Efficacy of disitamab vedotin (RC48) plus tislelizumab and S-1 as first-line therapy for HER2-overexpressing advanced stomach or gastroesophageal junction adenocarcinoma: A multicenter, single-arm, phase II trial (RCTS).
Authors: Song Li, Zimin Liu, Yanguo Liu, Kainan Li, Lei Cong, Fangli Cao, Aina Liu, Haiyan Liu, Ling Li, Linli Qu, Yi Zhai, JISHENG LI, Duanbo Shi, Jiahui Chu, Xinyu Song, Di Zhang, Zhaodi Nan, Qian Xu, Shulun Nie, Lian Liu
Journal: Journal of Clinical Oncology (2024)

4009 Background: Integrating immunotherapy with trastuzumab and chemotherapy has shown a significant improvement in overall response rate (ORR) and progression-free survival (PFS) in HER2-overexpression gastric or gastroesophageal junction cancer (GC/GEJC). However, the overall survival (OS) did not achievestatistical significance, and there was no benefit in patients with a PD-L1 combined positive score (CPS) &lt;1. RC48, an antibody-drug conjugate drug, has proven its effect in advanced HER2-positive (HER2 3+ or 2+ by IHC, regardless of FISH positivity) GC/GEJC in later-line treatment setting. This trial was to assess the efficacy and safety of combining RC48, immunotherapy (Tislelizumab), and S-1 as a first-line treatment for HER2-overexpressing GC/GEJC. Methods: This was a single-arm, multi-center, phase II trial conducted in patients with HER2-overexpressing metastatic or unresectable GC/GEJC for first-line treatments. Participants 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 toxicities. The primary endpoint was ORR, while the secondary endpoints included disease control rate (DCR), PFS, OS, and safety. Results: A total of 47 patients were enrolled from 8 centers, median 65 (39 ~ 81) years old, 37 male, 37 GC and 8 GEJC, and all adenocarcinoma. Of them, 30 (63.8%) were HER2 IHC 3+, 11 (23.4%) HER2 IHC 2+/FISH+, and 6 (12.8%) IHC 2+/FISH-. Patients with PD-L1 CPS≥5, ≥1 accounted for 14.9%, 36.2% respectively. With a median follow-up duration of 116.5 days, patients received a median of 5.0 treatment cycles. As of January 20, 2024, 40 patients were included for efficacy analysis, and 44 patients for safety. The ORR reached 95.0% (38/40, 95% CI: 83.1-99.4%), clinical Complete Response rate was 20.0% (5/40, 95% CI: 4.2-26.8%), and the DCR was 100.0% (95% CI: 91.2-100.0%). The median PFS and OS were not reached, while the 6-month and 9-month PFS rates were 100.0% and 80.8%, the 6-month and 9-month OS rates were 100.0% and 83.8%. ORR among the HER2 IHC 3+, IHC 2+/FISH+, and IHC 2+/FISH- groups showed no significant difference (93.3%, 100.0%, 100.0%). ORR for patients with CPS≥1 or &lt; 1 were 100.0%, 92.9%, respectively. One stage IVA GC patient (cT4bN3M0, HER2 3+, CPS 0) and another stage IVB GEJC one (cT3N2M1, HER2 2+/FISH+, CPS≥5) received radical surgery and both achieved pathological complete response. Grade 3/4 treatment-related adverse events occurred in 40.9% of patients, notably neutropenia, fatigue, and diarrhea. Conclusions: The combination of RC48, Tislelizumab, and S-1 showed notable efficacy with manageable safety in the first-line treatment of advanced HER2-overexpressing GC/GEJC patients. These findings support further exploration in this context. Clinical trial information: NCT05586061 .