Datopotamab Deruxtecan Granted FDA Breakthrough Therapy Designation for EGFR-Mutated NSCLC
Key Insights
The FDA granted Breakthrough Therapy Designation to datopotamab deruxtecan (Dato-DXd) for EGFR (search)-mutated non-small cell lung cancer (search) (NSCLC).
The designation is based on Phase 2 TROPION-Lung05 data, indicating a potential benefit in previously treated patients.
Datopotamab deruxtecan is a TROP2 (search)-directed antibody-drug conjugate being jointly developed by AstraZeneca and Daiichi Sankyo.
The FDA has granted Breakthrough Therapy Designation to datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with previously treated, locally advanced or metastatic EGFR (search)-mutated non-small cell lung cancer (search) (NSCLC). This designation aims to expedite the development and review of promising therapies for serious conditions. The decision is based on clinical data from the Phase 2 TROPION-Lung05 trial, which evaluated Dato-DXd in patients with NSCLC harboring EGFR mutations who had progressed on prior therapies.
Clinical Data and Trial Design
The TROPION-Lung05 trial is a Phase 2 study designed to assess the efficacy and safety of Dato-DXd in patients with locally advanced or metastatic NSCLC with actionable genomic alterations, specifically those with EGFR (search) mutations. These patients had previously been treated with platinum-based chemotherapy and at least one tyrosine kinase inhibitor (TKI). The primary endpoint of the trial is objective response rate (ORR), while 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.
TROPION-Lung01, a Phase 3 trial, evaluated Dato-DXd versus docetaxel in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. The dual primary end points of the study are PFS and OS.
TROPION-PanTumor01 is a Phase 1 study evaluating the safety and preliminary efficacy of Dato-DXd for patients with relapsed/refractory advanced solid tumors.
Datopotamab Deruxtecan: A TROP2-Directed ADC
Datopotamab deruxtecan is an antibody-drug conjugate (ADC) directed against TROP2 (search), a protein frequently overexpressed in various cancers, including NSCLC. The ADC comprises a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via tetrapeptide-based cleavable linkers. This design allows for targeted delivery of the cytotoxic payload to TROP2-expressing tumor cells, potentially enhancing efficacy while minimizing off-target toxicity.
Current Treatment Landscape and Unmet Needs
EGFR-mutated NSCLC (search) is often initially treated with EGFR (search) tyrosine kinase inhibitors (TKIs). However, most patients eventually develop resistance and experience disease progression, necessitating subsequent chemotherapy. The emergence of Dato-DXd offers a potential new treatment option for these patients, addressing a significant unmet medical need.
Development and Collaboration
Datopotamab deruxtecan is being jointly developed by AstraZeneca and Daiichi Sankyo. Daiichi Sankyo has six ADCs in clinical development across multiple types of cancers, being developed utilizing its DXd ADC technology. In addition to Dato-DXd, Daiichi markets Enhertu, a HER2 (search)-directed ADC for HER2-mutated breast, lung and gastric cancers, in partnership with AstraZeneca. Daiichi and Merck (search) are co-developing and co-commercializing three ADCs — patritumab deruxtecan/MK-1022, raludotatug deruxtecan/MK-5909 and ifinatamab deruxtecan/MK-2400.
Regulatory Context
AstraZeneca and Daiichi Sankyo have withdrawn their BLA for Dato-DXd in advanced or metastatic nonsquamous NSCLC based on Phase 3 data from the TROPION-Lung01 trial. Feedback from the FDA informed the decision to submit a new BLA for patients within this population and subsequently withdraw the previously submitted BLA for nonsquamous NSCLC.