AstraZeneca, Daiichi’s TROP2 drug fails Phase 3 breast cancer survival goal

AstraZeneca and Daiichi Sankyo have encountered a significant setback in their ongoing development of the TROP2-directed antibody-drug conjugate, known as datopotamab deruxtecan (Dato-DXd), for breast cancer treatment. The drug failed to achieve statistical significance in the overall survival (OS) portion of a key late-phase clinical trial, potentially impacting its ongoing review by the U.S. Food and Drug Administration (FDA).

The TROPION-Breast01 Phase 3 study assessed Dato-DXd against the investigator’s choice of chemotherapy in over 700 patients with previously treated, unresectable or metastatic hormone receptor-positive (HR-positive), HER2-low or HER2-negative breast cancer. Despite initial promising results in progression-free survival (PFS), where Dato-DXd showed a median PFS of 6.9 months compared to 4.9 months for chemotherapy, it fell short in the OS endpoint. This trial's outcome could complicate its regulatory approval process, as noted by analysts from Jefferies.

Dato-DXd has been anticipated to achieve substantial market success, with Jefferies analysts projecting global peak sales that could reach $9.4 billion, including $1.2 billion specifically from breast cancer treatments. The drug is currently under FDA review with a Prescription Drug User Fee Act (PDUFA) target date set for January 29, 2025.

AstraZeneca has suggested that the disappointing OS results might have been influenced by patients using other antibody-drug conjugates (ADCs) for breast cancer approved during the trial, including AstraZeneca’s own drug, Enhertu. When the PFS data was initially released, the OS data was still immature but showed a favorable trend for Dato-DXd.

Despite the setback, Susan Galbraith, the head of oncology R&D at AstraZeneca, mentioned that the company plans to continue discussions with regulatory authorities and use the trial data to inform and improve their broader breast cancer development program for Dato-DXd. This program includes additional studies on other breast cancer subtypes such as triple-negative breast cancer and HR-low, HER2-negative breast cancer, as well as combinations with immunotherapy in other Phase 3 trials.

In comparison, Dato-DXd’s potential market competitor, Trodelvy, an ADC developed by Gilead, demonstrated a 14.4-month OS versus 11.2 months for chemotherapy in a similar population during its Phase 3 trial. Trodelvy, which also targets TROP2, received FDA approval for label expansion to include HR-positive, HER2-negative breast cancer in February of the previous year.

Beyond breast cancer, Dato-DXd is also being evaluated for the treatment of previously treated advanced nonsquamous non-small cell lung cancer (NSCLC). However, similar to the breast cancer study, Dato-DXd did not meet its OS target in the 600-participant TROPION-Lung01 trial, despite achieving the PFS endpoint.

The mixed results of Dato-DXd in critical trials underscore the challenges in developing effective treatments for complex cancers. While the initial PFS results are promising, the failure to meet the OS endpoint in two significant studies raises questions about the drug’s overall efficacy and its future in the competitive oncology market. AstraZeneca and Daiichi Sankyo are likely to face increased scrutiny from regulatory bodies as they continue to pursue approval and further development of Dato-DXd.