Trastuzumab Deruxtecan Improves Survival in HER2+ Metastatic Gastric Cancer

The safety profile of trastuzumab deruxtecan in the phase 3 DESTINY-Gastric04 trial was consistent with the established safety profile of the agent.

Trastuzumab deruxtecan (Enhertu; T-DXd) exhibited a statistically significant and clinically meaningful improvement in overall survival (OS) vs ramucirumab (Cyramza) plus paclitaxel in patients with second-line HER2-positive unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a news release on findings from the phase 3 DESTINY-Gastric04 trial (NCT04704934).¹

The global, open-label, phase 3 DESTINY-Gastric04 trial evaluated the safety and efficacy of 6.4 mg/kg of T-DXd vs ramucirumab plus paclitaxel in this patient population following disease progression on or after a trastuzumab (Herceptin)-containing regimen who have not received any additional systemic therapy. Data from the trial will be presented at an upcoming medical meeting and shared with regulatory 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 Research and Development at Daiichi Sankyo, said in the news release.¹ “With these phase 3 DESTINY-Gastric04 trial 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.”

In the trial, patients were randomly assigned 1:1 to received either T-DXd or ramucirumab plus paclitaxel. Patients in the T-DXd arm received 6.4 mg/kg of T-DXd as an intravenous infusion every 3 weeks on day 1 of 21-day cycles.² Patients in the comparator arm received 8 mg/kg of ramucirumab as an intravenous infusion on days 1 and 15 of a 28-day cycle, as well as 80 mg/m² of paclitaxel as an intravenous infusion on days 1, 8, and 15.

The primary end point of the trial was OS. Secondary end points included progression-free survival per investigator assessment, objective response rate, duration of response, disease control rate, and safety. Currently, DESTINY-Gastric04 has enrolled 494 patients from Asia, Europe, and South America.

An independent data monitoring committee recommended unblinding the trial based on the efficacy of T-DXd at a planned interim analysis. The safety profile of T-DXd in the phase 3 DESTINY-Gastric04 trial was consistent with the established safety profile of the agent.

T-DXd is a specifically engineered HER2-directed antibody-drug conjugate. For those who have experienced disease progression following first-line therapy for metastatic HER2-positive gastric cancer, no HER2-directed agents have demonstrated a survival benefit in the second-line metastatic setting in a randomized clinical trial.

“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 Research & Development at AstraZeneca, said in the news release.¹ “The results of the phase 3 DESTINY-Gastric04 trial 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.”

Adult patients with pathologically documented, locally or centrally confirmed HER2-positive gastric and GEJ adenocarcinoma previously treated in the metastatic setting were eligible for trial enrollment. In addition, patients were included if they experienced disease progression on or after a trastuzumab-based therapy; had an ECOG performance status score of 0 or 1 at screening; and had adequate bone marrow, renal, hepatic, and blood clotting function within 14 days of random assignment.

Those ineligible for enrollment included those with anticancer therapy following trastuzumab-based treatment; a medical history of myocardial infarction within 6 months before enrollment; or a history of interstitial lung disease (ILD) that required steroids, current ILD, or suspected ILD not ruled out by imaging at screening.

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 4, 2025. https://tinyurl.com/4xn689yt
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 4, 2025. https://tinyurl.com/uct3cny9