AstraZeneca and Daiichi Sankyo’s TROP2-directed antibody-drug conjugate (ADC) has again failed to improve overall survival (OS) in a phase 3 trial. The latest miss happened in breast cancer, a setting in which Gilead Sciences' rival Trodelvy significantly improved OS in a prior late-phase study.
The AstraZeneca and Daiichi trial compared datopotamab deruxtecan (Dato-DXd) to investigator’s choice of chemotherapy in patients with inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative breast cancer. Patients had received endocrine-based therapy and at least one systemic therapy before joining the study.
OS was statistically no better in the Dato-DXd cohort than in the control group, causing the study to miss one of its dual primary endpoints. AstraZeneca and Daiichi previously reported a hit on the other dual primary endpoint, which looked at progression-free survival (PFS).
The partners' Monday statement about the OS flop lacks any data. AstraZeneca and Daiichi said the OS data numerically favored Dato-DXd when they shared the interim results 11 months ago. The latest press release lacks any mention of the OS data favoring Dato-DXd.
AstraZeneca and Daiichi did provide a potential explanation for the failure to improve OS. The partners said other ADCs were approved during the trial, and “subsequent treatment following patients’ disease progression or treatment discontinuation is likely to have affected survival results.” AstraZeneca started the study in October 2021.
Enhertu, another AstraZeneca and Daiichi ADC, first won FDA approval in breast cancer in 2019, but the regulator expanded the label in 2022 to cover its use as a second-line therapy and in HER2-low patients. Gilead won approval for Trodelvy in pretreated HR+/HER2- metastatic breast cancer in February 2023.
A recent Journal of Clinical Oncology paper about the Dato-DXd study’s PFS endpoint listed the treatments patients received after disease progression or discontinuation. In the control cohort, 14.2% of patients received an ADC, compared to 4.1% of people in the Dato-DXd group.
Gilead linked Trodelvy to a statistically significant 3.2-month improvement in OS over chemotherapy in a phase 3 breast cancer trial. While Dato-DXd failed to replicate its rival’s success, Susan Galbraith, Ph.D., executive vice president of oncology R&D at AstraZeneca, said in a statement that “there is evidence of the clinical value of datopotamab deruxtecan in this setting.”
AstraZeneca plans to continue talks with regulators and apply insights from the trial to the development of Dato-DXd in breast cancer. The FDA accepted a filing for approval in breast cancer earlier this year on the strength of the PFS results and interim OS data. The agency's decision on whether to approve Dato-DXd in the indication is due in the first quarter of 2025.
By then, the FDA is scheduled to have ruled on whether to approve the ADC in non-small cell lung cancer. Like in breast cancer, Dato-DXd failed to improve OS but did move the needle on PFS.