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

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

Online: http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-20-3416

Issue: Clin Cancer Res . 2021 Apr 15;27(8):2139-2147.


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 nonprogression 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. Interpretation: 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.