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

Results from the international phase 3 DESTINY-Gastric04 trial have demonstrated that trastuzumab deruxtecan significantly improves survival in patients with metastatic or unresectable HER2-positive gastric or gastroesophageal junction adenocarcinoma (GEJA) who have progressed following first-line trastuzumab-based treatment. It is the first phase 3 study to confirm the superiority of HER2-directed therapy in the second-line setting for this population.

Dr Kohei Shitara (National Cancer Centre Hospital East, Kashiwa, Japan) presented the Destiny-Gastric04 (NCT04704934) trial results [1], which were simultaneously published in the New England Journal of Medicine [2].

A total of 494 patients were enrolled, with 246 randomised to receive trastuzumab deruxtecan and 248 to receive standard chemotherapy comprising paclitaxel and ramucirumab; 60% had gastric cancer, while the remaining 40% had GEJA. 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 (trastuzumab deruxtecan) 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), meeting the primary endpoint and indicating a 30% relative reduction in the risk of death with trastuzumab deruxtecan.

PFS was also significantly longer in the trastuzumab deruxtecan 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. The objective response rate was 44.3% in the trastuzumab deruxtecan arm versus 29.1% in the control group (P<0.001). The disease control rate, which includes patients with either response or stable disease, was 91.9% for trastuzumab deruxtecan and 75.9% for chemotherapy.

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 trastuzumab deruxtecan group and 73.8% in the paclitaxel with ramucirumab group. Nearly all participants in both groups experienced at least 1 adverse event. The most common adverse events in the trastuzumab deruxtecan 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, which carry 5-year survival rates between 5% and 10%, 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: “Trastuzumab deruxtecan is approved for patients with metastatic HER2-positive gastric cancer or GEJA 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;392(1):1–12.

Medical writing support was provided by Dr Rachel Giles.
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Posted on 2 June 20252 June 2025