Phase 3 Trials Begin for Datopotamab Deruxtecan Combinations in Advanced Nonsquamous NSCLC

On October 30, 2024, significant progress was made in the global fight against lung cancer with the dosing of the first patients in three pivotal phase 3 trials. These trials aim to evaluate the efficacy and safety of datopotamab deruxtecan (Dato-DXd) combined with other treatments in patients suffering from locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). Datopotamab deruxtecan is a TROP2 directed antibody-drug conjugate (ADC) developed by Daiichi Sankyo and AstraZeneca.

The first of these trials, TROPION-Lung10, assesses the combination of datopotamab deruxtecan with rilvegostomig, AstraZeneca’s PD-1/TIGIT bispecific antibody, or rilvegostomig alone, against pembrolizumab in patients with previously untreated NSCLC exhibiting high PD-L1 expression and no actionable genomic alterations. The primary endpoints include progression-free survival (PFS) and overall survival (OS) in TROP2 positive tumors, while secondary endpoints focus on objective response rate (ORR) and duration of response (DoR). This trial will include approximately 675 patients across multiple continents.

TROPION-Lung14 focuses on patients with previously untreated NSCLC harboring EGFR mutations. It compares the effectiveness of datopotamab deruxtecan combined with osimertinib, AstraZeneca’s EGFR tyrosine kinase inhibitor, against osimertinib alone. The primary endpoint is PFS, with secondary endpoints examining central nervous system (CNS) PFS, ORR, OS, and safety. Around 580 patients will participate in this global trial.

The third trial, TROPION-Lung15, involves patients with NSCLC who have EGFR mutations and whose disease has progressed following prior osimertinib treatment. This study tests datopotamab deruxtecan alone or in combination with osimertinib against platinum-based chemotherapy. The dual primary endpoints are PFS for both monotherapy and combination therapy versus chemotherapy. Secondary endpoints include CNS PFS, ORR, DoR, OS, and safety. This trial will enroll approximately 630 patients worldwide.

Dr. Mark Rutstein, Global Head of Oncology Clinical Development at Daiichi Sankyo, highlighted the importance of these trials in understanding the potential role of datopotamab deruxtecan in treating different types and stages of lung cancer. He underscored the commitment to exploring the full potential of this novel ADC through a comprehensive clinical program, which now includes seven phase 3 trials.

Dr. Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer at AstraZeneca, emphasized the promising potential of combining an ADC with targeted treatments or bispecific immunotherapies. He noted that these innovative combinations could lead to more robust and lasting tumor responses in lung cancer patients. The initiation of these trials demonstrates AstraZeneca's dedication to exploring synergies within their oncology pipeline and the broad applicability of datopotamab deruxtecan across various NSCLC settings.

Datopotamab deruxtecan is a key element in the ADC portfolios of both Daiichi Sankyo and AstraZeneca, representing a significant advancement in targeting TROP2, a protein expressed in a majority of NSCLC tumors. The clinical development program for datopotamab deruxtecan includes over 20 trials across multiple cancer types, with a strong focus on lung and breast cancer.

This collaboration between Daiichi Sankyo and AstraZeneca began in 2019, aimed at jointly developing and commercializing ADCs like ENHERTU and datopotamab deruxtecan. The partnership leverages Daiichi Sankyo's proprietary DXd ADC technology, which combines a monoclonal antibody with cytotoxic payloads via cleavable linkers, enhancing the delivery of cancer treatments to targeted cells.

The ongoing trials represent a crucial step in addressing the unmet needs of lung cancer patients, particularly those with specific genetic profiles or who have experienced disease progression. The outcomes of these studies could pave the way for new treatment standards, offering hope for improved patient outcomes and survival rates in this challenging cancer type.