A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF-Mutant Colorectal Cancer

被引：202

作者：

van Geel, Robin M. J. M. ^{[1
]}

Tabernero, Josep ^{[2
,3
]}

Elez, Elena ^{[2
,3
]}

Bendell, Johanna C. ^{[4
]}

Spreafico, Anna ^{[5
]}

Schuler, Martin ^{[6
,7
]}

Yoshino, Takayuki ^{[8
]}

Delord, Jean-Pierre ^{[9
]}

Yamada, Yasuhide ^{[10
]}

Lolkema, Martijn P. ^{[11
,12
]}

Faris, Jason E. ^{[13
]}

Eskens, Ferry A. L. M. ^{[12
]}

Sharma, Sunil ^{[14
]}

Yaeger, Rona ^{[15
]}

Lenz, Heinz-Josef ^{[16
]}

Wainberg, Zev A. ^{[17
]}

Avsar, Emin ^{[18
]}

Chatterjee, Arkendu ^{[18
]}

Jaeger, Savina ^{[19
]}

Tan, Eugene ^{[18
]}

Maharry, Kati ^{[20
]}

Demuth, Tim ^{[21
]}

Schellens, Jan H. M. ^{[1
,22
]}

机构：

[1] Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

[2] Univ Autonoma Barcelona, Vall Hebron Univ Hosp, Barcelona, Spain

[3] Univ Autonoma Barcelona, Inst Oncol, Barcelona, Spain

[4] Sarah Cannon Res Inst Tennessee Oncol, Nashville, TN USA

[5] Princess Margaret Canc Ctr, Toronto, ON, Canada

[6] Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Essen, Germany

[7] Univ Hosp Essen, German Canc Consortium DKTK, Essen, Germany

[8] Natl Canc Ctr Hosp East, Chiba, Japan

[9] Inst Claudius Regaud, Toulouse, France

[10] Natl Canc Ctr, Tokyo, Japan

[11] Univ Med Ctr Utrecht, Utrecht, Netherlands

[12] Erasmus MC Canc Inst, Rotterdam, Netherlands

[13] Massachusetts Gen Hosp, Boston, MA 02114 USA

[14] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA

[15] Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA

[16] Univ Southern Calif, Keck Sch Med, Los Angeles, CA 90033 USA

[17] UCLA Med Ctr, Santa Monica, CA USA

[18] Nova Pharmaceut Corp, E Hanover, NJ USA

[19] Novartis Inst Biomed Res, Cambridge, MA USA

[20] Array BioPharma Inc, Boulder, CO USA

[21] Novartis Pharma AG, Basel, Switzerland

[22] Univ Utrecht, UIPS, Utrecht, Netherlands

来源：

CANCER DISCOVERY | 2017年 / 7卷 / 06期

关键词：

GENE COPY NUMBER; WILD-TYPE; COLON-CANCER; MAPK PATHWAY; EGFR; INHIBITION; RAF; BIOMARKERS; KRAS; FLUOROURACIL;

D O I：

10.1158/2159-8290.CD-16-0795

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：610 / 619

页数：10

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