Remaining Research Questions in Advanced Melanoma

Transcript:Robert H.I. Andtbacka, MD, CM: I’d like to then move on and really talk about, for just a few minutes here, where the unmet needs are. I think we’ve made great strides in really treating patients with metastatic melanoma. But, Mike, stage IV disease, if you were to give me 3 things that are truly the unmet needs at the moment that we need to determine, what are those 3 things for you?

Michael A. Postow, MD: I think the most important questions really are who can we select to give treatment with the least side effects possible to still get a response or some favorable anti-tumor effect, who do we justify more aggressive kind of combinatorial treatment of some form, and how do we make those decisions? That is on the biomarker area, and we still have a way to go, unfortunately, until we can really have something that’s ready for clinical primetime. Aside from the BRAF and MEK combination—which we clearly know that combination is to be given together in the BRAF-mutant patient for whom you’re considering targeted therapy—with immune therapies in other combinations, we still really don’t have proof yet that you have to give combination treatment to patients that can increase toxicity to all patients or should be treating. And we need longer term information on that in terms of overall survival.

So, I think number 1, who can we get away with giving the least toxic treatment and still having a benefit? Number 2, I would still say that brain metastases remain an unmet clinical need. We need to think about, as a field, how do we study these patients with brain metastases? We’ve been in patterns where patients are excluded from clinical trials with brain metastases and then, subsequently, we’re later conducting phase II trials to see the efficacy of these approved drugs in the brain. I would advocate that we have to think about this earlier in development, and try to incorporate these patients as we’re learning about the drugs for the first time. And then, the third unmet need in clinical management of stage IV patients is really trying to understand better about managing toxicities in these patients. We’re often left to overall sharing our clinical experiences with these patients, but we haven’t really done as many trials as we need about the right way to manage these side effects. Unlike in some types of approaches where we have specific immunosuppression that can be used to treat specific toxicities that are caused by some drugs, we don’t have that in melanoma yet. And so, we need to have a better idea of how to support all of our patients that can have tremendous benefit from these treatments, but can also have some side effects, and how we can mitigate any adverse events in those situations. So, we’ve come a long way. It’s all very exciting. I think we’ll continue to move the ball forward quickly.

Robert H.I. Andtbacka, MD, CM: Any other unmet needs from anyone in stage IV? Tony, any additional unmet needs?

Antoni Ribas, MD, PhD: The main unmet need is the patients who don’t respond to these therapies.

Robert H.I. Andtbacka, MD, CM: If we look at the immunotherapies here, we have 25% to 30% of patients who, in the first scan that we do at 3 months, just don’t respond. And I think we need to understand those patients.

Antoni Ribas, MD, PhD: Yes. Actually, the primary resistance to anti-PD-1 therapy is around 60% to 70%. We know we can improve those numbers by giving the combination of ipilimumab and nivolumab, but there still seems to be a ceiling of what combination immunotherapy can do, and we’ve talked a lot about the toxicities. But, it’s the patients who do not respond that we need to understand who they are, why their immune system is not poised to be turned on by taking away its brakes. Do we need to turn it on in some other way? Do we need to take away some immune suppressive cells or factors that the tumor is making that is preventing immune system from attacking? But, from the BRAF and MEK inhibitor therapy—which is outstanding therapy, initially, in the majority of patients—resistance develops in many cases, but not all. And we’ve studied over the last 5 years a lot, even longer than that, what the mechanisms of resistance are that would define many of them. But, there is this subset of them that we don’t really know, and that is not allowing us to do the next step, which is turn this excellent initial therapy into a long-lasting therapy. We hope that by doing the triple therapy, BRAF/MEK plus PD-1 or PD-L1, we may turn some of those transient responses to the long-lasting responses, but we still don’t know and that’s requiring clinical trials that are ongoing.

Michael A. Davies, MD, PhD: Certainly, the other issue is those patients who do achieve those initial responses, but then progress. So, again, increasingly, we’re seeing patients who have progressed on PD-1, who’ve progressed on BRAF/MEK. What do you do now? And so, that is a completely open space where we don’t have any effective therapies at this point, an area of very active investigation, but truly an unanswered question and unmet clinical need.

Transcript Edited for Clarity