Abstract

TPS878 Background: Fluoropyrimidine-based chemoradiotherapy (CRT) and subsequent radical surgery (SRS) are widely accepted as standard treatment for patients (pts) with locally advanced rectal cancer (LARC). Pathological complete remission (pCR) rates are associated with improved clinical outcomes. An important target, high-frequency microsatellite instability (MSI-H), was identified for which anti-PD-1 antibodies confirmed robust antitumor activity in metastatic colorectal cancer (mCRC). Recently, improved therapeutic effects by combining an immune checkpoint inhibitor with radiotherapy (RT) have been reported in pts with other cancer types. Furthermore, sequential use of an anti-PD-1 antibody after RT has demonstrated synergistic effects in in vivo models. The purpose of this study is to investigate safety, efficacy, and proof-of-concept (POC) of nivolumab (Nivo) monotherapy plus SRS after pre-CRT in non-MSI-H and MSI-H pts with LARC. Methods: The inclusion criteria are: LARC in the lower/middle rectum; clinical stage, T3–4 N-any M0; age ≥20 years; and 50.4 Gy of concurrent pre-CRT completed with daily 1,650 mg/m2 of capecitabine. Within 2 weeks after pre-CRT, 240 mg of Nivo is administered every 2 weeks 5 times before SRS, which is performed at least 2 weeks after Nivo treatment. The purpose of P1b is to evaluate dose-limiting toxicity and determine the recommended P2 dose (RP2D). In P2, the efficacy and safety of Nivo at RP2D are evaluated. The primary endpoint is the pCR rate by independent central assessment in pts with non-MSI-H LARC. Secondary endpoints include disease-free and overall survival and adverse events. Fifty pts including 40 non-MSI-H and 10 MSI-H pts will be enrolled. As an exploratory biomarker study, repeated biopsies from primary sites and blood collections will be performed 4 times during the treatment courses (before and after pre-CRT, during Nivo treatment, and at SRS), and phenotypes of immune-competent cells, neoantigens, T cell receptor repertoire, and enteric bacteria will be evaluated. As of September 2017, P1b has been completed and P2 is ongoing. Clinical trial information: NCT02948348.

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