Ep. 1: Efficacy, Safety, and Management of Dato-DXd in EGFR-Mutated Lung Cancer
Key Points
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Datopotamab deruxtecan (Dato-DXd) demonstrated an overall response rate (ORR) of 45% with a median duration of response (DOR) of 6 to 7 months in heavily pretreated EGFR-mutated non–small cell lung cancer (NSCLC).
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The approval applies across common and uncommon EGFR mutations, including exon 20 alterations, after progression on tyrosine kinase inhibitors (TKIs) and chemotherapy.
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Proactive, multidisciplinary toxicity management is essential to optimize patient outcomes.
In this Clinical Insights discussion, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, were joined by a multidisciplinary panel featuring Blanca A. Ledezma, NP, of UCLA Health; Aaron Lisberg, MD, of UCLA Health; and Sarah B. Sunshine, MD, of the University of Maryland School of Medicine, to review the recent approval of Dato-DXd in EGFR-mutated NSCLC.
Clinical Trial Data Supporting Dato-DXd Approval
Dr. Lisberg reviewed the two pivotal studies that led to the FDA approval of Dato-DXd in this setting: TROPION-Lung05 and TROPION-Lung01. Dato-DXd is a TROP2-directed antibody–drug conjugate (ADC) delivering a topoisomerase I inhibitor payload, similar to trastuzumab deruxtecan but with a different molecular target.
TROPION-Lung05 was a single-arm phase 2 trial enrolling patients with advanced or metastatic NSCLC harboring actionable genomic alterations, most commonly EGFR mutations. Among the 78 patients with EGFR-mutant disease, all progressed after EGFR TKIs—typically osimertinib—and prior chemotherapy. TROPION-Lung01, a phase 3 trial, evaluated Dato-DXd across a broader NSCLC population, including both squamous and nonsquamous histologies, with and without actionable mutations.
The approval was based on a pooled analysis of 117 patients with EGFR-mutated NSCLC from both trials. Across these studies, Dato-DXd demonstrated an ORR of approximately 45% and a median DOR of 6 to 7 months. Importantly, benefit was observed across common sensitizing EGFR mutations as well as uncommon variants, including exon 20 alterations.
Toxicity Profile and Proactive Management Strategies
Ms. Ledezma emphasized that patient education and proactive toxicity management are essential to optimizing outcomes with Dato-DXd. Key adverse events include interstitial lung disease or pneumonitis, stomatitis and mucositis, dermatologic reactions, and ocular toxicities.
Baseline assessment is critical, particularly for respiratory symptoms, as many patients with advanced NSCLC already have underlying pulmonary compromise. Early recognition of worsening symptoms is necessary to distinguish disease progression or infection from treatment-related pneumonitis, prompting timely imaging, treatment interruption, and corticosteroid initiation when indicated.
Preventive strategies were highlighted as central to care delivery. These include routinely using prophylactic eye drops multiple times daily, avoiding use of contact lenses, practicing meticulous oral hygiene, and starting steroid mouth rinses early to reduce mucositis severity. The panel stressed the importance of practical adherence strategies, such as social cues and caregiver involvement, rather than rigid schedules that may be unrealistic for patients coping with advanced cancer.
Dr. Sunshine’s involvement as an ophthalmologist underscored the importance of multidisciplinary collaboration, particularly for managing ocular toxicities, which are increasingly recognized with TROP2-directed ADCs.