Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E–Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study

Abstract

PURPOSE BEACON CRC evaluated encorafenib plus cetuximab with or without binimetinib versus investigators' choice of irinotecan or FOLFIRI plus cetuximab in patients with BRAFV600E–mutant metastatic colorectal cancer (mCRC), after progression on 1-2 prior regimens. In the previously reported primary analysis, encorafenib, binimetinib plus cetuximab (ENCO/BINI/CETUX; triplet) and encorafenib plus cetuximab (ENCO/CETUX; doublet) regimens improved overall survival (OS) and objective response rate (ORR; by blinded central review) versus standard of care. The purpose of this analysis was to report updated efficacy and safety data. METHODS In this open-label, phase III trial, 665 patients with BRAF V600E–mutant mCRC were randomly assigned 1:1:1 to receive triplet, doublet, or control. Primary end points were OS and independently reviewed ORR comparing triplet to control. OS for doublet versus control was a key secondary end point. Updated analyses include 6 months of additional follow-up and ORR for all randomized patients. RESULTS Patients received triplet (n = 224), doublet (n = 220), or control (n = 221). Median OS was 9.3 months (95% CI, 8.2 to 10.8) for triplet and 5.9 months (95% CI, 5.1 to 7.1) for control (hazard ratio [HR], 0.60 [95% CI, 0.47 to 0.75]). Median OS for doublet was 9.3 months (95% CI, 8.0 to 11.3) (HR v control, 0.61 [95% CI, 0.48 to 0.77]). Confirmed ORR was 26.8% (95% CI, 21.1% to 33.1%) for triplet, 19.5% (95% CI, 14.5% to 25.4%) for doublet, and 1.8% (95% CI, 0.5% to 4.6%) for control. Adverse events were consistent with the prior primary analysis, with grade ≥ 3 adverse events in 65.8%, 57.4%, and 64.2% for triplet, doublet, and control, respectively. CONCLUSION In the BEACON CRC study, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients in the metastatic setting compared with standard chemotherapy. Based on the primary and updated analyses, encorafenib plus cetuximab is a new standard care regimen for previously treated patients with BRAF V600E mCRC.

Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines

“…70,80,81,83 In the updated analysis, confirmed ORR results by blinded independent review based on all randomized patients were 26.8% (95% CI 21.1% to 33.1%) for triplet, 19.5% (95% CI 14.5% to 25.4%) for doublet, and 1.8% (95% CI 0.5% to 4.6%) for control. 83 For median PFS, the updated results were 4.5 months (95% CI 4.2-5.4 months), 4.3 months (95% CI 4.1-5.4 months), and 1.5 months (95% CI 1.5-1.9 months) for triplet, doublet, and control, respectively, with HRs of 0.42 (95% CI 0.33-0.53) and 0.44 (95% CI 0.35-0.55) for the triplet and doublet, respectively, compared with the control. 83 These data compare favorably with the prior results from studies of irinotecan and cetuximab with or without vemurafenib.…”

“…The OS results were consistent across a broad range of subgroups. 83 Efficacy was similar when binimetinib was added to the encorafenib plus cetuximab regimen and both regimens had significantly improved efficacy and quality of life assessments relative to the control in patients with BRAF V600E-mutated mCRC whose disease had progressed after one or two prior regimens. 70,80,81,83 In the updated analysis, confirmed ORR results by blinded independent review based on all randomized patients were 26.8% (95% CI 21.1% to 33.1%) for triplet, 19.5% (95% CI 14.5% to 25.4%) for doublet, and 1.8% (95% CI 0.5% to 4.6%) for control.…”

“…83 Efficacy was similar when binimetinib was added to the encorafenib plus cetuximab regimen and both regimens had significantly improved efficacy and quality of life assessments relative to the control in patients with BRAF V600E-mutated mCRC whose disease had progressed after one or two prior regimens. 70,80,81,83 In the updated analysis, confirmed ORR results by blinded independent review based on all randomized patients were 26.8% (95% CI 21.1% to 33.1%) for triplet, 19.5% (95% CI 14.5% to 25.4%) for doublet, and 1.8% (95% CI 0.5% to 4.6%) for control. 83 For median PFS, the updated results were 4.5 months (95% CI 4.2-5.4 months), 4.3 months (95% CI 4.1-5.4 months), and 1.5 months (95% CI 1.5-1.9 months) for triplet, doublet, and control, respectively, with HRs of 0.42 (95% CI 0.33-0.53) and 0.44 (95% CI 0.35-0.55) for the triplet and doublet, respectively, compared with the control.…”

“…83 For median PFS, the updated results were 4.5 months (95% CI 4.2-5.4 months), 4.3 months (95% CI 4.1-5.4 months), and 1.5 months (95% CI 1.5-1.9 months) for triplet, doublet, and control, respectively, with HRs of 0.42 (95% CI 0.33-0.53) and 0.44 (95% CI 0.35-0.55) for the triplet and doublet, respectively, compared with the control. 83 These data compare favorably with the prior results from studies of irinotecan and cetuximab with or without vemurafenib. 59,79 The safety and tolerability profiles of both the triplet and the doublet combinations were consistent with the known profiles of the component agents.…”

Incidence and prognostic factors in patents (pts) with mutant BRAF (mBRAF) metastatic colorectal cancer (mCRC) in Russia.

“…в группе контроля. При этом не отмечено различий между двойной и тройной комбинацией таргетных препаратов ни в отношении выживаемости без прогрессирования, ни в отношении общей выживаемости (ОР 0,95, 95% ДИ 0,74-1,21) [4,25]. Проведенный многофакторный анализ выделил только два фактора с независимым неблагоприятным прогнозом -метастазы в забрюшинные лимфоузлы и метастазы в надпочечники.…”