Research Summary

Trastuzumab Deruxtecan Improves Survival in HER2-Positive Metastatic Gastric Cancer

Miranda Manier, BA

Key Highlights

  • Trastuzumab deruxtecan extended median overall survival compared with ramucirumab plus paclitaxel (14.7 vs 11.4 months).
  • Progression-free survival and objective response rates also favored trastuzumab deruxtecan.
  • Rates of grade 3 or more adverse events were similar between treatment groups.
  • Interstitial lung disease or pneumonitis was more frequent with trastuzumab deruxtecan but mostly low-grade.

A phase 3 international trial comparing trastuzumab deruxtecan with ramucirumab plus paclitaxel in human epidermal growth factor receptor 2 (HER2)–positive metastatic gastric or gastroesophageal junction adenocarcinoma showed that trastuzumab deruxtecan provided a significant survival benefit. Among 494 patients previously treated with trastuzumab-based therapy, trastuzumab deruxtecan extended median overall survival to 14.7 months compared with 11.4 months for ramucirumab plus paclitaxel. Progression-free survival and objective response rates were also higher with trastuzumab deruxtecan, while safety outcomes were generally comparable, aside from an increased rate of interstitial lung disease or pneumonitis that was mostly low-grade.

Patients with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma have limited therapeutic options after progression on trastuzumab-based regimens, and prognosis remains poor. Ramucirumab plus paclitaxel has been a widely used second-line standard regardless of HER2 status, but durable outcomes have been modest. Given promising activity in earlier studies, trastuzumab deruxtecan was evaluated as a potential alternative to improve survival in this patient population.

In this randomized trial, patients with HER2-positive metastatic gastric or gastroesophageal junction adenocarcinoma confirmed by biopsy after progression on trastuzumab-based therapy were assigned to receive either trastuzumab deruxtecan at 6.4 mg/kg or ramucirumab plus paclitaxel. The primary endpoint was overall survival, with secondary endpoints including progression-free survival, objective response, disease control, duration of response, and safety.

The trial enrolled 494 patients. Median overall survival was 14.7 months with trastuzumab deruxtecan compared with 11.4 months for ramucirumab plus paclitaxel, corresponding to a hazard ratio for death of 0.70 (95% CI, 0.55–0.90; P = .004). Progression-free survival also improved with trastuzumab deruxtecan (hazard ratio for disease progression or death, 0.74; 95% CI, 0.59–0.92). Confirmed objective response was observed in 44.3% of patients receiving trastuzumab deruxtecan versus 29.1% in the comparator arm.

Adverse events were frequent in both treatment groups. Medication-related events of any grade occurred in 93% of patients who received trastuzumab deruxtecan and 91.4% of those who received ramucirumab plus paclitaxel. Rates of grade 3 or higher adverse events were comparable at 50% and 54.1%, respectively. Interstitial lung disease or pneumonitis was more common in the trastuzumab deruxtecan group (13.9%) than in the comparator group (1.3%), though nearly all cases with trastuzumab deruxtecan were grade 1 or 2; only one grade 3 event was observed.

“Trastuzumab deruxtecan led to significantly longer overall survival than ramucirumab plus paclitaxel among patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma,” Kohei Shitara, MD, and colleagues concluded.

Reference:
Shitara K, Van Cutsem E, Gümüş M, et al. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med. 2025;393(4):336-348. doi:10.1056/NEJMoa2503119