Liposomal irinotecan plus sintilimab and lenvatinib for second-line advanced HER2-negative gastric/gastro-esophageal junction adenocarcinoma: A phase II trial.

Abstract

e16035 Background: Effective second-line treatment options are limited for advanced gastric/gastro-esophageal junction (G/GEJ) adenocarcinoma after failure of first-line therapy, especially in immunotherapy-pretreated patients. Immunotherapy combined with anti-angiogenic agents exhibits synergistic antitumor activity, while liposomal irinotecan offers improved efficacy and safety versus conventional irinotecan. This phase II study evaluated the efficacy and safety of a novel combination of liposomal irinotecan, an anti-PD-1 antibody (Sintilimab), and a multi-targeted tyrosine kinase inhibitor (Lenvatinib) in this setting. Methods: This was a prospective, single-arm, open-label, single-center phase II trial. Patients with histologically confirmed advanced HER2-negative G/GEJ adenocarcinoma who progressed on or after first-line therapy were enrolled. The regimen consisted of liposomal irinotecan (70 mg/m² IV, day 1), Sintilimab (200 mg IV, day 1), and Lenvatinib (8 mg or 12 mg orally once daily based on body weight < 60 kg or ≥60 kg) in 3-week cycles for up to 6 cycles. Maintenance therapy with sintilimab plus lenvatinib was optional for responders or stable disease. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. Results: Between July 2024 and January 2026, 25 patients were enrolled. The median age was 65 years, and 84% were male. Notably, 56.0% of patients received first-line immunotherapy combined with chemotherapy previously, and 64.0% had positive PD-L1 expression. As of the data cutoff (January 8, 2026), 22 patients (88%) remained on treatment. Two patients experienced disease progression (PFS: 6.07 and 6.87 months), and one patient was lost to follow-up. Mature PFS and OS data are pending longer-term follow-up. Among 20 patients with at least one post-baseline tumor assessment (RECIST 1.1), the ORR was 55% (95% CI, 34.2%-74.2%) and the DCR was 100% (95% CI, 83.9%-100.0%). Tumor shrinkage was observed in all evaluable patients. Treatment-related adverse events (TRAEs) of any grade occurred in 88% (22/25) of patients. The most common any-grade TRAEs were diarrhea (28%), fatigue (12%), and vomiting (16%). Grade ≥3 TRAEs were reported in 12% of patients, including diarrhea (4%), leukopenia (4%), thrombocytopenia (4%), and intestinal obstruction (4%). No treatment-related deaths occurred. Conclusions: The combination of liposomal irinotecan, Sintilimab, and Lenvatinib demonstrated promising antitumor activity with a manageable safety profile as a second-line therapy for advanced HER2-negative G/GEJ adenocarcinoma. These encouraging results warrant further validation in larger randomized controlled trials. Clinical trial information: NCT06499610 .