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

4059 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, including RC48 and Trastuzumab Deruxtecan, combined with anti-PD1 antibody, have also shown promising efficacy in this population. This study reports updated survival 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) first-line 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 (PD) or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: 57 patients from 9 centers were enrolled, 71.9% HER2 IHC 3+, 17.5% IHC 2+/FISH+, and 10.5% IHC 2+/FISH-. 14.9% and 36.2% had CPS≥5 and ≥1, respectively. Median follow-up was 11.8 months. In the intent-to-treat population, the confirmed ORR (cORR) was 89.4% (51/57, 95% CI: 78.5-96.0%), the median PFS (mPFS) was 12.7 months (95% CI: 10.9-NA), and the 18-month OS rate (18m-OSr) was 72.7% (95% CI: 60.0-88.5%). In the per-protocol set (excluding patients with no PD at the first assessment but refused a second evaluation), the cORR was 92.7% (51/55, 95% CI: 82.4-98.0%), the mPFS was 13.2 months (95% CI: 10.9-NA), and the 18m-OSr was 76.3% (95% CI: 63.0-91.7%). In the HER2-positive and -negative subgroups, the ORRs were 92.1% (95% CI: 81.1-97.8%) and 66.7% (95% CI: 22.3-95.7%), the mPFS was 12.6 months (95% CI: 11.0-NA) and 7.7 months (95% CI: 7.1-NA), and the 18m-OSr was 74.7% (95% CI: 61.3-91.1%) and 62.5% (95% CI: 32.0-100%), respectively. 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%), the mPFS was 16.8 months (95% CI: 11.3-NA) and 11.4 months (95% CI: 8.5-NA), and the 18m-OSr was 80.4% (95% CI: 62.1-100%) and 67.4% (95% CI: 50.7-89.5%), respectively. The grade 3-4 treatment-related adverse events (AEs) was 63.2%. The most common AEs were neutropenia, fatigue, and leukopenia. An exploratory study with longitudinal sequencing of circulating tumor DNA is ongoing. Conclusions: The combination of RC48, tislelizumab and S-1 as a first-line therapy shows encouraging response rates and survival benefits in HER2-overexpressing GC/GEJC, especially in HER2-positive or CPS ≥1 patients, supporting further evaluation in randomized controlled trials. Clinical trial information: NCT05586061 .