Differential Outcomes in Codon 12/13 and Codon 61 <i>NRAS</i>-Mutated Cancers in the Phase II NCI-MATCH Trial of Binimetinib in Patients with <i>NRAS</i>-Mutated Tumors.

Abstract

Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for <i>NRAS</i>-mutated cancers. Patients enrolled in the NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next-generation sequencing. Patients with <i>NRAS</i>-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 <i>post hoc</i> analysis examined the association of <i>NRAS</i> mutation type with outcome. In total, 47 eligible patients with a refractory solid tumor harboring a codon 12, 13, or 61 <i>NRAS</i> mutation were treated. Observed toxicity was moderate, and 30% of patients discontinued treatment because of binimetinib-associated toxicity. The ORR was 2.1% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 <i>NRAS</i> mutation achieved a durable partial response (PR). A patient with <i>NRAS</i> codon 61-mutated colorectal cancer had an unconfirmed PR, and two other patients with <i>NRAS</i> codon 61-mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer bearing a <i>NRAS</i> codon 61 mutation (<i>n</i> = 8) had a significantly longer OS (<i>P</i> = 0.03) and PFS (<i>P</i> = 0.007) than those with codon 12 or 13 mutations (<i>n</i> = 16). Single-agent binimetinib did not show promising efficacy in <i>NRAS</i>-mutated cancers. The observation of increased OS and PFS in patients with codon 61 <i>NRAS</i>-mutated colorectal cancer merits further investigation.