FDA Grants Accelerated Approval to Dato-DXd for EGFR+ NSCLC

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 received prior EGFR-directed therapy and platinum-based chemotherapy.¹

The regulatory decision was supported by pooled data from the phase 2 TROPION-Lung05 (NCT04484142) and phase 3 TROPION-Lung01 (NCT04656652) trials, which demonstrated that patients treated with Dato-DXd (n = 114) achieved an overall response rate (ORR) of 45% (95% CI, 35%-54%). The median duration of response (DOR) was 6.5 months (95% CI, 4.2-8.4).

Dato-DXd is recommended at a dose of 6 mg/kg, with a maximum of 540 mg for patients weighing at least 90 kg. The antibody-drug conjugate is given once every 3 weeks until disease progression or unacceptable toxicity.

The prescribing information includes warnings and precautions for interstitial lung disease (ILD)/pneumonitis, ocular adverse effects (AEs), stomatitis, and embryo-fetal toxicity.

Dato-DXd Background

In November 2024, when a biologics license application (BLA) for the use of Dato-DXd in its now-approved NSCLC indication was submitted, another BLA was voluntarily withdrawn.² The withdrawn BLA was seeking the approval of the agent for the treatment of patients with advanced or metastatic nonsquamous NSCLC.

In January 2025, Dato-DXd was approved by the FDA for the treatment of adult patients with unresectable or metastatic, hormone receptor–positive, HER2-negative breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.³

TROPION-Lung05 Overview

This phase 2 study enrolled patients with advanced NSCLC harboring at least 1 actionable genomic mutation who had received at least 1 prior line of targeted therapy and 1 to 2 prior lines of therapy containing a cytotoxic agent.⁴ Radiographic disease progression following the most recent therapy was also required.

Among the 137 patients enrolled, 78 harbored EGFR mutations. All patients received Dato-DXd at 6 mg/kg once every 3 weeks.

A Glance at TROPION-Lung01

This phase 3 study included patients with advanced NSCLC harboring at least 1 actionable genomic mutation who had previously received 1 to 2 approved targeted therapies, platinum-based chemotherapy, and no more than 1 anti–PD-(L)1 monoclonal antibody. No prior docetaxel was allowed.

Patients were randomly assigned 1:1 to receive Dato-DXd at 6 mg/kg once every 3 weeks (n = 299) or docetaxel at 75 mg/m² once every 3 weeks (n = 305). Among the patients treated in the Dato-DXd arm, 39 had EGFR mutations.

Additional Pooled Data

In a presentation at the 2024 ESMO Asia Congress, findings from the pooled analysis of TROPION-Lung05 and TROPION-Lung01 showed that patients (n = 117) achieved a confirmed ORR of 42.7% (95% CI, 33.6%-52.2%), with best responses comprising complete response (CR; 4.3%), partial response (38.5%), stable disease (41.0%), progressive disease (PD; 10.3%), non-CR/non-PD (2.6%), and not evaluable (3.4%). The median DOR was 7.0 months (95% CI, 4.2-9.8), and the disease control rate was 86.3% (95% CI, 78.7%-92.0%).

The median progression-free survival and overall survival were 5.8 months (95% CI, 5.4-8.2) and 15.6 months (95% CI, 13.1-19.0), respectively.

Regarding safety, any-grade treatment-related AEs (TRAEs) were reported in 95% of patients in the pooled population, and the rate of grade 3 or higher TRAEs was 23%. TRAEs led to dose reductions in 22% of patients, dose delays in 23% of patients, and treatment discontinuation in 5% of patients. No TRAEs led to death, and serious TRAEs occurred in 8% of patients.

The most common grade 1/2 TRAEs included stomatitis (50%), alopecia (49%), nausea (46%), fatigue (17%), decreased appetite (14%), constipation (15%), vomiting (11%), rash (11%), and pruritus (10%).

AEs of special interest comprised stomatitis/oral mucositis (any-grade, 69%; grade 3, 9%), ocular surface AEs (32%; 3%), and adjudicated, drug-related ILD (4%; 1%).

References

1. FDA grants accelerated approval to datopotamab deruxtecan-dlnk for EGFR-mutated non-small cell lung cancer. FDA. 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. Datopotamab deruxtecan new BLA submitted for accelerated approval in the US for patients with previously treated advanced EGFR-mutated non-small cell lung cancer. News release. AstraZeneca. November 12, 2024. Accessed June 23, 2025. https://www.astrazeneca.com/media-centre/press-releases/2024/dato-dxd-new-bla-submitted-nsq-bla-withdrawn.html
3. FDA approves datopotamab deruxtecan-dlnk for unresectable or metastatic, HR-positive, HER2-negative breast cancer. FDA. January 17, 2025. Accessed June 23, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-datopotamab-deruxtecan-dlnk-unresectable-or-metastatic-hr-positive-her2-negative-breast
4. Ahn M-J, 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