Monday’s failure to improve overall survival in breast cancer “further dents belief” in the companies’ Dato-DXd and “likely complicates regulatory discussions for approval of this indication,” Jefferies analyst Peter Welford wrote in a note to investors.
AstraZeneca and Daiichi Sankyo announced on Monday that their investigational antibody-drug conjugate datopotamab deruxtecan missed its overall survival goal in the Phase III TROPION-Breast01 study.
The partners did not reveal specific figures in their announcement, only noting that datopotamab deruxtecan (Dato-DXd) “did not achieve statistical significance in the final overall survival (OS) analysis.” TROPION-Breast01 enrolled breast cancer patients with inoperable or metastatic disease and whose tumors were positive for HR and were either negative or had low levels of HER2. All participants had undergone prior rounds of endocrine-based therapy and at least one systemic treatment.
Despite falling short of significance on OS, Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, maintained that “there is evidence of the clinical value of datopotamab deruxtecan” in metastatic HR-positive breast cancer patients. The companies will “apply insights” from TROPION-Breast01 to better inform their clinical development for Dato-DXd in breast cancer, Galbraith said.
The partners will also continue regulatory discussions for Dato-DXd. The antibody-drug conjugate (ADC) is currently being reviewed by the FDA, with a target action date in the first quarter of 2025.
Dato-DXd’s Biologics License Application, which the regulator accepted in April 2024, is backed by progression-free (PFS) survival from TROPION-Breast01. In October 2023, the companies posted findings from the late-stage study showing that Dato-DXd cut the risk of death or disease progression by 37%, compared with the investigator’s choice of chemotherapy. The effect was highly statistically significant, with a p-value less than 0.001.
Median PFS was longer by two months in the Dato-DXd arm. In addition, confirmed objective response rate was 36.4% in patients treated with the ADC versus 22.9% in chemotherapy counterparts. At the time, OS data were still immature but showed a numerical trend in favor of Dato-DXd.
Ken Takeshita, Daiichi Sankyo’s global head of R&D, pointed to these early findings in Monday’s announcement, noting that Dato-DXd’s PFS benefit is “supported by multiple meaningful secondary measures, including patient-reported outcomes.”
The ADC appears to be safe overall. Monday’s updated readout did not show new Grade 3 or higher cases of interstitial lung disease.
Designed using Daiichi Sankyo’s proprietary platform, Dato-DXd is an investigational ADC that targets the TROP2 protein, which is a protein that is expressed in many cancers. Dato-DXd caries an exatecan derivative payload that can trigger cell death when internalized by the target tumor cell.
Monday’s readout is Dato-DXd’s second OS stumble in recent weeks. Earlier this month, AstraZeneca and Daiichi Sankyo revealed detailed results from the Phase III TROPION-Lung01 study, showing that the ADC could only reduce the risk of death by 16% in patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Dato-DXd is under regulatory review in this indication, with a target action date of Dec. 20.
Jefferies analyst Peter Welford in a note to investors wrote that after its NSCLC stumble, failing to improve OS in breast cancer “further dents belief” in Dato-DXd. This setback, Welford continued, “likely complicates regulatory discussions for approval of this indication.”
When it comes to NSCLC, Welford wrote that that the FDA “may call an advisory committee meeting to discuss Dato-DXd in this indication, which could exacerbate widespread concerns on its likely approvability, and perhaps delay the 20 Dec PDUFA decision date.”
Correction (Sept. 24): This article has been updated to reflect Dato-DXd’s 16% OS improvement in non-squamous NSCLC. A previous version incorrectly put this figure at 6%. BioSpace regrets the error.
