Combined talimogene laherparepvec and binimetinib in patients with NRAS-mutated melanoma induces anti-tumor immunity

Immune checkpoint blockade can produce long-lasting responses in patients with metastatic melanoma; notably, combined CTLA-4/PD-1 blockade has been associated with approximately 52% melanoma specific 10-year survival. Yet, nearly half of patients experience minimal clinical benefit, and intensified regimens come with substantial risk of severe immune-related toxicity. The precise determinants of immunotherapy response are incompletely defined, reflecting a complex interplay between tumor biology and host immunity. This is especially consequential for patients whose disease progresses on checkpoint blockade, for whom effective salvage options are limited. In a series of patients with NRAS-mutated melanoma refractory to checkpoint inhibitors, we found that intratumoral administration of talimogene laherparepvec (T-VEC) combined with MEK inhibitor binimetinib induced exceptional clinical responses by amplification of pre-existing T cell responses and induction of de novo tumor-reactive immunity.