Rationale for immune checkpoint inhibitors plus targeted therapy in metastatic melanoma

Importance: In recent years, the management of metastatic melanoma has been transformed by the emergence of immune checkpoint inhibitors and targeted therapies that significantly improve patient survival. The complementary response kinetics of these treatment approaches, supported by mechanistic evidence that targeted therapy affects immune aspects of the tumor microenvironment, suggest that the optimal combination or sequencing of immune checkpoint inhibitors and targeted therapy may provide additional clinical benefit. Observations: Clinical responses to BRAF and/or MEK inhibitors are associated with immune changes within the tumor microenvironment that have the potential to increase the sensitivity of BRAF V600-mutant melanoma to immune checkpoint inhibitors. The combination of immune checkpoint inhibitors with targeted therapy may therefore increase duration of response, improve tumor control, extend survival, and increase the proportion of patients experiencing durable benefit. A targeted therapy-immune checkpoint inhibitor sequencing approach may also be supported by this evidence, but clinical questions regarding optimal timing, duration, and patient selection remain. Conclusions and relevance: This review outlines the rationale and preclinical evidence that support immune checkpoint inhibitor plus targeted therapy combination and sequencing strategies in melanoma and highlights the results available to date from clinical trials exploring these approaches to treatment. Several late-stage trials are under way looking to answer open questions in this field and address the continuing debate surrounding up-front combination vs sequencing. As phase 3 data have begun to emerge, trial designs and available data from key studies are discussed in the context of their resultant implications for clinical practice