Trastuzumab Deruxtecan(T-DXd) and Afatinib Combination in HER2-low Advanced Gastric Cancer

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.