Advances in Systemic Therapy for Melanoma - Episode 5

Data in Melanoma: Observing Trials and Unmet Needs


Jeffrey S. Weber, MD, PhD: The data—actually, they were data I presented at ASCO—suggested, Michael, that you could have long-term survival with BRAF/MEK therapy.

Caroline Robert, MD, PhD: Sure.

Michael A. Postow, MD: Right. And Jeff, to take one of your quotes, one of the urban legends in melanoma has always been, “Everyone responds with targeted therapy and then everyone progresses.” And that’s, as we know now, just not true. There is a group of people who do incredibly well long-term with dabrafenib and trametinib or vemurafenib and cobimetinib. Those are the patients with good prognostic factors, as one would expect. So, those are the patients it’s really, really difficult to know what to do with.

Caroline Robert, MD, PhD: Do you stop the drugs?

Michael A. Postow, MD: Usually, those patients stay on the drugs with the targeted therapies. I think to your point, Dr. Robert: I think that it’s an important one. A lot of patients—and I think this is a lot of the value for immune therapy—have that immediate response. You may or may not stop for toxicity or other reasons. Then, the treatment-free interval after finishing treatment, and remaining in a long-term partial response or complete response, is very, very impressive for all treatment with immune therapies. And I think that’s a big advantage.

Caroline Robert, MD, PhD: That’s an element that I take into consideration, I must say.

Jeffrey S. Weber, MD, PhD: And it’s always BRAF/MEK therapy. Is there any place for a single BRAF inhibitor?

Reinhard G. Dummer, MD: Well, if there are cardiac problems sometimes or ocular toxicity, that can be a reason to exclude a MEK inhibitor, but this is the exception. In general, you prefer the combination. You have a better outcome concerning efficacy, and you have a better tolerability. I would say, in general, the combinations are better tolerated than the monotherapy.

Jeffrey S. Weber, MD, PhD: I will make one interesting observation though. The only way we will ever settle the issue of immunotherapy first versus targeted therapy first is to do a randomized trial, and that started in the United States as a Cooperative Group trial. I just don’t know that it’s ever going to get done, because there appears to be a preconceived notion that everyone should start with immunotherapy. We are victims of our biases, and that will complicate that trial.

Axel Hauschild, MD, PhD: This study could be done in Europe easily, I tell you. The 300 patients you need for this study, they would be recruited in 2 months.

Jeffrey S. Weber, MD, PhD: Will the EORTC do such a study?

Caroline Robert, MD, PhD: Yes, but there is a problem, an administrative problem, where we cannot.

Axel Hauschild, MD, PhD: No, I heard about the same issue in the United States. There is a more gut feeling driving the decision, and once you sign on for a clinical trial, you must be convinced that it is ethically correct to randomize patients either to BRAF plus MEK inhibitors or to ipilimumab plus nivolumab. If you’re not convinced that this is the right schedule for your patient, I think you shouldn’t contribute to the clinical trial. That’s the issue.

Michael A. Postow, MD: But the Italians are running a study where they’re randomizing patients to BRAF/MEK and ipilimumab/nivolumab, and I hope that it will give us some information. In that study, there’s a third arm, too, which is interesting. It is a run of the BRAF and MEK inhibition and then a switch to immune therapy to really try to get to that other notion that’s been out there, that maybe you start a BRAF-mutant patient with targeted therapy for some duration of time and then switch to immune therapy.

Axel Hauschild, MD, PhD: I was asked this in the plenary session room today, and I had the observation with 2 personal friends. I need to say, they’re 2 women in their early 50s who are both suffering from metastatic melanoma, stage 4. One of them had a very high tumor load and she was suffering, and we believed she was dying immediately. She was in such bad shape: ECOG 2 to 3, hospitalized, really bad. And both of them got BRAF plus MEK inhibition, and after 9 months, one had 90% shrinkage of the lesion and the other had 80% shrinkage. One was switched after 9 months and the other one after 12 months, without progressive disease, to a PD-1 inhibitor alone. And fortunately, one is 1 year, 9 months—the other is 2 years—in almost complete response or complete response.

Jeffrey S. Weber, MD, PhD: That is something that we do ad hoc, and again, we have the gut feeling that’s a good thing to do.

Axel Hauschild, MD, PhD: But that’s not evidence-based medicine.

Caroline Robert, MD, PhD: We have an EORTC trial that is going to be initiated very soon, where we evaluate the combination of immunotherapy preceded, or not, by 3 months of targeted therapy.

Axel Hauschild, MD, PhD: I like it.

Caroline Robert, MD, PhD: So, I really think it’s good to do that in the frame of a clinical trial, so that we can have at least some conclusion.

Jeffrey S. Weber, MD, PhD: So that we can be data driven.

Transcript Edited for Clarity