Jeffrey S. Weber, MD, PhD: The big area of research and controversy in melanoma is, what do you do when someone has been on these effective therapies and has become resistant—with either resistant or recurrent disease? Mike, do you biopsy patients who progress on BRAF/MEK inhibition? Do you want to find out what the mechanism of resistance is, or is this something that would not impact on your management, and you just wouldn’t do it?

Michael A. Davies, MD, PhD: Certainly, working at a large academic center, it’s a high priority for us to find those clinical scenarios that have truly unmet needs. So, specifically within the targeted therapy world, the reason we developed the combination of BRAF and MEK inhibitors was because of biopsying patients who progressed on single-agent BRAF inhibitor therapy. The fact of the matter is that the therapies we have now are actually a product of collecting those types of tumor samples.

Georgina Long, MD, PhD: You wouldn’t do it for clinical use. You do it for your research program to try and push the field forward and find better and newer drugs, right?

Michael A. Davies, MD, PhD: Correct.

Georgina Long, MD, PhD: But, as a clinician out there in the community who’s not part of an academic research program—sure, if you can get in on it, add your samples, but you wouldn’t do it to make a clinical decision, would you?

Michael A. Davies, MD, PhD: Particularly in terms of standard therapies—there are actually a number of clinical trials like NCI-MATCH where you can actually do biopsies and do molecular profiling. If there is a targetable lesion, they can get matched up to a clinical trial for that. And so, in that way, it could potentially impact clinical care. But if we’re talking about standard of care and FDA-approved agents, it’s not quite clear that biopsy at this point would help inform us. Certainly, one of the things we do know for patients progressing on targeted therapy is that the BRAF mutation is still there. We don’t see patients converting to a BRAF wild-type phenotype.

Jeffrey S. Weber, MD, PhD: So, Jason, do you think there’s a different manner or biology of progression in someone who gets targeted therapy or someone who gets immunologic therapy? Is there any difference?

Jason J. Luke, MD: Well, I think there’s certainly a biological difference. The clinical difference would be harder to exactly profile. I think with targeted therapy, as well as the use of immunotherapy earlier on, we commonly see that lesions that were present will start to progress. We do sometimes see that with targeted therapy, there will be new lesions. But the broad point I would like to make in that space is that if you see disease control with 1 progressing lesion or 1 new lesion and so on and so forth, the multidisciplinary approach of handling that lesion—especially in a community where perhaps they’re not going to have access to 8 novel trials of new agents—really maximizes the treatments that we do have.

And so, even in the university setting, I’ve started to use a lot more stereotactic radiation to sites of progression, sometimes even to multiple sites at once. If the patient has been deriving benefit from a therapy, whether it be PD-1 or BRAF/MEK inhibition, if I think I can control those 2 sites and keep them and they seem to be doing well, I employ those strategies quite confidently.

Jeffrey S. Weber, MD, PhD: Although, what are the triggers for switching? In other words, it seems to me that we’ve developed a philosophy over the last decade, whether it be for targeted or immunotherapy, that you can treat beyond progression. We’re a little reticent to switch. Mike, when do you switch?

Michael A. Davies, MD, PhD: I think one of the things that’s worth talking about, too, is relatively new data thinking about targeted therapy. There was a trial published in Lancet Oncology, and actually a similar experience reported at ASCO, where patients who were BRAF-mutant and treated with targeted therapy progressed and went on to receive immunotherapy, and then progressed on immunotherapy and were then rechallenged with BRAF/MEK combinations. And in both of those studies, while there is some heterogeneity—particularly in the data that were presented at ASCO—there was a very reasonable response rate for rechallenging with targeted therapy.

The data are that those forces that drive for the selection of resistant clones in the presence of targeted therapy, those same molecular changes, may not be so favorable when patients are off of the targeted therapy. Those resistant clones may actually disappear, such that if somebody develops resistance to targeted therapy, that is not necessarily a permanent change. So, when you talk about these refractory patients, I think this is an example of where we have this new paradigm, potentially, of being able to go to therapies that worked previously.

Jeffrey S. Weber, MD, PhD: Georgina, would you rechallenge with targeted therapy? Let’s say you get a response to targeted therapy transiently, they go on immunotherapy, and then they progress: Would you go back to targeted therapy?

