Jeffrey S. Weber, MD, PhD: We talked about what you do when someone relapses after adjuvant therapy. What if someone presents to you de novo, Hussein, and they never had adjuvant therapy or had adjuvant therapy years ago? How do you decide—let’s say, in a BRAF-mutated patient—who gets BRAF/MEK? Who gets immunotherapy? Is it the single agent? Is it the dual agent? How do you make those decisions, and how do you present it to the patient?

Hussein A. Tawbi, MD, PhD: That’s a very good question. Just to back up a little bit, I do think the adjuvant therapies are defining new phenotypes of metastatic melanoma. All our currently approved therapies have been proven in the setting when there was no adjuvant therapy. All the clinical trials that have been conducted that led to approvals were phase III randomized trials, every single one of them in the first-line setting in previously untreated patients. This gave us really great data and gave us great agents in our hands and at our disposal now to treat our patients. Unfortunately, targeted versus immunotherapy has never been compared head-to-head in the first-line setting in melanoma to date. There are ongoing trials that have tried for several years to answer that question, but at this point we don’t have the answer to that.

In general, what we do know in the first-line setting for metastatic melanoma is that we have single-agent nivolumab and we have single-agent pembrolizumab, which have both substantial response rates and improvements in overall survival. We also have combination immunotherapy with ipilimumab and nivolumab that improves response rate, seems to improve PFS [progression-free survival], and has a modest impact on overall survival, but it also comes at the risk of doubling if not tripling the toxicity rate.

For BRAF-mutant patients, we have now 3 combination therapies—dabrafenib-trametinib, vemurafenib-cobimetinib, and encorafenib-binimetinib—that are also proven to have substantial response rates, significant impact on PFS, and improvements in overall survival. So when a BRAF-mutated patients shows up, I have a lot of choices to choose among. I think we all separate this into 2 kinds of general questions: immunotherapy or targeted therapy. We do think that immunotherapy has the more durable impact in general. In case we don’t have clinical trials specific for that population, we can consider single-agent immunotherapy or combination versus targeted.

A lot of the time, both the patient preference and I can tell you in our institution, we veer more toward immunotherapy. Then we start asking the question: Do you do combination versus single agent? And in those situations, we really take a lot of clinical characteristics into consideration. Are these patients with a high tumor burden? Are these patients with a high LDH [lactate dehydrogenase]? Importantly, as we’re going to discuss later, are these patients with brain metastases at the time of diagnosis in metastatic disease? Those things can actually push us toward using ipilimumab and nivolumab in combination if you have a high tumor burden, high LDH, and definitely brain metastases.

In patients who have a low LDH and low tumor burden, single-agent immunotherapy is a reasonable approach. At our institution, we tend to keep targeted therapy for the second line, although there is no data for BRAF/MEK in the second line after PD-L1 programmed death-ligand 1 resistance. There are very specific situations in which some patients can have, as we discussed earlier, autoimmune disorders. We’re still trying to understand in those populations the safety of immunotherapy and how effective it can be. That may point us more toward targeted therapy.

Transcript Edited for Clarity