In era of immunotherapy: the value of trastuzumab beyond progression in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer.

Background: For patients with human epidermal growth factor receptor-2 (HER2)-positive advanced or metastatic gastric cancer who have progressed on first-line trastuzumab therapy, the clinical value of the continuous use of trastuzumab beyond progression (TBP) is controversial.

Objectives: The present study was conducted to evaluate the efficacy and explore new treatment strategies of TBP for patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer in the era of cancer immunotherapy.

Design: Retrospective analysis.

Methods: Patients with HER2-positive advanced or metastatic gastric cancer who have failed first-line treatment based on trastuzumab-targeted therapy from June 2019 to December 2020 were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Survival curves of patients were estimated by the Kaplan-Meier method and compared using the log-rank test.

Results: In all, 30 patients received TBP with chemotherapy, immunotherapy, or anti-angiogenic therapy, and the other 26 patients received treatment of physician's choice without trastuzumab. The median PFS in the TBP and non-TBP population was 6.0 [95% confidence interval (CI) = 3.8-8.2] and 3.5 (95% CI = 2.2-4.8) months, respectively (p = 0.038), and the median OS was 12.3 (95% CI = 10.4-14.2) and 9.0 (95% CI = 6.6-11.4) months (p = 0.008). The patients who received TBP treatment had more favorable PFS and OS than the non-TBP population. In the TBP group, patients who received trastuzumab plus chemotherapy and immunotherapy had higher ORR (40.0% versus 16.7%), DCR (90.0% versus 50.0%), and showed a significant improvement in PFS (7.0 versus 1.9 m) compared to TBP with chemotherapy alone. Subgroup analysis suggested that patients with male, HER2 positive with immunohistochemistry score 3+ and PFS of first-line treatment less than 6 months had a greater benefit from TBP. The incidence of Grade 3-4 adverse events in the TBP and non-TBP groups was 43.3% and 38.5%.

Conclusion: The continuous use of TBP improves PFS and OS in patients with trastuzumab-resistant HER2-positive advanced or metastatic gastric cancer with well-tolerated toxicity. In the era of immunotherapy, TBP combined with chemotherapy and immunotherapy may further enhance the clinical benefit and provide a new treatment strategy.

Trial registration: This study is a retrospective study, which does not require clinical registration.