Daiichi Sankyo and AstraZeneca have initiated three global, randomized Phase 3 trials to investigate the efficacy and safety of datopotamab deruxtecan (Dato-DXd)-based combinations in patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC). These trials, TROPION-Lung10, TROPION-Lung14, and TROPION-Lung15, aim to evaluate the potential of Dato-DXd in treating different lines and types of lung cancer.
TROPION-Lung10: Dato-DXd Plus Rilvegostomig vs. Pembrolizumab
TROPION-Lung10 is a three-arm, open-label trial randomizing patients in a 2:1:2 ratio to receive either datopotamab deruxtecan (6.0 mg/kg) plus rilvegostomig (750 mg), rilvegostomig (750 mg) monotherapy, or pembrolizumab (200 mg) monotherapy. The study focuses on adult patients with previously untreated locally advanced or metastatic nonsquamous NSCLC with high PD-L1 expression (tumor cells [TC] ≥ 50%) and without actionable genomic alterations. The dual primary endpoints are progression-free survival (PFS) and overall survival (OS) in patients with TROP2 positive tumors receiving datopotamab deruxtecan in combination with rilvegostomig versus the pembrolizumab arm. The trial will enroll approximately 675 patients across multiple regions.
TROPION-Lung14: Dato-DXd Plus Osimertinib vs. Osimertinib
TROPION-Lung14 is evaluating datopotamab deruxtecan (6.0 mg/kg) in combination with osimertinib (80 mg) versus osimertinib (80 mg) monotherapy in adult patients with previously untreated locally advanced or metastatic nonsquamous NSCLC harboring EGFR mutations (Exon 19 deletion and/or L858R). The randomized phase is preceded by a safety run-in period involving approximately 20 patients. The primary endpoint is PFS as assessed by blinded independent central review (BICR). The trial plans to enroll approximately 580 patients globally.
TROPION-Lung15: Dato-DXd With or Without Osimertinib vs. Chemotherapy
TROPION-Lung15 is randomizing patients in a 1:1:1 ratio to evaluate datopotamab deruxtecan (6.0 mg/kg) as monotherapy, datopotamab deruxtecan in combination with osimertinib (80 mg), or platinum-based doublet chemotherapy (pemetrexed with carboplatin or cisplatin followed by pemetrexed maintenance). This trial includes adult patients with locally advanced or metastatic nonsquamous NSCLC with at least one EGFR mutation (G719X, Ex19del, S768I, L858R, and/or L861Q) whose disease progressed on prior osimertinib treatment. The dual primary PFS endpoints are assessed by BICR for datopotamab deruxtecan monotherapy versus chemotherapy and datopotamab deruxtecan in combination with osimertinib versus chemotherapy. Approximately 630 patients will be enrolled.
Significance of the Trials
These trials are crucial for understanding the potential role of datopotamab deruxtecan in treating NSCLC patients across different lines and types of the disease. According to Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo, the growing TROPION clinical program demonstrates a commitment to understanding the full potential of datopotamab deruxtecan in lung cancer.
Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, noted that combining an antibody drug conjugate with a targeted treatment or bispecific immunotherapy may drive stronger and more durable tumor responses. The initiation of these trials illustrates a commitment to exploring potential synergies within the oncology pipeline and the full potential of this TROP2 directed antibody drug conjugate.
About Advanced NSCLC
NSCLC accounts for approximately 85% of lung cancer cases, with nonsquamous histology representing about 75% of NSCLC tumors. EGFR mutations occur in 14% to 38% of all NSCLC tumors worldwide, predominantly in tumors with nonsquamous histology. While current treatments like immune checkpoint inhibitors, platinum-based chemotherapy, and EGFR TKIs have improved outcomes, most patients eventually experience disease progression, highlighting the need for new therapeutic strategies. TROP2 is broadly expressed in the majority of NSCLC tumors, but there is currently no approved TROP2 directed ADC for lung cancer treatment.
