Sequencing Therapies in BRAF Wild-Type Melanoma


Jeffrey S. Weber, MD, PhD: Let’s segue to the next logical issue, which is that patients have been given the checkpoint inhibitor but they’re BRAF wild-type, and ipilimumab/nivolumab, pembrolizumab alone, or nivolumab alone fails. Then what do you do?

Axel Hauschild, MD, PhD: This is the biggest problem for us at the moment. In some patients, you can take a rebiopsy of another lesion not from the same organ, simply because in 5% of patients you might have discordant results between different organs: cutaneous metastasis, and so on. And we are sometimes using the cobas testing in a secondary analysis, which means we have another 5% option that the patient is carrying a significant mutation, the V600E mutation, which is not detected by all routine sequencing, just to mention this. So, for these patients, I think the most important clinical question is if the combination of ipilimumab and nivolumab is useful in second and third-line treatment, and this has not been discovered. I hope so, but I guess that it is like all the other treatments, that it is less good compared to first-line, and therefore, I would prefer to give ipilimumab plus nivolumab in the first-line setting.

Jeffrey S. Weber, MD, PhD: Caroline, in your institution, how many lines of therapy are patients now getting?

Caroline Robert, MD, PhD: We also have the same kind of problem, of course. If you have used immunotherapy first-line in a BRAF wild-type patient, then you end up being in a situation where we were years ago. Now we have problems with this situation, so we use a clinical trial if we can. Coming back to Axel’s point—to check if we did not miss the mutation—you can also look for it in the blood, because there are now some tests on circulating DNA that can help us. If the patient is metastatic, it begins to be more and more sensitive. But then, yes, we use a clinical trial if we can. I’m very happy to be in a center where we have a lot of clinical trials, including phase I trials. But then, if not, it happens to us: We go back to chemotherapy. Then, there is a sort of urban legend that says that patients who have been treated with immunotherapy respond better to chemotherapy. I don’t know if it’s true.

Jeffrey S. Weber, MD, PhD: Does anyone think that’s true? That’s an interesting point.

Caroline Robert, MD, PhD: I saw some very spectacular responses to chemotherapy after immunotherapy, but we know that they could sometimes happen without it. I don’t know. I think we are not going to do clinical trials to check that, because we have more exciting drugs to test. But there is an effort by some colleagues to collect this information.

Jeffrey S. Weber, MD, PhD: At this table, we have at least a century of experience. That’s a lot of experience. So, does anyone think that patients who fail immunotherapy—now, are you saying primarily refractory? Or, they may have had a response and then progressed?

Caroline Robert, MD, PhD: I don’t know, because I don’t have enough data.

Jeffrey S. Weber, MD, PhD: Take either category. Would they have a better response to carboplatin and Taxol (paclitaxel) or dacarbazine? Does anyone think so? Reinhard?

Reinhard G. Dummer, MD: I hardly dare to say it, but I think it might be. I have a few patients in mind, where we use this as a bridging therapy. Sometimes, we use this in symptomatic patients, and I have had a few patients with very surprising responses. Actually, we are somehow retreating with targeted therapy. These data are out there, and we are also retreating with immunotherapy.

Caroline Robert, MD, PhD: Yes.

Reinhard G. Dummer, MD: Sometimes, I think it’s good to give a break. You need to do something. If we don’t do anything, I think it’s tricky. Using chemotherapy—and I really would call it a bridging therapy—might be a good idea. Especially in Paris, there are a number of papers about v, chemotherapy-induced cell death, and the release of antigens that might help to reset the scene. I also think that the implication of the T cells that are out there is that maybe, if you reset, if you have chemotherapy-induced lymphopenia, this might result in autocrine stimulation of the T-cell compartment and maybe a resetting of the T-cell repertoire. I think chemotherapy is not dead.

Transcript Edited for Clarity

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