AstraZeneca/Daiichi Sankyo's TROP2 ADC Dato-DXd Launches Phase III Trial in First-Line NSCLC in China

On April 22, Daiichi Sankyo initiated the first open-label, randomized Phase III clinical trial in China for its TROP2 ADC drug Dato-DXd (Dato-DXd), in combination with pembrolizumab versus pembrolizumab monotherapy as a first-line treatment for untreated advanced or metastatic PD-L1 high expression (TPS≥50%) NSCLC patients without driver gene alterations. This is the Chinese segment of the global multicenter Phase III clinical trial, Tropion-Lung08.

Clinical Trial Details (CTR20220788)

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

Dato-DXd (development code: DS-1062) has previously achieved positive results in the Phase 1b clinical trial TROPION-Lung02. This clinical trial originated from the first collaboration between Daiichi Sankyo and Merck in May 2020. On October 25 last year, Daiichi Sankyo and AstraZeneca jointly announced a second clinical trial collaboration with Merck to initiate a Phase 3 clinical trial evaluating the Trop-2-targeted ADC drug Dato-DXd (DS-1062) in combination with Keytruda as a first-line treatment for PD-L1-positive advanced/metastatic NSCLC without targetable genetic mutations, known as the Tropion-Lung08 study. The global first registration time for this clinical trial was January 2022.(*Targetable genomic mutations include: EGFR, ALK, ROS1, NTRK, BRAF, RET, MET, or other known actionable mutations)

Under the terms of the agreement, Daiichi Sankyo will lead the TROPION-Lung08 study. The trial plans to enroll approximately 740 patients, with primary endpoints being progression-free survival (PFS) and overall survival (OS) as assessed by BICR.

Daiichi Sankyo pointed out that although immunotherapy has become the first-line standard treatment for lung cancer without targetable genetic mutations, at least 40% to 60% of patients do not respond to immunotherapy and experience disease progression. Therefore, new therapies are still urgently needed in clinical practice. TROP-2 is expressed in almost all subtypes of lung cancer; however, there are currently no TROP-2 targeted therapies approved for treating NSCLC. Thus, exploring the combination of TROP-2 targeted therapy with PD-1 could potentially improve outcomes for lung cancer patients.

Dato-DXd is designed using Daiichi Sankyo's proprietary DXdADC technology and is one of the three main ADC products in Daiichi Sankyo's oncology pipeline. The drug consists of a humanized anti-TROP2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload, an exatecan derivative, via a cleavable tetrapeptide-based linker.

AstraZeneca entered into a significant collaboration with Daiichi Sankyo in July 2020, acquiring co-development and commercialization rights for Dato-DXd in all global regions except Japan for an upfront payment of $1 billion, $1 billion in development milestones, and $4 billion in sales milestones.

Currently, Daiichi Sankyo and AstraZeneca are globally conducting the TROPION series of clinical trials to evaluate the efficacy and safety of Dato-DXd in various solid tumors, including NSCLC, triple-negative breast cancer (TNBC), HR-positive/HER2-negative breast cancer, small cell lung cancer, urothelial cancer, gastric cancer, and esophageal cancer. Clinical trials in combination with other anticancer therapies (including immunotherapy) are also underway.

At the 2021 ESMO, Daiichi Sankyo presented data from the NSCLC cohort of the Phase 1 first-in-human trial TROPION-PanTumor01 study of DS-1062. Among 34 evaluable patients with specific genomic alterations (including EGFR mutations: 85%; ALK fusions: 9%; ROS1 fusions: 3%; and RET fusions: 3%), 12 PRs (35%) and 14 SDs (41%) were observed. At a median follow-up of 13.4 months (7-28 months), the median duration of response (DOR) was 9.5 months (95% CI: 3.3-NE).

Source: Daiichi Sankyo, 2021 ESMO