Sequencing and Combinations of Molecularly Targeted and Immunotherapy for BRAF-Mutant Melanoma

Abstract

Recent advances in molecular targeted therapy and immunotherapy have revolutionized the treatment of metastatic melanoma. Combined BRAF inhibitors and MEK inhibitors have been approved for the treatment of BRAF-mutant metastatic melanoma and have become a new standard of care. However, acquired resistance is still a significant concern with BRAF and MEK inhibitor combination therapy. Checkpoint inhibitors appear to produce durable responses in patients with both BRAF-mutant and wild-type melanoma, with the combination of anti-PD-1 and anti-CTLA-4 appearing to be particularly beneficial relative to single-agent anti-PD-1 in patients with BRAF-mutant tumors. The increasing number of effective treatment options for patients with BRAF-mutant metastatic melanoma has led to new questions regarding which agent/approach or sequence of agents is optimal and in which patient and whether combinations of approaches (MAPK inhibition plus checkpoint inhibition) could produce superior outcomes relative to the use of agents in sequence. MAPK inhibitors can provide early and high rates of response, but with a shorter duration of effect. In contrast, immune checkpoint inhibitors have slower onset of action but offer more durable responses and potentially longer-term disease control. Retrospective data appear to suggest that immunotherapy should be the first option in the majority of patients with BRAF-mutant melanoma, although such conclusions are subject to considerable biases and are therefore far from certain. Several randomized trials are prospectively evaluating the sequence questions and will soon provide more definitive data for the population as a whole and hopefully for specific subsets of patients and particular sequencing schedules. The triple combinations of BRAF/MEK inhibitors with PD-1 pathway blockers appear promising, with several combinations being evaluated in clinical trials. Preliminary results have demonstrated high response rates and good tolerability, although the ability of such regimens to produce the sustained off-treatment responses characteristic of immunotherapy remains unknown. There remains an urgent need to complete ongoing clinical trials so that we can provide a rational treatment approach for each patient in the foreseeable future.