Critique of article by Amikar Sehdev, MD
Assistant Professor of Medicine
Indiana University
Indianapolis, IN
The BRAF V600E or V600K mutations are found in about 50% of patients with metastatic melanoma. The best first-line treatment of these patients remains unknown. Randomized trials (NCT02224781; NCT02631447) are currently underway to answer this important question. Most clinicians favor starting treatment with either anti-PD-1 (nivolumab or pembrolizumab) alone or combined immunotherapy with anti-PD-1 and anti-CTLA4 (ipilimumab) except in patients with symptomatic disease and rapid clinical decline.
This is mainly because of various advantages of immunotherapy. First, immunotherapy with anti-PD-1 alone offers a relatively lower rate of severe toxicity (15%) and durable responses despite discontinuation of therapy in patients with complete responses (CRs) (Robert et al: J Clin Oncol 2018;10;36:1668-1674), making it a good treatment choice for patients with low burden of disease (for example, unresectable large lymphadenopathy or pulmonary metastases only) and for patients who will not be considered good candidates for combined immunotherapy or BRAK/MEK inhibition due to higher rates of severe toxicity associated with these treatments (55% with nivolumab and ipilimumab (Larkin et al: NEJM 2019;381:1535-15462) and 34-59% with BRAF/MEK inhibitors (Larkin et al: NEJM 2019;381:1535-1546).
Second, the CR rates with nivolumab plus ipilimumab are much higher than with anti-PD1 alone or BRAF/MEK inhibitors (22% vs 19% versus 16%, respectively).
Third, nivolumab plus ipilimumab has also shown best responses in melanoma patients with brain metastases (traditionally considered a poor-prognostic group), strengthening the efficacy of treatment (Tawbi et al: NEJM 2018;379:722-730). Nonetheless, BRAF/MEK inhibitors have many advantages also, including quick onset of action (~two weeks), high response rates (64-75%) and the usual conveniences of oral therapy (such as less frequent medical visits and ease of taking pills at home). However, lack of durable complete responses and high severe toxicity rates (34-59%) usually lead to discontinuation of these drugs.
The treatment of metastatic melanoma is evolving, and perhaps the best strategy would be to combine immunotherapy with BRAF/MEK inhibitors. Trials are ongoing (NCT02967692) to explore combinations of immunotherapy with BRAF/MEK inhibitors based on the success of phase I and II trials (Ribas et al: Ann Oncol 2017;28[suppl; abstr 1216O]; Ascierto et al: Ann Oncol 2018;29:viii442-466).
In summary, there is lack of evidence in current literature to guide first-line treatment of metastatic melanoma with BRAF mutation, but trials are underway to answer this important question and patients should be encouraged to participate in these ongoing clinical trials.
