Triplet combination of BRAF, MEK and PD-1/PD-L1 blockade in melanoma: the more the better?

Purpose Of Review: Patients with advanced or metastatic v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutated melanoma can be treated with a BRAF inhibitor in combination with a MAPK/ERK kinase (MEK) inhibitor, achieving high but short-lived response rates. Immune checkpoint inhibitors (ICIs), in contrast, give lower response rates but more durable responses. Preclinical and translational data indicate that combining BRAF and MEK inhibitors with ICI could exceed the limitations of each class and potentially lead to longer lasting responses.

Recent Findings: Vemurafenib, dabrafenib and encorafenib are designed to block mutated forms of BRAF, which cause abnormal signalling inside cancer cells leading to tumour growth. Trametinib, binimetinib and cobimetinib are designed to target and inhibit MEK1/2, proteins in a cell signalling pathway that help cell growth and survival. Pembrolizumab, nivolumab, durvalumab and atezolizumab are ICIs which can inhibit the pathway of programmed death-1/ programmed death-ligand-1 proteins, allowing tumours to avoid detection by the immune system.

Summary: Treating patients with targeted therapy would allow the release of antigens from tumour cells, which could be more easily acknowledged by the immune system. Efficacy can also be increased by combining ICIs with the aim of maintaining a longer response. The possibility to administer three drugs in combination, would allow to induce tumour regression and produce an immune response with a synergistic effect.