Regorafenib-Avelumab combination in patients with microsatellite stable colorectal cancer (REGOMUNE) : a single arm, open-label, phase II trial

Clinical cancer research, janvier 2021

Sophie Cousin, Coralie Cantarel, Jean-Philippe Guégan, Carlos Gomez-Roca, Jean-Philippe Metges, Antoine Adenis, Simon Pernot, Carine A Bellera, Michèle Kind , Celine Auzanneau, François Le Loarer, Isabelle Soubeyran, Alban Bessede, Antoine Italiano

DOI: 10.1158/1078-0432.CCR-20-3416


Purpose: Regorafenib is synergistic with immune-checkpoint inhibition in colorectal cancer pre-clinical models.

Experimental design: This is a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks/4, 160mg QD; Avelumab 10 mg/kg IV was given every 2 weeks, beginning at C1D15 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: 1-year non-progression rate, progression-free survival and overall survival, safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 Day 1.

Results: 48 patients were enrolled in 4 centers. 43 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 progression-free survival and overall survival were 3.6 months (95%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 tumour-associated macrophages was significantly associated with adverse progression-free survival (1.8 vs 3.7 months, p=0.002) and overall survival: 3.7 months vs not reached, p=0.002). Increased tumor infiltration by CD8+ T cells at C2D1 as compared to baseline was significantly associated with better outcome.

Conclusions: The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of MSS-colorectal cancer patients. Computational pathology through quantification of immune cells infiltration may improve patient selection for further studies investigating this approach.