DESTINY-Gastric04 Trial of T-DXd Shows OS Benefit in HER2+ Gastric Cancer

Arturo Loaiza-Bonilla, MD, MSEd, systemwide chief of hematology and oncology at St. Lukes University Health Network and co-founder and chief medical officer at Massive Bio, explains the background and findings of the phase 3 DESTINY-Gastric04 trial (NCT04704934).

The DESTINY-Gastric04 trial demonstrated that fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) significantly improves overall survival (OS) compared with ramucirumab (Cyramza) plus paclitaxel in patients with HER2-positive unresectable or metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJ) after prior trastuzumab therapy. Presented at the 2025 ASCO Annual Meeting and published in The New England Journal of Medicine, the trial showed a median OS of 14.7 months (95% CI, 12.1-16.6) with T-DXd vs 11.4 months (95% CI, 9.9-15.5) with ramucirumab plus paclitaxel, representing a 30% reduction in the risk of death (HR 0.70; P =.0044). Six-, 12-, and 24-month OS rates were also higher with T-DXd.

Progression-free survival was improved with T-DXd (6.7 months vs 5.6 months; HR 0.74; P = .0074), along with higher 6- and 12-month PFS rates. The confirmed overall response rate was significantly greater with T-DXd at 44.3% compared to 29.1%, with longer duration of response (7.4 vs 5.3 months). Disease control rate was 91.9% with T-DXd, including complete responses in 3% of patients, compared to 75.9% with ramucirumab plus paclitaxel.

The trial enrolled 494 patients globally, randomized 1:1 to receive either T-DXd every three weeks or ramucirumab plus paclitaxel on a 28-day cycle. Eligible patients had HER2-positive disease confirmed post-progression on trastuzumab and no active central nervous system metastases. Key exclusion criteria included interstitial lung disease or pneumonitis.

Safety profiles showed treatment-emergent adverse events (TEAEs) of any grade in over 90% of patients in both arms. Grade 3 or higher neutropenia was most common. Interstitial lung disease/pneumonitis occurred in 13.9% of T-DXd patients versus 1.3% in the comparator group. TEAEs led to dose modifications and discontinuations in both groups.

REFERENCE:

Shitara K, Gumus M, Pietrantonio F, et al. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study. Presented at: 2025 American Society of Clinical Oncology Annual Meeting; May 30-June 3, 2025. Chicago, IL. Abstract 4002.