T-DXd Improves OS in Unresectable/Metastatic HER2+ Gastric/GEJ Adenocarcinoma

Second-line treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) led to a statistically significant and clinically meaningful improvement in overall survival (OS) compared with ramucirumab (Cyramza) plus paclitaxel in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) unresectable and/or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, meeting the primary end point of the phase 3 DESTINY-Gastric04 trial (NCT04704934).1

Based on data from a planned interim analysis, the study’s independent data monitoring committee recommended unblinding the trial. Safety data for T-DXd were consistent with the established toxicity profile of the agent.

Findings from DESTINY-Gastric04 will be presented at an upcoming medical meeting and shared with global health authorities.

“[T-DXd] is the first HER2-directed medicine to demonstrate an improvement in OS in a randomized phase 3 trial in the second-line metastatic setting of patients with HER2-positive gastric cancer, reinforcing previous findings seen in our other earlier-phase gastric cancer trials,” Ken Takeshita, MD, global head of Oncology R&D at Daiichi Sankyo, stated in a news release. “With these DESTINY-Gastric04 results, we will work with global regulatory authorities to seek approval in regions where [T-DXd] is not currently indicated as a second-line option, as well as work to secure full approval in regions where [T-DXd] is conditionally approved.”

DESTINY-Gastric04 was a global, randomized, open-label trial that enrolled patients at least 18 years of age with pathologically documented gastric or GEJ adenocarcinoma who were previously treated in the metastatic setting and experienced disease progression on or after first-line therapy with a trastuzumab (Herceptin)- or an approved trastuzumab biosimilar–containing regimen.2 Prior neoadjuvant or adjuvant therapy with a trastuzumab-containing regimen was considered a prior line of therapy if a patient experienced disease progression on or within 6 months of completing neoadjuvant or adjuvant therapy. Neoadjuvant or adjuvant therapy that did not contain trastuzumab was not considered a prior line of therapy. Patients needed to have locally or centrally confirmed HER2-positive disease (IHC 3+ or IHC 2+ and evidence of HER2 amplification by ISH) on a tumor biopsy obtained after disease progression on or after a first-line trastuzumab- or approved trastuzumab biosimilar-containing regimen. Other key inclusion criteria consisted of a performance status of 0 or 1; and adequate bone marrow, renal, hepatic function, and blood clotting function within 14 days of enrollment.

Patients were excluded if they received anticancer therapy after trastuzumab-containing treatment; had a medical history of myocardial infarction within 6 months of enrollment or symptomatic congestive heart failure; had a history of (non-infectious) interstitial lung disease (ILD) or pneumonitis requiring steroids, current ILD or pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging; and underwent prior complete pneumonectomy.

Patients were randomly assigned to receive T-DXd at 6.4 mg/kg once every 3 weeks on day 1 of each 21-day cycle; or ramucirumab at 8 mg/kg on days 1 and 15 of each 28-day cycle plus paclitaxel at 80 mg/m2 on days 1, 8, and 15 of each cycle.

OS served as the trial’s primary end point. Secondary end points included progression-free survival, objective response rate, duration of response, disease control rate, and safety.

“We are committed to advancing the care of patients with metastatic gastric cancer and continuing to understand the role of [T-DXd] in earlier lines of treatment,” Susan Galbraith, MBBChir, PhD, executive vice president of Oncology Hematology R&D at AstraZeneca, stated in a news release.1 “The results of DESTINY-Gastric04 show that second-line treatment with [T-DXd] can extend survival compared with a chemotherapy-based regimen and should be considered for all eligible patients with HER2-positive metastatic gastric cancer.”

References

1. Enhertu demonstrated statistically significant and clinically meaningful improvement in overall survival in patients with HER2 positive metastatic gastric cancer at interim analysis of DESTINY-Gastric04 phase 3 trial. News release. Daiichi Sankyo. March 3, 2025. Accessed March 3, 2025 https://www.daiichisankyo.com/files/news/pressrelease/pdf/202503/20250303_E.pdf
2. Trastuzumab deruxtecan for subjects with HER2-positive gastric cancer or gastro-esophageal junction adenocarcinoma after progression on or after a trastuzumab-containing regimen (DESTINY-Gastric04). ClinicalTrials.gov. Updated October 24, 2024. Accessed March 3, 2025. https://clinicaltrials.gov/study/NCT04704934