Differential Outcomes in Codon 12/13 and Codon 61 NRAS-Mutated Cancers in the Phase 2 NCI-MATCH Trial of Binimetinib in Patients with NRAS-Mutated Tumors

Purpose: Preclinical and clinical data suggest that downstream inhibition with a MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers. Patients and Methods: Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with NRAS-mutated tumors, except melanoma, were enrolled in subprotocol Z1A, a single-arm study evaluating binimetinib 45 mg twice daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post-hoc analysis examined the association of NRAS mutation type with outcome. Results: In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 NRAS mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1 of 47 patients). A malignant ameloblastoma patient harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A NRAS codon 61 mutated colorectal cancer patient had an unconfirmed PR, and two other NRAS codon 61 mutated colorectal patients had stable disease for at least 12 months. In an exploratory analysis, colorectal cancer patients bearing a NRAS codon 61 mutation (n = 8) had a significantly longer OS (p = 0.03) and PFS (p = 0.007) than those with codon 12 or 13 mutations (n = 16). Conclusions: Single-agent binimetinib did not show promising efficacy in NRAS-mutated cancers. The observation of increased OS and PFS in codon 61 NRAS-mutated colorectal cancer patients merits further investigation.