Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer
Open accessAbstract
BACKGROUND: V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).
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In 665 patients with metastatic BRAF V600E colorectal cancer, combined BRAF and EGFR inhibition improved activity over BRAF inhibitor monotherapy.
“The potential improvement in activity observed for the combination is consistent with outcomes reported in 665 patients who had metastatic colorectal cancer with a BRAF V600E mutation, in which combined BRAF and EGFR inhibition led to improved activity over BRAF inhibitor monotherapy.33”
From Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated <i>KRAS</i> G12C (2023) · cites this paper as [33]
The Results report that 665 patients were randomized, and the Discussion reports improved survival and response with BRAF–EGFR combination therapy. But the trial compared those combinations with cetuximab plus irinotecan-based chemotherapy, not BRAF inhibitor monotherapy. The latter comparison appears only as background, not as an outcome demonstrated in the 665-patient trial. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIn the Phase III BEACON trial, triple therapy with encorafenib, binimetinib, and cetuximab showed no significant changes compared with encorafenib plus cetuximab in BRAFV600E colorectal cancer.
“This recommendation is based on the Phase III BEACON trial, which evaluated dual and triple therapy for BRAFV600E CRC using encorafenib, binimetinib (MEK inhibitor), and cetuximab and showed no significant changes between the triple therapy and encorafenib plus cetuximab [5].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [5]
The Trial Design section identifies BEACON as a phase 3 trial comparing these regimens in BRAF V600E-mutated metastatic colorectal cancer. The Discussion reports that the triplet-versus-doublet overall-survival estimate favored the triplet, but its 95% confidence interval included no difference. The Statistical Analysis section says the trial was not powered for a formal comparison between those groups, so the broader claim of no significant changes between them is not established. (LLM, conf=0.84)
Experimental — accuracy not yet measuredOnly 22% of BRAFV600E colorectal cancer patients who received one previous line of therapy respond to encorafenib plus cetuximab, and resistance ultimately develops in the majority of patients.
“Despite the significant benefit of FDA-approved encorafenib plus cetuximab therapy, only 22% of patients who received one previous line of therapy respond to this approach, and resistance ultimately develops in the majority of patients [5,6].”
From Inhibition of fatty acid synthase enhances therapeutic efficacy and delays acquired resistance to BRAF-targeted therapy in colorectal cancer (2026) · cites this paper as [5]
The Efficacy section reports a 22% response rate to encorafenib plus cetuximab among patients with only one previous line of therapy. The Discussion says resistance ultimately develops in many patients, but refers to the triplet regimen and does not establish that it develops in a majority receiving the doublet. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAdding EGFR inhibitors to BRAF-targeted therapy improves efficacy in BRAFV600E colorectal cancer.
“the phase III BEACON trial led to the approval of encorafenib (BRAFi) and cetuximab (EGRFi) for the treatment of pretreated metastatic BRAFV600E CRC patients, as it demonstrated a significant survival improvement over the standard-of-care (irinotecan-based chemotherapy and EGFRi) (9.3 vs 5.9 months, HR 0.61, P < 0.001) [17, 18].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [17]
The Efficacy section reports that encorafenib plus cetuximab significantly improved overall survival over the irinotecan-based control regimen in previously treated patients with BRAF V600E–mutated metastatic colorectal cancer. But the cited paper reports 8.4 versus 5.4 months and a hazard ratio of 0.60 for that doublet, not the citing sentence’s 9.3 versus 5.9 months and 0.61. The paper also does not document regulatory approval. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCombined 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 [17]
The Efficacy section reports that combined BRAF and EGFR blockade improved median overall survival in patients with BRAF V600E–mutated metastatic colorectal cancer: 8.4 months with the doublet versus 5.4 months with control therapy. The introductory passage describes preclinical EGFR feedback after BRAF inhibition, but does not say that combined blockade proved synthetic lethality in those models. The copy provides no page number for these passages. (LLM, conf=0.87)
Experimental — accuracy not yet measured
The combination of encorafenib and cetuximab is the only EMA- and FDA-approved molecularly targeted regimen for patients with BRAFV600E CRC.
“Currently, the combination of encorafenib (BRAFi) and cetuximab (EGFRi) is the only EMA- and FDA-approved molecularly targeted regimen for patients with BRAFV600E CRC [17, 18].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [17]
The Discussion reports that encorafenib plus cetuximab improved survival and response rates in patients with BRAF V600E-mutated metastatic colorectal cancer. It does not say that the combination is approved by the EMA or FDA, or that it is the only approved molecularly targeted regimen. Searches for those regulatory claims found no supporting passage in our copy; page numbers were not provided. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe triple combination of BRAF, EGFR, and MEK inhibition has shown higher response rates and improved efficacy in patients with BRAF-mutant CRC.
