Jeffrey S. Weber, MD, PhD: Jason, what about extracranially? There’s this urban legend that you could give a brief burst of BRAF/MEK inhibition, light up the tumor, and then give immunotherapy. Do you do that in practice?

Jason J. Luke, MD: I rarely do that in practice currently. I think that that’s actually an open question. I think great data was generated now—it seems like a long time ago, but really not too long ago—to show that actually, after initiation of a BRAF inhibitor and, presumably, with the combination, you do see an initial influx of CD8 T cells into tumors. That was mostly from data in cutaneous lesions, although some from deeper lesions, suggesting that you could then amplify an immune response. Now, I think that that’s a fraught area, because the interrogation of those infiltrating TILs is not exactly well characterized for us to know whether or not that’s truly making the tumor inflamed in the broad sense of gamma—interferon associated gene expression. But it does suggest that you could have a benefit.

I think that’s actually a separate question, though, around this idea of using the therapies in an optimally sequenced way for an individual patient. So, if we think that we could reduce the LDH, bring down the disease burden, and then give the patient an opportunity to get the most benefit—find another therapy—that’s using it in a slightly different manner. And I think both questions are probably important, but they are not necessarily overlapping.

Jeffrey S. Weber, MD, PhD: Let’s segue for just one moment. We haven’t talked about toxicity. We’ve danced around the issue of the fact that our therapies can be very effective, but at what cost? So, Mike, how do you talk to the patients, and how do you monitor them for side effects when you’re giving immunotherapies?

Michael A. Davies, MD, PhD: I think that conversation really starts with trying to explain to the patients how immunotherapy is different from chemotherapy—so, the fact that the mechanism is so different, the way that it works is so different, but it also means that the side effects are different. I certainly talk with the patients extensively about how important it is to communicate to physicians when they do have side effects, because I think the experience that we’re all building up is that as long as we are actually able to hear about the side effects relatively early, our interventions are very successful at getting those under control. The patients whom we’ve had extreme difficulty with are patients who don’t actually report the side effects that they’re having, and they present when the side effects are extremely advanced and can be quite refractory to treatment at that time.

The key for us is really emphasizing that communication, particularly with the data that patients who have had autoimmune toxicities from immunotherapy are often patients who actually, in terms of the anti-tumor effect, have a very good response, and for whom holding therapy or using immunosuppressive treatments to control side effects doesn’t seem to abrogate that anti-tumor effect. And so, we are trying to reassure patients, because there’s often a lot of fear. They don’t want doctors to stop their treatment, but we must really reinforce that “no, this is really a case where the dangerous thing is for us not to know about the side effects that you’re having.”

Jeffrey S. Weber, MD, PhD: Yes, there’s no question. We have the world’s expert on intralesional therapy here. So, Robert, have you routinely been using T-VEC, the injectable engineered herpesvirus, alone? Or do you think it should ultimately be used with a checkpoint inhibitor?

Robert H.I. Andtbacka, MD, CM: That’s a very good question, Jeff. So, I think that in patients with earlier disease—these are the patients with in-transit and lymph node metastases, such as the stage 3B and 3C patients—and also some patients with distant lymph node and cutaneous lesions, the stage 4 M1C, M1A patients. There, I think T-VEC by itself can actually be very effective, and we know that the response rate in those patients—the global overall response rate—is 52%. So, actually, it’s a very high response rate. Now, what we do not know is, in those patients specifically, what’s the response rate to the checkpoint inhibitor?

For instance, the ipilimumab data we presented at ASCO yesterday were the results of the 264 study, which was ipilimumab alone versus T-VEC/ipilimumab in a phase II randomized clinical trial with patients with unresectable stage 3B, 3C, or 4 melanoma. Looking specifically at that patient population, these earlier patients with stage 3B, 3C, or 4 M1A melanoma, the response rate to ipilimumab in that patient population was 19%. So, I think it is clear that in this patient population, the injectable therapies seem to be more effective.

Now, we don’t usually use ipilimumab after first-line therapy for these patients. We use PD-1 inhibitors more often. But we also know from the data there that the response rate to PD-1 inhibitors in that patient population is on the order of about 27% to 35%. So, to answer your question, I think that in these patients with earlier disease—patients who have a limited amount of disease—using an intralesional therapy such as T-VEC is very appropriate, and we can get durable responses.

In addition, we have also presented data that show that in these patients who have not yet developed lung, liver, and other distant metastases—there are some patients who actually will have an increased time to developing those—the T-VEC seems to potentially prevent those patients from developing them. Having said that, though, in patients with more advanced disease—patients who have lung, liver, and other disease—I do think that these oncolytic immunotherapies should be used in combination. The 264 study also showed yesterday that in those patients, it definitely is more beneficial to use these in combination.

We also have ongoing studies looking at this specifically with PD-1 inhibitors. There’s a 265 study in which we are randomizing patients to receive intralesional T-VEC/pembrolizumab versus an intralesional placebo, which I think is very important, because the whole question is, what does that intralesional therapy really do? Can we just inject something into the lesion and get the same immune response? And we don’t know the answer to that. So, in that control arm, we have intralesional saline that we’re injecting with pembrolizumab. That study will also tell us—we hope definitively—if combining these 2 therapies, intralesional therapies and the PD-1 inhibitors, is more beneficial than pembrolizumab by itself.

Jeffrey S. Weber, MD, PhD: We’ll get back to T-VEC in just a little while, because you’re talking about it used upfront.

Transcript Edited for Clarity