SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated, microsatellite stable, BRAFV600E metastatic and/or unresectable colorectal cancer.

TPS3640 Background: Patients with microsatellite stable (MSS), BRAF V600E metastatic colorectal cancer (mCRC) experience poor survival outcomes. Second-line treatment with the BRAF inhibitor encorafenib (E) and anti-EGFR antibody cetuximab (C) is an approved treatment combination, with overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.1 months. Anti-PD-1 antibodies like nivolumab (N) are ineffective as monotherapy for patients with MSS, BRAF V600E mCRC. In preclinical models of MSS, BRAF V600E CRC, inhibition of BRAF and EGFR induces loss of expression of mismatch repairs genes and promotes a microsatellite instability-high phenotype, which may prime these tumors for response to immunotherapy. In support of these findings, a single-institution clinical trial of E + C + N for 26 patients with MSS, BRAF V600E mCRC reported an ORR of 50% and median PFS of 7.2 months. We hypothesize that the addition of N to E + C will improve median PFS for patients with MSS, BRAF V600E mCRC. Methods: In this prospective phase II clinical trial (N=84), patients with previously treated MSS, BRAF V600E mCRC are randomized 2:1 into 2 arms, respectively: experimental treatment (E + C + N) or standard treatment (E + C). No prior BRAF, EGFR, or immunotherapy agents are allowed. All patients receive E (300 mg PO daily) and C (500 mg/m 2 IV every 14 days), and patients in the experimental arm receive N (480 mg IV every 28 days). The primary endpoint is PFS. Secondary endpoints include overall survival, best overall response, duration of response, and safety/tolerability. Using a one-sided α= .10 and power 80%, we target an improvement in median PFS from 4.2 to 7.3 months (hazard ratio 0.57). Additional patient specimens will be collected for exploratory correlative research. As of 2/2024, 50 of 84 planned participants have been enrolled. Clinical trial information: NCT05308446 .