Daiichi Sankyo and AstraZeneca have initiated three Phase 3 clinical trials to evaluate the efficacy and safety of datopotamab deruxtecan (Dato-DXd) based combinations in patients with non-small cell lung cancer (NSCLC). These trials, TROPION-Lung10, TROPION-Lung14, and TROPION-Lung15, aim to assess the potential of Dato-DXd in various lines and types of lung cancer, addressing significant unmet needs in this patient population.
TROPION-Lung10: Dato-DXd Plus Rilvegostomig vs. Pembrolizumab in High PD-L1 NSCLC
TROPION-Lung10 is a global, multicenter, open-label, three-arm Phase 3 trial designed to evaluate the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) in combination with rilvegostomig (750 mg) or rilvegostomig (750 mg) monotherapy versus pembrolizumab (200 mg) monotherapy. This trial focuses on adult patients with previously untreated locally advanced or metastatic nonsquamous NSCLC with high PD-L1 expression (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, both assessed by blinded independent central review (BICR). Key secondary endpoints include PFS and OS in the intention-to-treat (ITT) population, objective response rate (ORR), and duration of response (DoR) in both TROP2 biomarker positive and ITT populations. The trial plans to enroll approximately 675 patients across Asia, Europe, North America, Oceania, and South America.
TROPION-Lung14: Dato-DXd Plus Osimertinib vs. Osimertinib in EGFR-Mutated NSCLC
TROPION-Lung14 is a global, randomized, multicenter, open-label Phase 3 trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) in combination with osimertinib (80 mg) versus osimertinib (80 mg) monotherapy. The study targets adult patients with previously untreated locally advanced or metastatic nonsquamous NSCLC harboring an EGFR mutation (Exon 19 deletion and/or L858R). A single-arm safety run-in period involving approximately 20 patients precedes the randomized portion to evaluate the combination therapy's safety.
The primary endpoint of TROPION-Lung14 is PFS as assessed by BICR. Key secondary endpoints include central nervous system (CNS) PFS, ORR, OS, and safety. Approximately 580 patients will be enrolled across multiple regions.
TROPION-Lung15: Dato-DXd Monotherapy or Plus Osimertinib vs. Chemotherapy After Osimertinib Progression
TROPION-Lung15 is a global, multicenter, open-label, three-arm Phase 3 trial where patients will be randomized in a 1:1:1 ratio to evaluate the efficacy and safety of datopotamab deruxtecan (6.0 mg/kg) as monotherapy or in combination with osimertinib (80 mg) versus platinum-based doublet chemotherapy (pemetrexed in combination with carboplatin or cisplatin followed by pemetrexed maintenance). This trial is for adult patients with locally advanced or metastatic nonsquamous NSCLC with at least one EGFR mutation (G719X, Ex19del, S768I, L858R, and/or L861Q) and with disease progression following prior treatment with osimertinib.
The dual primary PFS endpoints are assessed by BICR for datopotamab deruxtecan monotherapy versus chemotherapy and datopotamab deruxtecan in combination with osimertinib versus chemotherapy. Key secondary endpoints include investigator-assessed CNS PFS, ORR, DoR, OS, and safety. The trial aims to enroll approximately 630 patients globally.
Addressing Unmet Needs in NSCLC
NSCLC accounts for approximately 85% of all lung cancer cases, with a significant proportion exhibiting nonsquamous histology and EGFR mutations. While first-line treatments like immune checkpoint inhibitors and EGFR TKIs have improved outcomes, most patients eventually experience disease progression. Datopotamab deruxtecan, a TROP2-directed antibody-drug conjugate (ADC), represents a novel approach to target NSCLC, as TROP2 is broadly expressed in the majority of NSCLC tumors.
Cristian Massacesi, MD, Chief Medical Officer and Oncology Chief Development Officer at AstraZeneca, stated, "The initiation of these additional three phase 3 trials of datopotamab deruxtecan in combination with our agents, osimertinib and rilvegostomig illustrates our commitment to exploring potential synergies within our oncology pipeline as well as the full potential and combinability of this TROP2 directed antibody drug conjugate across multiple segments and settings of non-small cell lung cancer."
These trials are part of a comprehensive global clinical development program evaluating datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer, and HR-positive, HER2-negative breast cancer. The program includes seven Phase 3 trials in lung cancer and five Phase 3 trials in breast cancer, assessing Dato-DXd as a monotherapy and in combination with other anticancer treatments.
