What is your preferred first-line treatment for metastatic melanoma in a patient with a class 2/non-V600 BRAF mutation?

Class II BRAF mutations have intermediate kinase activity and are much less likely than V600E or V600K mutations to respond to traditional BRAF+MEK inhibitor therapy. Targeted therapy should not be used as a front-line therapy in these patients. Immunotherapy (and immunotherapy-based front-line clinical trials) should be considered first-line. The primary standard of care options for frontline immunotherapy are a single-agent PD-1–based treatment or combination ipilimumab plus nivolumab. Deciding between these approaches can be more of an art than a science. Certainly, comorbidities and functional status are factors along with a patient’s willingness and ability to tolerate side effects. Data from the ABC and CheckMate 204 trials on intracr...

Class II BRAF mutations have an intermediate level of constitutional kinase activation through RAS dependent dimers and the current FDA approved BRAF inhibitors are monomer selective. There are some dimer selective agents currently under investigation such as αC-IN inhibitor and RAF inhibitor PLX8394. Given the rarity of these mutations and exclusion from trials, benefit of BRAF/MEKi has not been clearly demonstrated in large clinical trials. However, there are some reports of responses to MEK inhibitors and a more recent report also suggests some activity of BRAF/MEKi combination although response rates may be less compared to Class I V600 mutations. Whenever possible, these patients should be enrolled in clinical trials. In the absence of...

My preferred first-line treatment in this setting is combination checkpoint inhibitor therapy with ipilimumab + nivolumab. As @Dr. First Last and @Dr. First Last have noted, Class II BRAF mutations are less likely to respond to traditional BRAF+MEK targeted therapy.

In addition, I prefer this regimen because the combination has a roughly 50% chance of long term benefit, without the need for additional therapy. (Larkin et al., PMID 31562797). If I have the chance to potentially cure someone of this deadly disease, I will give it my best effort, and in my experience of treating melanoma over the past 26 years, this combination offers the best chance of achieving that goal. This combination obviously carries the potential for excess toxicity b...

The answers already given are excellent. I would only agree that front line immunotherapy, either standard or on a trial, is likely the best choice. If there is a clinical trial with a targeted agent that offers the possibility of similar long term benefits, that would also be an excellent first choice, but that is unlikely.