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

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(BLA) for the use of Dato-DXd in its now-approved NSCLC indication was submitted, another BLA was voluntarily withdrawn.2 The withdrawn BLA was seeking the approval of the agent for the treatment of patients with advanced or metastatic nonsquamous NSCLC.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