Hussein A. Tawbi, MD, PhD: In metastatic melanoma, testing for the BRAF mutation is very important up front, so we know if our patients have the option of being treated with targeted therapy. All the currently approved therapies in the metastatic setting have actually been approved in the first-line setting. BRAF/MEK inhibition was dabrafenib-trametinib, vemurafenib-cobimetinib, and now encorafenib-binimetinib. All 3 combinations have been tested in the first-line setting.

Nivolumab—single-agent. Ipilimumab—single-agent. Pembrolizumab—single-agent. These are all approved in the first-line setting. And then we have data on nivolumab in combination with ipilimumab, where we have some improvement in PFS [progression-free survival] and a modest improvement in OS [overall survival]. Again, the combination is approved in the first-line setting. Technically, all the data we have at our disposal is really for: What do you start your patients with? What happens to your patient if you start with a certain therapy first? We don’t have great data to guide us on what to do in the second-line setting. I think that is actually where a lot of the confusion and a lot of the debate on what you should start with comes from.

What we do know is targeted therapy is highly effective and it works very quickly but also has a limited duration of response. What we know from immunotherapy is that you have potentially lower response rates if you start with a single-agent option. However, almost every response that you get with immunotherapy tends to be more durable if not very durable. If you can achieve a complete response, for instance, with immunotherapy, those responses look as if they’re durable for many years. Partial responses seem to be durable, but some of those patients can still progress.

We discuss all those aspects with patients. We generally err on the side of using immunotherapy unless the patient has some reason to start with BRAF-targeted therapy first, such as a need for quick responses. We say this knowing that sometimes those patients who need quick responses have high LDH [lactate dehydrogenase] levels and have performance status issues. Those are the patients who actually have the shortest PFS with targeted therapy. If we use targeted therapy in the first line, we’re already using it as a strategy to move to immunotherapy as quickly as possible.

The last point I will make in this setting is there’s some really convincing data in brain metastases that immunotherapy, with a combination of ipilimumab and nivolumab, is the most effective approach that we have for those patients. For those patients who have untreated brain metastases, we highly recommend the use of ipilimumab and nivolumab. Targeted therapy is effective for those patients. It shows intracranial responses as high as 58%. But those responses in the brain seem to be a lot less durable. For that particular population, I think the choice is swinging significantly toward using the immunotherapy combination up front.

Transcript Edited for Clarity