9, which is also known as the TLR9 agonists. There’s a trial out there with SD-101. Jason, I think you were involved in one with CMP-001. These agents are intratumoral injections that are supposed to stimulate dendritic cells, for example, which are antigen-presenting cells. They release more interferon-alpha. They cause more maturation of these cells, which can lead to an augmented T-cell response.

The notion behind some of this is how to make these tumor microenvironments more inflamed, more hot, more potentially amenable to T cell-mediated responses. The problem, though, at least in my experience, is that in my practice, I don’t see a lot of patients with injectable disease. A lot of my patients end up having visceral disease, and that may not be injectable. I certainly don’t want to inject into the liver very easily or the lung. Even with radiographic imaging guidance, it’s a tricky situation.

Even patients who do have injectable disease, which I said was few and far between for me, it is a challenging situation in administering the drugs. They’re not the easiest drugs to give. I certainly think that it opens doors for this particular patient population.

Jeffrey S. Weber, MD, PhD: The ipilimumab/tilsotolimod trial is also the same kind of scenario. That’s attractive because, as Jason said, let’s say you start out with nivolumab alone or pembrolizumab alone or nivolumab plus X, where X is not ipilimumab, if you progress, then you can go to ipilimumab plus Y. That has some attractions that we don’t have any data on. There were phase 1/2 data, correct, Su, if I’m not wrong?

Sunandana Chandra, MD: Yes. The phase 1/2 data there showed a response rate of a little less than 40%, I believe. It was a small number of patients. Some were between 25 and 30 patients. The data are quite early.

Jeffrey S. Weber, MD, PhD: That’s now in phase 3. Jason, there’s the lenvatinib/pembrolizumab trial. I’ve heard some good things about that. I don’t know if those are publicly known. I’m not sure that that’s been presented, but I like the idea of this pan-TKI [tyrosine kinase inhibitor] plus pembrolizumab.

Jason J. Luke, MD, FACP: There are VEGF TKIs, sort of these dirty TKIs, lenvatinib or cabozantinib or axitinib and many of them, which across a number of disease states now actually look quite promising in combination with an anti–PD-1. They’ve been approved in some indications that are obvious, like kidney cancer. That’s where VEGF agents are super-active. Even in other diseases that are epithelial in origin, and you really wouldn’t expect VEGF blockade to have that much activity, cervical cancer and now colorectal prostate, and now melanoma.

Jeffrey S. Weber, MD, PhD: Hepatocellular too, right?

Jason J. Luke, MD, FACP: Yes. It’s looking very exciting that these combinations may actually be able to overcome some of the resistance mechanisms that we’ve suggested. I wonder to what extent they are targeted therapy and to what extent they’re chemotherapy because they do a lot of things. All the same, when we’re thinking about salvaging patients who have progressed on PD-1, I think it’s all hands on deck. Certainly the initial results do sound promising.

Transcript Edited for Clarity