First-line (1L) trastuzumab deruxtecan (T-DXd)–based regimens in advanced HER2-expressing gastric cancer (GC), gastroesophageal junction adenocarcinoma (GEJA), or esophageal adenocarcinoma (EA): Safety results from DESTINY-Gastric03 (DG-03) Part 2 arms D and F, and Part 4.

4022 Background: T-DXd 6.4 mg/kg monotherapy is approved in several countries for advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC/GEJA after an indicated HER2-directed regimen. Early data have shown promising antitumor activity with 1L T-DXd + immunotherapy + chemotherapy for advanced HER2+ GCs. Here, we report an approximate time-matched analysis of safety results for DG-03 Part 2 arms D and F, and Part 4. Methods: DG-03 (NCT04379596) is a Phase 1b/2, open-label, multipart trial. Part 2 (arms A–F) enrolled patients (pts) with previously untreated advanced HER2+ (IHC 3+ or IHC 2+/ISH+) GC/GEJA/EA. Pts in arm D received T-DXd 6.4 mg/kg + pembrolizumab (pembro) + fluoropyrimidine (FP; 5-fluorouracil or capecitabine), and pts in arm F received T-DXd 5.4 mg/kg + pembro + FP. In Part 4, pts with previously untreated advanced HER2-expressing (IHC 3+, IHC 2+/ISH+, IHC 2+/ISH−, or IHC 1+) GC/GEJA/EA were enrolled and received T-DXd 5.4 mg/kg + rilvegostomig (rilve; a monovalent, Fc-reduced, bispecific IgG1 antibody against PD-1 and TIGIT receptors) + FP. HER2 status was based on local testing. Secondary endpoints included frequency of adverse events (AEs) and serious AEs. Results: As of Feb 15, 2023, Aug 19, 2024, and Oct 16, 2025, 43, 32, and 62 pts received treatment (Tx) in Part 2 arm D, Part 2 arm F, and in Part 4, respectively. Median (range) total duration of Tx for both T-DXd and pembro was 6.1 (0.5–13.3) months (mo) in Part 2 arm D, and 6.9 (0.7–10.3) mo for T-DXd and 7.5 (0.7–10.3) mo for pembro in Part 2 arm F. Median (range) total duration of Tx for both T-DXd and rilve was 6.5 (0.7–14.7) mo in Part 4. A summary of safety data is shown in the Table. Drug-related adjudicated interstitial lung disease (ILD)/pneumonitis events occurred in 2 pts (5%) in Part 2 arm D, no pts in Part 2 arm F, and 2 pts (3%) in Part 4. Conclusions: Results with T-DXd (5.4 mg/kg)–based regimens were generally consistent with the known safety profiles of each agent; no new signals were observed. Safety data support use of pembro/rilve as combination partners for T-DXd (5.4 mg/kg) in advanced HER2-expressing GCs. Clinical trial information: NCT04379596 . n (%) Part 2 arm D T-DXd 6.4 mg/kg + pembro + FP (n=43) Part 2 arm F T-DXd 5.4 mg/kg + pembro + FP (n=32) Part 4 T-DXd 5.4 mg/kg + rilve + FP (n=62) AEs 43 (100) 31 (97) 60 (97) Drug-related AEs* 40 (93) 27 (84) 55 (89) Grade ≥3 AEs 38 (88) 15 (47) 31 (50) Drug-related Grade ≥3 AEs* 33 (77) 11 (34) 24 (39) Serious AEs 25 (58) 12 (38) 22 (36) Drug-related serious AEs* 19 (44) 5 (16) 12 (19) AEs leading to discontinuation of any IP 16 (37) 7 (22) 7 (11) Drug-related AEs leading to death 4 (9) † 0 1 (2) ‡ *Assessed by the investigator as possibly related to any investigational product (IP); † ILD/pneumonitis (n=2), respiratory failure due to pneumonitis/pneumocytis jirovecii infection (n=1), febrile neutropenia (n=1); ‡ pneumonia.