P-159 Trastuzumab deruxtecan (T-DXd) in patients with HER2-positive gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma who have progressed on or after a trastuzumab-containing regimen (DESTINY-Gastric04): A randomized phase 3 study

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor. T-DXd is approved globally to treat HER2-positive (HER2+) metastatic breast cancer, and to treat HER2+ GC after trastuzumab-based therapy (United States and Israel) or GC that has progressed after chemotherapy (Japan). In the primary analysis of DESTINY-Gastric01 (DS8201-A-J202; NCT03329690), an open-label, multicenter, randomized, phase 2 trial in patients with HER2+ advanced GC or GEJ adenocarcinoma, T-DXd demonstrated clinically relevant improvement compared with standard of care in objective response rate (ORR; 51% versus 14%; P P = 0.01) in the third-line or later (Shitara, N Engl J Med 2020). The DESTINY-Gastric04 study aims to evaluate the efficacy and safety of T-DXd compared with the combination of ramucirumab and paclitaxel in patients with HER2+ GC or GEJ adenocarcinoma in the second-line setting. DESTINY-Gastric04 (NCT04704934) is a global, multicenter, open-label, 2-arm, randomized, phase 3 study in patients with HER2+ metastatic and/or unresectable GC or GEJ adenocarcinoma. Eligible patients must be adults (according to local regulations), with an ECOG performance status of 0 or 1 at screening, with documented GC or GEJ adenocarcinoma that has been previously treated in the metastatic first-line setting (including neoadjuvant or adjuvant therapy if progression on or within 6 months of completing therapy) with a trastuzumab-containing regimen. HER2-positivity (IHC 3+ or IHC 2+/ISH+) must be centrally confirmed on tumor biopsies obtained after progression on or after trastuzumab. Patients must not have received anticancer therapy after a first-line trastuzumab-containing regimen. Patients will be randomized 1:1 to receive T-DXd (6.4 mg/kg every 3 weeks) or ramucirumab (8 mg/kg on days 1 and 15 of a 28-day cycle) in combination with paclitaxel (80 mg/m2 on days 1, 8, and 15 of a 28-day cycle). This study is actively enrolling from 24 different countries across Europe and Asia with approximately 490 participants planned. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity of T-DXd. NCT04704934. Under the guidance of authors, assistance in medical writing and editorial support was provided by Laura Halvorson, PhD, of ApotheCom, and was funded by Daiichi Sankyo, Inc. This study was funded by Daiichi Sankyo, Inc., and AstraZeneca.