Disitamab vedotin (RC48), tislelizumab, and S-1 as first-line therapy for HER2-overexpressing advanced gastric or gastroesophageal junction adenocarcinoma (GC/GEJC): Updated survival and exploratory biomarker results from the RCTS trial.

4065 Background: Anti-PD1 antibody has significantly improved survival in patients with HER2-overexpressing and PD-L1 combined positive score (CPS) ≥1 GC/GEJC when added to trastuzumab and chemotherapy. Recent trials revealed that HER2-targeted antibody-drug conjugates combined with anti-PD1 antibody, have also shown promising efficacy in this population. We report updated survival, safety, and exploratory biomarker results of RC48 combined with tislelizumab and the oral fluoropyrimidine S-1 as first-line therapy for patients with HER2-overexpressing GC/GEJC. Methods: This single-arm, multicenter clinical trial enrolled patients with unresectable or metastatic HER2-overexpressing (IHC 3+ or 2+, regardless of FISH status) GC/GEJC. Patients received RC48 (2.5 mg/kg), tislelizumab (200 mg), and S-1 (40–60 mg BID for 14 days) every 3 weeks until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Exploratory analyses included dynamic peripheral T-cell receptor (TCR) sequencing and longitudinal circulating tumor DNA/cell-free DNA (cfDNA) profiling. Results: 57 patients were enrolled, 71.9% HER2 IHC 3+, 17.5% IHC 2+/FISH+, and 10.5% IHC 2+/FISH-; 45.6% had CPS ≥1. Until Dec 31, 2025, the median follow-up was 28.2 months. In the ITT population, the confirmed ORR was 89.5% (95% CI: 78.5–96.0%), including 8.8% complete responses; disease control rate was 98.2%. Median PFS was 13.8 months (95% CI: 10.3–24.0), and median OS was 31.9 months (95% CI: 22.1–not reached). In the CPS ≥1 and CPS < 1 subgroups, ORRs were 92.3% (95% CI: 74.9–99.1%) and 87.1% (95% CI: 70.2–96.4%), with median PFS 16.7 vs 10.0 months and median OS 31.9 vs 25.4 months, respectively. Grade ≥3 treatment-related adverse events occurred in 64.9%, mainly decreased white blood cell count (29.8%), decreased neutrophil count (12.3%), anemia (10.5%), and peripheral motor neuropathy (10.5%). In patients with paired TCR samples, higher treatment-induced clonal expansion score was associated with improved PFS (HR 0.34; P = 0.017) and OS (HR 0.33; P = 0.037), with particularly prognostic discrimination in the CPS < 1 subgroup. In patients with longitudinal cfDNA, cfDNA tumor fraction increases preceded imaging-defined progression in most patients who progressed. Conclusions: The combination of RC48, tislelizumab and S-1 as a first-line therapy shows encouraging response rates and updated survival with manageable safety in HER2-overexpressing GC/GEJC, including patients with CPS < 1. TCR clonal expansion may serve as a robust biomarker of antitumor immune activation, independent of PD-L1 expression levels. Clinical trial information: NCT05586061 .