HER2-targeted therapy has improved outcomes in advanced gastric and gastroesophageal junction adenocarcinoma, but resistance and heterogeneous HER2 expression continue to limit long-term disease control. A phase II study has now evaluated whether combining the HER2-directed antibody-drug conjugate disitamab vedotin with tislelizumab and S-1 could provide an effective first-line option for patients with HER2-overexpressing disease.
The article, “First-Line Disitamab Vedotin, Tislelizumab, and S-1 in HER2-Overexpressing Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: A Single-Arm, Phase II Trial,” was published in the Journal of Clinical Oncology on June 26, 2026.
Authors: Song Li, Zimin Liu, Yanguo Liu, Kainan Li, Lei Cong, Fangli Cao, Aina Liu, Haiyan Liu, Ling Li, Linli Qu, Yi Zhai, Feng Wang, Dongmei Zhou, Qijun Yi, Ping Wang, Jisheng Li, Duanbo Shi, Jiahui Chu, Di Zhang, Qian Xu, Shulun Nie, Mingchi Ma, Shuyi Song, Pei Wang, and Lian Liu.
Background
Disitamab vedotin is a HER2-directed antibody-drug conjugate carrying the microtubule inhibitor monomethyl auristatin E. Its cleavable linker produces a bystander effect, which may extend activity beyond tumor cells with strong HER2 expression and help address intratumoral HER2 heterogeneity.
The combination with PD-1 blockade was supported by the possibility that ADC-induced tumor cell death could enhance antigen release and immune activation. Investigators therefore evaluated disitamab vedotin with the PD-1 inhibitor tislelizumab and the oral fluoropyrimidine S-1 as first-line therapy for advanced HER2-overexpressing gastric or gastroesophageal junction adenocarcinoma.
Study Design
This multicenter, single-arm phase II trial enrolled patients in China with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma who had received no prior systemic therapy for advanced disease. HER2 overexpression was defined as IHC 3+ or IHC 2+, regardless of in situ hybridization status. This definition included both conventionally HER2-positive tumors and a smaller group with IHC 2+/ISH− disease.
Patients received disitamab vedotin 2.5 mg/kg and tislelizumab 200 mg intravenously on day 1, together with oral S-1 40–60 mg twice daily on days 1–14 of each 21-day cycle.
The primary endpoint was confirmed objective response rate by independent central review. Secondary endpoints included progression-free survival, overall survival, duration of response, disease control rate, and safety.
Patient Population
Between February 2023 and July 2024, 57 patients were enrolled. The median age was 65 years, and 80.7% were men. Most patients had metastatic disease, while 7.0% had unresectable locally advanced disease. HER2 expression was IHC 3+ in 71.9%, IHC 2+/ISH+ in 17.5%, and IHC 2+/ISH− in 10.5%.
PD-L1 CPS was below 1 in 54.4% of patients, while 45.6% had CPS ≥1. All tumors were mismatch repair proficient and microsatellite stable. At the December 31, 2025 data cutoff, the median follow-up was 28.2 months.
Key Findings
The confirmed objective response rate was 89.5%, including complete responses in 8.8% and partial responses in 80.7% of patients. Five patients achieved stable disease, and only one had progressive disease as the best overall response. The disease control rate was 98.2%.
Median progression-free survival was 13.8 months, median overall survival was 31.9 months, and median duration of response was 13.3 months.
Activity was observed across PD-L1 subgroups. In patients with CPS ≥1, the objective response rate was 92.3%, median progression-free survival was 16.7 months, and median overall survival was 31.9 months.
Among patients with CPS <1, the objective response rate remained high at 87.1%, with median progression-free survival of 10.0 months and median overall survival of 25.4 months.
Responses were also reported across HER2 expression groups. The objective response rate was 90.2% in IHC 3+ tumors, 100% in IHC 2+/ISH+ tumors, and 66.7% in the small IHC 2+/ISH− subgroup. These subgroup findings should be interpreted cautiously because of the limited sample size and nonrandomized design.
Safety profile
Treatment-related adverse events occurred in 98.2% of patients, while grade 3 or higher treatment-related adverse events occurred in 64.9%. The most common grade 3 or higher adverse events from any cause were decreased neutrophil count, decreased white blood cell count, anemia, and peripheral motor neuropathy.
Peripheral motor neuropathy of grade 3 or higher occurred in 10.5% of patients, consistent with the known toxicity profile of the MMAE payload used in disitamab vedotin. Pneumonitis occurred in seven patients, including four grade 1 events, two grade 2 events, and one grade 3 event. No grade 4 or 5 pneumonitis was reported.
Six patients discontinued all study treatment because of treatment-related adverse events. Two grade 5 adverse events were reported—one myocardial infarction in a patient with pre-existing unstable angina and one event recorded as disease progression. Neither was considered related to study treatment.
Exploratory Biomarker Findings
Exploratory T-cell receptor sequencing suggested that treatment-induced T-cell clonal expansion was associated with longer survival. Patients with a high clonal expansion score had a median progression-free survival of 20.5 months compared with 8.0 months in those with a low score. Median overall survival was 32.8 versus 18.7 months.
This association was also observed among patients with PD-L1 CPS <1, suggesting that treatment-induced immune changes may warrant further investigation alongside baseline PD-L1 expression. These findings were exploratory and require prospective validation.
Longitudinal cell-free DNA analysis showed that estimated tumor fraction generally tracked changes in radiographic tumor burden. In six of seven patients who experienced disease progression, increases in tumor fraction preceded imaging-defined progression, with a median lead time of 1.4 months.
Transcriptomic analysis at progression identified enrichment of epithelial–mesenchymal transition, hypoxia, and TGF-β signaling. These findings suggest that resistance may involve tumor-intrinsic biological changes, although the analysis was based on a small number of samples.
Limitations
The main limitation was the single-arm design, which prevents direct comparison with current first-line standards and does not allow the contribution of each treatment component to be determined. The relatively high proportion of patients with low metastatic burden may also have contributed to the favorable outcomes and may limit extrapolation to patients with more extensive disease.
The trial included only 57 patients and was conducted entirely in China using an S-1 chemotherapy backbone, which may limit generalizability to regions where capecitabine or intravenous fluoropyrimidines are more commonly used.
The IHC 2+/ISH− subgroup included only six patients, making conclusions about activity in this population particularly uncertain. The biomarker analyses were also exploratory, involved small sample sets, and were not adjusted for multiple comparisons.
Takeaway
First-line disitamab vedotin, tislelizumab, and S-1 demonstrated a high response rate and encouraging survival outcomes in patients with HER2-overexpressing advanced gastric or gastroesophageal junction adenocarcinoma.
Activity was observed in patients with both PD-L1 CPS ≥1 and CPS <1 tumors, as well as across the different HER2-expression subgroups. However, the single-arm design means that the findings cannot establish superiority over current standards of care.
Randomized trials are needed to confirm the efficacy of the regimen, better define the patients most likely to benefit, and clarify its place within the rapidly evolving first-line HER2-targeted treatment landscape.
The full article is available in the Journal of Clinical Oncology.
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