@article{c7d4598314dd4316a4707505bea74e5a,
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",
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 ¼ 8) had a significantly longer OS (P ¼ 0.03) and PFS (P ¼ 0.007) than those with codon 12 or 13 mutations (n ¼ 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.",
author = "Cleary, {James M.} and Victoria Wang and Heist, {Rebecca S.} and Kopetz, {E. Scott} and Mitchell, {Edith P.} and Zwiebel, {James A.} and Kapner, {Kevin S.} and Chen, {Helen X.} and Shuli Li and Gray, {Robert J.} and McShane, {Lisa M.} and Rubinstein, {Larry V.} and Patton, {David R.} and Funda Meric-Bernstam and Dillmon, {Melissa S.} and Williams, {P. Mickey} and Hamilton, {Stanley R.} and Conley, {Barbara A.} and Aguirre, {Andrew J.} and O'Dwyer, {Peter J.} and Harris, {Lyndsay N.} and Arteaga, {Carlos L.} and Chen, {Alice P.} and Flaherty, {Keith T.}",
note = "Funding Information: J.M. Cleary reports grants from Merck and Tesaro; nonfinancial support from AstraZeneca and Esperas Pharma; and personal fees from BMS outside the submitted work. V. Wang reports grants from the NIH during the conduct of the study. R.S. Heist reports other from Novartis, Daichii Sankyo, EMD Serono, Tarveda, and Apollomics; grants from Novartis, Corvus, Incyte, Genentech Roche, Mirati, Turning Point, BMS, Daichii Sankyo, AbbVie, Agios, Exelixis, and Lilly outside the submitted work. E.S. Kopetz reports personal fees from Roche, Genentech, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis, Lilly, Boehringer Ingelheim, Boston Biomedical, AstraZeneca/MedImmune, Bayer Health, Pierre Fabre, EMD Serono, Redx Pharma, Jacobio, Natera, Repare Therapeutics, Daiichi Sankyo, Lutris, Pfizer, Ipsen, and HalioDx outside the submitted work. R.J. Gray reports grants from the NCI during the conduct of the study. F. Meric-Bernstam reports personal fees from Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffmann-La Roche, Genentech, IBM Watson, Jackson Laboratory, Kolon Life Sciences, OrgiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics, Tyra Biosciences, Xencor, Zymeworks, Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology, Seattle Genetics, Silverback Therapeutics, Spectrum Pharamaceuticals, Zentalis, Chugai Biopharmaceuitcals, Mayo Clinic, and Rutgers Cancer Institute of New Jersey; grants from Aileron Therapeutics, AstraZeneca, Bayer Healthcare, Calithera, Curis, CytomX, Daiichi Sankyo, DebioPharm, eFFECTOR Therapeutics, Genentech, Guardant Health, Klus Pharma, Millennium Pharmaceuticals Inc, Novartis, Puma Biotechnolgy, and Taiho Pharmaceutical; and nonfinancial support from Beth Israel Deaconess Medical Center outside the submitted work. A.J. Aguirre reports personal fees from Merck, Arrakis Therapeutics, and Oncorus; grants from Deerfield Management, Novo Ventures, Syros, and Mirati outside the submitted work. P.J. O{\textquoteright}Dwyer reports personal fees from Array outside the submitted work. C.L. Arteaga reports grants from Lilly, Pfizer, and Takeda and personal fees from Novartis, Lilly, Immunomedics, Merck, Daiichi Sakyo, TAIHO Oncology, AstraZeneca, OrigiMed, Arvinas, and Clovis outside the submitted work; holds minor stock options in Provista and used to hold minor stock options in Y-TRAP; serves in the scientific advisory board of the Susan G. Komen Foundation; and reports that none of these relationships has any relationship with or relevance to his role as coauthor of this article. K.T. Flaherty reports personal fees from Loxo Oncology, Funding Information: This study was coordinated by the ECOG-ACRIN Cancer Research Group (P.J. O{\textquoteright}Dwyer and Mitchell D. Schnall) and was supported by the NCI of the NIH under the following award numbers: CA180820, CA180794, CA180858, CA180867, CA180870, and CA189997. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Array BioPharma provided the study drug for this study. The work of J.M. Cleary is supported by DFCI Hale Family Center for Pancreatic Cancer, Team Evan Schumacher, Haya Linde Memorial Fund, and the Pancreatic Cancer Collective New Therapies Challenge Grant, an initiative of the Lustgarten Foundation and Stand Up To Cancer, grant number SU2C-AACR-PCC-02-18. Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. S.R. Hamilton is the recipient of the Frederick F. Becker Distinguished University Chair in Cancer Research at the University of Texas. Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
month = jun,
day = "1",
doi = "10.1158/1078-0432.CCR-21-0066",
language = "English (US)",
volume = "27",
pages = "2996--3004",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "11",
}