Increased treatment options and improved survival in real-world patients with HER2-positive advanced gastric cancer from 2011 to 2023.

Abstract

Background: Although the emergence of multiple therapeutic agents has benefited patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC), chronological improvements in treatment outcomes for real-world patients remain unclear.

Objectives: The present study aimed to evaluate the treatment features of various agents according to their approval periods and investigate outcomes in daily practice.

Design: Retrospective observational study.

Methods: We retrospectively evaluated the clinical outcomes of patients with HER2-positive AGC who received first-line fluoropyrimidine-containing chemotherapy between 2011 and 2023 according to the approval period of each agent in Japan: group A (pre-immunotherapy approval), 2011-2016; group B (nivolumab approval for third-line or later treatment), 2017-2019; and group C (trastuzumab deruxtecan approval for third-line treatment), 2020-2023.

Results: In total, 309 patients were enrolled (n = 159, 69, and 81 in groups A, B, and C, respectively). Significant differences were observed among the three groups in terms of the proportion of patients with Eastern Cooperative Oncology Group performance status of 0 or ⩾1 (p = 0.02), HER2 status of 3+ or 2+/FISH+ (p = 0.03), prior gastrectomy (p = 0.008), diffuse-type histology (p = 0.016), peritoneal metastases (p < 0.0001), and lymph node metastases (p = 0.007). The median overall survival (OS) rates were 19.5, 20.6, and 23.5 months in groups A, B, and C, respectively, with no significant difference among the groups. Progression-free survival in the first-line setting did not significantly differ among the three groups. Multivariate analyses revealed primary tumor location, prior gastrectomy, peritoneal metastases, and liver metastases as independent prognostic factors for OS. Inverse probability of treatment weighting analysis showed no significant difference in OS between groups A and B (hazard ratio (HR), 0.86; 95% confidence interval (CI): 0.70-1.05) but superior OS in group C over group A (HR, 0.54; 95% CI: 0.43-0.68) and group B (HR, 0.72; 95% CI: 0.55-0.95). Moreover, 53.3%, 61.4%, and 66.1% of patients in groups A, B, and C, respectively, received third-line treatment. The most commonly administered third-line treatments were irinotecan (63%) in group A, immunotherapy (43%) in group B, and trastuzumab deruxtecan (70%) in group C. The proportion of patients receiving trastuzumab deruxtecan at any line gradually increased across the three groups (7.5%, 30.4%, 44.4%; p < 0.0001).

Conclusion: The emergence of novel agents and treatment modalities may have contributed to improvements in the survival of patients with HER2-positive AGC. This highlights the benefits of effective treatment strategies, including efforts to identify biomarkers and develop new agents.