AstraZeneca and Daiichi Sankyo's Enhertu has become the first HER2-directed drug to mount a patient survival benefit in a randomized clinical trial in second-line metastatic stomach cancer, the partners said on Monday.

Enhertu significantly extended the lives of patients with previously treated HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma in the phase 3 Destiny-Gastric04 study, according to the partners’ press release. For the study, investigators pitted the HER2-targeted antibody-drug conjugate against Eli Lilly’s VEGFR inhibitor Cyramza and chemotherapy.

An independent data monitoring committee noted the “statistically significant and clinically meaningful” overall survival improvement during a planned interim analysis and recommended unblinding the trial, the companies said Monday. 

The latest trial win won’t affect Enhertu’s regulatory status in the U.S. Back in 2021, the FDA approved Enhertu in stomach cancer following prior treatment with a trastuzumab (Herceptin)-based regimen. That second-line nod was based on results from the phase 2 Destiny-Gastric01 trial in a third-line setting, which showed that Enhertu reduced the risk of death by 41% versus chemotherapy alone.

Enhertu boasts stomach cancer approvals in more than 65 countries. AZ and Daiichi plan to use the latest Destiny-Gastric04 results to seek approvals in markets where Enhertu is not indicated as a second-line option, or to secure full approvals where the drug is only conditionally approved.

Stomach cancer has traditionally been a tough nut for researchers to crack. In 2023, the FDA narrowed an approval for Merck & Co.’s Keytruda in first-line HER2-positive gastric or gastroesophageal junction cancer, limiting the PD-1 inhibitor’s use to patients whose tumors express PD-L1. The move came after an interim analysis of the Keynote-811 trial found a negative overall survival trend for Keytruda among the subgroup of patients with PD-L1-negative disease.

Meanwhile, AZ and Daiichi just launched the four-arm phase 3 Destiny-Gastric05 trial to test Enhertu as a first-line treatment for HER2-positive stomach cancer. The study currently bears a primary completion date in 2028.

Since its initial FDA approval in 2019, Enhertu has repeatedly made history. Its achievements include pioneering the HER2-low breast cancer category and a recent FDA go-ahead in HER2-ultralow disease.

Last year, the drug also gained a unique tumor-agnostic indication which allows it to treat patients with any HER2-positive tumors who’ve already received primary systemic treatment and who have no other satisfactory alternatives.