AstraZeneca and Daiichi Sankyo have announced the voluntary withdrawal of their marketing authorization application (MAA) in the European Union for datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). The decision follows feedback from the European Medicines Agency (EMA) regarding data from the Phase III TROPION-Lung01 trial.
The TROPION-Lung01 trial was a global, randomized, multicenter, open-label study evaluating the efficacy and safety of Dato-DXd versus docetaxel in patients with advanced or metastatic NSCLC, both with and without actionable genomic alterations, who had received prior systemic therapy. The trial's dual primary endpoints were progression-free survival (PFS) and overall survival (OS).
TROPION-Lung01 Trial Results
While primary results from TROPION-Lung01, presented at the European Society for Medical Oncology (ESMO) 2023 Congress, demonstrated a statistically significant improvement in PFS with Dato-DXd compared to docetaxel, the final OS analysis did not reach statistical significance. Specifically, median OS was 12.9 months with Dato-DXd versus 11.8 months with docetaxel (HR, 0.94; 95% CI, 0.78-1.14; P = .530). In the subgroup of patients with nonsquamous NSCLC, median OS was 14.6 months for Dato-DXd versus 12.3 months for docetaxel (HR, 0.84; 95% CI, 0.68-1.05).
According to a news release from Daiichi Sankyo, feedback from the EMA's Committee for Medicinal Products for Human Use (CHMP) following results of the phase 3 TROPION-Lung01 trial informed the decision to withdraw the MAA.
Ongoing Development and Future Plans
Despite this setback, AstraZeneca and Daiichi Sankyo remain committed to developing Dato-DXd for lung cancer. "AstraZeneca and Daiichi Sankyo will continue to work to bring datopotamab deruxtecan to patients with lung cancer in the EU who can benefit and are committed to unlocking the potential of this medicine in lung cancer through our robust clinical development programme which includes seven pivotal trials in various lung cancer settings," the companies stated.
It should be noted that AstraZeneca and Daiichi Sankyo’s application in the EU for datopotamab deruxtecan for the treatment of hormone receptor (HR)-positive, HER2-negative metastatic breast cancer based on the TROPION-Breast01 Phase III trial remains under review.
Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan is a TROP2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed by AstraZeneca and Daiichi Sankyo. It is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
NSCLC Landscape
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022, with almost half a million of those cases occurring in Europe. NSCLC accounts for approximately 80% of lung cancer cases. While immunotherapy and targeted therapies have improved outcomes in the first-line setting, most patients eventually experience disease progression and require chemotherapy. For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.
Other Regulatory Actions
In November 2024, the companies also announced that they voluntarily withdrew a biologics license application (BLA) seeking FDA approval for Dato-DXd in patients with advanced or metastatic nonsquamous NSCLC. The companies submitted a new BLA seeking the approval of the antibody-drug conjugate for the treatment of adult patients with locally advanced or metastatic NSCLC harboring EGFR mutations who have received prior systemic therapies, including an EGFR-directed therapy.
