Interim analysis of neoadjuvant chemoradiotherapy with sequential ipilimumab and nivolumab in rectal cancer (CHINOREC): A prospective randomized, open-label, multicenter, phase II clinical trial.

e15604 Background: Immune checkpoint inhibitors (ICI) do not seem to be effective in solid cancers, which lack an immunogenic priming. Radiotherapy (RT) can induce an immunogenic cell death (ICD) and thereby restore the susceptibility to ICI, especially in microsatellite stable (MSS) cancers. This study evaluates safety, tolerability and feasibility of neoadjuvant chemoradiotherapy (CRT) with concomitant ipilimumab (IPI) and nivolumab (NIVO) in locally advanced rectal cancer (LARC). Here we present the first requisite interim analysis. Methods: This is a prospective, randomized, open-label, multicenter, phase II investigator- initiated trial (IIT). Key eligibility criteria are patients with LARC and the medical need for a neoadjuvant CRT, without metastatic disease that is considered incurable by local therapies. In total 80 patients will be randomized (ratio 30:50) to receive either neoadjuvant CRT alone (50 Gy in 2 Gy fractions over 25 working days + concurrent capecitabine 1650 mg/m2/d PO) or in combination with a single dose of IPI 1 mg/kg IV at day 7, following 3 cycles of NIVO 3 mg/kg IV Q2W, starting on day 14. Patients undergo surgery within 10-12 weeks post CRT. The primary endpoint is safety of neoadjuvant CRT with sequential IPI and NIVO following surgical resection. Surgical complications are graded by the “Clavien-Dindo Classification” v2.0 and treatment-related adverse events (TRAEs) by the Common Terminology Criteria of Adverse Events (CTCAE) v5.0. Interim analyses for the surgical complication “reoperation” will be assessed after every 10th patient in the IPI/NIVO treatment arm. Reoperation numbers are compared to historically known and published ratios. If the observed case numbers are above the calculated upper 95% confidence interval (95% CIup), the study will be terminated. Results: From 06/2020-02/2022, 36 patients have been accrued, of whom 23 were randomized to the CRT+IPI/NIVO arm. Of these, the first 10 patients who underwent successful surgery were used for the present interim analysis. No patient experienced a surgical complication with the need for a reoperation (3Grade IIIb). Any surgical complication occurred in 8 (80%) patients, with the most common being Grade I (70%) and Grade II (50%) events. Conclusions: The addition of sequentially applied IPI and NIVO to neoadjuvant CRT does not increase the number of surgical reoperation rates. The study meets it’s interim analysis criteria to be safe to continue accrual. Clinical trial information: NCT04124601.