Clinical activity of mitogen-activated protein kinase (MAPK) inhibitors in patients with MAP2K1 (MEK1)-mutated metastatic cancers: A systematic review and meta-analysis.
Authors: Dankner Matthew , Petrecca Sarah , Fabi Francois , Nowakowski Alexander , Rajadurai Charles Vincent , Rousselle Emmanuelle , Stein Andrew , Bian David Jiahua , Tai Peter , Belaiche Alicia , Li Meredith , Lazaratos Anna-Maria , Quaiattini Andrea , Normanno Nicola , Arcila Maria E. , Elkrief Arielle , Ladanyi Marc , Rose April A. N. 
Published: June 2023

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Background: MAP2K1 (MEK1) mutations are potentially actionable driver mutations in cancer. MAP2K1 mutations can be classified into 3 classes according to molecular characteristics. The efficacy of MAPK inhibitors (MAPKi) for the treatment of MAP2K1 mutant tumors is not well understood. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors, and to evaluate the relationship between MAP2K1 mutation class and clinical activity of MAPKi in patients with MAP2K1 mutant metastatic solid tumors. Methods: We interrogated AACR GENIE (v13) to identify all tumors with Class 1/2/3 MAP2K1 mutant solid tumors. We performed a systematic review and meta-analysis of individual patient data from patients with MAP2K1 mutant cancer published between 2010-22. Key inclusion criteria were: MAP2K1 mutation, solid tumor, metastatic disease, treatment with MAPKi and available treatment response data. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall response rate (RR) and duration of response (DOR). Chi-squared and Log-Rank tests were used to evaluate statistical significance of differences between groups. Results: MAP2K1 driver mutations were present in 917/167,423 (0.5%) tumors in the AACR GENIE dataset. MAP2K1 mutants were most commonly identified in melanoma, colorectal (CRC) and non-small cell lung cancer (NSCLC). In solid tumors, Class 2 mutations were the most prevalent (n=310, 63%) followed by Class 1 (n=119, 24%) and Class 3 (n=66, 13%). Co-occurring MAPK pathway activating mutations (KRAS, NRAS, HRAS, NF1, BRAF, RAF1, or EGFR) were significantly more likely (P<0.0001) to occur in Class 1 (82.3%), versus Class 2 (30.9%) or Class 3 (10.6%) MAP2K1 mutant tumors. We identified 55 patients with MAP2K1 mutant tumors who received MAPKi (n=16/30/6/3 for Class 1/2/3/unclassified, respectively). Of these, (n=22, 18, 12, 3) had melanoma, CRC, NSCLC, or other cancers, respectively. Patients were treated with BRAFi (n=12), MEKi (n=24), BRAF+MEKi (n=2), ERKi (n=1) or EGFRi (n=16). Co-occurring MAPK pathway mutations were present in 51% of tumors. In the entire cohort, the RR was 24% and median PFS was 3.3 months. The RR did not differ according to mutation class, cancer type or MAPKi regimen. However, patients with Class 2 mutations experienced longer PFS (4.0 months) and DOR (23.8 months) compared to patients with Class 1, 3 or unclassified MAP2K1 mutations (PFS 3.0 months, P=0.035; DOR 4.2 months, P=0.04). Conclusions: Class 2 MAP2K1 mutations are RAF-regulated oncogenic mutations with a relatively low incidence of co-occurring MAPK pathway activating mutations. Some patients with Class 2 MAP2K1 mutations may derive durable therapeutic benefit from MAPKi. Prospective clinical studies with MAPK inhibitors are warranted in patients with MAP2K1-mutated metastatic cancer.