Preoperative Chemoradiotherapy Plus Nivolumab Before Surgery in Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer Patients

Background: Preoperative chemoradiotherapy (CRT) and surgical resection are standard treatment for locally advanced rectal cancer (LARC). Combining immune-checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. Methods: In phase I, we investigated the feasibility of sequentially-combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. Results: Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathological complete response (pCR) was centrally confirmed in 30% (11/37; 90% CI, 18 %-44%) and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30) (p=0.004, Fisher9s exact test) were observed in those with PD-L1 tumor proportion score {greater than or equal to}1% and <1%, respectively; immunohistochemical staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15) (p=0.003, Fisher9s exact test) were observed for CD8+-T cell / effector regulatory-T cell (CD8/eTreg) ratios of {greater than or equal to} 2.5 and < 2.5, respectively, in tumor-infiltrating lymphocytes. Conclusions: CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.