P-146 Efficacy and safety of FLOT combined with apatinib and sintilimab as a neoadjuvant therapy regimen for locally advanced gastric or gastroesophageal junction adenocarcinoma: An open-lable, single-arm, phase II study

Immune checkpoint inhibitor (ICI) sintilimab which targeting programmed death-1 (PD-1) plus CapeOx regimen showed a significant efficacy and well-manageable toxicity as neoadjuvant therapy (NAT) setting for patients with local advanced gastric or gastro-esophageal junction(G/GEJ) adenocarcinoma. Low dose anti-angiogenic agent apatinib promote tumor vascular normalization and modulate the tumor immunosuppressive microenvironment, which facilitates drug delivery and enhancing the anti-tumor effect of anti-PD-1 antibody immunotherapy. FLOT is the preferred neoadjuvant chemotherapy regimen, while evidence-based efficacy and safety of FLOT combined with ICI and anti-angiogenesis as NAT for LAGC patients is inadequate. Here, we first report the interim analysis (IA) data from a single-arm phase II trial, which first evaluated the efficacy and safety of FLOT combined with sintilimab and apatinib as NAT in patients with locally advanced G/GEJ adenocarcinoma. Pathological-confirmed naïve treatment patients (age≥18) with radiologic evaluable primary G/GEJ adenocarcinoma at stage cT3 or cT4 and with ECOG status at 0-1 were enrolled. Participants received radical gastrectomy after four preoperative cycles of sintilimab (200 mg, IV, q21d) combined with apatinib (250 mg, P.O. Qd, day1-21) plus FLOT (docetaxel 50mg/m2, oxaliplatin 85mg/m2, 5-FU 2600mg/m2, leucovorin 200mg/m2, IV) therapy every 3 weeks. The primary endpoint was the pathological complete response (pCR) rate. Secondary endpoints include major pathological response (MPR) rate, objective response rate (ORR), disease control rate (DCR), incidence of adverse events (AE), R0 resection rate and postoperative complications. In this phase II clinical research, 44 patients were include, the median age is 56.5 years (range, 22-77), and 35 patients (79.5%) were male, and 23 (52.3%) patients with stage cT4. Tumor Regression Grade based on Becker criteria of: 14 (31.8%) patients achieved complete remission, 9 (20.5%) achieved partial remission, the pCR rate was 31.8% and MPR rate was 52.3%. Tumor response was assessed by RECIST version 1.1 criteria: 13 (29.5%) achieved complete response (CR), 21 (47.7%) achieved partial response (PR), 10 (22.7%) achieved stable disease (SD). The ORR and DCR were 77.3% and 100%, respectively. Downstaging of the T, N stage and overall TNM stage was observed in 37 (84.1%), 26 (59.1%) and 39 (88.6%) patients, respectively. A total of 1108 treatment-related adverse events (TRAEs) occurred during the preoperative treatment, 90.8% grade I-II TRAEs, 9.2% grade III TRAEs, no grade IV TRAEs. The most common TRAEs were vomiting (100%), Alopecia (95.5%), peripheral neuritis (50%) leucopenia (52.3%), elevated transaminase (43.2%), neutropenia (43.2%), hypertension (43.2%); the most common grade III TRAEs were vomiting (50%) and alopecia (18.2%). All the 44 (100%) patients underwent R0 resection, no deaths resulted from surgery. The most common complications are fever (34.1%), pneumonia (22.7%), and fat liquefaction (6.8%). Only 1 (2.3%) patient underwent a second operation due to gastrointestinal anastomotic bleeding and finally recovered. The survival benefit will be reported publicly after the follow-up completed. FLOT combined with apatinib and sintilimab as NAT showed an encouraging pCR and MPR rate, compelling ORR and DCR rate with manageable toxicities. This triplet regimen might provide a promising NAT option for patients with locally advanced G/GEJ adenocarcinoma.