Phase I/II trial of encorafenib, cetuximab, and nivolumab in microsatellite stable <i>BRAF</i> ^V600E metastatic colorectal cancer following progression on prior BRAF+EGFR targeted therapies.

182 Background: A BRAF V600E mutation, present in approximately 8-10% of all colorectal cancers (CRC), is a poor prognostic biomarker for patients with metastatic CRC. The BRAF V600E inhibitor encorafenib (E) and the anti-EGFR antibody cetuximab (C) are approved for refractory, BRAF V600E mCRC based upon on overall response rate (ORR) of 20% and median progression-free survival (PFS) of 4.2 months . A single-arm trial adding the anti-PD1 antibody nivolumab (N) to E+C in the same (BRAF-inhibitor naïve) population showed promising efficacy, with an ORR of 50% and median PFS of 7.4 months. We evaluated the efficacy of E+C+N in patients with microsatellite stable (MSS), BRAF V600E mCRC who had progressed on prior E+C. Methods: Patients with MSS, BRAF V600E mCRC with documented prior progression on E+C were eligible for treatment with E (300 mg PO daily), C (500 mg/m 2 q14 days), and N (480 mg IV q28days) were included in the study. Primary endpoint was best overall response by RECIST 1.1. Secondary endpoints were PFS, overall survival (OS), and toxicity (by CTCAE v5). Circulating tumor DNA assessment of molecular alterations in the MAPK pathway in association with response were performed by NGS. Descriptive statistics were used to summarize outcomes. Results: Among the 12 participants, none achieved a radiographic response, and 5 experienced stable disease. Disease control rate was 41.7% (95% CI, 13.8-69.6). Median PFS was 3.7 months (95% CI, 1.7-5.7), and median OS was 8.3 months (NE-NE). Four patients (16.7%) had concomitant MAPK-activating alterations at baseline, and APC , TP53 , and PIK3CA mutations were present in 25.0%, 66.7%, and 33.3% of patients, respectively. The presence of MAPK-activating mutation was not associated with disease progression (odds ratio 1.3; 95% CI 0.11-16; p=0.82). The most common grade 1-2 treatment-related adverse events (AEs) were anemia (N=5), arthralgia (N=5), rash (N=4), headache (N=4), and fatigue (N=3); 1 of the 12 patients experienced a grade 3 small bowel obstruction. Conclusions: In this pilot study, addition of N to E+C did not appear to overcome resistance to prior BRAF + EGFR targeted therapies in patients with MSS, BRAF V600E mCRC. While the addition of immunotherapy has demonstrated promising signal in early-phase clinical trials for this population, the benefit appears unlikely when offered sequentially after progression on BRAF combination therapies. Clinical trial information: NCT04017650 .