On February 19, 2024 AstraZeneca and Daiichi Sankyo’s reported that Biologics License Application (BLA) for datopotamab deruxtecan (Dato-DXd) has been accepted in the US for the treatment of adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) who have received prior systemic therapy (Press release, AstraZeneca, FEB 19, 2024, View Source [SID1234640216]). The Prescription Drug User Fee Act date, the Food and Drug Administration (FDA) action date for its regulatory decision, is during the fourth quarter of 2024.

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The BLA is based on results from the pivotal TROPION-Lung01 Phase III trial in which datopotamab deruxtecan demonstrated a statistically significant improvement for the dual primary endpoint of progression-free survival (PFS) compared to docetaxel, the current standard of care, in patients with locally advanced or metastatic NSCLC treated with at least one prior line of therapy. For the dual primary endpoint of overall survival (OS), interim results numerically favoured datopotamab deruxtecan over docetaxel in the overall population; however, results did not reach statistical significance at the time of data cut-off. In patients with nonsquamous NSCLC, datopotamab deruxtecan showed a clinically meaningful PFS benefit and a numerically favourable OS trend. The trial is ongoing and OS will be assessed at final analysis.

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Datopotamab deruxtecan has the potential to offer patients with previously treated advanced nonsquamous non-small cell lung cancer an effective and tolerable alternative to conventional chemotherapy. With regulatory discussions ongoing around the world and a parallel submission underway in the US in breast cancer, this is only the beginning of our efforts to make this novel treatment available to patients as quickly as possible."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "Today’s news is an important step forward in our goal of creating new standards of care that have the potential to transform the treatment of patients with non-small cell lung cancer. We are encouraged by the FDA’s acceptance of the BLA as we endeavour to make datopotamab deruxtecan the first TROP2-directed antibody drug conjugate approved to treat patients with nonsquamous non-small cell lung cancer after disease progression on prior systemic therapy. We look forward to working closely with the FDA to bring datopotamab deruxtecan to patients."

Results from TROPION-Lung01 were presented during a Presidential Symposium at the 2023 European Society for Medical Oncology Congress.

The safety profile of datopotamab deruxtecan was consistent with that observed in other ongoing trials with no new safety concerns identified.

A parallel BLA for datopotamab deruxtecan based on results from the pivotal TROPION-Breast01 Phase III trial is pending acceptance in the US for the treatment of adult patients with metastatic hormone receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer. Additional regulatory submissions for datopotamab deruxtecan in lung and breast cancer are underway globally.

Notes

Advanced non-small cell lung cancer
Nearly 250,000 lung cancer cases were diagnosed in the US in 2023.1 NSCLC is the most common type of lung cancer accounting for about 80% of cases.1 Approximately 70% and 30% of NSCLC tumours are of nonsquamous or squamous histology, respectively.2 While immunotherapy and targeted therapies have improved outcomes in the 1st-line setting, most patients eventually experience disease progression and receive chemotherapy.3-5 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.3-5

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.6 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.7,8

TROPION-Lung01
TROPION-Lung01 is an ongoing global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan versus docetaxel in patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations previously treated with at least one prior line of therapy. Patients with actionable genomic alterations were previously treated with platinum-based chemotherapy and an approved targeted therapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include investigator-assessed PFS, objective response rate, duration of response, time to response, disease control rate as assessed by both BICR and investigator, and safety. TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America and South America. For more information visit ClinicalTrials.gov.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, datopotamab deruxtecan is one of six ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 14 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer and HR-positive, HER2-negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan also is being evaluated in novel combinations in several ongoing trials.