Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer

Abstract

Background: First-line treatment with encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and fluorouracil [mFOLFOX6]) for BRAF V600E-mutated metastatic colorectal cancer, an aggressive subtype with a poor prognosis, was compared with standard care (chemotherapy with or without bevacizumab) in an open-label, phase 3 trial, which showed significance regarding one of the two primary end points, objective response according to blinded independent central review (odds ratio for EC+mFOLFOX6 vs. standard care, 2.44; one-sided P<0.001). This result led to accelerated Food and Drug Administration approval of this investigational combination therapy for BRAF V600E-mutated metastatic colorectal cancer, including as first-line therapy. Data on progression-free survival (the second primary end point) and an updated interim analysis of overall survival are now available.

Methods: We randomly assigned patients with untreated BRAF V600E-mutated metastatic colorectal cancer to receive EC, EC+mFOLFOX6, or standard care. The two primary end points were objective response (reported previously) and progression-free survival according to blinded independent central review in the EC+mFOLFOX6 group and the standard-care group. The key secondary end point was overall survival.

Results: Significantly longer progression-free survival was seen with EC+mFOLFOX6 than with standard care (median, 12.8 vs. 7.1 months; hazard ratio for progression or death, 0.53; 95% confidence interval [CI], 0.41 to 0.68; P<0.001). In an interim analysis, overall survival was significantly longer with EC+mFOLFOX6 than with standard care (median, 30.3 vs. 15.1 months; hazard ratio for death, 0.49; 95% CI, 0.38 to 0.63; P<0.001). The incidence of serious adverse events during treatment was 46.1% with EC+mFOLFOX6 and 38.9% with standard care. Safety profiles were consistent with those known for each agent.

Conclusions: This trial showed significantly longer progression-free survival and overall survival with first-line treatment with EC+mFOLFOX6 than with standard care among patients with BRAF V600E-mutated metastatic colorectal cancer. (Funded by Pfizer and others; BREAKWATER ClinicalTrials.gov number, NCT04607421.).

Figure 1.. Analysis of Progression-Free Survival by Blinded Independent Central Review.

Panel A shows Kaplan-–Meier estimates of progression-free survival in the EC, EC+mFOLFOX6 and SOC arms. Panel B shows a forest plot of the analyses in pre-specified subgroups in the EC+mFOLFOX6 and SOC arms. *Analyses of EC versus SOC and EC versus EC+mFOLFOX6 are descriptive. CIs are not adjusted for multiplicity and should not be mistaken for hypothesis tests. Following a protocol amendment, enrollment into the EC arm was discontinued prematurely. ^†Subgroup analyses are exploratory and descriptive in nature; CIs are not adjusted for multiplicity and should not be interpreted as hypothesis tests. CI, confidence interval; EC, encorafenib and cetuximab; EC+mFOLFOX6, encorafenib and cetuximab plus oxaliplatin, leucovorin and 5-FU; HR, hazard ratio; SOC, standard of care.

Figure 1.. Analysis of Progression-Free Survival by Blinded Independent Central Review.

Panel A shows Kaplan-–Meier estimates of progression-free survival in the EC, EC+mFOLFOX6 and SOC arms. Panel B shows a forest plot of the analyses in pre-specified subgroups in the EC+mFOLFOX6 and SOC arms. *Analyses of EC versus SOC and EC versus EC+mFOLFOX6 are descriptive. CIs are not adjusted for multiplicity and should not be mistaken for hypothesis tests. Following a protocol amendment, enrollment into the EC arm was discontinued prematurely. ^†Subgroup analyses are exploratory and descriptive in nature; CIs are not adjusted for multiplicity and should not be interpreted as hypothesis tests. CI, confidence interval; EC, encorafenib and cetuximab; EC+mFOLFOX6, encorafenib and cetuximab plus oxaliplatin, leucovorin and 5-FU; HR, hazard ratio; SOC, standard of care.

Figure 2.. Analysis of Overall Survival.

Panel A shows Kaplan–Meier estimates of overall survival in the EC, EC+mFOLFOX6 and SOC. Panel B shows a forest plot of the analyses in pre-specified subgroups in the EC+mFOLFOX6 and SOC arms. Because the result of the interim analysis of overall survival was statistically significant, no further statistical test will be performed. *Analyses of EC versus SOC and EC versus EC+mFOLFOX6 are descriptive. CIs are not adjusted for multiplicity and should not be mistaken for hypothesis tests. Following a protocol amendment, enrollment into the EC arm was discontinued prematurely. ^†Subgroup analyses are exploratory and descriptive in nature; CIs are not adjusted for multiplicity and should not be interpreted as hypothesis tests. CI, confidence interval; EC+mFOLFOX6, encorafenib and cetuximab plus oxaliplatin, leucovorin and 5-FU; HR, hazard ratio; SOC, standard of care.

Figure 2.. Analysis of Overall Survival.

Panel A shows Kaplan–Meier estimates of overall survival in the EC, EC+mFOLFOX6 and SOC. Panel B shows a forest plot of the analyses in pre-specified subgroups in the EC+mFOLFOX6 and SOC arms. Because the result of the interim analysis of overall survival was statistically significant, no further statistical test will be performed. *Analyses of EC versus SOC and EC versus EC+mFOLFOX6 are descriptive. CIs are not adjusted for multiplicity and should not be mistaken for hypothesis tests. Following a protocol amendment, enrollment into the EC arm was discontinued prematurely. ^†Subgroup analyses are exploratory and descriptive in nature; CIs are not adjusted for multiplicity and should not be interpreted as hypothesis tests. CI, confidence interval; EC+mFOLFOX6, encorafenib and cetuximab plus oxaliplatin, leucovorin and 5-FU; HR, hazard ratio; SOC, standard of care.