title: A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in MetastaticBRAF-Mutant Colorectal Cancer.
abstract: Preclinical evidence suggests that concomitant BRAF and EGFR inhibition leads to sustained suppression of MAPK signaling and suppressed tumor growth inBRAFV600Ecolorectal cancer models. Patients with refractoryBRAFV600-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. Dose-limiting 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 withBRAF-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 withBRAF-mutant mCRC.Cancer Discov; 7(6); 610-9. ©2017 AACR.See related commentary by Sundar et al., p. 558This article is highlighted in the In This Issue feature, p. 539.
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Robin M J M
authors.initials: RMJM
authors.lastname: van Geel
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.affiliation: Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Elez
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Canada.
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.affiliation: West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), partner site University Hospital Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshino
authors.affiliation: Institut Claudius Regaud, Toulouse, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Delord
authors.affiliation: National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: University Medical Center Utrecht, Utrecht, the Netherlands.|Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jason E
authors.initials: JE
authors.lastname: Faris
authors.affiliation: Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Ferry A L M
authors.initials: FALM
authors.lastname: Eskens
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
authors.forename: Sunil
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.affiliation: Keck School of Medicine at the University of Southern California, Los Angeles, California.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.affiliation: UCLA Medical Center, Santa Monica, California.
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Emin
authors.initials: E
authors.lastname: Avsar
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Arkendu
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Savina
authors.initials: S
authors.lastname: Jaeger
authors.affiliation: Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
authors.forename: Eugene
authors.initials: E
authors.lastname: Tan
authors.affiliation: Array BioPharma Inc., Boulder, Colorado.
authors.forename: Kati
authors.initials: K
authors.lastname: Maharry
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Tim
authors.initials: T
authors.lastname: Demuth
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, the Netherlands. j.schellens@nki.nl.|Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands.
authors.forename: Jan H M
authors.initials: JHM
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D002219:Carbamates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013844:Thiazoles; C585539:Alpelisib; C000601108:encorafenib; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab