AstraZeneca, Daiichi Sankyo’s ADC Fails in Phase III Breast Cancer After Lung Cancer Setback

AstraZeneca and Daiichi Sankyo have announced that their investigational antibody-drug conjugate, datopotamab deruxtecan (Dato-DXd), failed to meet its overall survival (OS) goal in the Phase III TROPION-Breast01 study. This study included patients with inoperable or metastatic breast cancer whose tumors were HR-positive and either HER2-negative or low HER2. All participants had previously undergone endocrine-based therapy and at least one systemic treatment.

Although the specific figures were not disclosed, the companies stated that Dato-DXd "did not achieve statistical significance in the final overall survival analysis." Susan Galbraith, AstraZeneca’s executive vice president of oncology R&D, highlighted the clinical value of datopotamab deruxtecan in metastatic HR-positive breast cancer patients, despite this setback. She mentioned that the insights gained from TROPION-Breast01 would be used to better inform further clinical development for Dato-DXd in breast cancer.

Moreover, the partners plan to continue regulatory discussions for Dato-DXd. The drug is currently under review by the FDA, with a target action date set for the first quarter of 2025. The Biologics License Application (BLA) for Dato-DXd, accepted by the FDA in April 2024, is supported by progression-free survival (PFS) data from TROPION-Breast01. In October 2023, results from the late-stage study showed that Dato-DXd reduced the risk of death or disease progression by 37%, compared to chemotherapy, with a highly significant p-value of less than 0.001. The median PFS was extended by two months for patients in the Dato-DXd group. Additionally, the confirmed objective response rate was 36.4% for those treated with the drug, as opposed to 22.9% for those on chemotherapy. Although the OS data were still immature, they indicated a numerical advantage for Dato-DXd.

Ken Takeshita, Daiichi Sankyo’s global head of R&D, emphasized the significance of these early findings, noting that Dato-DXd’s PFS benefit was supported by several meaningful secondary measures, including patient-reported outcomes. The updated readout did not reveal any new Grade 3 or higher cases of interstitial lung disease, indicating that the drug appears to be overall safe.

Dato-DXd is designed using Daiichi Sankyo’s proprietary platform and targets the TROP2 protein, which is present in many cancers. The drug carries an exatecan derivative payload that triggers cell death when internalized by the target tumor cell.

This is the second recent OS setback for Dato-DXd. Earlier this month, AstraZeneca and Daiichi Sankyo revealed detailed results from the Phase III TROPION-Lung01 study. In this study, the ADC managed to reduce the risk of death by only 6% in patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). The drug is also under regulatory review for this indication, with a target action date of December 20.

Jefferies analyst Peter Welford noted that these results, combined with the earlier NSCLC setback, have further dented the belief in Dato-DXd and could complicate regulatory discussions for approval in breast cancer. Welford added that the FDA might call an advisory committee meeting to discuss Dato-DXd in the context of NSCLC, potentially exacerbating concerns about its approvability and possibly delaying the December 20 decision date.