Dataset Information

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

ABSTRACT:

Purpose

Preclinical and clinical data suggest that downstream inhibition with an 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% (1/47 patients). A patient with malignant ameloblastoma harboring a codon 61 NRAS mutation achieved a durable partial response (PR). A patient with NRAS codon 61-mutated colorectal cancer had an unconfirmed PR, and two other patients with NRAS codon 61-mutated colorectal had stable disease for at least 12 months. In an exploratory analysis, patients with colorectal cancer 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 patients with codon 61 NRAS-mutated colorectal cancer merits further investigation.

SUBMITTER: Cleary JM

PROVIDER: S-EPMC8542423 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Publications

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.

Cleary James M JM Wang Victoria V Heist Rebecca S RS Kopetz E Scott ES Mitchell Edith P EP Zwiebel James A JA Kapner Kevin S KS Chen Helen X HX Li Shuli S Gray Robert J RJ McShane Lisa M LM Rubinstein Larry V LV Patton David R DR Meric-Bernstam Funda F Dillmon Melissa S MS Williams P Mickey PM Hamilton Stanley R SR Conley Barbara A BA Aguirre Andrew J AJ O'Dwyer Peter J PJ Harris Lyndsay N LN Arteaga Carlos L CL Chen Alice P AP Flaherty Keith T KT

Clinical cancer research : an official journal of the American Association for Cancer Research 20210226 11

<h4>Purpose</h4>Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for <i>NRAS</i>-mutated cancers.<h4>Patients and methods</h4>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 da ...[more]

PMID: 33637626

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