▎ WuXi AppTec content team editor
About 20% of advanced gastric or gastroesophageal-conjugated adenocarcinomas overexpress the human epidermal growth factor receptor 2 (HER2), and more than a decade ago, the medical community chose the first-line standard therapy for the treatment of such cancers, that is, chemotherapy plus a combination of trastuzumab.
In fact, trastuzumab is a class of HER2 antibodies that can enhance the cross-presentation of HER2 by dendritic cells, thereby stimulating her2-specific T cell response, in addition to regulating the expression of programmed death receptor 1 (PD-1) and its ligands, increasing the number of tumor-infiltrating lymphocytes.
Based on these characteristics, in recent years, researchers have also tried to introduce immunotherapy to the existing first-line therapies to increase the therapeutic effect. According to multiple literature support, immune checkpoint inhibitors and trastuzumab can enhance the HER2-specific T cell response, promote the transport of immune cells and induce memory T cell expansion.
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With repeated validations of mouse experiments, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical School have promoted phase 2 clinical trials, and last year they published an article in The Lancet-Oncology, according to the Phase 2 one-arm trial, trastuzumab, pembrolizumab (humanized anti-PD-1 antibody) and chemotherapy combined can effectively improve the survival of PATIENTs with HER2-positive esophageal gastric cancer, and the combination of three drugs is also safe to use.
In the latest issue of the journal Nature, the team once again brought some of the results of a randomized, double-blind Phase 3 trial. A total of 434 volunteers participated in the trials, of which 217 received triple therapy and another 216 received trastuzumab, chemotherapy and placebo.
Overall, the response rate of patients in the 3-group and placebo groups to the therapy was 74.4% and 51.9%, respectively, and intuitively, the addition of pembrolizumab could improve the response rate to treatment by about 23%. The response to treatment was more pronounced in the 3-group group, which allowed some patients to shrink the tumor and induce a complete response (temporary complete remission), and the complete response rate increased from 3.1% to 11.3% in the placebo group. In addition, the proportion of patients who responded optimally increased significantly.
Among the volunteers who responded to treatment, the response of patients in the 3-group group also existed longer, and at least 70.3% of patients could maintain their response to the therapy after half a year, and this figure could be maintained at about 58.4% after 9 months, which was higher than that of the placebo group.
From the research observation, the incidence of side effects in the two groups did not differ much, and the common side effects included diarrhea, nausea and anemia, indicating that the addition of pembrolizumab did not significantly increase the risk of treatment.
The paper notes that compared with current first-line therapies, the results of the Phase 3 clinical trial suggest that the addition of pembrolizumab can further improve the clinical treatment effect of IR2-positive gastric cancer and gastroesophageal-conjugate adenocarcinoma that cannot be resected or metastasized.
This 3-link response is deeper, lasts longer, and safety remains manageable. At present, the Phase 3 clinical trial is still advancing as planned, and the research team will follow up to publish the main key data such as the overall survival and progression-free survival of patients.
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