Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer: Safety lead-in results from the phase III BEACON Colorectal Cancer Study

Eric Van Cutsem, Sanne Huijberts, Axel F Grothey, Rona Yaeger, Pieter Jan Cuyle, Elena Elez, Marwan Fakih, Clara Montagut, Marc Peeters, Takayuki Yoshino, Harpreet Wasan, Jayesh Desai, Fortunato Ciardiello, Ashwin Gollerkeri, Janna Christy-Bittel, Kati Maharry, Victor Sandor, Jan H.M. Schellens, Scott Kopetz, Josep Tabernero

Research output: Contribution to journalArticle

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Abstract

PURPOSE To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial (ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E–mutant tumors (one patient had a non–BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.

Original languageEnglish (US)
Pages (from-to)1460-1469
Number of pages10
JournalJournal of Clinical Oncology
Volume37
Issue number17
DOIs
StatePublished - Jan 1 2019

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Colorectal Neoplasms
Safety
Disease-Free Survival
Therapeutics
Survival
European Union
Standard of Care
Creatine Kinase
Treatment Failure
Urinary Tract Infections
Stroke Volume
Fatigue
MEK162
Cetuximab
encorafenib
Anemia
Neoplasms
Clinical Trials
Incidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer : Safety lead-in results from the phase III BEACON Colorectal Cancer Study. / Van Cutsem, Eric; Huijberts, Sanne; Grothey, Axel F; Yaeger, Rona; Cuyle, Pieter Jan; Elez, Elena; Fakih, Marwan; Montagut, Clara; Peeters, Marc; Yoshino, Takayuki; Wasan, Harpreet; Desai, Jayesh; Ciardiello, Fortunato; Gollerkeri, Ashwin; Christy-Bittel, Janna; Maharry, Kati; Sandor, Victor; Schellens, Jan H.M.; Kopetz, Scott; Tabernero, Josep.

In: Journal of Clinical Oncology, Vol. 37, No. 17, 01.01.2019, p. 1460-1469.

Research output: Contribution to journalArticle

Van Cutsem, E, Huijberts, S, Grothey, AF, Yaeger, R, Cuyle, PJ, Elez, E, Fakih, M, Montagut, C, Peeters, M, Yoshino, T, Wasan, H, Desai, J, Ciardiello, F, Gollerkeri, A, Christy-Bittel, J, Maharry, K, Sandor, V, Schellens, JHM, Kopetz, S & Tabernero, J 2019, 'Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer: Safety lead-in results from the phase III BEACON Colorectal Cancer Study', Journal of Clinical Oncology, vol. 37, no. 17, pp. 1460-1469. https://doi.org/10.1200/JCO.18.02459
Van Cutsem, Eric ; Huijberts, Sanne ; Grothey, Axel F ; Yaeger, Rona ; Cuyle, Pieter Jan ; Elez, Elena ; Fakih, Marwan ; Montagut, Clara ; Peeters, Marc ; Yoshino, Takayuki ; Wasan, Harpreet ; Desai, Jayesh ; Ciardiello, Fortunato ; Gollerkeri, Ashwin ; Christy-Bittel, Janna ; Maharry, Kati ; Sandor, Victor ; Schellens, Jan H.M. ; Kopetz, Scott ; Tabernero, Josep. / Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer : Safety lead-in results from the phase III BEACON Colorectal Cancer Study. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 17. pp. 1460-1469.
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abstract = "PURPOSE To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial (ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13{\%}), anemia (10{\%}), increased creatine phosphokinase (10{\%}), increased AST (10{\%}), and urinary tract infections (10{\%}). In 29 patients with BRAF V600E–mutant tumors (one patient had a non–BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48{\%} (95{\%} CI, 29.4{\%} to 67.5{\%}), median progression-free survival was 8.0 months (95{\%} CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95{\%} CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.",
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TY - JOUR

T1 - Binimetinib, encorafenib, and cetuximab triplet therapy for patients with BRAF V600E–mutant metastatic colorectal cancer

T2 - Safety lead-in results from the phase III BEACON Colorectal Cancer Study

AU - Van Cutsem, Eric

AU - Huijberts, Sanne

AU - Grothey, Axel F

AU - Yaeger, Rona

AU - Cuyle, Pieter Jan

AU - Elez, Elena

AU - Fakih, Marwan

AU - Montagut, Clara

AU - Peeters, Marc

AU - Yoshino, Takayuki

AU - Wasan, Harpreet

AU - Desai, Jayesh

AU - Ciardiello, Fortunato

AU - Gollerkeri, Ashwin

AU - Christy-Bittel, Janna

AU - Maharry, Kati

AU - Sandor, Victor

AU - Schellens, Jan H.M.

AU - Kopetz, Scott

AU - Tabernero, Josep

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PURPOSE To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial (ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E–mutant tumors (one patient had a non–BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.

AB - PURPOSE To determine the safety and preliminary efficacy of selective combination targeted therapy for BRAF V600E–mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial (ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35). PATIENTS AND METHODS Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with BRAF V600E–mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival. RESULTS Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with BRAF V600E–mutant tumors (one patient had a non–BRAF V600E–mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months). CONCLUSION In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated BRAF V600E–mutant mCRC.

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