Dermatologic Toxicities Associated With Novel Pan-RAS/RAF Inhibitors

Abstract

Background: The mitogen-activated protein kinase (MAPK) pathway plays a key role in cell-cycle regulation and tumor progression in cancer. Dermatologic toxicities (DTs) to newer pan-RAS (RMC-6236) and pan-RAF (LXH254/naporafenib) inhibitors are emerging. Therefore, knowledge of the morphologic patterns of DTs from pan-RAS/RAF inhibitors will enable quick diagnosis and appropriate management.

Methods: The clinical and histologic features of patients treated with pan-RAS or pan-RAF inhibitors for advanced stage RAS mutated malignancies were retrospectively reviewed.

Results: Associated DTs were identified in eight patients treated with either pan-RAS (n = 4) or pan-RAF (n = 4) plus MEK/ERK inhibitors for RAS mutated tumors (colorectal, lung, pancreatic, thyroid, melanoma). The patients ranged from 37 to 72 years of age. Five patients had initial clinical presentation of an acneiform eruption complicated by ulceration, flaccid vesicles, or diffuse exfoliative erythroderma. Maculopapular eruption, purpuric patches and papules, and eruptive dark nevi were the other clinical presentations. Skin biopsies were primarily inflammatory with histopathologic features of suppurative folliculitis (n = 2), dermal hypersensitivity reaction (n = 2), subcorneal acantholytic dermatosis (n = 1), subcorneal pustules (n = 1), ulcer (n = 1), and eruptive nevi (n = 1).

Conclusions: Treatment with novel pan-RAS/RAF inhibitors exhibits a spectrum of DTs that exhibit some overlap with small molecule inhibitors that target the MAPK pathway.

Keywords: LTT462; LXH254; RMC6236; dermatologic toxicities; naporafenib; pan‐RAF; pan‐RAS; small molecule inhibitors.