Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.

BACKGROUND Patients with metastatic colorectal cancer with the BRAF 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 In this open-label, phase 3 trial, we enrolled 665 patients with BRAF 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 A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

[1]  J. Desai,et al.  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 , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Dirk Schadendorf,et al.  Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. , 2018, The Lancet. Oncology.

[3]  D. Schadendorf,et al.  Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. , 2018, The Lancet. Oncology.

[4]  Gary Middleton,et al.  Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer. , 2018, Cancer discovery.

[5]  M. Kelsh,et al.  Prevalence of RAS and BRAF mutations in metastatic colorectal cancer (mCRC) patients by tumor location. , 2018 .

[6]  Ritika Kundra,et al.  Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer. , 2018, Cancer cell.

[7]  Lu Wang,et al.  Mechanisms of Acquired Resistance to BRAF V600E Inhibition in Colon Cancers Converge on RAF Dimerization and Are Sensitive to Its Inhibition. , 2017, Cancer research.

[8]  R. Sullivan,et al.  Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF-Mutant Melanoma , 2017, Clinical Cancer Research.

[9]  L. Diaz,et al.  Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). , 2017 .

[10]  F. Meric-Bernstam,et al.  Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation. , 2016, Cancer discovery.

[11]  Sabine Tejpar,et al.  BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression , 2016, Clinical Cancer Research.

[12]  J. Desai,et al.  Phase 2 results: Encorafenib (ENCO) and cetuximab (CETUX) with or without alpelisib (ALP) in patients with advanced BRAF-mutant colorectal cancer (BRAFm CRC). , 2016 .

[13]  H. Groen,et al.  Dabrafenib plus trametinib in patients with previously treated BRAF(V600E)-mutant metastatic non-small cell lung cancer: an open-label, multicentre phase 2 trial. , 2016, The Lancet. Oncology.

[14]  E. S. Kopetz,et al.  BRAF mutant colorectal cancer as a distinct subset of colorectal cancer: clinical characteristics, clinical behavior, and response to targeted therapies. , 2015, Journal of gastrointestinal oncology.

[15]  C. Atreya,et al.  Combined BRAF and MEK Inhibition With Dabrafenib and Trametinib in BRAF V600-Mutant Colorectal Cancer. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  P. Gibbs,et al.  Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  F. Pontén,et al.  High BRAF Mutation Frequency and Marked Survival Differences in Subgroups According to KRAS/BRAF Mutation Status and Tumor Tissue Availability in a Prospective Population-Based Metastatic Colorectal Cancer Cohort , 2015, PloS one.

[18]  Nikhil Wagle,et al.  Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. , 2015, Cancer discovery.

[19]  M. Berger,et al.  Pilot Trial of Combined BRAF and EGFR Inhibition in BRAF-Mutant Metastatic Colorectal Cancer Patients , 2015, Clinical Cancer Research.

[20]  C. Boni,et al.  Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. , 2014, The New England journal of medicine.

[21]  S. Kopetz,et al.  Progression-free survival remains poor over sequential lines of systemic therapy in patients with BRAF-mutated colorectal cancer. , 2014, Clinical colorectal cancer.

[22]  E. Van Cutsem,et al.  Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  A. McCullough.  Comprehensive genomic characterization of squamous cell lung cancers , 2013 .

[24]  Michael A. Davies,et al.  Resistance to BRAF Inhibition in BRAF-Mutant Colon Cancer Can Be Overcome with PI3K Inhibition or Demethylating Agents , 2012, Clinical Cancer Research.

[25]  Mari Mino-Kenudson,et al.  EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. , 2012, Cancer discovery.

[26]  R. Bernards,et al.  Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR , 2012, Nature.

[27]  Daniel J Sargent,et al.  Alternative end points to evaluate a therapeutic strategy in advanced colorectal cancer: evaluation of progression-free survival, duration of disease control, and time to failure of strategy--an Aide et Recherche en Cancerologie Digestive Group Study. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  P. Gibbs,et al.  Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer , 2011, Cancer.

[29]  A. Iafrate,et al.  BRAF Gene Amplification Can Promote Acquired Resistance to MEK Inhibitors in Cancer Cells Harboring the BRAF V600E Mutation , 2010, Science Signaling.

[30]  Sabine Tejpar,et al.  Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. , 2010, The Lancet. Oncology.

[31]  M. Okada,et al.  [New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1)]. , 2009, Gan to kagaku ryoho. Cancer & chemotherapy.

[32]  G. Fontanini,et al.  KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer , 2009, British Journal of Cancer.

[33]  Consortium , 2006 .

[34]  B. Wiens,et al.  The Fallback Procedure for Evaluating a Single Family of Hypotheses , 2005, Journal of biopharmaceutical statistics.

[35]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.