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

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

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

Cited by 232Colorectal Cancer Treatments and StudiesMelanoma and MAPK PathwaysLung Cancer Treatments and Mutations

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

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van Geel, Robin M.J.M., Tabernero, Josep, Elez, Elena, Bendell, Johanna C., Spreafico, Anna, Schuler, Martin, Yoshino, Takayuki, Delord, Jean-Pierre +15 more·2017·Cancer Discovery

DOI 10.1158/2159-8290.cd-16-0795PMC PMC5546207

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Abstract

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. 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 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. Cancer Discov; 7(6); 610–9. ©2017 AACR. See related commentary by Sundar et al., p. 558. This article is highlighted in the In This Issue feature, p. 539

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Combined BRAF and EGFR inhibition significantly improves response rates in BRAF V600E metastatic CRC patients (10% or 19%) and has become FDA-approved standard of care.
“Recent clinical trials report that combined BRAF and EGFR inhibition significantly improves response rates in BRAF (V600E) metastatic CRC patients (10% or 19%) [10, 13], and has now become the FDA-approved, standard of care.”
From An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy (2022) · cites this paper as [13]
The Results (Efficacy; page not provided) report a 19% response rate for dual BRAF–EGFR inhibition, and the Discussion reports a 10% rate in another study and describes improved efficacy. This phase Ib paper does not establish a statistically significant improvement or state that the combination was FDA-approved standard of care. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Combined EGFR and BRAF blockade proved synthetic lethality in preclinical models of BRAFV600E CRC and modestly improves survival of patients with advanced disease.
“Combined EGFR and BRAF blockade proved synthetic lethality in preclinical models of BRAFV600E CRC and modestly improves survival of patients with advanced disease [7, 8, 15–17].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [16]
The Introduction says preclinical evidence suggests combined EGFR and BRAF inhibition reduces proliferation and increases antitumor activity; it does not say synthetic lethality was proved. Results > Efficacy reports a 19% response rate and 3.7-month median progression-free survival for the dual combination, but does not establish improved overall survival. Page numbers are not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
In BRAFV600 colorectal cancer, targeting EGFR in combination with BRAF inhibition has led to an improvement in clinical efficacy.
“Indeed, in BRAFV600 colorectal cancer, targeting EGFR—the RTK thought to be the primary driver of feedback reactivation from preclinical studies—in combination with BRAF inhibition, has led to an improvement in clinical efficacy (34–39).”
From Vertical Pathway Inhibition Overcomes Adaptive Feedback Resistance to KRASG12C Inhibition (2020) · cites this paper as [35]
Two clinical trials showed that adding PI3K inhibitors to cetuximab did not improve PFS, ORR and OS in mCRC patients.
“However, two clinical trials showed that adding PI3K inhibitors to cetuximab did not improve PFS, ORR and OS in mCRC patients [68,69].”
From Drug Resistance in Colorectal Cancer: From Mechanism to Clinic (2022) · cites this paper as [69]

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Abstract CT136: Final biomarker analysis of the phase I study of the selective BRAF V600 inhibitor encorafenib (LGX818) combined with cetuximab with or without the α-specific PI3K inhibitor alpelisib (BYL719) in patients with advanced BRAF-mutant colorectal cancer
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Self-citation
Phase I study of the selective BRAFV600 inhibitor encorafenib (LGX818) combined with cetuximab and with or without the α-specific PI3K inhibitor BYL719 in patients with advanced BRAF-mutant colorectal cancer.
van Geel, R. M. J. M., Élez, E., Bendell, J. C., Faris, J. E., Lolkema, M. P., Eskens, F. A. L. M., Spreafico, A., Kavan, P., Delord, J., Schüler, M., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.3514 · Cited by 44 · see citing works
Self-citation
Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC).
Tabernero, J. M., van Geel, R. M. J. M., Guren, T. K., Yaeger, R. D., Spreafico, A., Faris, J. E., Yoshino, T., Yamada, Y., Kim, T. W., Bendell, J. C., et al. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2016.34.15_suppl.3544 · Cited by 99 · see citing works
Self-citation

Authors: 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., Tan, E., Maharry, K., Demuth, T., & Schellens, J. H. M.
Affiliations: 1The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Universitat Autònoma de Barcelona (ES)
2Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain.
Sarah Cannon (US)
Princess Margaret Cancer Centre (CA)
5West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), partner site University Hospital Essen, Essen, Germany.
6National Cancer Center Hospital East, Chiba, Japan.
Institut Claudius Regaud (FR)
National Cancer Centre Japan (JP)
University Medical Center Utrecht (NL)
Massachusetts General Hospital (US)
Erasmus MC Cancer Institute (NL)
University of Utah (US)
Memorial Sloan Kettering Cancer Center (US)
University of Southern California (US)
UCLA Medical Center (US)
16Novartis Pharmaceutical Corporation, East Hanover, New Jersey.
Novartis (Switzerland) (CH)
Array BioPharma (United States) (US)
Utrecht University (NL)
Corresponding author: Schellens, Jan H.M.
ORCID: Tabernero, Josep
Bendell, Johanna C.
Spreafico, Anna
Yoshino, Takayuki
Delord, Jean-Pierre
Yamada, Yasuhide
Lolkema, Martijn P.
Eskens, Ferry A.L.M.
Yaeger, Rona
Lenz, Heinz-Josef
Wainberg, Zev A.
Chatterjee, Arkendu
Maharry, Kati
Schellens, Jan H.M.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2017-06-01
Volume: 7
Issue: 6
Pages: 610-619
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-16-0795
PMC: PMC5546207
OpenAlex: W2598954950
Semantic Scholar: f08561cbc6f4d52344eed025d3e11163cdf45bff
Cited by: 232
References: 46
Citations by year: 2026: 8 · 2025: 16 · 2024: 16 · 2023: 29 · 2022: 38 · 2021: 27 · 2020: 35 · 2019: 30 · 2018: 23 · 2017: 10
FWCI: 11.82
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
Research Publications (Maastricht University) (submittedVersion, other-oa)
Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
eScholarship (California Digital Library) (submittedVersion)
Research Publications (Maastricht University) (submittedVersion)
Utrecht University Repository (Utrecht University) (submittedVersion)
Funders: German Cancer Consortium (110534)
EU Seventh Framework Programme (259015)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: encorafenib, cetuximab, alpelisib, BRAF V600E mutation, metastatic colorectal cancer, Raf kinase inhibitor, EGFR inhibition, PI3Kα inhibitor, MAPK signaling, combination therapy, dose-limiting toxicity, maximum tolerated dose, triple therapy
MeSH terms: Cetuximab, Phosphoinositide-3 Kinase Inhibitors, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carbamates, Female, Humans, Male, Middle Aged, Mutation, Sulfonamides, Thiazoles, Colorectal Neoplasms, Disease-Free Survival, Maximum Tolerated Dose, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf

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

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