Randomized phase III study of sintilimab in combination with modified folfrinox versus folfrinox alone in patients with metastatic and recurrent pancreatic cancer in China: The CISPD3 trial.

560 Background: FOLFIRINOX or modified FOLFIRINOX (mFFX) is the standard of care for the first line treatment of metastatic pancreatic adenocarcinoma (PDAC). However, the prognosis still remains poor, novel treatment options are urgently need. Sintilimab, a human IgG4 monoclonal antibody that binds to programmed cell death receptor-1(PD-1), has shown remarkable efficacy in various cancers. We designed the CISPD3-trial in China, aimed to determine the efficacy and safety of the combination of Sintilimab and mFFX for metastatic or recurrent PDAC. Methods: In this single center, randomized, open-label, phase 3 trial, we enrolled patients with metastatic or recurrent PDAC to compare the efficacy and safety of Sintilimab combined with mFFX versus mFFX alone as first-line or second-line therapy. Patients eligible were randomly assigned (1:1) to Sintilimab (200 mg every 3 weeks) plus mFFX (irinotecan 85 mg/m 2 , oxaliplatin 68 mg/m 2 followed by 5-FU 2400 mg/m 2 , every 2 weeks) or mFFX. The primary endpoint was overall survival (OS), secondary endpoints included progression free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. This study is registered with ClinicalTrials.gov, NCT03977272. Results: From March 2019, to Dec 2020, 110 patients were enrolled and randomized to Sintilimab plus mFFX (n = 55) or mFFX (n = 55). 85.5% Patients had metastatic disease and 14.5% had recurrent disease, 7.3% Patients had previous first-line chemotherapy. The baseline characteristics of the subjects in these two arms were comparable. The median follow-up time for OS was 21.3 months (IQR 15.9-25.0) in Sintilimab plus mFFX group and 19.6 months (15.5-25.1) in mFFX group. The median OS was similar between Sintilimab plus mFFX (10.9 months) and mFFX arm (10.8 months) with HR = 1.083 (95% CI 0.6843 to 1.690). Median PFS was 5.9 months in Sintilimab plus mFFX arm and 5.73 months in mFFX arm (HR 0.9324, 95% CI, 0.6158 to 1.412). The ORR was 50% in the Sintilimab plus mFFX arm versus 23.9% in the mFFX arm (P = 0.010). The most common AE of Grade ≥ 3 are neutropenia (58.5% in the Sintilimab plus mFFX group vs. 44.4% in mFFX group), thrombocytopenia (17.0% vs. 11.1%), anemia (13.2% vs. 13.0%), vomiting (13.2% vs. 11.1%), increased aminotransferase (11.3% vs. 5.6%). 22.6% immune-related adverse events (irAEs) and 5.7% irAEs of grade ≥ 3 were observed in Sintilimab plus mFFX arm. The most common irAEs were pulmonary adverse event (13.2%) with 3 (5.7%) patients grade ≥ 3, among which 1 (1.8%) death was considered to be treatment-related. No new safety signals were identified. Conclusions: The addition of Sintilimab to mFFX improved ORR in advanced PDAC patients significantly, however no superior OS and PFS were observed. Toxicity was manageable. These data suggest that combined PD-1 blockade may expand the benefit of chemotherapy in PDAC. Clinical trial information: NCT03977272.