Dato-DXd Greenlit by FDA for Previously Treated EGFR-Mutated NSCLC

The safety and efficacy of Dato-DXd was evaluated in the TROPION-Lung01 and TROPION-Lung05 trials.

The FDA has granted acceleratedapproval to the antibody-drug conjugate datopotamab deruxtecan-dlnk (Datroway; Dato-DXd) for the treatment of adults with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) following previous EGFR-targeted therapy and platinum-based chemotherapy.¹

The approval is based on findings from the multicenter single-arm phase 2 TROPION-Lung05 trial (NCT04484142) and the multicenter, open-label, randomized controlled phase 3 TROPION-Lung01 trial (NCT04656652).

According to the FDA’s announcement, primary end points of objective response rate (ORR) and median duration of response (DOR), as assessed by blinded independent central review via RECIST v1.1, were found to be 45% (95% CI, 35%-54%) and 6.5 months (95% CI, 4.2-8.4), respectively.

The label for Dato-DXd, previously referred to as DS-1062a, includes warnings for interstitial lung disease (ILD) and pneumonitis, ocular adverse effects (AEs), stomatitis and oral mucositis, and embryo-fetal toxicity.

Additionally, it cites stomatitis, nausea, fatigue, leukocytopenia, hypocalcemia, alopecia, lymphocytopenia, decreased hemoglobin, constipation, neutropenia, dry eye, emesis, increased ALT, keratitis, increased AST, and increased ALP, as the most common AEs, including abnormal laboratory reports, associated with Dato-DXd.

Prior Data on TROPION-Lung01

Previous findings from the TROPION-Lung01 trial, which evaluated the efficacy and safety of Dato-DXd in patients with pretreated advanced or metastatic NSCLC, were reported in the Journal of Clinical Oncology.² Patients enrolled in TROPION-Lung01 were randomly assigned 1:1 to treatment with 6 mg/kg of Dato-DXd (n = 299) or 75 mg/m² of docetaxel (n = 305) administered intravenously once every 3 weeks until progression, unacceptable toxicity, or other reasons if applicable.

The primary analysis revealed a median progression-free survival (PFS) of 4.4 months (95% CI, 4.2-5.6) and 3.7 months (95% CI, 2.9-4.2) in the Dato-DXd and docetaxel arms, respectively. Likewise, the median DOR for all patients enrolled in the Dato-DXd arm was 7.1 months (range, 5.6-10.9), compared with 5.6 months (range, 5.4-8.1) in the docetaxel arm.

The median ages of patients in the Dato-DXd and docetaxel arms were 63 years (range, 26.0-84.0) and 64 years (range, 24.0-88.0), respectively. Stratification factors included histology, actionable genomic alteration status, geographic region, and immediate previous therapy with an anti-PD-1/PD-L1.

Treatment-related AEs of grade 3 or higher were reported in 25.6% of patients in the Dato-DXd arm and 42.1% of patients in the docetaxel arm. Any-grade adjudicated drug-related ILD or pneumonitis occurred in 8.8% and 4.1% of patients, respectively.

Findings from TROPION-Lung05

Dato-DXd’s efficacy and safety in treating advanced or metastatic NSCLC on or after targeted therapy and platinum-based chemotherapy was also evaluated in TROPION-Lung05.³ Out of 137 patients receiving 1 or more doses of Dato-DXd, 71.5% of patients received 3 or more lines of prior therapy, and 56.9% had EGFR-mutated cancer.

Median DOR was 7.0 months (95% CI, 4.2-9.8), with an overall disease control rate of 78.8% (95% CI, 71.0%-85.3%). Of patients with EGFR mutations, the ORR was 44%, compared with 35.8% in the overall population enrolled.

Grade 3 or higher TEAEs were reported in 28.5% of patients. The most common TRAEs was stomatitis, occurring at any grade in 56.2% of patients and at grade 3 or higher in 9.5% of patients. Additionally, 5 patients (3.6%) had adjudicated treatment-related ILD or pneumonitis, with 1 (0.7%) having a grade 5 event. Altogether, no new safety signals were found.

Reference

1. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. News release. June 23, 2025. Accessed June 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-datopotamab-deruxtecan-dlnk-egfr-mutated-non-small-cell-lung-cancer
2. Ahn MJ, Tanaka K, Paz-Ares L, et al. Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non-Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study. J Clin Oncol. 2025;43(3):260-272. doi:10.1200/JCO-24-01544
3. Sands J, Ahn MJ, Lisberg A, et al. Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. J Clin Oncol. 2025;43(10):1254-1265. doi:10.1200/JCO-24-01349