Clinical trials

Gastric cancer (GC) is the fifth most commonly diagnosed cancer, with over one million cases diagnosed annually worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression in GC (seen in 4.4% to 53.4% of patients in different reports) is predictive biomarker of response to HER2-targeting therapies. Trastuzumab in combination with cisplatin or oxaliplatin, and a fluoropyrimidine (capecitabine or 5-fluorouracil \[5-FU\]), is approved anti-HER2 therapy for first-line treatment of HER2-positive gastric or gastroesophageal junction (GEJ) cancer. Rilvegostomig 750 mg Q3W was selected as recommended Phase 2 dose based on all available ARTEMIDE-01 clinical safety, efficacy, PK, RO data as well as modeling analysis. The dose of 750 mg Q3W is predicted to achieve intra-tumoral RO of ≥ 90% in the majority of participants across a broad spectrum of conditions. This is a phase II study to initially assess the efficacy of perioperative Trastuzumab Deruxtecan (T-DXd) and Capecitabine combination with or without Rilvegostomig in patients with HER2 positive locally advanced unresectable GC and potentially by subsequent protocol amendment in HER2 low locally advanced GC. Other agents may also subsequently be assessed in this protocol, by protocol amendments . \---------------------------------------------------------------------------------------------------- Therefore, these studies provide robust evidence that immune checkpoint inhibitors plus chemotherapy, specifically the perioperative durvalumab plus FLOT regimen, can increase pCR rate and significantly improve long-term survival outcomes for patients with resectable gastric, GEJ, or esophageal cancer.

For patients who failed primary chemotherapy with MET amplification, The efficacy and safety of the chemotherapy are evaluated by using dervalumab and saboritinib in combination.

Despite recent advances, the prognosis of patients with advanced gastric cancer remains poor. At present, regimens that combine a platinum and fluorouracil agent either alone or in combination with a third drug such as epirubicin or taxane constitute the most effective treatment option in the first-line metastatic setting, resulting in a median OS of approximately 10 months. In the second-line setting, ramucirumab (a vascular endothelial growth factor receptor 2 antagonist) was recently approved by the United States Food and Drug Administration, and has demonstrated modest activity in patients with advanced gastric or GEJ adenocarcinoma who progressed after first-line platinum- or fluoropyrimidine-containing chemotherapy. Median OS was 5.2 months in the ramucirumab group versus 3.8 months in the placebo group. At the updated DCO of 03 June 2020 in the DS8201-A-J202 (DESTINY-Gastric01) study in HER2-positive GC or GEJ adenocarcinoma subjects assigned to T-DXd 6.4 mg/kg, T-DXd further demonstrated clinically meaningful efficacy. The median OS was 12.5 months for the T-DXd group and 8.9 months for the physician's choice group (HR = 0.60, 95% CI: 0.42, 0.86). In a prespecified subgroup analysis, the percentages of patients with an objective response were analyzed in HER2-low group. The response rate in HER2 2+ was 29% (8 of 28) with T-DXd monotherapy. Refer to the figure below for the response rate in HER2-low group in previous DESTINY trials. This is a two part, phase I/Ⅱ, open-label, single center study of afatinib in combination with T-DXd, in 2L/3L gastric cancer patients with HER2-low. The study design allows an investigation of combination dose of afatinib with T-DXd, with intensive safety monitoring to ensure the safety of the patients.