AstraZeneca and Daiichi Sankyo Submit Clinical Application for TROP2 ADC Datopotamab Deruxtecan (DS-1062a) in China

On July 29, the clinical trial application for Daiichi Sankyo's TROP2 antibody-drug conjugate DS-1062a (Dato-DXd, datopotamab deruxtecan) was accepted by the National Medical Products Administration (NMPA).

DS-1062a is developed using Daiichi Sankyo’s proprietary DXd ADC technology. It comprises a humanized anti-TROP2 monoclonal antibody conjugated to a novel topoisomerase I inhibitor payload via a tetrapeptide linker. The average drug-to-antibody ratio is 4, meaning that four cytotoxic drug molecules are attached to each antibody.

At the ASCO Annual Meeting in June 2021, Daiichi Sankyo and AstraZeneca presented updated data on DS-1062a for advanced or metastatic NSCLC, along with data from the Phase I TROPION-PanTumor01 trial for metastatic triple-negative breast cancer (TNBC).

As of January 8, 2021, in patients with NSCLC, the ORRs for the DS-1062a 4 mg, 6 mg, and 8 mg dose groups were 24%, 26%, and 24%, respectively; the PFS were 4.3, 6.9, and 5.2 months, respectively. The overall safety profile was manageable, with incidence rates of grade ≥3 treatment-related adverse events (TEAEs) of 14%, 16%, and 35%, respectively.

DS-1062a achieved an ORR of 43% in 21 efficacy-evaluable patients with previously treated TNBC, with 5 patients achieving confirmed CR/PR. The DCR (disease control rate) was 95%. Grade ≥3 TEAEs occurred in 33% of patients (n=8), and 25% of patients (n=6) required dose reduction due to adverse events.

The clinical development of DS-1062a for NSCLC is currently in Phase III, and a new Phase I cohort study has also been initiated for patients with HR+/HER2- breast cancer.

DS-1062a is one of the three major ADC assets in Daiichi Sankyo’s oncology pipeline and one of the most advanced programs within AstraZeneca’s ADC science platform. Among these, the HER2-ADC Enhertu has already received marketing approval, while the HER3-ADC, capable of conjugating eight cytotoxic payloads, is being developed for the treatment of early-stage NSCLC, in combination with osimertinib, and for other cancer types; it is currently in Phase II clinical trials.

In March 2019 and July 2020, respectively, AstraZeneca entered into collaborations with Daiichi Sankyo, valued at $6.9 billion and $6.0 billion, to jointly develop the HER2-ADC Enhertu and the TROP2-ADC DS-1062.