AstraZeneca and Daiichi Sankyo Submit BLA for TROP2 ADC Datopotamab Deruxtecan in Previously Treated Non-Squamous NSCLC

On February 19, AstraZeneca and Daiichi Sankyo jointly announced that the Biologics License Application (BLA) for their TROP2 ADC Datopotamab deruxtecan (Dato-DXd) has been accepted by the FDA. The indication is for adult patients with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) who have previously received systemic therapy. The PDUFA date is December 20, 2024. If approved, Dato-DXd will become the world’s first TROP ADC for the treatment of lung cancer.

Source: AstraZeneca official website

Datopotamab Deruxtecan is an ADC composed of a humanized, Trop2-targeting monoclonal antibody linked to the innovative DNA topoisomerase I inhibitor (DXd). DXd has a unique mechanism of action and is 10 times more potent than the common chemotherapy drug irinotecan. Additionally, this drug has a strong ability to penetrate cell membranes, enabling it to kill neighboring cancer cells after eliminating cancer cells that have ingested the ADC, producing a "bystander effect." Trop2 is a protein widely expressed in various solid tumors, including HR-positive, HER2-low or negative breast cancer. AstraZeneca and Daiichi Sankyo reached an agreement in July 2020 to collaborate on the development of datopotamab deruxtecan.

AstraZeneca and Daiichi Sankyo have launched more than 14 clinical trials worldwide to evaluate the efficacy of datopotamab deruxtecan in treating non-small cell lung cancer, triple-negative breast cancer, and HR-positive, HER2-low or negative breast cancer, among other cancer types.

The filing for marketing authorization is primarily based on the positive data from the pivotal Phase III TROPION-Lung01 study. The results showed that, compared with the current standard treatment docetaxel, Dato-DXd demonstrated a statistically significant and clinically meaningful improvement in one of the primary endpoints, progression-free survival (PFS).

Another primary endpoint of the study, overall survival (OS) data, is not yet mature. Although an early favorable trend of Dato-DXd over docetaxel has been observed, it did not reach the pre-specified threshold for statistical significance at the interim analysis. The trial is still ongoing to evaluate more mature OS data.

The safety profile of Dato-DXd was consistent with previous studies, with no new safety signals identified. Overall, interstitial lung disease (ILD) events of all grades were consistent with prior clinical trials, with the majority being low-grade events. Some Grade 5 events were observed in the trial.

Susan Galbraith, Executive Vice President of Oncology R&D at AstraZeneca, stated: "Datopotamab deruxtecan has the potential to provide an effective and tolerable alternative to traditional chemotherapy for patients with previously treated advanced non-squamous non-small cell lung cancer."

Ken Takeshita, MD, Global Head of R&D at Daiichi Sankyo, stated: "Today's news marks an important step forward in our efforts to establish new standards that have the potential to transform the treatment of non-small cell lung cancer. We are encouraged by the FDA’s acceptance of the BLA and hope that, through our efforts, datopotamab deruxtecan can become the first approved TROP2-directed antibody drug conjugate for patients with non-squamous non-small cell lung cancer whose disease has progressed after prior systemic therapy."

According to publicly available information, Gilead's Trodelvy is the world's first Trop2 ADC, but its clinical trial failure for non-small cell lung cancer indications has given new-generation Trop2 ADCs more opportunities to catch up. In China, Kelun Biotech's SKB264 is in the marketing evaluation phase and has partnered with Merck internationally, already initiating three global Phase III clinical trials intensively.

References:

1.https://www.astrazeneca.com/media-centre/press-releases/2024/fda-accepts-dato-dxd-bla-for-nonsquamous-nsclc.html

2. WuXi AppTec "Potential Blockbuster Trop2-Targeted ADC Reaches Phase 3 Clinical Endpoint, Global Marketing Application Imminent"

3. VCBeat "Daiichi-Sankyo/AstraZeneca TROP ADC Submits for Market Approval in the US"