Combined BRAF and MEK inhibition in BRAF^V600E mutant melanoma: a synergistic and potentially safe combination partner with immunotherapy

The combination of immune checkpoint blockade using PD-1 and or CTLA-4 inhibition with BRAF inhibition for BRAF^V600 mutant advanced melanoma is a potentially attractive option given the substantial anti-tumor activity of these two treatment modalities. However, initial clinical trials indicated that combined inhibition of CTLA-4 and BRAF may be associated with intolerable toxicity. MEK inhibition, when added to BRAF inhibition, enhances the inhibitory effect on MAPK pathway signaling in BRAF mutant cells while limiting paradoxical activation of the MAPK pathway in BRAF wild type cells, leading to enhanced clinical efficacy and possibly toxicity of combined BRAF/MEK inhibition compared to BRAF inhibition alone. This provides a rationale for the addition of MEK inhibition in a combined BRAF-directed immunotherapy approach. However, MEK inhibition had been associated with decreased T cell function in vitro. Expanding on previous studies in an adoptive transfer model with TCR transgenic T cells (pmel) recognizing the melanoma differentiation antigen (MDA) gp100 endogenously expressed on syngeneic BRAF^V600E mutant SM1 melanoma, Hu-Liewskovan perform systematic analyses of T cell frequencies and functionality, immune cell subtypes in the tumor microenvironment, and gene expression signatures. The studies show that the addition of MEK inhibition to combined BRAF inhibition and two different immunotherapy modalities [adoptive T cell transfer (ACT) and PD-1 inhibition] does not impede T cell function in vivo, has favorable effects on immune suppressive cells, and provides superior tumor control. These data support the investigation of combined BRAF/MEK inhibition with immunotherapy in patients with advanced melanoma.