Trastuzumab Deruxtecan for HER2-Positive Esophagogastric Cancer in U.S. and European Patients

The antibody–drug conjugate trastuzumab deruxtecan (T-DXd) has substantial activity across a spectrum of HER2-positive cancers. In HER2-positive gastric cancer, second or later line use of T-DXd is approved in the U.S. based on superiority for this agent over conventional chemotherapy, as reported in the DESTINY-Gastric01 trial conducted in Japan and South Korea (NEJM JW Oncol Hematol Jun 11 2020 and N Engl J Med 2020 382:2419).

Investigators now report results from DESTINY-Gastric02, an industry-sponsored, multicenter, phase 2 trial evaluating T-DXd (6.4 mg/kg intravenously every 3 weeks) in patients recruited in the U.S. and Europe. Patients were required to have disease progression on trastuzumab-based first-line chemotherapy. Of 89 patients screened, 79 (89%) were eligible and met the criterion of retention of HER2-positive status on central review of repeat pretreatment biopsy. One third of patients had gastric primaries and two thirds had gastroesophageal junction primaries; 86% of cancers were HER2-positive IHC 3+ and 13% were IHC 2+/FISH+. No patient had prior gastrectomy and 94% had two or more metastatic disease sites.

The primary endpoint of centrally confirmed response was 38% and median duration of response was 8.1 months. Median progression-free survival was 5.5 months and overall survival was 12.1 months. The most common grade 3 or higher treatment-related adverse events were hematologic. Interstitial lung disease, a known side effect of T-DXd, occurred in 8 patients (10%) with a median time to onset of 80.5 days and included two grade 1 cases, four grade 2 cases, and two grade 5 fatal events.