DESTINY-Gastric04 Trial

Design — Phase 3, randomized, open-label; T-DXd (Enhertu) vs ramucirumab + paclitaxel, 2L HER2+ (IHC 3+ or IHC 2+/ISH+) gastric/GEJ adenocarcinoma after a prior trastuzumab-based regimen (NCT04704934). (ASCO 2025 LBA4002 / NEJM)

OS (primary) — Median 14.7 vs 11.4 months; HR 0.70 (95% CI 0.55-0.90; p=0.0044) — statistically significant, primary endpoint met. (ASCO 2025 / NEJM)

PFS — Median 6.7 vs 5.6 months; HR 0.74 (95% CI 0.59-0.92; p=0.007). (ASCO 2025 / NEJM)

Safety — Interstitial lung disease/pneumonitis in 13.9% of T-DXd patients (mostly Grade 1-2); active ILD monitoring required per class labeling; profile otherwise consistent with known T-DXd toxicity. (ASCO 2025 / NEJM)

Regulatory — Enhertu is FDA approved in HER2-positive gastric/GEJ adenocarcinoma after a prior trastuzumab-based regimen (initial U.S. approval Jan 15, 2021, DESTINY-Gastric01 basis). DG04 is the first Phase 3 confirmatory trial supporting this indication. (FDA.gov)

Sponsor / Drug — Daiichi Sankyo / AstraZeneca; T-DXd (Enhertu), a HER2-directed antibody-drug conjugate. (FDA label)

Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated July 21, 2026.

Progression-Free Survival (PFS) — Primary Endpoint

Median PFS was 6.7 months with trastuzumab deruxtecan (T-DXd) vs. 5.6 months with ramucirumab+paclitaxel (HR 0.74, 95% CI 0.59-0.92, P=0.007). Primary endpoint met.

Overall Survival (OS)

Median OS was 14.7 months with T-DXd vs. 11.4 months with ramucirumab+paclitaxel (HR 0.7, 95% CI 0.55-0.90, P=0.0044). Clinically meaningful OS benefit.

Safety & Tolerability

Interstitial lung disease/pneumonitis occurred in 13.9% of T-DXd patients (mostly grade 1-2); ongoing ILD monitoring remains essential per class labeling. Overall safety profile consistent with known T-DXd toxicity.

Clinical Implications

✅ Phase 3 confirmatory evidence for T-DXd in 2L HER2+ gastric/GEJ. DESTINY-Gastric04 confirms T-DXd superiority over ramucirumab+paclitaxel in 2L HER2+ gastric/GEJ in a Western-inclusive phase 3 population. Supports T-DXd as a preferred 2L+ regimen; ILD monitoring remains essential.

What is the DESTINY-Gastric04 trial?

DESTINY-Gastric04 (NCT04704934) is the first Phase 3, randomized, open-label trial of trastuzumab deruxtecan (T-DXd, Enhertu) versus ramucirumab plus paclitaxel in patients with HER2-positive (IHC 3+ or IHC 2+/ISH+) locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who progressed on or after a first-line trastuzumab-containing regimen. It was presented at ASCO 2025 (LBA4002) and published in the New England Journal of Medicine.

What were the DESTINY-Gastric04 overall survival results?

DESTINY-Gastric04 met its primary endpoint. Median overall survival was 14.7 months with T-DXd versus 11.4 months with ramucirumab plus paclitaxel (HR 0.70; 95% CI 0.55-0.90; p=0.0044), a statistically significant and clinically meaningful improvement. Median progression-free survival was 6.7 versus 5.6 months (HR 0.74; 95% CI 0.59-0.92; p=0.007).

Is Enhertu (T-DXd) FDA approved for HER2-positive gastric cancer?

Yes. Enhertu (fam-trastuzumab deruxtecan-nxki) is FDA approved for adults with locally advanced or metastatic HER2-positive (IHC 3+) gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen. That indication was first approved on January 15, 2021 based on DESTINY-Gastric01. DESTINY-Gastric04 is the first Phase 3 confirmatory trial supporting it; it is not a separate new U.S. approval.

What is the main safety concern with T-DXd in DESTINY-Gastric04?

Interstitial lung disease (ILD)/pneumonitis is the key monitored risk: it occurred in about 13.9% of patients treated with T-DXd, mostly Grade 1-2. Active ILD monitoring and prompt management are required per class labeling. The remaining safety profile was consistent with the known toxicity of T-DXd.

How does DESTINY-Gastric04 change second-line treatment of HER2-positive gastric cancer?

DESTINY-Gastric04 provides the first Phase 3 head-to-head evidence that T-DXd is superior to ramucirumab plus paclitaxel in second-line HER2-positive gastric/GEJ cancer, in a Western-inclusive population. It supports T-DXd as a preferred second-line option for patients who progressed after a trastuzumab-based regimen, with ongoing ILD monitoring essential.