Global Phase 3 Clinical Trial of TROP2-Targeted ADC Datopotamab Deruxtecan in Combination with PD-1 Inhibitor Keytruda for First-Line Treatment of NSCLC to Commence

On October 25, 2021, Daiichi Sankyo and AstraZeneca jointly announced a clinical trial collaboration and supply agreement with a subsidiary of MSD. Daiichi Sankyo will lead a global Phase 3 clinical trial to evaluate the efficacy of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) in combination with MSD’s blockbuster PD-1 inhibitor Keytruda versus Keytruda monotherapy as first-line treatment for patients with advanced or metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations. The tumors of these patients highly express PD-L1.

Lung cancer is the second most common cancer globally and a leading cause of cancer-related mortality, with NSCLC accounting for 80%–85% of cases. Although the introduction of targeted therapies and immune checkpoint inhibitors in recent years has improved outcomes for patients with advanced NSCLC, the majority of patients harbor tumors lacking known targetable genomic alterations. The current standard of care for first-line treatment of these patients is immunotherapy with or without platinum-based chemotherapy. However, tumors in at least 40%–60% of patients are unresponsive to initial therapy and experience disease progression, with progression-free survival (PFS) for most patients remaining less than one year.

TROP2 is a transmembrane glycoprotein widely expressed in several types of solid tumors, including NSCLC. AstraZeneca and Daiichi Sankyo entered into a $6 billion R&D collaboration last year to co-develop Dato-DXd (DS-1062). This ADC utilizes Daiichi Sankyo's DXd ADC technology, conjugating a TROP2-targeting monoclonal antibody with a novel DNA topoisomerase I inhibitor (DXd). A previous clinical trial in NSCLC patients with specific genomic alterations demonstrated that Dato-DXd achieved an objective response rate (ORR) of 35%.

▲ Introduction to Dato-DXd (DS-1062) (Image source: Daiichi Sankyo official website)

By blocking the PD-1/PD-L1 signaling pathway, Keytruda enhances the anti-tumor response of the body's immune cells. It has been approved globally for the treatment of multiple cancer types, including seven indications previously approved in China, covering melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, and second-line treatment for esophageal cancer, among others.

This collaboration is based on the positive results from a Phase 1b clinical trial reported in May 2020. This Phase 1b trial evaluated the safety and efficacy of Dato-DXd in combination with Keytruda, with or without platinum-based chemotherapy, in patients with advanced or metastatic NSCLC (without targetable genomic alterations).

References:

[1] Second Clinical Trial Collaboration Initiated to Evaluate Datopotamab Deruxtecan in Combination with Keytruda® (pembrolizumab) in Patients with Metastatic Non-Small Cell Lung Cancer. Retrieved October 25, 2021, from https://www.businesswire.com/news/home/20211025005113/en/

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