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 Tan; Kati Maharry; Tim Demuth; Jan H.M. Schellens

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

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

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

154 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 language	English
Pages (from-to)	610-619
Journal	Cancer Discovery
Volume	7
Issue number	6
DOIs	https://doi.org/10.1158/2159-8290.CD-16-0795
Publication status	Published - 1 Jan 2017

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10.1158/2159-8290.CD-16-0795

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Van Geel, R. M. J. M., Tabernero, J., Elez, E., Bendell, J. C., Spreafico, A., Schuler, M., Yoshino, T., Delord, J. P., Yamada, Y., Lolkema, M. P., Faris, J. E., Eskens, F. A. L. M., Sharma, S., Yaeger, R., Lenz, H. J., Wainberg, Z. A., Avsar, E., Chatterjee, A., Jaeger, S., ... Schellens, J. H. M. (2017). A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer. Cancer Discovery, 7(6), 610-619. https://doi.org/10.1158/2159-8290.CD-16-0795

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

abstract = "{\textcopyright} 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.",

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

year = "2017",

month = jan,

day = "1",

doi = "10.1158/2159-8290.CD-16-0795",

language = "English",

volume = "7",

pages = "610--619",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

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Van Geel, RMJM, Tabernero, J, Elez, E, Bendell, JC, Spreafico, A, Schuler, M, Yoshino, T, Delord, JP, Yamada, Y, Lolkema, MP, Faris, JE, Eskens, FALM, Sharma, S, Yaeger, R, Lenz, HJ, Wainberg, ZA, Avsar, E, Chatterjee, A, Jaeger, S, Tan, E, Maharry, K, Demuth, T & Schellens, JHM 2017, 'A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer', Cancer Discovery, vol. 7, no. 6, pp. 610-619. https://doi.org/10.1158/2159-8290.CD-16-0795

TY - JOUR

T1 - A phase Ib dose-escalation study of encorafenib and cetuximab with or without alpelisib in metastatic BRAF-mutant colorectal cancer

AU - Van Geel, Robin M.J.M.

AU - Tabernero, Josep

AU - Elez, Elena

AU - Bendell, Johanna C.

AU - Spreafico, Anna

AU - Schuler, Martin

AU - Yoshino, Takayuki

AU - Delord, Jean Pierre

AU - Yamada, Yasuhide

AU - Lolkema, Martijn P.

AU - Faris, Jason E.

AU - Eskens, Ferry A.L.M.

AU - Sharma, Sunil

AU - Yaeger, Rona

AU - Lenz, Heinz Josef

AU - Wainberg, Zev A.

AU - Avsar, Emin

AU - Chatterjee, Arkendu

AU - Jaeger, Savina

AU - Tan, Eugene

AU - Maharry, Kati

AU - Demuth, Tim

AU - Schellens, Jan H.M.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - © 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.

AB - © 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.

U2 - 10.1158/2159-8290.CD-16-0795

DO - 10.1158/2159-8290.CD-16-0795

M3 - Article

SN - 2159-8274

VL - 7

SP - 610

EP - 619

JO - Cancer Discovery

JF - Cancer Discovery

IS - 6

ER -

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

Abstract

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