“the triple combination of BRAF, EGFR, and MEK inhibition has shown higher response rates and improved efficacy in patients with BRAF-mutant CRC [238,239].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [239]
In the BEACON trial, triplet therapy with encorafenib, binimetinib, and cetuximab improved survival versus doublet and control groups in patients with BRAF V600E mutations; median overall survival was 9.0 months versus 5.4 months.
“This trial demonstrated improved survival in the triplet therapy group versus the doublet and control groups. Specifically, median overall survival was longer in the triplet therapy group (9.0 months) versus the other groups (5.4 months), as was the response rate and progression-free survival.”
From Update on Targeted Therapy and Immunotherapy for Metastatic Colorectal Cancer (2024) · cites this paper as [39]
Improved survival using targeted therapies has resulted from not only the discovery of new drugs that target actionable driver mutations but also the elucidation of the mechanisms for compensatory signaling pathways that are activated in response to target inhibition.
“Improved survival using targeted therapies has resulted from not only the discovery of new drugs that target actionable driver mutations but also the elucidation of the mechanisms for compensatory signaling pathways that are activated in response to target inhibition [14].”
From Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment (2024) · cites this paper as [14]
Median overall survival was 9 months on the triplet regimen compared to 5.4 months in the control group in the BEACON trial.
“The median OS was 9 months on the triplet regimen compared to 5.4 months in the control group (P < 0.0001, 75].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [28]
In the randomized portion of the BEACON trial, the confirmed objective response rate for the triplet treatment was 26% versus 2% for the control.
“Within the randomized portion of the BEACON trial, the confirmed ORR for the triplet treatment was much better than that for the control (26% vs. 2%).”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [28]
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BackgroundExploring and bypassing resistance to targeted therapies in colorectal cancer
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- Authors
- Kopetz, S., Grothey, A., Yaeger, R., Van Cutsem, E., Desai, J., Yoshino, T., Wasan, H., Ciardiello, F., Loupakis, F., Hong, Y. S., Steeghs, N., Guren, T. K., Arkenau, H.-T., Garcia-Alfonso, P., Pfeiffer, P., Orlov, S., Lonardi, S., Elez, E., Kim, T.-W., Schellens, J. H. M., Guo, C., Krishnan, A., Dekervel, J., Morris, V., Calvo Ferrandiz, A., Tarpgaard, L. S., Braun, M., Gollerkeri, A., Keir, C., Maharry, K., Pickard, M., Christy-Bittel, J., Anderson, L., Sandor, V., & Tabernero, J.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- From the University of Texas M.D. Anderson Cancer Center, Houston (S.K., V.M.); West Cancer Center and Research Institute, OneOncology, Germantown, TN (A. Grothey); Memorial Sloan Kettering Cancer Center, New York (R.Y., A.K.); University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium (E.V.C., J. Dekervel); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (J. Desai, C.G.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); Hammersmith Hospital, Division of...
- Oslo University Hospital (NO)
- ORCID
- Kopetz, Scott
- Grothey, Axel
- Yaeger, Rona
- Desai, Jayesh
- Yoshino, Takayuki
- Wasan, Harpreet
- Ciardiello, Fortunato
- Loupakis, Fotios
- Hong, Yong Sang
- Steeghs, Neeltje
- Guren, Tormod K.
- Arkenau, Hendrik-Tobias
- Pfeiffer, Per
- Orlov, Sergey
- Lonardi, Sara
- Kim, Tae-Won
- Schellens, Jan H.M.
- Guo, Christina
- Krishnan, Asha
- Dekervel, Jeroen
- Morris, Van
- Tarpgaard, L.S.
- Gollerkeri, Ashwin
- Maharry, Kati
- Anderson, Lisa
- Tabernero, Josep
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2019-10-24
- Volume
- 381
- Issue
- 17
- Pages
- 1632-1643
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2977895282
- Semantic Scholar
- ffb20682723dcd13b49af89a5ada6b116a8d98a0
- Cited by
- 1,491
- References
- 36
- Citations by year
- 2026: 154 · 2025: 184 · 2024: 245 · 2023: 184 · 2022: 230 · 2021: 275 · 2020: 204 · 2019: 13
- FWCI
- 75.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (acceptedVersion, other-oa)
- Hispana (acceptedVersion, cc-by-nd)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- RIUVic (UVic-UCC) (submittedVersion, cc-by-nd)
- UCL Discovery (University College London) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Funders
- Array BioPharma
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- BRAF V600E mutation, metastatic colorectal cancer, encorafenib, binimetinib, cetuximab, BRAF inhibitor combination therapy, EGFR signaling, overall survival, objective response rate, irinotecan, FOLFIRI, adverse events, targeted therapy
- MeSH terms
- Cetuximab, Electrocorticography, Irinotecan, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Carbamates, Female, Humans, Male, Middle Aged, Mutation, Sulfonamides, Colorectal Neoplasms, Survival Analysis, Disease Progression, Proto-Oncogene Proteins B-raf, Kaplan-Meier Estimate, Intention to Treat Analysis
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