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Second-line Enhertu improved key survival end points versus Cyramza plus paclitaxel for HER2+ gastric cancer or gastroesophageal junction adenocarcinoma.
Second-line Enhertu improved key survival end points versus Cyramza plus paclitaxel for HER2+ gastric cancer or gastroesophageal junction adenocarcinoma: © stock.adobe.com.
Among patients with HER2-positive unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJ), second-line treatment with Enhertu (fam-trastuzumab deruxtecan-nxki) had a clinically meaningful and statistically significant benefit when compared with Cyramza (ramucirumab) plus paclitaxel. The investigative combination specifically improved overall survival rates among patients.
These findings were generated by the phase 3 DESTINY-Gastric04 trial, data from which was simultaneously shared during a press briefing during the 2025 ASCO Annual Meeting, as well as published in The New England Journal of Medicine.
At a median follow-up of 16.8 months for Enhertu and 14.4 months for Cyramza plus paclitaxel, the median overall survival was 14.7 months versus 11.4 months , respectively, with a 30% reduction in risk of death. The 6-month overall survival rates were 83.5% versus 74.4%, respectively, the 12-month overall survival rates were 57.6% versus 48.9%, and the 24-month overall survival rates were 29.0% versus 13.9%.
The median progression-free survival with Enhertu was 6.7 months (95% CI, 5.6-7.1) versus 5.6 months with Cyramza plus paclitaxel. The six-month progression-free survival rate was 52.6% versus 41.5%, respectively, and the 12-month progression-free survival rate was 22.9% versus 13.6%.
The confirmed overall response rate was 44.3% in all patients who received Enhertu and 29.1% in all patients who received Cyramza plus paclitaxel; the difference was 15.1%. The duration of response was 7.4 months versus 5.3 months, respectively. At six months, the duration of response rate was 58.4% versus 35.7%, respectively, and at 12 months, it was 29.7% versus 15.0%.
The disease control rate was 91.9% with Enhertu; 3.0% of patients (seven patients) achieved a complete response, 41.3% (97 patients) achieved a partial response, 47.7% (112 patients) achieved stable disease, 5.5% (13 patients) had progressive disease, and 2.6% (six patients) were not evaluable. In patients who received Cyramza plus paclitaxel, the disease control rate was 75.9%; 1.3% of patients (three patients) achieved a complete response, 27.8% (66 patients) achieved a partial response, 46.8% (111 patients) achieved stable disease, 9.3% (22 patients) had progressive disease and 14.8% (35 patients) were not evaluable.
“Enhertu demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with [Cyramza plus paclitaxel] in patients with HER2-positive metastatic GC/GEJ in the second line setting,” stated presenting study author Dr. Kohei Shitara, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, in the presentation. “DESTINY-Gastric04 confirmed Enhertu as the global [second line] standard-of-care therapy for patients with HER2-positive metastatic GC/GEJ.”
Overall survival (OS): the length of time from either the date of diagnosis or the start of treatment for a disease that patients diagnosed are alive.
Progression-free survival (PFS): the length of time during and after the treatment that a patient lives with the disease but it does not get worse.
Overall response rate (ORR): the proportion of patients who have a partial or complete response to therapy.
DESTINY-Gastric04 was a global, multicenter trial that randomly assigned approximately 494 patients to receive either 6.4 milligrams per kilogram (mg/kg) of intravenous Enhertu once every three weeks (246 patients) or intravenous Cyramza at 8 mg/kg on days one and 15 of each 28-day cycle and paclitaxel at 80 mg/m2 on days one, eight and 15 of each 28-day cycle (248 patients).
Eligible patients had HER2-positive GC/GEJ with HER2 status confirmed locally or centrally on a biopsy obtained after progression on Herceptin (trastuzumab). Patients also had no clinically active central nervous system metastases.
Exclusion criteria included a history of noninfectious interstitial lung disease or pneumonitis that was treated with glucocorticoids, active interstitial lung disease or pneumonitis, or suspected of having interstitial lung disease or pneumonitis that could not be ruled out by imaging.
The trial’s primary end point was OS. Key secondary end points included progression-free survival per investigator assessment, confirmed overall response rate per investigator assessment, duration of response per investigator assessment and safety.
Drug-related treatment-emergent side effects of any grade affected 93.0% (227 of 244 patients) of patients who received Enhertu and 91.4% (213 of 233 patients) of patients who received Cyramza plus paclitaxel; drug-related treatment-emergent side effects of grade 3 or higher affected 50.0% and 54.1% of patients. The most common drug-related side effects that were grade 3 or higher for Enhertu was neutropenia (28.7%), anemia (13.7%) and leukopenia (12.4%) ramucirumab.
It was also noted that interstitial lung disease/pneumonitis occurred in 13.9% of patients who received Enhertu and 1.3% who received Cyramza plus paclitaxel.
Drug-related treatment-emergent side effects were associated with dose discontinuation, dose interruption, dose reduction, and death, respectively, in 11.5%, 38.5%, 31.1%, and 1.6% of patients who received Enhertu, and in 13.3%, 51.1%, 36.1%, and 0.9%, respectively, of patients who received Cyramza plus paclitaxel.
“These results warrant further evaluation of Enhertu in the context of first-line therapy,” wrote the authors of the study in the paper.
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