SO-37 Short-term results of VOLTAGE-A: Nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stability and microsatellite instability-high, locally advanced rectal cancer (EPOC 1504)

Chemoradiotherapy (CRT) followed by radical surgery is the standard therapy for patients with locally advanced rectal cancer (LARC). Sequential use of an anti-PD-1 antibody after radiation demonstrates synergistic effects in in vivo models, and an anti-PD-1 antibody is effective in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer. We studied nivolumab and radical surgery following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. phase I investigated the feasibility of 240 mg q2 weeks x 5 cycles of nivolumab and radical surgery after the quality-assured CRT. In phase II, the efficacies and safeties for both patients with microsatellite stable (MSS) (cohort A1) and MSI-H (cohort A2) LARC were evaluated. In cohort A-1, the primary endpoint was a centrally confirmed pathological complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR=10% and 30% was 37 patients, with a 1-sided alpha of 5% and power of 90%. In Cohort A-2, 5 patients were included in an exploratory manner. Sequential use of nivolumab 240 mg q2 weeks x 5 cycles and radical surgery were well tolerated. From Jan/2017 to Oct/2019, a targeted number of patients was included and assessed. In cohort A-1, 30% (11/37; 90% CI 18-44%) of pCR (AJCC grade 0) rate and 38% (14/37) of major pathological response (MPR) (AJCC grade 0+1) rate were observed. Clinical CR was observed in one additional patient (3%) refusing surgery after nivolumab. The median neoadjuvant rectal (NAR) score was 8.4 (range: 0.0-50.4). pCR rates of 60% (6/10) and 19% (5/27) were seen in patients with tumor cells with PD-L1 ≥1% and < 1% immunohistochemistry staining, respectively (p=0.038, Fisher exact test), performed on biopsy samples taken pre-CRT. pCR rates of 62% (8/13) and 10% (1/10) were seen in 23 patients with pre-CRT tumor samples analyzable by flow cytometry, according to CD8+ T cell /effector regulatory T cell (CD8/eTreg) ratios ≥2 and < 2, respectively (p=0.029, Fisher exact test). In cohort A-2, 60% (3/5) of pCR rate and 0.9 (range: 0.9-20.4) of median NAR score were observed. As of Jan/2020, only 2 patients (1 local and 1 metastatic) in cohort A-1 and none in cohort A-2 recurred. Immune-related severe adverse events were observed in 3 patients (grade 3 myasthenia, grade 3 interstitial nephritis, and grade 2 peripheral motor neuropathy); all fully recovered and received radical surgery. During the follow-up period, one additional patient with grade 2 colitis was observed. No treatment-related deaths were observed. Promising pCR rates of 30% and 60%, with mild toxicities, were shown in MSS and MSI-H LARC patients treated with nivolumab plus radical surgery after CRT, suggesting that it is a candidate therapy for the future non-surgical approach.