AstraZeneca and Daiichi Sankyo's ADC flops in Phase III in breast cancer after lung cancer fiasco

AstraZeneca And Daiichi Sankyo announced on Monday that its experimental antibody-drug conjugate Datopotamab Deruxtecan the overall survival target was missed in the phase III TROPION-Breast01 study.

The partners did not provide specific numbers in their announcement, but noted that datopotamab deruxtecan (Dato-DXd) “did not reach statistical significance in the final overall survival (OS) analysis.” TROPION-Breast01 enrolled breast cancer patients with unresectable or metastatic disease whose tumors were HR-positive and either negative or low in HER2. All participants had previously received endocrine-based therapy and at least one systemic treatment.

Although significance was not reached in terms of overall survival, Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, insisted that “there is evidence of clinical value of datopotamab deruxtecan” in patients with metastatic HR-positive breast cancer. The companies will “apply lessons learned” from TROPION-Breast01 to better support their clinical development of Dato-DXd in breast cancer, Galbraith said.

The partners will also continue regulatory discussions for Dato-DXd. The antibody drug conjugate (ADC) is is currently being reviewed from the FDA, with a target date in the first quarter of 2025.

Dato-DXd's biologics application, which the regulator accepted in April 2024, is supported by the progression-free survival (PFS) of TROPION-Breast01. In October 2023, the companies published results from the late-stage study showing that Dato-DXd Reduction in the risk of death or disease progression by 37%compared with the chemotherapy chosen by the investigator. The effect was highly statistically significant with a p-value of less than 0.001.

The median PFS was two months longer in the Dato-DXd arm. In addition, the confirmed objective response rate was 36.4% in patients treated with ADC versus 22.9% in patients receiving chemotherapy. At this time, OS data were not yet mature but showed a numerical trend in favor of Dato-DXd.

Ken Takeshita, global head of research and development at Daiichi Sankyo, pointed to these initial results in his announcement Monday, noting that Dato-DXd's PFS benefit “is supported by several meaningful secondary metrics, including patient-reported outcomes.”

The ADC appears to be safe overall. Updated results on Monday showed no new cases of grade 3 or higher interstitial lung disease.

Developed using Daiichi Sankyo's proprietary platform, Dato-DXd is an experimental ADC targeting the TROP2 protein, which is present in many cancers. Dato-DXd contains an exatecan derivative payload that can induce cell death when internalized by the target tumor cell.

Monday's results are Dato-DXd's second OS error in recent weeks. Earlier this month, AstraZeneca and Daiichi Sankyo revealed detailed results from the Phase III TROPION-Lung01 study, which shows that the ADC was only able to reduce the risk of death in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) by 6%. Dato-DXd is currently being reviewed by the regulatory authorities in this indication. Target date for the action: December 20.

Jefferies analyst Peter Welford wrote in a note to investors that after the failure in NSCLC, the lack of improvement in overall survival in breast cancer “further weakens confidence in Dato-DXd.” This setback, Welford continued, “likely complicates regulatory discussions for approval in this indication.”

Regarding NSCLC, Welford wrote that the FDA “could potentially convene an advisory committee meeting to discuss Dato-DXd in this indication, which could increase widespread concerns about its likely approvability and potentially delay the PDUFA decision date of December 20.”