AstraZeneca/Daiichi Sankyo Initiates Phase III TROPION-Breast01 Trial of TROP2 ADC Dato-DXd in China

On January 24, AstraZeneca/Daiichi Sankyo registered and initiated the first clinical trial in China for their TROP-2 ADC product Dato-DXd. This is the Chinese segment of the global Phase 3 clinical trial TROPION-Breast01, which plans to recruit 700 participants globally, including 106 in China. The initial registration on ClinicalTrials.gov was in October 2021.

Source: Insight Database (http://db.dxy.cn/v5/home/)

Dato-DXd has made the most progress in NSCLC, with multiple clinical trials already initiated, advancing as far as Phase 3. In terms of therapy types, it explores both later-line treatment for recurrent/refractory disease and the efficacy of combination therapy with immunotherapy for first-line treatment of metastatic NSCLC. At the end of October 2021, based on Phase 1b clinical data of the combination therapy with Keytruda, Daiichi Sankyo and Merck once again reached a Phase 3 collaboration. Currently, the Phase 3 clinical trial TROPION-Lung08 study of this combination therapy has been initiated.

According to the R&D daily report's key product development plan, the next major cancer type Dato-DXd will focus on exploring is breast cancer, followed by expansion to other solid tumors based on NSCLC and breast cancer.

Currently, only the Phase I FIH clinical TROPION-PanTumor01 data (NCT03401385) for Dato-DXd has been released. This clinical trial explored the safety and preliminary efficacy of the drug in cohorts with NSCLC, triple-negative breast cancer (TNBC), HR+/HER2- breast cancer, and other cancer types, with results disclosed at the 2021 ESMO Congress and the SABCS conference.

In the TNBC cohort, a total of 44 patients were enrolled, with 70% from the United States and 30% from Japan. The median number of treatment lines was 3 (1-10), and 30 patients (68%) had previously received ≥2 lines of therapy, including 19 who had undergone immunotherapy and 13 who had been treated with TopoI inhibitor-based ADC therapy.

As of July 30, 2021, the ORR assessed by BICR was 34% (15/44), and the DCR was 77% (34/44). When the scope was narrowed down to the patient group that had not previously received ADC therapy based on TopoI inhibitors (n=27), the ORR reached 52% (14/27), and the DCR reached 81% (22/27).

In terms of the duration of efficacy, the median DoR was not reached (range: 2.7-7.4+ months), and at the data cutoff, the majority of patients' therapeutic responses were still ongoing.

In terms of safety, the incidence of treatment-related TEAEs across all grades was 90% (43/44), with a ≥Grade 3 event rate of 23% (10/44).

The Phase 3 clinical trial launched in China this time is the TROPION-Breast01 study, which plans to recruit 700 participants globally to explore the efficacy of Dato-DXd compared with physician-selected therapies in second- and third-line HR+/HER2- metastatic breast cancer (mBC). The dual primary endpoints of the trial are PFS and OS assessed by BICR, while the secondary endpoints include PFS, ORR, DoR, TTR, DCR, etc., evaluated by investigators.

In the field of breast cancer, the TROPION-Breast01 study is the only Phase 3 clinical trial currently being conducted for Dato-DXd. Meanwhile, in the TNBC field, apart from the Phase 1 study, there is an ongoing Phase 1b/2 clinical trial exploring a combination therapy with AstraZeneca's PD-L1 monoclonal antibody durvalumab. Daiichi Sankyo will subsequently consider initiating a Phase 3 clinical trial targeting TNBC.

Through two key products, Enhertu and Dato-DXd, Daiichi-Sankyo aims to provide comprehensive treatment coverage for all genetic subtypes and lines of therapy in breast cancer.

Of course, speaking solely about Dato-DXd, its main advantage or leading area currently lies in NSCLC. Similar to Enhertu, Dato-DXd is not the first-in-class product for the TROP2 target, but compared to Gilead's already marketed Trodelvy (sacituzumab govitecan), Dato-DXd has made more progress and explored deeper in NSCLC, with each product having distinct differentiation features. Also similar to Enhertu, Dato-DXd potentially holds advantages in DAR optimization and payload selection.

The above information is from Daiichi Sankyo's 2021 R&D Day materials (released on December 15, 2021).