Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, <i>BRAF</i><sup>V600E</sup> metastatic colorectal cancer.
Van K. Morris, Christine M. Parseghian, Michelle Escano, Benny Johnson, Kanwal Raghav, Arvind Dasari, Ryan Huey, Michael J. Overman, Jason Willis, Michael Sangmin Lee, Robert A. Wolff, Bryan K. Kee, John Paul Shen, Maria Pia Morelli, Alda L. Tam, Wai Chin Foo, Lianchun Xiao, Scott Kopetz
Abstract
12 Background: Encorafenib (E) and cetuximab (C) offers short-lived response and survival benefit for patients (pts) with MSS, BRAF V600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAF V600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAF V600E metastatic CRC were eligible. No prior BRAF inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m 2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H 0 : p≤.22; H a : p≥.45, where p= percentage of pts with radiographic response) was employed using a one-sided α=.05 and β=.20. In the first stage, ≥ 4/15 responses were needed in order for the trial to enroll 11 additional pts. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: All 26 pts have been enrolled - 23 patients treated, and 21 evaluable for response so far. Median age is 59 years (range, 32-85), and 14 (54%) are female. No dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events (AE) occurred in 4/22 (18%) patients. Grade 3 AEs included colitis, maculopapular rash, leukocytosis, and elevated amylase/lipase (all N=1). Grade 4 AEs in a single patient were myositis/myocarditis. Overall response rate is 45% (95% CI, 23-68), and disease control rate is 95% (95% CI, 75-100). Median PFS is 7.3 months (95% CI, 5.5-NA). Median OS is 11.4 months (95% CI, 7.6-NA). For the 9 pts thus far with responses, median duration of response is 8.1 months (95% CI, 7.3-NA). Updated results will be presented. Conclusions: E + C + N is effective and well-tolerated for pts with MSS, BRAF V600E metastatic CRC. The E+C+N regimen met its predefined efficacy endpoint and suggests a role for immunotherapy as a novel combination approach for this specific subpopulation of MSS metastatic CRC. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAF V600E metastatic CRC will activate in early 2022. Clinical trial information: NCT04017650.