Georgina Long, MD, PhD: I would in certain circumstances, but again, it would be a multidisciplinary team approach. Patients are very different and very heterogeneous, so you’d have to consider the patient in front of you. For example, if a patient progressed in 1 very easily resectable site on immunotherapy, I tend to find—this is gut feel we’re talking about now, and just experience—that progression on the immunotherapy after a response is typically slow and easy to manage. So, I would manage it with local therapy in that situation. However, if they develop multiple sites of progression or multiple brain metastases, you may be forced to switch therapy or consider other therapies. But again, the bottom line is, it does need to be tailored to the individual patient and done with a multidisciplinary approach of using radiotherapy, surgery, and maybe switching drugs. You need to look at the whole picture.

Jeffrey S. Weber, MD, PhD: Jason, how many lines of therapy are your patients getting? Do you think about IL-2 at all?

Jason J. Luke, MD: So, 2 questions—1 is about lines of therapy, 1 is about IL-2. The answer to lines of therapy is that patients get many, many lines of therapy now, because we have this idea of recycling therapies. We’re always looking for how we can maximize what we got: How do we think about the next step? And for many patients, especially at a referral center like an academic center, we see a lot of younger patients, so then we’re really trying to think of how we are going to plan this out over a very long period of time. I actually don’t even know what the median number of lines of therapy is that my patients get.

Now, is IL-2 one of them? I would have to say it’s less common that I refer for IL-2 at this point. I think that’s partly because of what we just said: Patients will cycle through many lines of therapy, and IL-2 is still a difficult treatment to tolerate. So, they have to be in pretty good shape in order to consider that. We do consider it at some point. I have referred a few people in the last year, and I have to say, I’ve seen patients go into CRs after they’ve been refractory to all other available therapy. It’s still something that’s out there, but I would say it’s not commonly used.

Jeffrey S. Weber, MD, PhD: And then the question is, what do you do in someone who is BRAF wild-type who fails ipilimumab/nivolumab? What’s your next step? Robert, what do you recommend to patients?

Robert H.I. Andtbacka, MD, CM: I think those are really difficult patients. And in that setting, we recommend a clinical trial for those patients.

Jeffrey S. Weber, MD, PhD: What about T-VEC? Does T-VEC work in a relapsed or recurrent immunotherapy-resistant patient?

Robert H.I. Andtbacka, MD, CM: That’s a very good question. First of all, we have to remember that for the use T-VEC on an intralesional therapy, we’ve primarily used it in patients who have dermal subcutaneous or lymph node metastases that we can inject. We have not routinely used it in visceral lesions; not that we couldn’t do it, but it hasn’t been part of the clinical trials. So, I think that in this specific situation, if we have a patient who has been on a checkpoint inhibitor, PD-1 inhibitor, or ipilimumab and they’re BRAF wild-type, the next question is, what do we do then? We can use these oncolytic immunotherapies to try to change the tumor microenvironment.

Now, we’ve done this—not necessarily with T-VEC but with other clinical trials that we’ve reported on—where we actually found that often, when you do a biopsy of these lesions, they have very few tumor-infiltrating lymphocytes. And for us to think about it, in order for these checkpoint inhibitors to work, we really need to have the lymphocytes in the tumor. We can then inject them with these oncolytic viruses to change the tumor microenvironment. We reported on several of these cases where, at that point in time, we can also reinitiate some of those checkpoint inhibitors to try to get a response. Now, whether or not that works consistently, we don’t know, but we are currently running clinical trials where we can do that. One of those options is potentially T-VEC, but also other oncolytic immunotherapies.

Michael A. Davies, MD, PhD: Jeff, can I just mention chemotherapy? It’s something that does not have a role in frontline therapy, but in the NCCN guidelines, it’s actually an option for second- or third-line therapy. One of the things we end up talking about with colleagues at meetings, the impression some of us have, is that we have seen patients who were refractory to immune therapy and subsequently treated with chemotherapy who’ve not only had responses, but responses that seem much more durable than what we’re used to seeing with chemotherapy. We’ve published a case report on this—I know others have published case reports on this—that there is another option there, particularly for your patients who aren’t eligible for clinical trials. You can see very dramatic responses to chemotherapy, I’ve found, in the immunotherapy-refractory patients.

Transcript Edited for Clarity