Trastuzumab Deruxtecan Extends PFS in HER2-Mutant NSCLC

AstraZeneca reported that trastuzumab deruxtecan (Enhertu, AstraZeneca and Daiichi Sankyo) significantly prolonged progression-free survival (PFS) compared with pembrolizumab plus platinum-pemetrexed chemotherapy as first-line therapy for unresectable, locally advanced or metastatic HER2-mutant, non-squamous non-small cell lung cancer (NSCLC) in the phase 3 DESTINY-Lung04 trial. The findings were presented at the 2026 World Conference on Lung Cancer.

The global, randomized, open-label trial enrolled 454 patients whose tumors harbored HER2 exon 19 or 20 mutations. Participants were assigned 1:1 to trastuzumab deruxtecan 5.4mg/kg or pembrolizumab plus platinum-pemetrexed chemotherapy. The primary endpoint was PFS assessed by blinded independent central review; secondary endpoints included objective response rate (ORR), duration of response, overall survival (OS), and safety.

Median PFS was 14.3 months with trastuzumab deruxtecan and 8.3 months with pembrolizumab plus chemotherapy, corresponding to a 37% reduction in the risk of disease progression or death (hazard ratio, 0.63; 95% CI, 0.50-0.79; P<0.0001). ORR was 70.0% and 44.5%, respectively, while median duration of response was 13.4 and 9.7 months.

At the June 9, 2026, data cutoff, OS data were 46.9% mature. Median OS was 29.3 months with trastuzumab deruxtecan and 33.1 months with the comparator (hazard ratio, 1.15; 95% CI, 0.88-1.52). No formal hypothesis testing was performed, and no OS benefit was observed. AstraZeneca said imbalances in subsequent therapies between groups may limit interpretation.

Grade 3 or higher treatment-related adverse events occurred in 34.1% and 33.6% of patients, respectively. Adjudicated interstitial lung disease or pneumonitis occurred in 20.8% of patients receiving trastuzumab deruxtecan, including five grade 3, one grade 4, and four grade 5 events. The release did not report a first-line regulatory approval; trastuzumab deruxtecan is approved for previously treated metastatic NSCLC with activating HER2 mutations.

Source: AstraZeneca. Enhertu demonstrated a median progression-free survival of 14.3 months as 1st-line therapy in patients with HER2-mutant advanced non-small cell lung cancer in DESTINY-Lung04 phase 3 trial. Press release. AstraZeneca; September 14, 2026. Accessed September 15, 2026.