A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer

Robin M.J.M. Van Geel, Josep Tabernero, Elena Elez, Johanna C. Bendell, Anna Spreafico, Martin Schuler, Takayuki Yoshino, Jean Pierre Delord, Yasuhide Yamada, Martijn P. Lolkema, Jason E. Faris, Ferry A.L.M. Eskens, Sunil Sharma, Rona Yaeger, Heinz Josef Lenz, Zev A. Wainberg, Emin Avsar, Arkendu Chatterjee, Savina Jaeger, Eugene TanKati Maharry, Tim Demuth, Jan H.M. Schellens

Research output: Contribution to journalArticleResearchpeer-review

84 Citations (Scopus)

Abstract

© 2017 AACR. Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth in BRAFV600E colorectal cancer models. Patients with refractory BRAFV600-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 PI3Kα inhibitor (alpelisib). The primary objective was to determine the maximum tolerated dose (MTD) or a recommended phase II dose. Doselimiting toxicities were reported in 3 patients receiving dual treatment and 2 patients receiving triple treatment. The MTD was not reached for either group and the phase II doses were selected as 200 mg encorafenib (both groups) and 300 mg alpelisib. Combinations of cetuximab and encorafenib showed 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. SIGNIFICANCE: Herein, we demonstrate that dual- (encorafenib plus cetuximab) and triple- (encorafenib plus cetuximab and alpelisib) combination treatments are tolerable and provide promising clinical activity in the difficult-to-treat patient population with BRAF-mutant mCRC.
Original languageEnglish
Pages (from-to)610-619
JournalCancer Discovery
Volume7
Issue number6
DOIs
Publication statusPublished - 1 Jan 2017

Fingerprint Dive into the research topics of 'A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer'. Together they form a unique fingerprint.

Cite this