WCLC 2026: Primary Results From DESTINY-Lung04 Trial of First-Line T-DXd for HER2-Mutant NSCLC
By: Julia Cipriano, MS
Posted: Friday, October 23, 2026
In the global phase III DESTINY-Lung04 trial, first-line treatment with the HER2-directed antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) significantly improved progression-free survival compared with standard-of-care chemoimmunotherapy in patients with advanced HER2-mutant non–small cell lung cancer (NSCLC). The primary results, presented by Julia Rotow, MD, of Dana-Farber Cancer Institute, Boston, at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (Abstract PL03.08/1052), also showed higher response rates and longer durations of response.
“These results support T-DXd as a new first-line option…,” the investigators wrote.
A total of 454 patients with treatment-naive unresectable locally advanced or metastatic HER2-mutant (exon 19 or 20) disease were randomly assigned in a 1:1 ratio to receive 5.4 mg/kg of intravenous T-DXd every 3 weeks or pembrolizumab plus platinum-based chemotherapy and pemetrexed. Follow-up data were provided for a median of 21.6 months with T-DXd and 20.4 months with chemoimmunotherapy.
Treatment with T-DXd resulted in a significant 6-month improvement in median progression-free survival compared with chemoimmunotherapy (14.3 vs 8.3 months; hazard ratio [HR] = 0.63; P < .0001). Objective response rates were higher with T-DXd (70.0% vs 44.5%; odds ratio = 2.93), as was median duration of response (13.4 vs 9.7 months). Median overall survival was 29.3 months with T-DXd and 33.1 months with chemoimmunotherapy (HR = 1.15), with reported imbalances in subsequent HER2-directed and immunotherapy-based treatments confounding interpretation of the results, according to the investigators.
The observed safety profile appeared generally consistent with previous reports of T-DXd. Drug-related grade 3 or higher adverse events were documented in 34.1% of patients treated with T-DXd and 33.6% of those who received chemoimmunotherapy. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 20.8% and 2.3% of patients, respectively, with most events in the T-DXd group (78.7%) and all events in the chemoimmunotherapy group classified as grade 1 or 2.
