FDA Filing for Datopotamab Deruxtecan in EGFR-Mutated NSCLC
核心洞察
AstraZeneca and Daiichi Sankyo submitted a BLA to the FDA for accelerated approval of datopotamab deruxtecan in EGFR (搜索)-mutated NSCLC.
The submission is based on Phase II TROPION-Lung05 trial data and supported by Phase III TROPION-Lung01 and Phase I TROPION-PanTumor01 trials.
The companies voluntarily withdrew a previous BLA for nonsquamous NSCLC following FDA feedback.
AstraZeneca and Daiichi Sankyo have submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) seeking accelerated approval for datopotamab deruxtecan (Dato-DXd) in adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFR (搜索)) non-small cell lung cancer (搜索) (NSCLC) who have received prior systemic therapies, including EGFR-directed therapy. The decision to file is supported by data from the Phase II TROPION-Lung05 trial, as well as data from the TROPION-Lung01 Phase III and TROPION-PanTumor01 Phase I trials. The new BLA submission follows the voluntary withdrawal of a previous BLA for datopotamab deruxtecan in patients with advanced or metastatic nonsquamous NSCLC based on the TROPION-Lung01 Phase III trial, informed by feedback from the FDA. The companies are jointly developing datopotamab deruxtecan, a TROP2 (搜索)-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo.
Clinical Trial Data
The new BLA is based on results from the TROPION-Lung05 Phase II trial and supported by data from the TROPION-Lung01 Phase III and TROPION-PanTumor01 Phase I trials. TROPION-Lung05 is a global, multicenter, single-arm, open-label Phase II trial evaluating the efficacy and safety of datopotamab deruxtecan in patients with locally advanced or metastatic NSCLC with actionable genomic alterations. Patients enrolled had progressed on or after one regimen of platinum-based chemotherapy and at least one TKI (with or without other systemic therapies). 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. The trial enrolled 137 patients globally in Asia, Europe and North America.
TROPION-Lung01 is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan 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 endpoints of TROPION-Lung01 are PFS as assessed by BICR and OS. Key secondary endpoints include investigator-assessed PFS, ORR, DOR, TTR, and DCR as assessed by both BICR and investigator, and safety. TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America.
TROPION-PanTumor01 is a first-in-human, open-label, two-part, multicentre Phase I trial evaluating the safety and preliminary efficacy of datopotamab deruxtecan in patients with advanced solid tumours that have relapsed or are refractory to standard treatment or for which no standard treatment is available. The dose escalation portion of the trial enrolled patients with NSCLC to assess the safety and tolerability of datopotamab deruxtecan to determine the recommended dose for expansion (6 mg/kg). The dose expansion part of TROPION-PanTumor01 is enrolling several different cohorts including patients with NSCLC, triple-negative breast cancer (TNBC), HR-positive, HER2-low or negative breast cancer, SCLC, urothelial, gastric, pancreatic, castration-resistant prostate and esophageal cancer.
Management Commentary
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, noted that TROPION-Lung01 was designed to test the potential to improve upon standard-of-care chemotherapy in a broad, previously treated, advanced lung cancer (搜索) patient population. Galbraith stated that the results, together with data from TROPION-Lung05, showed an especially pronounced benefit for patients with an EGFR mutation (搜索) which informed discussions with the FDA and the decision to seek accelerated approval of datopotamab deruxtecan in this patient population.
Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, emphasized the challenges in treating EGFR-mutated non-small cell lung cancer (搜索) following disease progression, given the complexity and variability of these mutations often lead to resistance. Takeshita expressed hope that the potential approval of datopotamab deruxtecan could offer renewed hope for patients with this formidable disease.
NSCLC Landscape
Lung cancer (搜索) is broadly split into small-cell lung cancer (SCLC) or NSCLC, the latter accounting for about 80% of cases. Approximately 10-15% of patients with NSCLC in the US and Europe, and 30-40% of patients in Asia have an EGFR mutation (搜索). For patients with tumors that have an EGFR mutation, the established 1st-line treatment in the metastatic setting is an EGFR (搜索)-tyrosine kinase inhibitor (TKI). While EGFR-TKIs have improved outcomes in the 1st-line setting, most patients eventually experience disease progression and receive chemotherapy. TROP2 (搜索) is a protein broadly expressed in the majority of NSCLC tumours. There is currently no TROP2-directed ADC approved for the treatment of lung cancer.