Tislelizumab Plus Chemotherapy Is Active, Tolerable in Advanced Gastric/GEJ Cancer

The addition of tislelizumab to irinotecan, paclitaxel, oxaliplatin, and 5-flourouracil (5-FU)/leucovorin (POFI) was proven active and had a manageable safety profile when used as frontline therapy in patients with advanced, HER2-negative, mismatch repair–proficient gastric and gastroesophageal junction adenocarcinoma, according to data from the phase 1/2 SYLT-023 trial (NCT05319639) that were presented at the 2025 Gastrointestinal Cancers Symposium.

At the data cutoff date of September 18, 2024, the confirmed objective response (ORR) rate in patients with measurable disease (n = 13) was 100% (complete response [CR], 6.7%; partial response, 80.0%) per RECIST 1.1). Of the 2 patients with non-measurable disease, 1 had CR (6.7%) and the second had non-CR/non-progressive disease (6.7%). In the total patients, the ORR was 93.5% (n = 14) and the disease control rate (DCR) was 100% (n = 15).

The median progression-free survival (PFS) was 10.51 months (95% CI, 7.44-13.58) and the median overall survival (OS) was 14.75 months (95% CI, 5.48-24.02). The median duration of response was 7.39 months (95% CI, 5.34-9.44).

“Tislelizumab plus POFI was well tolerated and showed preliminary antitumor activity in [patients with] advanced gastric cancer, [and] a phase 2 study at the recommended phase 2 dose [RP2D] is ongoing,” lead study author Liyu Su, of Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China, and coauthors, wrote in the poster.

Gastric cancer is the fifth most common cancer globally, with a high incidence in China. Despite the activity of tislelizumab plus platinum and fluoropyrimidine-based chemotherapy in patients with advanced gastric cancer, evidenced in the phase 3 RATIONALE-305 trial (NCT03777657), outcomes remain poor.

However, stronger cytotoxic agents could potentiate higher levels of immunogenic cell death, leading to better T-cell activation and subsequent activity of checkpoint inhibition. This, coupled with data showing improved outcomes with paclitaxel plus modified FOLFOX vs FOLFOX and antitumor activity with irinotecan in advanced gastric cancer, served as the basis for the present study.

The study enrolled patients between the ages of 18 and 70 years who had received a histologically or cytologically confirmed diagnosis of advanced unresectable adenocarcinoma of the gastric or gastroesophageal junction. Eligibility criteria required that patients have an evaluable lesion per RECIST 1.1, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of at least 3 months. Prior chemotherapy or radiation therapy was not allowed apart from chemotherapy received in the (neo)adjuvant setting that had been completed more than 6 months prior to relapse.

At all dose levels, patients received tislelizumab at 200 mg every 2 weeks (Q2W), oxaliplatin at 85 mg/m2 Q2W, levoleucovorin at 200 mg/m2 Q2W, and 5-FU at 2400 mg/m2 over the course of 46 hours Q2W. Those in dose level 1 (n = 3) received irinotecan at 135 mg/m2 Q2W and paclitaxel at 45 mg/m2 Q2W; those in dose level 2 (n = 3), received irinotecan at 150 mg/m2 Q2W and paclitaxel at 45 mg/m2 Q2W; those in dose level 3 (n = 3), received irinotecan at 135 mg/m2 Q2W and paclitaxel at 67.5 mg/m2 Q2W; and those in dose level 4 (n = 6) received irinotecan at 135 mg/m2 Q2W and paclitaxel at 90 mg/m2 Q2W.

The primary end points were safety and tolerability, the maximum tolerated dose (MTD), and RP2D. Secondary end points were PFS, ORR, DCR, and OS.

Among the 15 total patients, the median age was 65 years (range, 36-72). The majority of patients were male (80.0%), 65 years of age or older (60.0%), and had an ECOG performance status of 0 (80.0%) with a primary tumor located in the gastric tract (86.7%). The primary histologic type was undifferentiated (73.3%), and the primary tumor was present in most cases (93.3%). Approximately one-third of patients (66.7%) had at least 2 metastatic organs involved, with sites including the lymph nodes (86.7%), liver (33.3%), peritoneum (20.0%), lung (6.7%), and others (13.3%). Most patients did not receive prior chemotherapy as required by the eligibility criteria (80.0%). PD-L1 combined positive score (CPS) was 0 in 60.0% of patients, at least 1 in 40.0%, and 5 or higher in 33.3%.

Additional efficacy results broken down by CPS indicated that the median PFS in patients with a score below 1 was 11.14 months (95% CI, 10.72-15.03) vs 8.76 months (95% CI, 8.5-11.16) in those with a score of 1 or higher. The median OS in patients with scores below 1 and 1 or higher, respectively, was 12.29 months (95% CI, 12.14-14.64) vs 20.88 months (95% CI, 20.46-27.67).

Regarding safety, one dose-limiting toxicity of grade 4 neutropenia occurred within 28 days in dose level 4, but the MTD was not reached. The RP2D was determined to be 135 mg of irinotecan every 2 weeks, 90 mg of paclitaxel every 2 weeks, 85 mg/m2 of oxaliplatin, 200 mg/m2 of leucovorin, 2400 mg/m2 of 5-FUl for 46 hours every 2 weeks, and 200 mg of tislelizumab every 2 weeks.

All patients experienced treatment-related adverse effects (TRAEs); 73.3% of patients experienced grade 3 or higher events. TRAEs included anemia (all grade, 100.0%; grade ≥3, 26.7%, respectively) leukocytopenia (86.67%; 33.33%) neutropenia (93.33%; 66.67%), decreased platelet count (53.33%; 0%), elevated alkaline phosphatase (53.33%; 0%), and hypokalemia (40.0%; 13.33%). Notably, no deaths were deemed treatment related.

Disclosures: Dr Su has no relationships to disclose.

Reference

Su L, Ye Z, Zhuo C, et al. 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. J Clin Oncol. 2025;43(suppl 4):450. doi:10.1200/JCO.2025.43.4_suppl.450