Frontline Therapy for BRAF-Mutated Unresectable Melanoma

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Several factors can be utilized to determine the optimal treatment for patients with BRAF-mutated unresectable melanoma, explains Anna Pavlick, DO. Outside of BRAF status, treatment can be tailored using the volume of disease, rate of progression, symptoms, and LDH level.

In a patient with BRAF-positive melanoma with brain metastases, BRAF inhibition is a reasonable frontline therapy. However, in patients with low-volume disease, low LDH, good performance status, and no symptoms, immunotherapy can be administered, Pavlick notes.

This strategy for selecting between targeted therapy and immunotherapy is effective in many situations; however, the newly approved PD-1 inhibitors may shift this paradigm. Predictors of poor response to ipilimumab, such as LDH level, may not apply to nivolumab and pembrolizumab or combination immunotherapies, explains Richard Joseph, MD. As a result, these therapies could have potential as frontline therapies for patients with higher-volume disease.

Rapid and durable responses are being achieved with the PD-1 and PD-L1 inhibitors and significant tumor regression is being reported with combination immunotherapies, explains Omid Hamid, MD. This is something that was previously seen only with targeted therapies. Given these impressive findings, research is looking to move immunotherapy forward in the treatment landscape for patients with melanoma.

At this point, the optimal timing and duration for BRAF therapy is unclear, notes Howard Kaufman, MD. When using BRAF-targeted therapy, Kaufman typically starts with monotherapy, but says a case can be made for combined BRAF- and MEK-targeted therapies. As the data mature, the combination of dabrafenib and trametinib is starting to look better than dabrafenib alone in terms of overall survival, Joseph adds.

Various strategies exist for the frontline treatment of patients with unresectable melanoma, with a prevailing notion being that the most effective therapy should be utilized first. While the combined targeted therapies with MEK and a BRAF inhibitor is the most effective option, the side effects can be more challenging, specifically pyrexia, notes Joseph. Whether or not to utilize the combination upfront can be tailored based on a patient's performance status and other comorbidities, notes Pavlick.