The Ave–Rec Trial: Phase II Trial of PDL1/PD1 Blockade with Avelumab after Chemoradiotherapy for Locally Advanced Resectable T3B-4/N1-2 Rectal Cancer

PURPOSE: Long-course chemoradiotherapy (LCCRT) for locally advanced rectal cancer (LARC) achieves a pathologic complete response (pCR) in approximately 10% to 30% of cases. Radiotherapy exerts both immunostimulatory and immunosuppressive effects. Inhibition of PDL1 may augment the immunostimulatory response. We hypothesize that administering avelumab following LCCRT may enhance tumor response and reduce relapse rates. PATIENTS AND METHODS: This was a phase II single-arm trial. Eligible patients had MRI stage T3b to 4/N1 to 2/M0 LARC within 12 cm from the anal verge. Treatment consisted of long-course chemoradiotherapy (LCCRT) with 50.4 Gy and 5-fluorouracil or capecitabine, followed by four cycles of avelumab (10 mg/kg every 2 weeks). Surgical resection was performed 10 to 12 weeks after completion of LCCRT. Fresh tumor biopsies/ctDNA were taken before LCCRT, before avelumab, and at surgery. The primary endpoint was pCR, reported centrally. Secondary endpoints were imaging responses and toxicity, and exploratory endpoints were translational studies (immune evaluation by multiplex IHC and biopsy-derived tumoroids), distant relapse-free survival, and relapse sites. RESULTS: Thirty-seven patients entered the trial, of whom 33 received avelumab and 32 had surgery. The overall response rate by pelvic MRI (N = 33) was 48%. By 2-[¹⁸F]fluoro-2-deoxy-D-glucose PET, there were 10 complete metabolic responses (CMR) and 18 partial metabolic responses (PMR). Regression score 0 (modified Ryan pCR) was observed in 19% of patients (N = 6), and regression score 1 in 16% (N = 5). Overall, 34% of patients (N = 11) had a major pathologic response. Tumors with greater PDL1 expression showed superior pCR/tumor regression. Tumoroid studies indicated intact cellular machinery for PDL1/HLA class-1 expression modulated by IFNγ. No immune-related grade 3 adverse events were observed, and postoperative complications were as expected. The median follow-up was 3.1 years, the 3-year estimated time to progression was 82%, distant relapse-free survival was 80%, and disease-free survival was 80%. CONCLUSIONS: The Ave-Rec phase II study demonstrated that avelumab after LCCRT is deliverable and tolerable, with significant imaging responses and a major pathologic response rate. Tumoral immune cell subsets/checkpoint expression was predictive of pathologic response. The addition of immune checkpoint inhibitors warrants further evaluation in patients with LARC.