Intralesional Therapy in Metastatic Melanoma

Transcript: Axel Hauschild, MD: Let’s make a cut here and use the last minute of this section to discuss intralesional approaches. There is so much clinical trial data out there. It’s confusing for those who are not experts in this field. T-VEC, Merrick, has an established role. It’s approved as single-agent therapy. But we are waiting for data from the MASTERKEY-265 randomized clinical trial that looks at pembrolizumab plus or minus T-VEC.

Caroline Robert, MD, PhD: Maybe you can explain what T-VEC is again?

Merrick I. Ross, MD: Yes. This whole concept of oncolysis is an interesting concept. Whether you use T-VEC, or other viruses, or other agents to stimulate a local response that can initiate a systemic immune response is really an interesting concept. In theory, it makes sense to combine these approaches with anti—PD-1 [anti–programmed cell death protein 1] therapy because they could be synergistic with one another. Maybe you increase or change the tumor microenvironment and increase the expression of PD-L1 [programmed death-ligand 1] and T-cell infiltration into the tumor that could lend itself to a better response rate with a backbone of anti–PD-1.

So T-VEC, as a single agent, is approved in the United States and Europe. We see a different kind of label, but this is approved by both agencies. But in reality, only a limited number of patients would be appropriate for monotherapy. It’s for patients who have relatively long disease-free intervals with a pretty indolent course and local and in-transit metastases. For those patients, if they have a lot of other underlying comorbidities, you could use single-agent T-VEC and have really excellent responses and very good control. But the future of this is in a combination regimen.

So the MASTERKEY-265 trial was a randomized trial of single-agent PD-1—pembrolizumab, in particular—versus the combination of T-VEC and PD-1, assuming that they have injectable lesions. That accrual has been complete. The phase Ib trial has been published, showing a very nice response rate. I think it was 62%. The results provided some really interesting translational information, showing that you can increase PD-L1 expression, gamma interferon expression, and CD8 infiltration of T cells into the tumor. So we’re looking forward to the long-term results of that particular trial, and I think it’s a paradigm that we’re going to see, particularly in patients who develop resistance to PD-1. The addition of an intralesional therapy or an oncolytic therapy will hopefully change a nonresponder into a responder.

Axel Hauschild, MD: So Merrick, for me, the most interesting abstract from this ESMO [European Society for Medical Oncology] conference is the one on the PD-1—refractory patients.

Merrick I. Ross, MD: Yes.

Axel Hauschild, MD: Which used a toll-like receptor 9 [TLR9] agonist. IMO-2125 was the cryptic name. At least for a German’s tongue it’s difficult. Tilsotolimod—is that the right pronunciation in the United States as well?

Merrick I. Ross, MD: Is that harder than talimogene laherparepvec?

Michael A. Davies, MD, PhD: IMO-2125 rolls off the tongue much more easily.

Axel Hauschild, MD: OK, good. This is an interesting study because it was a crumble of ipilimumab, which we are likely to give in the second-line setting anyway, combined with an intralesional agent. Is anyone at the table willing to give a comment on these clinical trial results?

Jason J. Luke, MD, FACP: Absolutely. I think this is a paradigm that we’re going to see build out further. In this population, we are using an injectable synthetic toll-like receptor 9 agonist, which is a molecule that is part of the normal virus-sensing machinery in your body that will drive the development of an immune response. Here, you’ve put it directly in the tumor, to try to drive that response, in combination with ipilimumab. Researchers saw that even in PD-1—refractory tumors, they were getting up to a 30% response rate that really did look beneficial out over a long period of time.

I guess the reason I wanted to jump in and feel so excited about this is because they are not the only company with TLR9s, and that’s not the only node downstream within the type 1 interferon pathway. And so there are molecules—other TLRs as well as STING [stimulator of interferon genes] agonists, RIG-I [retinoic acid-inducible gene I] agonists, and so on and so forth—that look to be very, very interesting as they come forward in the future, when we look to see how we can sort of capture patients back after they have had progression on initial treatment with PD-1 and CTLA-4 [cytotoxic T-lymphocyte antigen 4].

Axel Hauschild, MD: Do you see any advantage in one over the other—of the STING agonist versus a toll-like receptor agonist? Is there a clear difference?

Jason J. Luke, MD, FACP: I think it’s too early to determine that yet. These pathways are very similar, but they are not exactly the same. We don’t understand them well enough to say whether one would be better than the other. My guess is that in the end it will come down to pharmacokinetic and pharmacodynamic properties.

Caroline Robert, MD, PhD: Yes, and I think we need to make 2 points. First, for the evaluation, I think it’s very important that when we evaluate, we evaluate the injected and the noninjected lesions differently.

Merrick I. Ross, MD: Absolutely.

Caroline Robert, MD, PhD: Because there was a mix, and it was discrediting the field. Secondly, I think we also have to work…. This is not so easy to inject. If you inject too much of the STING agonist, for example, you have the opposite effect. We have to be smart when using that option. We also have to develop a very good relationship with our interventional radiologists, so they can go and inject properly, not only in the skin and the lymph nodes but in the other organs.

Michael A. Davies, MD, PhD: I have to say that with the injectable therapies, again, there is something very intrinsically logical about this approach. I think the results look quite promising. The part that is interesting is the idea that we’re going to have to compare this with systemic administration of therapy eventually. Again, thinking again about Jason’s report at ASCO [American Society of Clinical Oncology Annual Meeting] last year with systemic ipilimumab plus PD-1 therapy, how will that combine? It’s essentially based on deciding what the right thing to combine with ipilimumab is in the second-line setting after PD-1. And to this point, it is one of the interesting parts. We talk about many of these things. We still haven’t really compared things head-to-head. It’s a good thing to get to the point of saying that, yes, we’re seeing enough activity to make it worth doing those types of trials.

Merrick I. Ross, MD: But here’s the challenge: registration. It’s going to be very difficult for the FDA to figure out a way to get these therapies registered and approved. No one is going to use these therapies as monotherapy, so there is not really space to approve TLR9 as monotherapy. They’re going to have to be approved based on combination therapy, and that’s going to be a challenge.

Jason J. Luke, MD, FACP: It’s a challenge, but it’s doable.

Merrick I. Ross, MD: I agree.

Jason J. Luke, MD, FACP: Cobimetinib was approved in the United States only in combination with vemurafenib, right? So it’s not as if there is no precedent.

Transcript Edited for Clarity