PURPOSE: MAP2K1/MEK1 mutations are potentially actionable drivers in cancer. MAP2K1 mutations have been functionally classified into three groups according to their dependency on upstream RAS/RAF signaling. However, the clinical efficacy of MAPK pathway inhibitors (MAPKi) for MAP2K1 mutant tumors is not well defined. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors to evaluate the relationship between MAP2K1 mutation Class and clinical activity of MAPKi. METHODS: We interrogated AACR GENIE (v13) to analyze solid tumors with MAP2K1 mutations. We performed a systematic review and meta-analysis of published reports of patients with MAP2K1 mutant cancers treated with MAPKi according to PRISMA guidelines. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate (ORR), duration of response (DOR), and overall survival (OS). RESULTS: In the AACR GENIE dataset, Class 2 MAP2K1 mutations (63%) were more prevalent than Class 1 (24%) and Class 3 (13%) mutations (P<0.0001). Co-occurring MAPK pathway activating mutations were more likely to occur in Class 1 versus Class 2 or 3 MAP2K1 mutant tumors (P<0.0001). Our systematic meta-analysis of the literature identified 46 patients with MAP2K1 mutant tumors who received MAPKi. In these patients, ORR was 28% and median PFS was 3.9 months. ORR did not differ according to MAP2K1 mutation class or cancer type. However, patients with Class 2 mutations experienced longer PFS (5.0 months) and DOR (23.8 months) compared to patients with Class 1, 3 or unclassified MAP2K1 mutations (PFS 3.5 months, P=0.04; DOR 4.2 months, P=0.02). CONCLUSION: Patients with Class 2 MAP2K1 mutations represent a novel subgroup that may derive benefit from MAPKi. Prospective clinical studies with novel MAPKi regimens are warranted in these patients.

April A. N. Rose conflicts of interest: I = Immediate Family Member Inst = Institutional Research Funding: Canadian Institutes of Health Research (CIHR), Canadian Cancer Society, Conquer Cancer Foundation of ASCO, TransMedTech Institute, Jewish General Hospital Foundation, Canada Foundation for Innovation, Fonds de Recherche du Quebec Sante, Merck (Inst), AstraZeneca (Inst), Seagen (Inst), Pfizer (Inst) Consultant: AstraZeneca Canada, Advanced Accelerator Applications/Novartis, Pfizer Employment: Merck (I) Stock Ownership: Merck (I) All the other authors have no conflicts of interest to declare.

ER acknowledges a Marathon of Hope Cancer Centers Network Health Informatics and Data Science Award. AANR acknowledges salary support from a Fonds de recherche du Quebec Sante (FRQS) Chercheuses-Boursieres Cliniciennes Award. This research was supported by funding from the TransMedTech Institute and Apogee Canada Research Excellence Fund, and a Conquer Cancer Foundation of ASCO Career Development Award to AANR.

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