Tislelizumab (Tisle) combined with POFI (irinotecan, paclitaxel, oxaliplatin and 5-FU/levoleucovorin) as first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (AGC): OS analysis results of the SYLT-023.

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Background: Tisle is an anti-PD-1 antibody. The combination of Tisle + XELOX/FP is a first-line treatment of AGC in China. Both irinotecan and paclitaxel have also shown antitumor activity in AGC. In this phase I/II study, we explore the safety, tolerability, and efficacy of Tisle + 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/m ² ): 135/45 (dl #1), 150/45 (dl #2), 135/67.5 (dl #3), and 135/90 (dl #4) in combination with tisle 200 mg plus oxaliplatin 85 mg/m ² , levoleucovorin 200 mg/m ² , and 5-FU 2400 mg/m ² for 46 hours every 2 weeks. Primary endpoints were safety, tolerability, and 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 GE junction cancer, 11 (73.3%) had undifferentiated 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 DLT. One DLT (grade 4 neutropenia) occurred within 28 days in dl #4. No maximum tolerated dose was reached; the RP2D was dl #4. As of 18th Sep 2024, confirmed objective response rate in 13 subjects with measurable disease was 100% (1 CR, 12 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. The median PFS was 10.51 (95% CI: 7.44, 13.58) months (versus 6.9 [5.7-7.2] months for ITT population for RATIONALE 305, ESMO 2023), the median DOR was 7.39 (95% CI: 5.34, 9.44) months, and the median OS was 14.75 (95% CI: 5.48, 24.02) months. The OS showed no significant differences between CPS ≥ 1 and CPS < 1. All subjects (100%) had AEs. Seven (n=7, 46.67%) of the 15 subjects reported grade ≥3 AEs, including neutropenia (n=7; 46.67%), leukopenia (n=3; 20%), anemia (n=2; 13.33%). Conclusions: Tisle+POFI was well tolerated and showed preliminary antitumor activity in AGC. A phase II study is ongoing. Clinical trial information: NCT05319639 .