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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 PI3Ka 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. (C) 2017 AACR.

Original languageEnglish
Pages (from-to)610-619
Number of pages10
JournalCancer Discovery
Issue number6
Publication statusPublished - Jun 2017


  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Antineoplastic Combined Chemotherapy Protocols
  • Carbamates
  • Cetuximab
  • Colorectal Neoplasms
  • Disease-Free Survival
  • Female
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Mutation
  • Phosphatidylinositol 3-Kinase
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins B-raf
  • Sulfonamides
  • Thiazoles
  • Clinical Trial, Phase I
  • Journal Article
  • Multicenter Study
  • EGFR
  • RAF
  • KRAS

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