Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial

Purpose: Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models. Patients and Methods: This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1. Results: Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8-5.4] and 10.8 months (95% CI, 5.9-NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n = 14, 30%), hypertension (n = 11, 23%), and diarrhea (n = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). Increased tumor infiltration by CD8(+) T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome. Conclusions: The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.

Automated summary

This study demonstrated that the combination of Regorafenib + avelumab has a synergistic effect in a subset of colorectal cancer patients, mobilizing antitumor immunity. Additionally, computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.