FDA Grants Accelerated Approval to Dato-DXd in Previously Treated EGFR+ NSCLC

US FDA

• The FDA has granted accelerated approval to datopotamab deruxtecan-dlnk (Datroway; Dato-DXd) for adult patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) who have previously received systemic therapies, including EGFR-targeted treatments.
• Findings from the phase 2 TROPION-Lung05 trial (NCT04484142) and the phase 3 TROPION-Lung01 (NCT04656652) trial support this approval.
• The recommended dose has been set at 6 mg/kg intravenously (IV) every 3 weeks, not to exceed 540 mg in patients weighing ≥90 kg, until disease progression or unacceptable toxicity.

The FDA has granted accelerated approval to Dato-DXd for the treatment of adults with locally advanced or metastatic NSCLC harboring EGFR mutations who have progressed on prior EGFR-targeted therapy and platinum-based chemotherapy. The approval marks a significant step forward for this patient population with limited postprogression options.¹

The approval is based on a pooled efficacy analysis from 2 clinical trials: TROPION-Lung05, a multicenter, single-arm phase 2 trial; and TROPION-Lung01, a global, open-label phase 3 study. Among 114 patients meeting the labeled criteria, the confirmed overall response rate (ORR) was 45% (95% CI, 35%-54%), with a median duration of response of 6.5 months (95% CI, 4.2-8.4), as assessed by blinded independent central review using RECIST v1.1.^1,2

Dato-DXd is a TROP2-directed antibody-drug conjugate (ADC) comprised of a humanized monoclonal antibody linked to a topoisomerase I inhibitor via a cleavable linker. It represents a novel, chemotherapy-free approach targeting TROP2-expressing NSCLC tumors following resistance to first-line therapies.

In previously reported findings from a larger pooled dataset (n = 117), the agent achieved an ORR of 42.7%, including 4.3% complete responses, with a disease control rate of 86.3% and a median progression-free survival (PFS) of 5.8 months. Median overall survival was 15.6 months, supporting the clinical benefit of Dato-DXd beyond traditional chemotherapeutics.²

The recommended dose is 6 mg/kg IV every 3 weeks, not to exceed 540 mg in patients weighing ≥90 kg, until disease progression or unacceptable toxicity.¹

The safety profile was consistent with prior ADC experience. While no grade 4/5 treatment-related adverse events were reported in the pivotal trials, stomatitis/oral mucositis (69%), ocular surface events (32%), and low-grade interstitial lung disease (ILD; 4%) were notable. The prescribing information includes boxed warnings and precautions for ILD/pneumonitis, ocular toxicity, stomatitis, and embryo-fetal harm.

This accelerated approval follows the agent’s breakthrough therapy designation, granted in December 2024,³ and is contingent upon confirmation of benefit in ongoing phase 3 studies. Dato-DXd is currently under investigation across multiple settings, including the TROPION-Lung14 trial (NCT06350097), which is evaluating the combination of Dato-DXd with osimertinib (Tagrisso) in first-line EGFR-mutated NSCLC.

This approval comes ahead of the expected FDA decision date under the Prescription Drug User Fee Act (PDUFA), which had been set for July 12, 2025.¹

REFERENCES:

1. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. News release. US FDA. June 23, 2025. Accessed June 23, 2025. https://tinyurl.com/mu5spftb

2.Ahn MJ, Sands J, Lisberg AE, et al. Efficacy and safety of datopotamab deruxtecan (Dato-DXd) in patients (pts) with previously-treated EGFR-mutated advanced non-small cell lung cancer (NSCLC): a pooled analysis of TROPION-Lung01 and TROPION-Lung05. Ann Oncol. 2024;35(suppl 4):S1630-S1631. doi:10.1016/j.annonc.2024.10.656

3. Datopotamab deruxtecan granted breakthrough therapy designation in U.S. for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. Daiichi-Sankyo. December 9, 2024. Accessed January 14, 2025. https://tinyurl.com/ym9e77m6