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

A new study led by researchers at Dana-Farber Cancer Institute found that first-line 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). The findings suggest T-DXd could become a new first-line treatment option for this patient population.

The results were presented at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC) in SEOUL, Republic of Korea on Sept. 14, 2026, by Julia Rotow, MD, clinical director of the Lowe Center for Thoracic Oncology and director of clinical research in thoracic oncology at Dana-Farber.

DESTINY-Lung04 is the first global randomized phase 3 trial to show that a HER2-directed therapy can outperform standard first-line chemoimmunotherapy in patients with HER2-mutant NSCLC. In the trial, median progression-free survival by blinded independent central review was 14.3 months with T-DXd, compared with 8.3 months with pembrolizumab plus chemotherapy, representing a 37% reduction in the risk of progression or death.

“DESTINY-Lung04 is the first phase 3 trial to demonstrate the benefit of a HER2-directed therapy vs global standard of care as upfront treatment for patients with HER2-mutant NSCLC,” said Rotow.

The study enrolled 454 previously untreated patients with unresectable locally advanced or metastatic nonsquamous NSCLC harboring HER2 exon 19 or exon 20 mutations. Patients were randomly assigned to receive either single-agent T-DXd every three weeks or pembrolizumab plus platinum chemotherapy and pemetrexed.

T-DXd also produced higher response rates than pembrolizumab plus chemotherapy. The objective response rate was 70.0% with T-DXd versus 44.5% with standard treatment, and median duration of response was 13.4 months versus 9.7 months.

“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 Rotow. “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, though investigators noted that differences in subsequent therapies between the groups complicated interpretation. The DESTINY-Lung04 findings support first-line T-DXd as an important new treatment option for patients with HER2-mutant NSCLC.