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A Phase 1b Dose-Escalation Study of Encorafenib (LGX818) and Cetuximab With or Without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer

van Geel RM, Tabernero J, Elez E, Bendell JC, Spreafico A, Schuler M, et al.


Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAF V600E colorectal cancer (CRC) models. Patients with refractory BRAF V600-mutant metastatic CRC (mCRC) were treated with a selective RAF kinase inhibitor (encorafenib) plus a monoclonal antibody targeting EGFR (cetuximab), with (n = 28) or without (n = 26) a PI3K-alpha inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase 2 dose. Dose-limiting toxicities were reported in three patients receiving dual- and two patients receiving triple-treatment. The MTD was not reached for either group and the Phase 2 doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib show promising clinical activity and tolerability in patients with BRAF-mutant mCRC; confirmed overall response rates of 19% and 18% were observed, and median progression-free survival was 3.7 and 4.2 months, for the dual- and triple-therapy groups, respectively.

Copyright ©2017, American Association for Cancer Research.

PMID: 28363909

DOI: 10.1158/2159-8290.CD-16-0795