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A Phase Ib Dose-Escalation Study of Encorafenib and Cetuximab with or without Alpelisib in Metastatic BRAF -Mutant Colorectal Cancer
Open accessPublished version of a preprint
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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“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]
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“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]
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“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]
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“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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Metadata
- 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
- Venue
- Cancer Discovery
- Published
- 2017-06-01
- Volume
- 7
- Issue
- 6
- Pages
- 610-619
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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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