SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated MSS, BRAF V600E metastatic colorectal cancer (mCRC).

3504 Background: BRAF V600E mutations are associated with poor survival yet increased immune activation among patients (pts) with microsatellite stable (MSS) mCRC. A prior single-institution trial of the BRAF inhibitor encorafenib (E) with the anti-EGFR antibody cetuximab (C) and the anti-PD-1 antibody nivolumab (N) reported an overall response rate (ORR) of 50% and median progression-free survival (PFS) of 7.2 months in pts with MSS, BRAF V600E mCRC, promising findings relative to historical controls with E+C. Methods: In this phase II SWOG/NCTN study (NCT05308446), pts with previously treated, MSS BRAF V600E mCRC were randomized 2:1 to receive E (300 mg PO daily) + C (500 mg/m 2 IV every 2 weeks) + N (480 mg IV every 4 weeks) vs E+C only. No prior exposure to BRAF, EGFR, or immune checkpoint therapies were allowed. The primary endpoint was PFS and targeted a hazard ratio (HR) of 0.57 with a 1-sided α=0.10 and 80% power. Randomization was stratified by prior lines of therapy (1 vs 2) and Zubrod PS (0 vs 1). Treatment response was assessed every 8 weeks radiographically (RECIST 1.1). Secondary endpoints were overall survival (OS), ORR, and treatment-related adverse events (TRAE) according to CTCAE v5. Differences in PFS by treatment arm were assessed via stratified log-rank test. Results: Of 88 pts enrolled, 85 were eligible and evaluable (57 E+C+N, 28 E+C). Participant characteristics are listed in Table. Median PFS was 5.8 months (95% CI 4.0-7.8) with E+C+N and 6.3 months (95% CI 5.0-11.4; p=0.64) with E+C; HR 1.10 (95% CI 0.65-1.86). ORR was 35% for E+C+N and 32% for E+C. OS was similar between E+C+N and E+C: median 13.5 months (95% CI 11.0-18.9) vs. 11.6 months (95% CI 9.2-15.6; p=0.29); HR 0.85 (95% CI 0.47-1.52). 31 out of 57 pts (54%) had grade 3-4 TRAEs for E+C+N, vs 10 out of 28 (36%; p=0.11) for E+C; Grade 3 TRAEs occurring in >10% pts treated with E+C+N included fatigue (14%) and arthralgia (11%). Conclusions: The addition of N to E+C did not improve survival outcomes in this study population of pts with pretreated MSS, BRAF V600E mCRC. Ongoing correlative studies seek to identify biomarkers associated with treatment benefit that may be applied to future efforts seeking to personalize treatment approaches for this biologically heterogeneous population. Clinical trial information: NCT05308446 . Patient demographics. E+C+N(N=57) E+C(N=28) AGE Median 64.3 66.1 SEX (%) Male 27 (47) 19 (68) Females 30 (53) 9 (32) PRIOR LINES SYSTEMIC THERAPY (%) 1 40 (70) 18 (64) 2 17 (30) 10 (36) PERFORMANCE STATUS (%) 0 32 (56) 16 (57) 1 25 (44) 12 (43)