Abstract CT061: Binimetinib in patients with tumors with NRAS mutations: NCI-MATCH ECOG-ACRIN Cancer Research Group subprotocol EAY131-Z1A
Authors: Cleary James M. , Wang Victoria , Heist Rebecca , Kopetz Scott , Mitchell Edith P. , Zwiebel James , Chen Helen X. , Li Shuli , Gray Robert , McShane Lisa , Rubinstein Larry , Patton David , Meric-Bernstam Funda , Dillmon Melissa , Williams Mickey , Hamilton Stanley , Conley Barbara , O'Dwyer Peter , Harris Lyndsay , Arteaga Carlos , Chen Alice , Flaherty Keith 
Published: September 2020

Abstract
Background: NRAS-mutations are established oncologic drivers in many malignancies with no effective targeted therapy options. Preclinical and clinical data have suggested that downstream inhibition with a MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers. Methods: Patients who enrolled in the multicenter NCI-MATCH trial master protocol underwent tumor biopsy and molecular profiling by targeted next generation sequencing with a custom Oncomine AmpliSeq™ panel. Patients with refractory solid tumors harboring codon 12, 13, or 61 NRAS-mutations were enrolled in subprotocol Z1A, a single arm study of binimetinib 45 mg twice daily. Patients with melanoma were excluded. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A post-hoc analysis examined association of NRAS-mutation allele with outcome and histology. Results: 47 eligible patients with refractory solid tumors harboring codon 12, 13, or 61 NRAS-mutations were treated on this trial. The most common cancer types enrolled on this subprotocol were colorectal adenocarcinoma (24/47, 51%), cholangiocarcinoma (7/47, 15%), low-grade papillary serous carcinoma of the ovary (3/47, 6%), and endometrioid endometrial adenocarcinoma patients (3/47, 6%). Observed toxicity was moderate, similar to previous reports, and 27.7% (13 of 47) of eligible patients discontinued binimetinib because of adverse events. The ORR was 2.1% (1 of 47 patients), and the median PFS was 3.5 months. The sole confirmed partial response (PR) was observed in a codon 61 NRAS-mutated indolent malignant ameloblastoma. One patient with a colorectal cancer harboring a NRAS codon 61 mutation had an unconfirmed PR, and two others with NRAS codon 61 mutated colorectal cancer had stable disease for at least 12 months. In a post-hoc analysis, patients with cancers bearing a codon 61 NRAS-mutation (n=22) had a significantly longer OS (p=0.04) and PFS (p=0.006) than those with tumors harboring codon 12 or 13 NRAS-mutations (n=25). Similarly, colorectal cancer patients with NRAS codon 61 mutations treated with binimetinib (n=8) had a significantly longer OS (p=0.03) and PFS (p=0.007) than those with NRAS codon 12 or 13 mutated (n=16) tumors. Conclusions: Single-agent binimetinib did not demonstrate promising efficacy in NRAS-mutated solid tumors. Further studies are needed to clarify whether the increased OS and PFS observed in codon 61 NRAS-mutated cancers reflects a more favorable prognosis for this subtype.
Citation Format: James M. Cleary, Victoria Wang, Rebecca Heist, Scott Kopetz, Edith P. Mitchell, James Zwiebel, Helen X. Chen, Shuli Li, Robert Gray, Lisa McShane, Larry Rubinstein, David Patton, Funda Meric-Bernstam, Melissa Dillmon, Mickey Williams, Stanley Hamilton, Barbara Conley, Peter O'Dwyer, Lyndsay Harris, Carlos Arteaga, Alice Chen, Keith Flaherty. Binimetinib in patients with tumors with NRAS mutations: NCI-MATCH ECOG-ACRIN Cancer Research Group subprotocol EAY131-Z1A [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT061.