AstraZeneca, Daiichi Sankyo ADC Misses Endpoint in Phase III NSCLC Study

Pictured: 3D illustration of antibody-drug conjuga

Pictured: 3D illustration of antibody-drug conjuga

Marcin Klapczynski/Getty Images/iStockphoto

AstraZeneca and Daiichi Sankyo’s investigational antibody-drug conjugate Dato-DXd failed to significantly improve overall survival in non-small cell lung cancer patients versus docetaxel.

Pictured: 3D illustration of antibody-drug conjugates carrying toxic payloads/iStock, Marcin Klapczynski

AstraZeneca and Daiichi Sankyo on Monday revealed additional data from the Phase III TROPION-Lung01 study, showing that their investigational antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) failed to significantly improve overall survival in non-small cell lung cancer patients.

The partners did not provide specific data in their announcement, only disclosing that overall survival (OS) outcomes in TROPION-Lung01 “numerically favored” Dato-DXd versus docetaxel. However, this effect “did not reach statistical significance in the overall trial population.”

In a subset of patients with non-squamous non-small cell lung cancer (NSCLC), Dato-DXd was able to elicit a “clinically meaningful improvement in OS,” according to the companies.

Despite falling short of its OS endpoint in the overall trial population, Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, in a statement said that these data still point to the potential of Dato-DXd to “replace conventional chemotherapy” in late-line NSCLC. The latest findings from TROPION-Lung01 “underscore our confidence in ongoing trials evaluating this therapy in first-line lung cancer,” Galbraith added.

TROPION-Lung01 is a randomized, open-label trial that enrolled more than 600 adult patients with advanced or metastatic NSCLC patients requiring systemic therapy after prior treatments. Its dual primary endpoints are OS and progression-free survival (PFS), while key secondary outcomes include objective response rate (ORR), duration of response and disease control rate.

At the European Society for Medical Oncology 2023 Congress, held in October 2023, AstraZeneca and Daiichi Sankyo presented PFS data from TROPION-Lung01. The antibody-drug conjugate (ADC) cut the risk of disease progression or death by 25% versus docetaxel, the current standard of care in this indication.

As in the case of OS, Dato-DXd’s effects appeared to be more pronounced in patients with non-squamous NSCLC. Its PFS benefit was “clinically meaningful” in this patient subset, reducing the risk of disease progression or death by 37% compared with docetaxel, according to the companies’ announcement at the time.

The ADC also had superior ORR and median duration of response relative to docetaxel.

Dato-DXd is currently being reviewed by the FDA for use in locally advanced or metastatic NSCLC. Its Biologics License Application, which the regulator accepted in February 2024, is backed by TROPION-Lung01. The target action date is Dec. 20, 2024.

An investigational ADC, Dato-DXd works by targeting the TROP2 antigen which is typically highly expressed on many malignancies including breast, colorectal, gastric and lung cancers. Dato-DXd carries a topoisomerase I inhibitor payload, which triggers cell death once internalized and released inside the cancer cell. The ADC can also elicit a bystander effect, which can destroy neighboring tumor cells.

Daiichi Sankyo and AstraZeneca are also developing Dato-DXd for various types of breast cancer.

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. Reach out to him on LinkedIn or email him at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

Tristan is an independent science writer based in Metro Manila, with more than eight years of experience writing about medicine, biotech and science. He can be reached at tristan.manalac@biospace.com, tristan@tristanmanalac.com or on LinkedIn.
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