DESTINY delivered: Trastuzumab deruxtecan extends survival in HER2-positive gastric cancer

The international phase 3 DESTINY-Gastric04 trial confirmed the superiority of human epidermal growth factor receptor (HER2)-directed therapy with trastuzumab deruxtecan (T-DXd) in the second-line setting for metastatic or unresectable HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have progressed following first-line trastuzumab-based treatment.

Metastatic HER2-positive gastric and GEJ cancers have a poor prognosis and carry 5-year survival rates between 5% and 10%. The DESTINY-Gastric04 (NCT04704934) trial, presented by Dr Kohei Shitara (National Cancer Centre Hospital East, Japan), investigated the survival effects of T-DXd compared to standard chemotherapy comprising paclitaxel and ramucirumab in this patient population [1]. The results were simultaneously published in the New England Journal of Medicine [2].

The trial enrolled 494 participants, with 246 randomised to receive T-DXd and 248 to receive standard chemotherapy; 60% had gastric cancer, while the remaining 40% had GEJ adenocarcinoma. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), confirmed objective response (complete or partial response lasting ≥4 weeks), disease control, duration of response, and safety.

After a median follow-up of 16.8 months (T-DXd) and 14.4 months (chemotherapy), the median OS was 14.7 months versus 11.4, respectively (HR 0.70; 95% CI 0.56–0.87; P=0.002; see Figure), meeting the primary endpoint and indicating a 30% relative reduction in the risk of death with T-DXd. PFS was also significantly longer in the T-DXd group: 6.7 months compared with 5.6 months in the chemotherapy group (HR 0.74; 95% CI 0.60–0.91; P=0.004), and a 26% reduction in the risk of progression or death was observed for the T-DXd arm. The objective response rate was 44.3% in the T-DXd arm versus 29.1% in the control group (P<0.001) and the disease control rate, which includes participants with either response or stable disease, was 91.9% for T-DXd and 75.9% for chemotherapy.

Figure: Overall survival of participants with HER2-positive unresectable/metastatic gastric or GEJ cancer treated with second-line trastuzumab deruxtecan versus standard chemotherapy [1]



^a Two-sided P value from a stratified log-rank test and stratified Cox proportional hazards model adjusted for stratification factor HER2 status.
CI, confidence interval; mOS, median overall survival; OS, overall survival; RAM + PTX, standard chemotherapy ramucirumab (RAM) + paclitaxel (PTX); T-DXd, Trastuzumab deruxtecan.

Safety outcomes were consistent with the known profile of the drugs. Grade ≥3 treatment-emergent adverse events occurred in 68.0% of participants in the T-DXd group and 73.8% in the paclitaxel with ramucirumab group. Nearly all participants, irrespective of treatment arms, experienced at least 1 adverse event. The most common adverse events in the T-DXd group were fatigue (48.0%), neutropenia (48.0%), nausea (44.3%), and anaemia (31.1%).

Given the poor prognosis of metastatic HER2-positive gastric and GEJ cancers, the 3.3-month improvement in OS is both statistically significant and clinically meaningful. ASCO’s official perspective on the findings, stated by Prof. Pamela Kunz (Yale Cancer Centre, CT, USA), explained: “T-DXd is approved for patients with metastatic HER2-positive gastric or GEJ adenocarcinoma who received a prior trastuzumab-based regimen based on previous phase 2 studies. These new results validate its role as a second-line standard-of-care.”

1. Shitara K, 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. Abstract LBA4002, ASCO Annual Meeting 2025, 30 May–3 June, Chicago, IL, USA.
2. Shitara K et al. N Engl J Med 2025; May 31. DOI: 10.1056/NEJMoa2503119.

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Posted on 30 July 2025