Phase 3 DESTINY-Lung04 Trial Shows First-Line Trastuzumab Deruxtecan Significantly Improves Progression-Free Survival in HER2-Mutant NSCLC

First global Phase 3 trial of first-line T-DXd in HER2-mutant NSCLC reports median PFS of 14.3 months versus 8.3 months with pembrolizumab plus chemotherapy

SEOUL, South Korea, Sept. 14, 2026 /PRNewswire/ -- First-line treatment with trastuzumab deruxtecan (T-DXd) significantly improved progression-free survival compared with pembrolizumab plus platinum-based chemotherapy in patients with advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC), according to primary results from the Phase 3 DESTINY-Lung04 trial presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC).

DESTINY-Lung04 is the first global Phase 3 trial to demonstrate a statistically significant and clinically meaningful improvement in progression-free survival with first-line single-agent T-DXd compared with standard-of-care pembrolizumab plus platinum doublet chemotherapy in this patient population. Median progression-free survival by blinded independent central review was 14.3 months with T-DXd versus 8.3 months with pembrolizumab plus chemotherapy, representing a six-month improvement (HR 0.63; 95% CI, 0.50-0.79; P<0.0001).

HER2-mutant NSCLC is an aggressive form of lung cancer associated with poor prognosis. According to the study investigators, many patients do not respond to first-line standard-of-care immunotherapy plus chemotherapy, underscoring the need for effective HER2-directed treatment options.

The global, open-label, randomized Phase 3 DESTINY-Lung04 trial enrolled treatment-naive patients with unresectable locally advanced or metastatic NSCLC harboring HER2 exon 19 or exon 20 mutations. A total of 454 patients were randomized 1:1 to receive T-DXd 5.4 mg/kg intravenously every three weeks or pembrolizumab plus platinum chemotherapy and pemetrexed. The primary endpoint was progression-free survival by blinded independent central review, with secondary endpoints including overall survival, objective response rate, progression-free survival 2, duration of response and safety.

T-DXd also produced a higher objective response rate than pembrolizumab plus chemotherapy. The objective response rate was 70.0% with T-DXd compared with 44.5% with pembrolizumab plus chemotherapy. Median duration of response was 13.4 months and 9.7 months, respectively.

"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, Boston, Mass. "The findings support T-DXd as a new first-line treatment option for this patient population, for whom more effective HER2-directed approaches are needed."

Median overall survival was 29.3 months with T-DXd and 33.1 months with pembrolizumab plus chemotherapy (HR 1.15; 95% CI, 0.88-1.52). Investigators noted that subsequent therapies were imbalanced between the treatment groups, primarily involving HER2-directed and immunotherapy-based treatments, which confounded interpretation of the overall survival results.

The safety profile of T-DXd was generally consistent with its known profile. Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 20.8% of patients treated with T-DXd, with most events classified as Grade 1 or 2 (78.7%), compared with 2.3% of patients receiving pembrolizumab plus chemotherapy. The study's safety analysis also reported Grade 3 or higher drug-related adverse events in 34.1% of patients receiving T-DXd and 33.6% receiving pembrolizumab plus chemotherapy.

The investigators concluded that T-DXd improved progression-free survival, response rates and durability of response compared with pembrolizumab plus chemotherapy, supporting T-DXd as a new first-line option for patients with advanced or metastatic HER2-mutant NSCLC.

About the IASLC:

The International Association for the Study of Lung Cancer (IASLC) is the only global organization dedicated solely to the study of lung cancer and other thoracic malignancies. Founded in 1974, the association's membership includes more than 10,000 lung cancer specialists across all disciplines in over 100 countries, forming a global network working together to conquer lung and thoracic cancers worldwide. The association also publishes the Journal of Thoracic Oncology, the primary educational and informational publication for topics relevant to the prevention, detection, diagnosis, and treatment of all thoracic malignancies. Visit www.iaslc.org for more information.

About the WCLC:

The WCLC is the world's largest meeting dedicated to lung cancer and other thoracic malignancies, attracting nearly 7,000 researchers, physicians, and specialists from more than 100 countries. The goal is to increase awareness, collaboration and understanding of lung cancer, and to help participants implement the latest developments across the globe. The conference will cover a wide range of disciplines and unveil several research studies and clinical trial results. For more information, visit https://wclc.iaslc.org/.

Contact: Chris Martin, IASLC Media Relations, [email protected] 

SOURCE International Association for the Study of Lung Cancer