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The safety and efficacy of encorafenib plus cetuximab with or without standard-of-care chemotherapy will be compared with that of chemotherapy alone in patients with BRAF V600E–mutated metastatic colorectal cancer as part of the phase 3 BREAKWATER trial.
The safety and efficacy of encorafenib (Braftovi) plus cetuximab (Erbitux) with or without standard-of-care (SOC) chemotherapy will be compared with that of chemotherapy alone in patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC) as part of the phase 3 BREAKWATER trial (NCT04607421).1
In September 2021, the FDA approved the combination of encorafenib and cetuximab for use in adult patients with mCRC and a BRAF V600E mutation following prior therapy, based on findings from the phase 3 BEACON CRC trial (NCT02928224).2 At a median follow-up of 12.8 months, the doublet resulted in a median overall survival (OS) of 9.3 months (95% CI, 8.0-11.3) vs 5.9 months (95% CI, 5.1-7.1) with the control regimen of cetuximab plus irinotecan or FOLFIRI (leucovorin calcium, 5-fluourourcil [5-FU], and irinotecan; HR, 0.60; 95% CI, 0.47-0.75).3 Moreover, the combination elicited an objective response rate (ORR) of 19.5% (95% CI, 14.5%-25.4%) vs 1.8% (95% CI, 0.5%-4.6%) with the control regimen.
“The data are certainly encouraging for the use of a BRAF and EGFR inhibitor,” lead study investigator Scott Kopetz, MD, PhD, FACP, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said in an interview with OncLive®. “[BREAKWATER] asks the question [of whether] response rates and activity can be higher when [encorafenib and cetuximab are] administered earlier in the treatment course, and also the potential for an interaction and synergy between cytotoxic chemotherapy and targeted therapies, as seen in many other settings within CRC.”
Previously, in stage 1 of the single-arm, phase 2 ANCHOR CRC trial (NCT03693170), the frontline combination of encorafenib, binimetinib (Mektovi), and cetuximab was found to result in a median progression-free survival (PFS) of 4.9 months (95% CI, 4.4-8.1) and an ORR of 50% (95% CI, 33.8%-66.2%) in previously untreated BRAF V600E-mutant metastatic colorectal cancer.3
Patients with mCRC whose tumors harbor BRAF V600E mutations have limited options available to them in the frontline setting. To date, these patients receive cytotoxic chemotherapy with or without anti-VEGF or anti-EGFR therapies. The BREAKWATER trial aims to address this unmet need by evaluating encorafenib plus cetuximab with or without chemotherapy as potential up-front treatment for this population.
“The evaluation of this combination in a first-line setting would help establish a new SOC for how and when patients with BRAF V600E–mutated tumors should receive targeted therapy,” Kopetz noted.
BREAKWATER will enroll patients with BRAF V600E–mutant mCRC, determined via tumor tissue or blood. To be eligible for enrollment, patients are required to have an ECOG performance status of 0 or 1, as well as acceptable bone marrow, hepatic, and renal function. To participate in the safety lead-in cohorts, patients needed to have evaluable disease per RECIST v1.1 criteria. To participate in the phase 3 portion of the study, patients were required to have measurable disease.
Patients will be excluded from the trial if they previously received a BRAF or EGFR inhibitor, or both oxaliplatin and irinotecan; have symptomatic brain metastases; or have microsatellite instability–high or deficient mismatch repair tumors, unless they are not ineligible to receive immune checkpoint inhibitors.
Thirty patients each will be enrolled to 2 safety lead-in cohorts, which will aim to evaluate the safety and tolerability of encorafenib plus cetuximab with FOLFIRI or mFOLFOX6 (oxaliplatin, leucovorin, and 5-FU) in this patient population. Patients in both cohorts will receive oral encorafenib at a daily dose of 300 mg and intravenous cetuximab at 500 mg/m2 given every 2 weeks; the doublet will be combined with FOLFIRI or mFOLFOX6, which will also be administered every 2 weeks.
Along with measuring safety and tolerability of the combinations in the safety lead-in portion of the research, investigators will also evaluate efficacy, pharmacokinetics, and drug-to-drug interaction of encorafenib with irinotecan or oxaliplatin as key secondary end points. Pharmacodynamics will serve as an exploratory end point.
Data collected from this portion of the trial will help determined with chemotherapy combination should be utilized in the phase 3 portion of the study. Here, participants will be randomized 1:1:1 to receive encorafenib plus cetuximab (arm A; n = 290), encorafenib plus cetuximab and FOLFIRI or mFOLFOX6 (arm B; n = 290), or FOLFIRI, mFOLFOX6, FOLFOXIRI (5-FU, oxaliplatin, and irinotecan), or CAPOX (oxaliplatin and capecitabine; control arm; n = 290).
Encorafenib and cetuximab will be administered at the same doses as the safety lead-in cohorts for arms A and B. For those who receive CAPOX, oxaliplatin will be given once every 3 weeks along with capecitabine, which will be given twice daily on days 1 through 14. CAPOX will be administered on a 21-day cycle, and all other treatments will follow a 28-day cycle. mFOLFOX6, FOLFIRI, and FOLFOXIRI will be administered every other week.
The primary end point of the phase 3 portion of the trial will be PFS by blinded independent review committee (BIRC) in arms A and B compared with the control arm. The key secondary end point is OS by BIRC in arms A and B vs the control arm.
Other secondary end points include ORR, duration of response, and time to response per BICR and investigator assessment, as well as investigator-assessed PFS, and PFS on next line of treatment for arms A and B vs the control arm, and arm A vs arm B.
Other end points of interest include PFS by BIRC and OS between arms A and B; safety and tolerability between arms A and B; quality of life; pharmacokinetics between arms A and B; and biomarker analyses. Again, pharmacodynamics will serve as an exploratory end point.
The open-label, international, multicenter, randomized trial began enrollment in December 2021. Approximately 60 patients are expected to enroll in the safety lead-in portion of the research, followed by approximately 870 patients in the phase 3 analysis.