First-line (1L) trastuzumab deruxtecan (T-DXd) with volrustomig and fluoropyrimidine in patients with HER2-low gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): DESTINY-Gastric03 (DG-03) part 5.

Abstract

TPS472 Background: T-DXd (6.4 mg/kg), a HER2-directed antibody-drug conjugate, is approved in several countries for patients with locally advanced or metastatic HER2+ (IHC 3+ or IHC 2+/ISH+) GC/GEJA who have received a prior trastuzumab (HER2-directed antibody)-based regimen. Currently, there are no HER2-directed treatments for HER2-low advanced or metastatic GCs. T-DXd has shown clinical benefit in HER2-low metastatic breast cancer, and initial activity in patients with HER2 IHC 2+/ISH− and IHC 1+ GC, and thus could be a promising treatment option for HER2-low GC/GEJA/EA. Current 1L standard of care for HER2+ GC/GEJA is trastuzumab, with or without pembrolizumab (anti-PD-1 antibody), plus fluoropyrimidine- and platinum-containing chemotherapy. DG-03 (NCT04379596) is a Phase 1b/2, open-label, dose-escalation (Part 1), expansion (Parts 2–4), and optimization (Part 5) study evaluating T-DXd with chemotherapy and/or immunotherapy in HER2+ and HER2-low, locally advanced/metastatic GC/GEJA/EA. In Part 2 of DG-03, 1L T-DXd with fluoropyrimidine and/or pembrolizumab demonstrated promising antitumor activity in metastatic HER2+ GC/GEJA/EA. Preclinical data have shown increased antitumor activity with volrustomig (a novel bispecific PD-1/CTLA-4 antibody) compared with a combination of anti-PD-1 and anti-CTLA-4 antibodies. Additionally, treatment with a bispecific anti-PD-1/anti-CTLA-4 antibody has shown clinical benefit in GC. Given the need for treatments for HER2-low GC/GEJA/EA, DG-03 Part 5 will assess 1L T-DXd with volrustomig and fluoropyrimidine in this population. Methods: In Part 5, patients with previously untreated HER2-low (IHC 2+/ISH− or IHC 1+) advanced or metastatic GC/GEJA/EA will receive T-DXd with volrustomig and fluoropyrimidine (5-fluorouracil or capecitabine). HER2 status will be locally assessed. Patients must have a local PD-L1 test result before treatment assignment. Approximately 30 patients are planned for enrollment; the safety profile will be initially assessed in the first six patients who complete ≥3 cycles of treatment. The primary endpoint is confirmed objective response rate by investigator assessment per RECIST 1.1. Secondary endpoints include disease control rate, duration of response, and progression-free survival by investigator assessment per RECIST 1.1; overall survival; safety (adverse events and serious adverse events); pharmacokinetics; and immunogenicity.