Safety and Efficacy of Targeted Therapy Versus Immunotherapy in Melanoma

Antoni Ribas, MD, PhD: In the last 2 or 3 years, I have changed my view of how up-front therapy for melanoma should be. It’s because we’ve had so much data that have advanced the field so quickly in a short period of time, that we’ve come from chemotherapy, with dacarbazine being the front-line therapy, to ipilimumab to then having the excitement with BRAF inhibitors alone and then in combination with MEK inhibitors. Then we had the PD-1—blocking antibodies. And then we have the PD-1–blocking antibodies in combination with CTLA-4–blocking antibodies and other combinations that are being tested. I think the majority of melanoma oncologists in the United States would agree that up-front therapy in patients with melanoma, regardless of BRAF status, would be a PD-1–blocking antibody, either alone or in combination with approval of ipilimumab and nivolumab, or as a single agent with pembrolizumab or nivolumab. The benefit of BRAF plus MEK inhibitors is a clear benefit in the majority of patients that have a BRAF-mutant melanoma. But as we know more about them, we see the biggest benefits in patients who have low LDH and less aggressive melanoma, as opposed to where they’re used most, which is with high LDH, more aggressive melanoma.

In that situation, the response rate to BRAF and MEK inhibitors is lower, but also the response rate to PD-1—blocking antibodies is lower. But the thing is, how durable are those responses? With BRAF and MEK inhibitors, the majority of responses will not be long-lasting. But with PD-1–blocking antibodies, we need to get the new data. If a patient has a high LDH and an aggressive melanoma, if that patient has a response to how durable it is—and my biased assessment from what I see in the field is that once there’s a response, it doesn’t matter if there was a high or a low LDH–most likely, around 75% of the cases, that’s going to be a long-lasting response.

Working in melanoma, we now have approval of PD-1—blocking antibodies up front and on any line. That’s different from other cancers where PD-1 or PD-L1–blocking antibodies are being approved in a certain situation before or after some other therapy. People learn from melanoma and imply in other cancers where these agents work. We would think that the best options are as early as possible and giving it to the majority of patients. So, even though we may have pathways based on evidence of clinical trials and what was the eligibility of one trial or another, these agents have such broad activity that I think should be tested up front in the majority of patients where there’s evidence that they can work.

I hope in the future that we’ll be able to select those patients where a single-agent PD-1—blocking antibody is going to work by having an incorporation of series of markers, not only PD-L1, but others. And that will allow us to better guide patients and say, “This percent of this indication is more likely to respond to the therapies alone, which ones may benefit from a combination and which patients we know that whatever we do, they’re going to be responding to PD-1– or PD-L1–blocking antibody.” We’re not there yet, but I think we’re going to get there in the next 2 or 3 years. And it may be first in melanoma, and then it’s going to be implemented in other histologies. But I hope that gets incorporated into the clinical pathways early on. These agents have made it into the clinic and benefited patients, because the right science was applied to patients. With all this in a paradigm, we’re going to treat patients better in the future by better selecting and guiding.

In the field of metastatic melanoma, we’ve had the advent of BRAF inhibitor—based therapy in the PD-1–blockade therapy, coming close in time into the clinic. This has made us rethink what would be the best up-front therapy and pull-up therapy on patients who have a BRAF-mutant melanoma, where we could go the targeted therapy way or the immunotherapy way.

We do not have a trial that tells us the right or the wrong answers to this one. There’s actually a clinical trial by the US Cooperative Group, by ECOG and SWOG, that’s comparing dabrafenib/trametinib, a BRAF and a MEK inhibitor, to ipilimumab and nivolumab, the CTLA-4— and PD-1–blocking antibodies. And patients are randomized up front to either therapy and then allowed to sequence whenever they progress. I think that study will tell us a lot more of what would be the right and the wrong answer. I don’t know the answer, but I know that if we can get a long-lasting response with an up-front therapy, we might as well try to do that first. With PD-1–blocking antibodies, we’ll have lower activity with a very low toxicity profile. And 2 or 3 years later, around one-third of the patients are alive and well, and going on with the therapy or having stopped at some point.

When we combine ipilimumab and nivolumab, CTLA-4— and PD-1–blocking antibodies, we’ll have higher activity, but also higher toxicity, and we need to try to manage that. The targeted therapies dabrafenib/trametinib or vemurafenib/cobimetinib are the two combinations that have been approved and that have higher activity, but the majority of patients will progress on therapy and will become resistant; it’s not all of them. There’s a tail in the curve that’s starting to be evident. We need to know where that tail of the curve lands: is it lower, the same, or higher than with the PD-1–blocking antibodies alone or in combination? My assessment of the field, it seems like that the tail is evident, but maybe a little bit lower. So, that’s why I would err on the side of trying to give a PD-1–blocking antibody up front to patients with metastatic melanoma.

The targeted therapies for melanoma are usually pill therapies—dabrafenib/trametinib or vemurafenib/cobimetinib—which are well accepted by patients, but you need to take them all the time. Patients, after a while, may start forgetting about it or they may have something that they need to do. And you have to take the pills twice a day. It becomes something that reminds you twice a day, “I’m being treated.”

Infusional therapies are IV treatments. Nobody likes to have an IV line placed in them, sitting there for 1 or 2 hours to get that therapy and have blood tests before and all of this. But, for the period of time that they’re not getting the IV, there’s no treatment to be thought about every day. I think it’s a good thing for patients to be able to forget about these and be able to go on with their rather normal life when they’re being treated and responding. And that may be a long-lasting response that may last years. So, I’m not sure. I haven’t asked a patient, “Would you rather have a pill for 2 years or an infusion for 2 years?” Maybe it would be the pill, but then in practice, some patients would like to not have a pill all the time. It’s a hard question to answer, but maybe the randomized trials will tell us. There’s quality-of-life assessment in the randomized trial compared to targeted therapy and immunotherapy. This would be a good one to try to get from there.