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Ref Type

Journal Article

PMID

(33637626)

Authors

Cleary JM, Wang V, Heist RS, Kopetz ES, Mitchell EP, Zwiebel JA, Kapner KS, Chen HX, Li S, Gray RJ, McShane LM, Rubinstein LV, Patton DR, Meric-Bernstam F, Dillmon MS, Williams PM, Hamilton SR, Conley BA, Aguirre AJ, O'Dwyer PJ, Harris LN, Arteaga CL, Chen AP, Flaherty KT

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	27	11	2021 Jun 01	2996-3004	Clin Cancer Res

URL

Abstract Text

Preclinical and clinical data suggest that downstream inhibition with an MEK inhibitor, such as binimetinib, might be efficacious for NRAS-mutated cancers.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.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).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.

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Molecular Profile	Treatment Approach
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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS G12X	Advanced Solid Tumor	no benefit	Binimetinib	Phase II	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in an objective response rate of 2.1% (1/47) that was deemed nonpromising in patients with advanced solid tumors harboring NRAS mutations at codon 12 (n=17), 13 (n=8), or 61 (n=22), with a 6-month progression-free survival (PFS) of 29.2%, a median PFS of 3.5 months, and a median overall survival of 10.5 months (PMID: 33637626; NCT02465060).	33637626
NRAS G13X	Advanced Solid Tumor	no benefit	Binimetinib	Phase II	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in an objective response rate of 2.1% (1/47) that was deemed nonpromising in patients with advanced solid tumors harboring NRAS mutations at codon 12 (n=17), 13 (n=8), or 61 (n=22), with a 6-month progression-free survival (PFS) of 29.2%, a median PFS of 3.5 months, and a median overall survival of 10.5 months (PMID: 33637626; NCT02465060).	33637626
NRAS Q61X	colorectal cancer	unknown	Binimetinib	Phase II	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) treatment did not demonstrate promising efficacy in patients with advanced solid tumors harboring NRAS mutations at codon 12 (n=17), 13 (n=8), or 61 (n=22), however, colorectal cancer patients harboring NRAS Q61 mutations (n=8) achieved longer overall survival (HR 0.34, p=0.03) and progression-free survival (HR 0.23, p=0.007) compared to those harboring mutations at G12 or G13 (n=16) (PMID: 33637626; NCT02465060).	33637626
NRAS Q61X	Advanced Solid Tumor	unknown	Binimetinib	Phase II	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) therapy led to a nonpromising objective response rate of 2.1% (1/47) in patients (pts) with advanced solid tumors harboring NRAS G12/13 or Q61 mutations, Q61-mutant pts achieved longer overall survival (13.1 vs 5.5 mo, p=0.04) and progression-free survival (5.8 vs 1.8 mo, p=0.006) compared to G12/13-mutant pts examining all tumor types, but not when colorectal caner was excluded (HR 0.84, p=0.70; HR 0.67, p=0.4, respectively) (PMID: 33637626; NCT02465060).	33637626
NRAS Q61K	colorectal cancer	predicted - sensitive	Binimetinib	Case Reports/Case Series	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in stable disease in two patient with colorectal cancer harboring NRAS Q61K, whom remained on treatment for 12 and 17 months until disease progression (PMID: 33637626; NCT02465060).	33637626
NRAS Q61R	colorectal cancer	predicted - sensitive	Binimetinib	Case Reports/Case Series	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in an unconfirmed partial response in a patient with colorectal cancer harboring NRAS Q61R, with a 48.2% tumor reduction at cycle 4, but the disease progressed at cycle 7 (PMID: 33637626; NCT02465060).	33637626
NRAS Q61R	ameloblastoma	predicted - sensitive	Binimetinib	Case Reports/Case Series	Actionable	In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in a partial response in a patient with metastatic malignant ameloblastoma harboring NRAS Q61R, and the patient stayed on treatment for 26 months (PMID: 33637626; NCT02465060).	33637626

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