Efficacy and safety of second-line therapy with serplulimab, lenvatinib, and paclitaxel in patients with gastric or gastroesophageal junction adenocarcinoma (GC/GEJC) for whom immunochemotherapy failed: A multicenter, single-arm, phase II trial (STIL

e16075 Background: PD-1 antibodies in combination with chemotherapy have become the standard first-line treatment for advanced GC/GEJC. However, it is unknown whether immunotherapy should be continued in the second-line setting. This trial aimed to evaluate the efficacy and safety of the PD-1 antibody serplulimab in combination with an anti-angiogenic multi-kinase inhibitor lenvatinib and paclitaxel in patients with GC/GEJC for whom first-line treatments of immunotherapy (IO) and chemotherapy failed. Methods: Eligible GC/GEJC patients met at least one of the following 3 criteria: 1) PD-L1 combined positive score (CPS) ≥1; 2) previous partial or complete response, or 3) progression-free survival (PFS) ≥6 months in first-line therapy. Patients received serplulimab (300 mg), lenvatinib (8 mg QD), and paclitaxel 135-175 mg/m² or nab-paclitaxel 260 mg/m², every 3 weeks for six cycles, followed by maintenance therapy with serplulimab and lenvatinib. The primary endpoint was objective response rate (ORR), and secondary endpoints included PFS, overall survival (OS), and safety. Results: A total of 47 patients from 8 centers were enrolled. Patients with CPS ≥1 accounted for 55.3%. The median first-line PFS (mPFS) was 8.3 months (range: 1.6-37.9 months), with 9.1 months for CPS<1 and 7.8 months for CPS≥1. Median follow-up duration was 6.3 months. Among the 41 patients who had undergone at least one assessment, the ORR was 51.2% (95% CI: 35.1%-67.1%). The mPFS was 7.1 months (95% CI: 6.1-NA) and the median OS (mOS) was 13.7 months (95% CI: 11.6-NA). In the CPS <1 and CPS ≥1 subgroups, the ORRs were 50.0% (95% CI: 27.2%-72.8%) and 52.4% (95% CI: 29.8%-74.3%), respectively. The mPFS was 14.5 months (95% CI: 6.1-NA) for CPS <1 and 6.2 months (95% CI: 3.0-NA) for CPS ≥1, with a hazard ratio (HR) of 0.3 (95% CI: 0.1-1.0, log-rank P = 0.045). The mOS was 14.5 months (95% CI: 10.2-NA) for CPS <1 and 11.6 months (95% CI: 6.7-NA) for CPS ≥1, with an HR of 0.3 (95% CI: 0.1-1.1, log-rank P=0.054). In subgroups with mPFS≥6 and <6 months in first-line treatment, mPFS was 11.3 (95% CI: 6.1-NA) and 4.3 months (95% CI: 2.9-NA; HR: 0.4, 95% CI: 0.1–1.6, log-rank P=0.20) and mOS was 14.5 (95% CI: 10.2-NA) and 13.4 months (95% CI: 5.1-NA; HR: 0.5, 95% CI: 0.1-2.0, log-rank P=0.35), respectively. The overall incidence of adverse events (AEs) was 72.3%, with 17.0% of patients experiencing grade 3-4 treatment-related AEs. The most common AEs were leukopenia, neutropenia, and numbness. Conclusions: Continual IO with serplulimab, combined with lenvatinib and paclitaxel, demonstrated promising efficacy and manageable safety in GC/GEJC patients who have benefited from prior IO. This regimen represents a potential new treatment option for patients for whom first-line immunochemotherapy failed. Clinical trial information: NCT05585580 .