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Positive results from the phase 3 DESTINY-Gastric04 trial (NCT04704934) have confirmed the efficacy of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in patients with HER2-positive unresectable and/or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.¹

The trial showed that T-DXd significantly improved overall survival (OS) compared with the standard second-line treatment of ramucirumab (Cyramza) plus paclitaxel in this patient population, meeting the primary end point of the DESTINY-Gastric04 study. Additionally, the safety profile observed in DESTINY-Gastric04 was consistent with previous studies.

At a planned interim analysis, the Independent Data Monitoring Committee recommended unblinding the trial due to the clear superiority of T-DXd. These findings will be shared with global regulatory authorities and presented at an upcoming medical meeting.

“[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,” in Ken Takeshita, MD, global head of Oncology research and development at Daiichi Sankyo, in a press 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.”

T-DXd is a HER2-directed antibody drug conjugate and the first HER2-targeted therapy to demonstrate a survival benefit in a randomized phase 3 trial for second-line metastatic HER2-positive gastric cancer. The agent is already approved in more than 65 countries based on earlier trials, including DESTINY-Gastric01 (NCT03329690), DESTINY-Gastric02 (NCT04014075), and DESTINY-Gastric06 (NCT04989816).

DESTINY-Gastric04 marks the first phase 3 trial to evaluate T-DXd for the treatment of patients with HER2-positive advanced gastric cancer.

About the DESTINY-Gastric04 Trial

The global, randomized, open-label DESTINY-Gastric04 trial is evaluating the efficacy and safety of T-DXd given at a dose of 6.4 mg/kg vs ramucirumab and paclitaxel in patients with HER2-positive unresectable and/or metastatic gastric or GEJ adenocarcinoma who have experienced disease progression after a trastuzumab-containing regimen. The study design defined HER2 positive as immunohistochemistry (IHC) 3+ or IHC 2+/in situ hybridization (ISH)+.

The trial enrolled 494 patients across Asia, Europe, and South America. Patients aged 18 years or older with pathologically documented gastric or GEJ adenocarcinoma 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 were eligible for enrollment in the trial.² Patients were also required 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.

Further, patients had to have an ECOG performance status of 0 or 1, and adequate bone marrow, renal, hepatic function, and blood clotting function within 14 days of enrollment in the trial.

The primary end point was OS, with secondary end points including progression-free survival, objective response rate, duration of response, and disease control rate.

“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,” said Susan Galbraith, MBBChir, PhD, executive vice president of Oncology Hematology research and development at AstraZeneca, in a press 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://tinyurl.com/y4mrpp9c

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