Clinical Activity of Mitogen-Activated Protein Kinase–Targeted Therapies in Patients With Non–V600 BRAF-Mutant Tumors

• Type of Material: Article
• Authors: Matthew Dankner, McGill University; Yifan Wang, McGill University; Rouhi Fazelzad, University of Toronto; Benny Johnson, The University of Texas. Houston, Texas; Caroline A Nebhan, Vanderbilt University; Ibiayi Dagogo-Jack, Harvard University; Nathaniel J Myall, Stanford University; Georg Richtig, Medical University of Graz; Jillian W.P Bracht, Quirón-Dexus University Institute; Marco Gerlinger, Queen Mary University of London; Eiji Shinozaki, Japanese Foundation for Cancer Research; Takayuki Yoshino, National Cancer Center Japan; Daisuke Kotani, National Cancer Center Japan; Jason Ronald Fangusaro, Emory University; Oliver Gautschi, University of Bern; Julien Mazieres, Universitaire de Toulouse; Jeffrey A Sosman, Northwestern University; Scott Kopetz, University of Texas, Houston, Texas; Vivek Subbiah, University of Texas, Houston, Texas; Michael A Davies, University of Texas, Houston, Texas; Anna L Groover, BioMed Valley Discoveries; Ryan J Sullivan, Harvard University; Keith T Flaherty, Harvard University; Douglas B Johnson, Vanderbilt University; Andrea Benedetti, McGill University; David W Cescon, University of Toronto; Anna Spreafico, University of Toronto; George Zogopoulos, McGill University; April A.N Rose, McGill University
• Language: English
• Date: 2022-08-17
• Publisher: American Society of Clinical Oncology
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by American Society of Clinical Oncology
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1200%2FPO.22.00107
• Title of Journal or Parent Work: JCO Precision Oncology
• Volume: 6
• Issue: 2022
• Start Page: e2200107
• Grant/Funding Information: G.Z. and A.A.N.R. acknowledge support from Fonds de Recherche du Québec—Santé (FRQS) Clinical Research Scholar awards.; This research was funded by a Conquer Cancer Foundation of ASCO Young Investigator Award and a Canadian Cancer Society Challenge Grant (Grant #707457) to AANR.; M.D. and Y.W. acknowledge support from Vanier Canada Graduate Scholarships.
• Keywords: MAPK Treatment Therapy; clinical trials; Cancer treatment; MAPK PATHWAY; Non-V600 mutations
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology; Health Sciences, Immunology

Abstract

PURPOSE: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established. METHODS: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration–approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, and MAPK TT type. Coprimary outcomes were response rate and progression-free survival. RESULTS: A total of 18,167 studies were screened, identifying 80 studies with 238 patients who met inclusion criteria. This included 167 patients with class 2 and 71 patients with class 3 BRAF mutations. Overall, 77 patients achieved a treatment response. In both univariate and multivariable analyses, response rate and progression-free survival were higher among patients with class 2 compared with class 3 mutations, findings that remain when analyses are restricted to patients with melanoma or lung primary cancers. MEK ± BRAF inhibitors demonstrated greater clinical activity in class 2 compared with class 3 BRAF-mutant tumors than BRAF or EGFR inhibitors. CONCLUSION: This meta-analysis suggests that MAPK TTs have clinical activity in some class 2 and 3 BRAF-mutant cancers. BRAF class may dictate responsiveness to current and emerging treatment strategies, particularly in melanoma and lung cancers. Together, this analysis provides clinical validation of predictions made on the basis of a mutation classification system established in the preclinical literature. Further evaluation with prospective clinical trials is needed for this population.