Second-Line Trastuzumab Deruxtecan for Patients With HER2-Positive Gastric/Gastroesophageal Junction Adenocarcinoma
According to results from the phase 3 DESTINY-Gastric04 trial, trastuzumab deruxtecan in the second line significantly improved outcomes compared to ramucirumab plus paclitaxel among patients with human epidermal growth factor receptor 2 (HER2)-positive unresectable or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.
Based on various study results, “trastuzumab deruxtecan was approved for patients with [HER2]–positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy… [and] ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status,” stated Kohei Shitara, MD, National Cancer Center Hospital East, Japan, and coauthors. Here, researchers “evaluate the efficacy and safety of trastuzumab deruxtecan as compared with ramucirumab plus paclitaxel as second-line therapy.”
In this open-label trial, 494 patients who experienced disease progression during trastuzumab-based treatment were randomized on a 1-to-1 basis to receive either 6.4 mg/kg of body weight based trastuzumab deruxtecan (n = 246) or 8 mg/kg of ramucirumab plus 80 mg/m2 of body-surface area based paclitaxel (n = 248) until disease progression or unacceptable toxicity. The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS), confirmed objective response, and safety.
At analysis, median OS was 14.7 months in the trastuzumab deruxtecan arm and 11.4 months in the ramucirumab plus paclitaxel arm (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.55 to 0.90; P = .004). Median PFS was 6.7 months and 5.6 months (HR 0.74; 95% CI, 0.59 to 0.92; P = .007), respectively. There was a confirmed objective response observed in 44.3% of patients in the trastuzumab deruxtecan arm and 29.1% of patients in the ramucirumab plus paclitaxel arm. Any grade treatment-related adverse events occurred in 93% of patients in the trastuzumab deruxtecan arm and 91.4% of patients in the ramucirumab plus paclitaxel arm. Grade ≥3 treatment-related adverse events occurred in 50% and 54.1% of patients, respectively. Adjudicated treatment-related interstitial lung disease or pneumonitis occurred in 13.9% of patients in the trastuzumab deruxtecan arm (grade 3, n = 1) and 1.3% of patients in the ramucirumab plus paclitaxel arm (grade 3, n = 2).
“This trial showed that trastuzumab deruxtecan had superior efficacy as second-line therapy over ramucirumab plus paclitaxel in patients with HER2-positive unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma,” concluded Dr Shitara et al. “These results warrant further evaluation of trastuzumab deruxtecan in the context of first-line therapy.”
Source:
Shitara K, Van Cutsem E, Gümüş M, et al. Trastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer. N Engl J Med. Published online: May 31, 2025. doi: 10.1056/NEJMoa2503119
