KEY TAKEAWAYS
- The DG-03 phase 2 trial aimed to assess the efficacy and safety of T-DXd with FP, platinum, and anti-PD-1 in 1L HER2+ esophageal/gastric/GEJA.
- The primary endpoints were to determine ORR, safety, and tolerability.
- Researchers noticed T-DXd with FP and pembrolizumab showed promising efficacy in HER2+ esophageal/gastric/GEJA.
The study investigates trastuzumab deruxtecan (T-DXd), a HER2-directed antibody-drug conjugate, which is approved at a dose of 6.4 mg/kg for patients with metastatic HER2-positive (HER2+) gastric/gastroesophageal junction adenocarcinoma (GEJA) who have previously undergone trastuzumab-based treatment.
Recent advances in first-line (1L) treatment for HER2+ gastric/GEJA have demonstrated that combining dual PD-1 and HER2 blockade with fluoropyrimidine (FP; 5-fluorouracil or capecitabine) and platinum-based regimens yields improved outcomes compared to traditional chemotherapy and trastuzumab.
Yelena Y. Janjigian and the team aimed to explore the efficacy of T-DXd in combination with FP and an anti-PD-1 agent in the 1L setting for esophageal/gastric/GEJA.
They performed an inclusive analysis of patients enrolled in DG-03 Part 2 (NCT04379596), who had 1L HER2+ esophageal, gastric, or gastroesophageal junction adenocarcinoma. Patients were globally enrolled, regardless of PD-L1 status and were randomized to receive standard of care, T-DXd monotherapy, or T-DXd-based combinations, with randomization except for arm F.
The study stratified patients by HER2 status. The primary endpoint was an investigator-assessed confirmed objective response rate (ORR) per RECIST 1.1, with safety and tolerability also evaluated.
About 307 patients were enrolled, with 229 receiving treatment. Baseline and disease characteristics were not balanced across arms. Combining T-DXd with FP/pembrolizumab (pembro) 200 mg demonstrated durable clinical benefit in patients with HER2+ central PD-L1 CPS ≥1 esophageal/gastric/GEJA.
Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 21 (11%) T-DXd-treated patients (arm B [6.4 mg/kg], n=4; arm C [6.4 mg/kg + FP], n=4; arm D [6.4 mg/kg + FP + pembro], n=8; arm E [6.4 mg/kg + pembro], n=5), with 3 deaths (arm D, n=2; arm E, n=1).
The study concluded that the combination of T-DXd + FP + pembro showed promising antitumor activity in esophageal/gastric/GEJA, warranting further investigation. Although tolerability was lower with T-DXd 6.4 mg/kg + FP + pembro, the overall safety profile was manageable.
The trial was sponsored by the AstraZeneca.
Source: https://cslide.ctimeetingtech.com/esmo2024/attendee/confcal/show/session/43
Clinical Trial: https://clinicaltrials.gov/study/NCT04379596
Janjigian Y.Y, Van Laarhoven H.W, Young Rha S, et al. (2024). “Trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2-positive (HER2+) esophageal, gastric or gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03 (DG-03).” Presented at ESMO 2024 (Abstract 1401O).
