T-DXd significantly extends progression-free survival in HER2-mutant NSCLC

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. 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."

Julia Rotow, MD, Dana-Farber Cancer Institute, Boston, Mass.

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.