Trastuzumab deruxtecan significantly improved progression-free survival over pembrolizumab plus platinum-based chemotherapy for patients with advanced or metastatic HER2-mutant non–small cell lung cancer (NSCLC) who were being treated in the first-line setting, according to phase III DESTINY-Lung04 trial findings presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC; Abstract PL03.08).
“These results demonstrate substantial improvements in progression-free survival and response with first-line trastuzumab deruxtecan for patients with advanced or metastatic HER2-mutant NSCLC,” said Julia Rotow, MD, of the Dana-Farber Cancer Institute. “The findings support trastuzumab deruxtecan as a new first-line treatment option for this patient population, for whom more effective HER2-directed approaches are needed.”
Study Methods
The global, open-label, randomized, registrational phase III DESTINY-Lung04 trial enrolled patients with treatment-naive unresectable locally advanced or metastatic HER2-mutant NSCLC, including exons 19 or 20 mutations (n = 454). Patients were randomly assigned 1:1 to receive either trastuzumab deruxtecan or pembrolizumab plus platinum chemotherapy of cisplatin or carboplatin and pemetrexed. Patients were stratified by smoking status and the presence or history of brain metastases.
The primary endpoint was progression-free survival by blinded independent central review, and secondary endpoints included overall survival, objective response rate, duration of response, and safety.
Key Findings
Trastuzumab deruxtecan induced a statistically significant improvement in progression-free survival compared with pembrolizumab and chemotherapy, demonstrating a median progression-free survival of 14.3 months (95% confidence interval [CI] = 12.4–16.5) vs 8.3 months (95% CI = 7.0–9.9), respectively (hazard ratio [HR] = 0.63; 95% CI = 0.50–0.79; P < .0001).
The objective response rate was 70% (95% CI = 63.6%–75.9%) in the trastuzumab deruxtecan arm vs 44.5% (95% CI = 37.9%–51.2%) in the chemoimmunotherapy arm (odds ratio [OR] = 2.93; 95% CI = 2.00–4.34). The median duration of response was 13.4 months (95% CI = 10.4–17.2) with trastuzumab deruxtecan compared with 9.7 months (95% CI = 7.0–11.1) with pembrolizumab and chemotherapy.
The median overall survival was 29.3 months (95% CI = 26.2–33.4) with trastuzumab deruxtecan vs 33.1 months (95% CI = 27.7–40.7) with pembrolizumab plus chemotherapy (HR = 1.15; 95% CI = 0.88–1.52).
Subsequent therapies were imbalanced between the treatment arms, but primarily included HER2-directed and immunotherapy-based therapies.
The rates of drug-related adverse events and grade 3 or higher events were similar between the two treatment arms. Drug-related events led to treatment discontinuation in 15.9% of patients in each arm. There were four drug-related fatal events in the trastuzumab deruxtecan arm and one in the pembrolizumab and chemotherapy arm.
Adjudicated drug-related interstitial lung disease/pneumonitis was observed in 20.8% of patients in the trastuzumab deruxtecan arm and in 2.3% of patients in the chemoimmunotherapy arm, and most events were grade 1 or 2. Left ventricular ejection fraction decrease was reported in 3.1% of patients in the antibody-drug conjugate arm vs 0.5% in the chemoimmunotherapy arm.
DISCLOSURES: For full disclosures of the study authors, visit abstractsonline.com.
