Trastuzumab Deruxtecan as Second-Line Treatment in HER2-Positive Gastric Cancer

Trastuzumab deruxtecan is approved in the U.S. for second- or later-line treatment and globally for third- or later-line treatment of human epidermal growth factor receptor 2 (HER2)–positive esophagogastric adenocarcinoma after disease progression on first-line trastuzumab-based treatment. Investigators now report results of the industry-sponsored, open-label, phase 3 DESTINY-Gastric04 trial of second-line treatment of unresectable or metastatic HER2-positive esophagogastric adenocarcinoma after disease progression on trastuzumab.

Patients with central confirmation of retained HER2-positive status received standard weekly paclitaxel and ramucirumab or trastuzumab deruxtecan every 3 weeks at 6.4 mg/kg. Of the 494 patients treated, 61% had gastric and 39% had gastroesophageal junction primaries, 84% were immunohistochemical (IHC) 3+ and 15% IHC 2+ and in situ hybridization (ISH)–positive, and 25% had experienced disease progression after less than 6 months of first-line therapy.

The primary endpoint of overall survival was superior for trastuzumab deruxtecan compared with paclitaxel–ramucirumab (14.7 vs. 11.4 months; hazard ratio, 0.7), as were progression-free survival (6.7 vs. 5.6 months; HR, 0.74) and objective response (44.3% vs 29.1%). Rates of drug-related serious adverse events for the two treatments were similar, with interstitial lung disease (mostly grade 2; grade 3 in one patient) occurring in 14% of patients treated with trastuzumab deruxtecan.