Background: Tislelizumab is a humanised IgG4 monoclonal antibody with high affinity and binding specificity for PD-1. Combined with fluoropyrimidine + platinum (XELOX or FP), it is approved in China as first-line treatment of advanced gastric cancer (AGC). Both irinotecan and paclitaxel have also shown antitumor activity in advanced gastric/gastroesophageal junction adenocarcinoma. In this phase I/II study, we explore the safety, tolerability, and efficacy of tislelizumab + irinotecan, paclitaxel, oxaliplatin and 5-FU (POFI) as first-line treatment of HER-2 negative, pMMR AGC. Methods: In a phase I dose finding study using a standard 3+3 design, subjects received four escalating dose levels (dl) of irinotecan/paclitaxel (mg/m²): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tislelizumab 200 mg plus oxaliplatin 85 mg/m², levoleucovorin 200 mg/m², and 5-FU 2400 mg/m² for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and recommended phase 2 dose (RP2D). Results: Fifteen subjects with treatment naïve AGC were enrolled (3 each in dl #1, dl #2, and dl #3 and 6 in dl #4). The median age was 65 years (range 36-72); 80% were male. Two subjects (13.3%) were diagnosed with gastroesophageal junction cancer, 9 (60%) had poorly differentiated disease, and 5 (33.3%) had liver metastasis. PD-L1 CPS scores were: 5 (n=5); 1 (n=1); and 0 (n=9). All subjects were evaluated for dose-limiting toxicity (DLT). One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. All subjects had ≥1 treatment-related adverse event (TRAE) and 10 (66.7%) had ≥1 grade 3-4 TRAE per NCI CTC-AE 5.0. The most frequent grade 3-4 TRAEs were neutropenia (n=8; 53.3%), anemia (n=2; 13.3%), and increased glutamyl transpeptidase (n=2 pts; 13.3%). Confirmed objective response rate in 13 subjects with measurable disease was 100% (1 complete response [CR], 12 partial responses [PR]) per RECIST 1.1. Of the 2 subjects with non-measurable disease, one was a CR and the other was non-CR/non-PD. Survival data are immature. Conclusions: Tislelizumab+POFI was well tolerated and showed preliminary antitumor activity. A phase II study at the RP2D is ongoing. Clinical trial information: NCT05319639.