FDA Grants Priority Review to Dato-DXd in Advanced EGFR-Mutated NSCLC

• The FDA has accepted and granted priority review to the biologics license application (BLA) for datopotamab deruxtecan (Dato-DXd).
• This investigational treatment is intended for adults with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) who have previously received systemic therapies, including EGFR-targeted treatments.
• The FDA’s decision is expected by July 12, 2025, under the Prescription Drug User Fee Act.

The FDA has accepted and granted priority review to the BLA for Dato-DXd for adult patients with locally advanced or metastatic EGFR-mutated NSCLC who have previously received systemic therapies, including EGFR-targeted treatments.¹

Findings from the phase 2 TROPION-Lung05 trial (NCT04484142), the phase 3 TROPION-Lung01 (NCT04656652) trial, and phase 1 TROPION-PanTumor01 (NCT03401385) trial support this BLA.

A pooled analysis of patients with previously treated advanced or metastatic EGFR-mutated NSCLC from TROPION-Lung01 and TROPION-Lung05 (n = 117) showed a confirmed objective response rate (ORR) of 42.7% (95% CI, 33.6%-52.2%), including a complete response rate of 4.3%. The median duration of response was 7.0 months (95% CI, 4.2-9.8), with a disease control rate of 86.3% (95% CI, 78.7%-92.0%), a median progression-free survival (PFS) rate of 5.8 months (95% CI, 5.4-8.2), and a median overall survival (OS) rate of 15.6 months (95% CI, 13.1-19.0).²

“Treating [patients with] advanced EGFR-mutated NSCLC presents a significant challenge due to the limited efficacy of available treatments once the disease has progressed following frontline therapies, including the use of an EGFR [tyrosine kinase inhibitor],” said Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, in a press release.¹ “If approved, Dato-DXd could become the first TROP2-directed antibody-drug conjugate [ADC] for lung cancer, providing a promising option for patients.”

With this, the decision from the FDA is expected by July 12, 2025, under the Prescription Drug User Fee Act.¹

Dato-DXd is a TROP2-targeted ADC that combines a humanized monoclonal antibody with topoisomerase I inhibitor payloads using cleavable linkers. In November 2024, a new BLA was submitted to the FDA, seeking accelerated approval for Dato-DXd as a treatment for adults with metastatic or locally advanced NSCLC with EGFR mutations, who have previously undergone treatment. Then in December 2024, the agent was granted breakthrough therapy designation by the FDA for patients with advanced EGFR-mutated NSCLC who experienced progression on or after an EGFR TKI and platinum-based chemotherapy.³

Key findings from TROPION-Lung05 were observed in patients with actionable genomic alterations, including EGFR, ALK, ROS1, MET exon 14 skipping, or RET, who had progressed after targeted and cytotoxic therapies.² These patients received Dato-DXd at 6 mg/kg every three weeks. Similarly, TROPION-Lung01 compared Dato-DXd to docetaxel in patients with prior targeted therapies and platinum-based chemotherapy.

The pooled analysis of these trials showed a consistent safety profile, with no grade 4/5 treatment-related adverse effects (TRAEs) and manageable adverse events such as stomatitis/oral mucositis (69%), ocular surface events (32%), and low-grade interstitial lung disease (4%).

Dato-DXd is also under investigation in seven phase 3 trials for NSCLC, including combinations with osimertinib (Tagrisso). For example, the phase 3 TROPION-Lung14 trial is studying Dato-DXd with or without osimertinib in untreated patients with advanced EGFR-mutated NSCLC.

“Acquired resistance to frontline therapies and, ultimately, disease progression are unfortunate realities for most patients with advanced EGFR-mutated NSCLC,” added Susan Galbraith, MBBChir, PhD, executive vice president, oncology research and development, AstraZeneca, in the press release.¹ “This priority review, and the previously granted breakthrough therapy designation, recognize the potential for Dato-DXd to provide a much-needed option to patients whose disease has become resistant to current treatments.”

REFERENCES

1. Datopotamab deruxtecan granted priority review in the U.S. for patients with previously treated advanced EGFR-mutated non–small cell lung cancer. News release. Daiichi-Sankyo. January 13, 2025. Accessed January 14, 2025. https://tinyurl.com/246b2ntz

2. 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