Dato-DXd Receives FDA Priority Review in Pretreated EGFR-Mutated NSCLC

FDA

The FDA has accepted and granted priority review to the biologics license application (BLA) for datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) who have received prior systemic therapies, including an EGFR-directed therapy.¹ The Prescription Drug User Fee Act action date for the BLA is July 12, 2025.

The BLA submission is supported by findings from the phase 2 TROPION-Lung05 trial (NCT04484142), as well as the phase 3 TROPION-Lung01 (NCT04656652) and phase 1 TROPION-PanTumor01 (NCT03401385) studies. Data from a pooled analysis of patients with previously treated advanced or metastatic EGFR-mutated NSCLC in TROPION-Lung01 and TROPION-Lung05 demonstrated that the confirmed objective response rate (ORR) among patients with EGFR-mutated NSCLC (n = 117) was 42.7% (95% CI, 33.6%-52.2%), including a complete response (CR) rate of 4.3%.² The median duration of response (DOR) was 7.0 months (95% CI, 4.2-9.8) and the disease control rate (DCR) was 86.3% (95% CI, 78.7%-92.0%). The median progression-free survival (PFS) and overall survival (OS) values were 5.8 months (95% CI, 5.4-8.2) and 15.6 months (95% CI, 13.1-19.0), respectively.

“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 TKI,” Ken Takeshita, MD, global head, R&D, Daiichi Sankyo, stated in a news 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.”

Dato-DXd is an investigational TROP2-targeted ADC comprised of a humanized anti-TROP2 IgG1 monoclonal attached to multiple topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers. In December 2024, the FDA granted breakthrough therapy designation to Dato-DXd for the treatment of adult patients with locally advanced or metastatic EGFR-mutated NSCLC who experienced disease progression on or after treatment with an EGFR TKI and platinum-based chemotherapy.³

TROPION-Lung05 enrolled patients with at least 1 actionable genomic alteration, such as EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, or RET, who received at least 1 line of targeted therapy, 1 to 2 prior cytotoxic agent–containing therapies, including platinum-based chemotherapy, in the metastatic setting, and radiographic disease progression following their most recent line of treatment.² Patients received Dato-DXd at a dose of 6 mg/kg every 3 weeks (n = 137).

TROPION-Lung01 enrolled patients with actionable genomic alterations who received 1 to 2 prior approved targeted therapies in combination with platinum-based chemotherapy and a maximum of 1 anti–PD-L(1) monoclonal antibody. Patients were randomly assigned 1:1 to receive Dato-DXd at a dose of 6 mg/kg every 3 weeks (n = 299) or docetaxel at a dose of 75 mg/m² every 3 weeks (n = 305).

The end points of the pooled analysis included ORR, best overall response, DOR, DCR, DOR, and PFS all by blinded independent central review, as well as OS and safety. Seventy-eight patients from TROPION-Lung05 were included in the analysis as well as 39 patients from TROPION-Lung01. The median treatment duration with Dato-DXd was 6.1 months.

Safety data from the pooled analysis revealed that the overall safety profile of Dato-DXd was consistent with prior findings from TROPION-Lung05 and TROPION-Lung01, with no treatment-related adverse effects (TRAEs) associated with death and no grade 4 or 5 interstitial lung disease (ILD) deemed to be related to Dato-DXd. Any-grade TRAEs (95%), grade 3 or higher TRAEs (23%), and serious TRAEs (8%) were reported. TRAEs associated with dose delay, reduction, and treatment discontinuation occurred at rates of 23%, 22%, and 5%, respectively.

Any-grade adverse effects (AEs) of special interest consisted of stomatitis/oral mucositis (69%), ocular surface events (32%), and adjudicated drug-related ILD (4%). These AEs occurred at a grade 3 severity at rates of 9%, 3%, and 1%, respectively.

Dato-DXd is also being examined as monotherapy and a combination component for the treatment of patients with NSCLC across 7 phase 3 trials.¹ In the phase 3 TROPION-Lung14 trial (NCT06350097), osimertinib (Tagrisso) is being examined with or without Dato-DXd for the frontline treatment of patients with locally advanced or metastatic EGFR-mutated NSCLC. Additionally, the phase 3 TROPION-Lung15 study (NCT06417814) is evaluating Dato-DXd with or without osimertinib vs platinum-based chemotherapy in patients with locally advanced or metastatic EGFR-mutated NSCLC following progression on osimertinib.

“Acquired resistance to frontline therapies and, ultimately, disease progression are unfortunate realities for most patients with advanced EGFR-mutated NSCLC,” Susan Galbraith, MBBChir, PhD, executive vice president, Oncology R&D, AstraZeneca, added in the news release. “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 13, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202501/20250113_E1.pdf
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 13, 2025. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202412/20241209_E.pdf