AstraZeneca and Daiichi Sankyo have announced the submission of a new Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for datopotamab deruxtecan (Dato-DXd) for accelerated approval. The application targets the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations, specifically those who have progressed following prior systemic therapies, including EGFR-targeted treatments.
Datopotamab deruxtecan is an investigational TROP2-directed antibody-drug conjugate (ADC). It is designed using Daiichi Sankyo’s proprietary DXd ADC Technology. The drug 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.
TROPION-Lung05 Trial
The BLA submission is supported by data from the TROPION-Lung05 Phase II trial, a global, multicenter, single-arm, open-label study. This trial evaluated the efficacy and safety of datopotamab deruxtecan in NSCLC patients with actionable genomic alterations who had progressed on or after one regimen of 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 was objective response rate (ORR) as assessed by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), time to response (TTR), overall survival (OS), and safety.
NSCLC and EGFR Mutations
Lung cancer is a significant global health concern, with approximately 2.5 million cases diagnosed in 2022. NSCLC accounts for about 80% of all lung cancer cases. Among NSCLC patients, 10-15% in the US and Europe, and 30-40% in Asia, have EGFR mutations. These mutations are more common in tumors of nonsquamous histology.
The standard first-line treatment for EGFR-mutated NSCLC is an EGFR-tyrosine kinase inhibitor (TKI). While EGFR-TKIs have improved outcomes, most patients eventually experience disease progression and require subsequent therapies like chemotherapy. TROP2, the target of datopotamab deruxtecan, is broadly expressed in the majority of NSCLC tumors. Currently, there is no approved TROP2-directed ADC for lung cancer treatment.
Ongoing Clinical Development
Datopotamab deruxtecan is currently under evaluation in a comprehensive global clinical development program, including over 20 trials across multiple cancers. These include NSCLC, triple-negative breast cancer (TNBC), and HR-positive, HER2-low or negative breast cancer. The 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.
Collaboration
AstraZeneca and Daiichi Sankyo are collaborating to develop and commercialize datopotamab deruxtecan, except in Japan, where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is responsible for manufacturing and supply of datopotamab deruxtecan.
