The Ave-Rec trial: Phase II trial of PDL1/PD-1 blockade with Avelumab post Chemoradiotherapy for locally advanced resectable T3B-4/N1-2 Rectal cancer.

Purpose Long course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) results in 10-30% pathological complete response rate (pCR). Radiotherapy is both immuno-stimulatory and -suppressive. PDL1-inhibition may enhance its immuno-stimulatory effects. Hypothesis Avelumab given post-LCCRT may increase tumor response rates whilst reducing relapses. Patients And Methods Phase II single-arm trial. Eligible patients: MRI stage T3b-4/N1-2/M0 LARC, within 12cm from anal verge.Treatment LCCRT (50.4Gy + 5FU/Capecitabine). Post-LCCRT, 4 cycles avelumab (10mg/kg/q2 weeks), then resection 10-12 weeks post-LCCRT. Fresh tumor biopsy/ctDNA taken at pre-LCCRT, pre-avelumab and at surgery. Primary Endpoint pCR, reported centrally. Secondary endpoints; Imaging responses, Toxicity. Exploratory; Translational studies: immune-evaluation by multiplex immune-histochemistry and biopsy-derived tumoroids. Distant relapse-free survival and relapse sites. Results Thirty-seven patients entered: 33 received avelumab, 32 had surgery. ORR Pelvic MRI (N=33): 2 CR, 14 PR, 31 DCR.Fdg Pet 10 CMR, 18 PMR. The modified Ryan pCR (Regression score=0) 19% (N=6), Regression score=1, 16% (N=5): overall 34% (N=11) had a mPR. Tumors with greater PDL1 expression showed superior pCR/tumor regression. Tumoroid studies indicated intact cellular machinery for PDL1/HLA class-1 expression modulated by IFNg. No immune-related G3 AEs and post-operative complications were as expected. Median followup 3.1yrs: 3yr estimated TTP = 82%, DRFS = 80%, DFS = 80%. Conclusions The AveRec phase II study demonstrated avelumab post LCCRT is deliverable, tolerable, with significant imaging responses and mPR rate of 34%. Tumoral immune cell subsets/checkpoint expression predictive of pathological response. The addition of immune checkpoint inhibitors warrants further evaluation in patients with LARC.