First-Line HER2 ADC and Anti–PD-1 Plus Chemo Shows Efficacy in Gastric Cancer

Abstract

HER2 is overexpressed in a subset of gastric and gastroesophageal junction (G/GEJ) adenocarcinomas, representing a therapeutic vulnerability that may be targeted by a number of approved or emerging HER2-specific modalities. Disitamab vedotin is a HER2-targeting antibody–drug conjugate (ADC) connected via a cleavable linker to monomethyl auristatin E, a cytotoxic payload. The first domestically developed ADC to be approved in China, disitamab vedotin is approved for the treatment of G/GEJ adenocarcinoma with HER2 overexpression in the third-line setting after patients have received two rounds of chemotherapy. To explore whether HER2-targeting ADCs may provide benefit at earlier stages of disease, Li, Liu, and colleagues initiated a single-arm, multicenter phase II trial. Fifty-seven patients with unresectable or metastatic G/GEJ adenocarcinoma with HER2 overexpression received, as first-line therapy, a triplet combination of disitamab vedotin, the anti–PD-1 antibody tislelizumab, and oral S-1 chemotherapy. Disitamab vedotin and tislelizumab were administered intravenously on the first day of a 21-day cycle at 2.5 mg/kg and 200 mg, respectively, while oral S-1 was administered at 40–60 mg twice daily. The primary endpoint was confirmed objective response, as assessed by computed tomography or magnetic resonance imaging, and secondary endpoints included progression-free survival, overall survival, duration of response, and safety. The triplet combination achieved a confirmed objective response rate of 89.5% (n = 51/57), in which five patients exhibited a complete response. The combination led to a median progression-free survival of 13.8 months, overall survival of 31.9 months, and duration of response of 13.3 months. All 57 patients experienced an adverse event, including 26.3% (n = 15/57) with a serious adverse event and 19.3% (n = 11/57) with a treatment-related serious adverse event. Exploratory molecular analyses provided evidence that the triplet combination increased T-cell clonality on treatment compared with baseline in the subset of patients with progression-free survival of 12 months or longer, supporting expansion of an immune response. Overall, the results of this phase II trial support the safety and efficacy of first-line disitamab vedotin with tislelizumab and S-1 in the first-line treatment of patients with G/GEJ adenocarcinoma, suggesting that this regimen warrants further clinical evaluation.Li S, Liu Z, Liu Y, Li K, Cong L, Cao F, et al. First-Line Disitamab Vedotin, Tislelizumab, and S-1 in HER2-Overexpressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-Arm, Phase II Trial. J Clin Oncol 2026 Jun 26 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.