Neoadjuvant cadonilimab (PD-1/CTLA-4 bispecific antibody) plus FLOT chemotherapy in locally advanced gastric/gastroesophageal junction cancer (GC/GEJC): A prospective, multi-center, phase II study.

e16108 Background: FLOT remains the preferred neoadjuvant treatment (NAT) for locally advanced GC/GEJC, with evidence suggesting enhanced efficacy when plus PD-1 inhibitors. Cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, also exhibited survival benefits when combined with chemotherapy as first-line treatment for GC/GEJC. This study aimed to assess the efficacy and safety of Cadonilimab and FLOT as NAT in locally advanced GC/GEJC. Methods: Pathologically confirmed treatment-naïve patients (pts), aged 18-75, with radiologically evaluable primary GC/GEJC at stage cT3/4, ECOG PS 0-1, were enrolled. The study used simon-2 stage design with a total sample size of 38 pts and would be considered effective if more than 4 pts achieved pCR. Pts received surgery after completing NAT with Cadonilimab (10mg/kg, iv, Q3W) and FLOT (50mg/m² docetaxel, 85mg/m² oxaliplatin, 2600mg/m² 5-FU, and 200mg/m² leucovorin, iv). The primary endpoints were pCR and MPR rate. Secondary endpoints included ORR, DCR, R0 resection rate and safety (CTCAE 5.0). Results: In this phase II trial, initially enrolled 29 pts in stage I, with an additional 9 pts in stage II. Of the 34-evaluable pts, 30 pts underwent surgery. The median age was 57 years (range, 38-74), with 88.2% male and 64.7% diagnosed as stage cT4. According to RECIST1.1 criteria, 5 pts (14.7%) achieved CR, and 21pts (61.8%) achieved PR, with an ORR of 76.5% and DCR of 100.0%. According to Becker criteria for Tumor Regression Grade: 6 pts (20.0%) achieved TRG1a, 9 pts (30.0%) reached TRG1b, with a pCR rate of 20.0% and MPR rate of 50.0%. Pts with diffused and poorly differentiated tumors had higher rates of pCR and MPR (36.4%, 81.8%) than the overall population. A notable tumor downstaging was observed: 86.7% in T stage, 70.0% in N stage, and 70.0 in overall TNM stage. During the NAT phase, all 34 pts experienced TRAEs. Mild to moderate TRAEs (grade 1-2) were observed in 73.5% (25 patients), while 26.5% (9 patients) experienced grade 3 TRAEs. There were no reports of grade 4-5 or severe TRAEs. The most common TRAEs were nausea (100.0%), alopecia (97.1%), vomiting (85.3%), fatigue (85.3%), electrolyte disturbance (79.4%) and rash (73.5%). In post-surgery, all 30 pts achieved R0 resection. Surgical complications were relatively minor, predominantly fever (46.7%), ascites (30.0%) and pneumonia (23.3%). The survival benefit will be reported after the follow-up completed. Conclusions: Neoadjuvant Cadonilimab plus FLOT chemotherapy exhibit encouraging anti-tumor effectiveness and manageable toxicities, particularly in pts with diffused Lauren`s classification and poorly differentiation. This immunochemotherapy regimen might provide a promising alternative NAT option for locally advanced GC/GEJC. Clinical trial information: ChiCTR2200066893.