Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.

Abstract

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m2) in T3–4 NanyM0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic 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 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and < 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8+ lymphocyte /regulatory T cell (CD8/Treg) ratios ≥2 and < 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/Treg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.