AstraZeneca and Daiichi Sankyo have announced the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with previously treated advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). This submission seeks accelerated approval based on data from the TROPION-Lung05 Phase II trial.
TROPION-Lung05 Trial
The TROPION-Lung05 trial is a global, multicenter, single-arm, open-label Phase II study. It evaluated the efficacy and safety of datopotamab deruxtecan in patients with locally advanced or metastatic NSCLC harboring actionable genomic alterations, who had progressed on or after platinum-based chemotherapy and at least one tyrosine kinase inhibitor (TKI). The trial enrolled 137 patients across Asia, Europe, and North America.
The primary endpoint of TROPION-Lung05 is objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary endpoints include duration of response (DoR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), time to response (TTR), overall survival (OS), and safety.
Datopotamab Deruxtecan (Dato-DXd)
Datopotamab deruxtecan is an investigational TROP2-directed antibody-drug conjugate (ADC). It utilizes Daiichi Sankyo’s proprietary DXd ADC Technology. The ADC comprises a humanized anti-TROP2 IgG1 monoclonal antibody, developed with Sapporo Medical University, linked to a topoisomerase I inhibitor payload (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
A comprehensive global clinical development program is underway, encompassing over 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across various cancers, including NSCLC, triple-negative breast cancer (TNBC), and hormone receptor (HR)-positive, HER2-low or negative breast cancer. This program includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer, assessing datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments.
Lung Cancer Context
Lung cancer remains a significant global health challenge, with nearly 2.5 million cases diagnosed worldwide in 2022. NSCLC accounts for approximately 80% of all lung cancer cases. Among NSCLC patients, 10-15% in the US and Europe, and 30-40% in Asia, harbor EGFR mutations. The standard first-line treatment for these patients is typically an EGFR-tyrosine kinase inhibitor (TKI). However, most patients eventually experience disease progression and require subsequent chemotherapy.
TROP2 is a protein broadly expressed in the majority of NSCLC tumors. Currently, there is no approved TROP2-directed ADC for the treatment of lung cancer.
