P-228VOLTAGE: Multicenter phase Ib/II study of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy (CRT) with capecitabine in patients with locally advanced rectal cancer (LARC)

Introduction: Fluoropyrimidine-based Chemoradiotherapy (CRT) and subsequent radical surgery is widely accepted as the standard treatment for patients with Locally Advanced Rectal Cancer (LARC). Higher pathological complete response (pCR) rates are associated with good clinical outcomes. Recently, improved therapeutic effects have been reported in patients with various types of cancer by combining an immune checkpoint inhibitor with radiotherapy (RT). The purpose of this study is to investigate safety, efficacy and proof-of-concept (POC) of nivolumab monotherapy plus subsequent radical surgery following preoperative CRT with capecitabine, in patients with LARC. Here, we present the results of the phase Ib and the preliminary results of phase II part. Methods: The Phase Ib part was designed to determine the recommended phase II dose (RP2D) in a “3 + 3” cohort-based design of nivolumab (240mg every 2 weeks, maximum of 5 times) and subsequent radical surgery. The Phase II part was designed to evaluate the efficacy and safety of RP2D of nivolumab and surgery for both primary and locally recurrent LARC, respectively. Patients with T3–4 Nany M0 primary LARC or locally recurrent LARC treated with 50.4Gy of RT plus 1,650 mg/m2 of capecitabine were enrolled. The primary endpoint is the pCR rate of primary non-MSI-H LARC by independent central assessment. Disease-free and overall survival, and treatment-related adverse events, are evaluated as secondary endpoints. Totally 52 patients including 5 primary MSI-H (high-level microsatellite instability), 37 primary non-MSI-H, and 10 locally recurrent LARC will be enrolled. Results: Three patients primary LARC were enrolled in phase Ib part. All 3 patients received the full, planned administration of nivolumab without dose modification, as well as radical surgery. During nivolumab treatment, only a single grade 1 pruritus event was observed. During surgery, one grade 2 gastritis, one grade 1 nausea, one grade 1 pain and one grade 1 extrapyramidal disorder were observed, none of which was related to the surgery. No dose limiting toxicities (DLTs) were observed in phase Ib part. Preliminary efficacy assessment of phase Ib/II by local pathologists demonstrated 4 pCR of the 7 patients with primary LARC, including 2 of 3 in phase Ib and 2 of 4 in phase II part, respectively. As of February 2018, 13 patients who received the RP2D were enrolled in the phase II part. Conclusion: Nivolumab monotherapy and subsequent radical surgery following preoperative CRT were safely performed in patients with LARC. According to the preliminary efficacy assessment, promising pCR rate was observed.