BAYONET trial: A multicenter phase II trial of staged combination with encorafenib + binimetinib + cetuximab following encorafenib + cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer.

3559 Background: While the doublet combination of encorafenib (ENCO) + cetuximab (CET) is a standard treatment for patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC), poor prognosis is expected after disease progression. As resistant mechanisms to BRAF + EGFR blockade, several MAPK pathway alterations, including RAS and RAF mutations, have been reported, suggesting that additional blockade of MAPK signaling may be an effective strategy. Furthermore, preclinical studies demonstrated that BRAF V600E-mutant colorectal cancer cell lines resistant to BRAF inhibitor + anti-EGFR antibody were sensitive to the triple combination of BRAF inhibitor + MEK inhibitor + anti-EGFR antibody. Methods: BAYONET is a single-arm, multicenter phase II trial designed to evaluate the efficacy and safety of the staged combination with ENCO, binimetinib (BINI), plus CET for patients with BRAF V600E-mutant mCRC who were refractory to ENCO plus CET. The main eligibility criteria are as follows: RAS wild-type/ BRAF V600E-mutant mCRC; age ≥ 20; ECOG PS 0 or 1; within 4 weeks from the last administration of previous ENCO or CET; no administration of other systemic therapy after refractoriness to ENCO + CET; complete response, partial response, or ≥4 months of stable disease was observed in the previous ENCO + CET. Included patients receive the combination treatment of ENCO (300 mg once a day) + BINI (45 mg twice a day) + CET (400 mg/m 2 initial dose and then 250 mg/m 2 once a week) in a 28-day cycle. The primary endpoint of this trial is 12-week progression-free survival (PFS) rate. The targeted sample size was calculated to be 30 on the basis of a power of 80%, a significance level of 10% (one-sided), a threshold of 20%, and an expected 12-week PFS rate of 40%. Pretreatment ctDNA analysis was performed using the Guardant360 assay. Results: Among 30 patients, all had microsatellite-stable or mismatch repair-proficient tumors, and 21 (70%) of patients received prior <3 treatment lines. The locally assessed 12-week PFS rate was 33.3% (80% CI, 21.8–46.6). Since the lower limit of 80% CI exceeded 20%, the primary endpoint was met. With a median follow-up duration of 9.8 months (range, 2.1–35.8), the median PFS was 2.0 months (95% CI, 1.6–4.2), and the median overall survival was 14.7 months (95% CI, 7.1–18.7). Patients who achieved 12-week PFS had significantly lower ctDNA BRAF V600E VAF (median, 0.2%; range, 0-18%) compared to those who did not achieve it (median, 4.2%; range, 0-41%). Grade 3 or higher adverse events were observed in 50% of patients, most commonly anemia (20%), creatine kinase increase (13%), and diarrhea (10%). No new safety signal was identified. Conclusions: Staged combination with ENCO+BINI+CET showed potential to achieve disease control for patients with BRAF V600E-mutant mCRC who were refractory to ENCO+CET. Clinical trial information: jRCTs031210510.