AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) demonstrated a statistically significant improvement in Progression-Free Survival (PFS) compared with pembrolizumab plus platinum-pemetrexed chemotherapy in the first-line treatment of patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous Non-Small Cell Lung Cancer (NSCLC), according to results from the Phase 3 DESTINY-Lung04 trial.

In the primary PFS analysis, Enhertu reduced the risk of disease progression or death by 37 percent compared with pembrolizumab plus chemotherapy. Median PFS was 14.3 months with Enhertu compared with 8.3 months with pembrolizumab plus chemotherapy, representing a six-month difference. The PFS trend was consistent across key subgroups, including patients with or without brain or liver metastases, different smoking histories, HER2 exon 19 or exon 20 mutations, and de novo or recurrent disease.

Enhertu also produced an Objective Response Rate (ORR) of 70.0 percent, compared with 44.5 percent for pembrolizumab plus chemotherapy. Median duration of response was 13.4 months with Enhertu and 9.7 months with the comparator regimen. 

The trial enrolled 454 patients who were randomised 1:1 to receive either Enhertu at 5.4 mg/kg or pembrolizumab combined with platinum-based chemotherapy and pemetrexed. Patients had treatment-naive, unresectable locally advanced or metastatic non-squamous NSCLC harbouring HER2 exon 19 or exon 20 mutations. 

At the data cut-off of June 9, 2026, overall survival (OS) data were 46.9 percent mature, and no formal hypothesis testing for OS had been conducted. Median OS was 29.3 months with Enhertu and 33.1 months with pembrolizumab plus chemotherapy at this analysis. Differences in subsequent treatments between the study arms, including greater use of HER2-directed therapies in the pembrolizumab-plus-chemotherapy group, may affect interpretation of the current OS results. 

The safety profile of Enhertu was generally consistent with its established safety profile, with no new safety concerns identified. Grade 3 or higher treatment-related adverse events occurred in 34.1 percent of patients receiving Enhertu and 33.6 percent receiving pembrolizumab plus chemotherapy. Neutropenia was the most common Grade 3 or higher adverse event occurring in at least 5 ercent of patients in both groups. 

Interstitial Lung Disease (ILD) or pneumonitis occurred in 20.8 percent of patients in the Enhertu arm. Most reported events were Grade 1 or Grade 2, while Grade 3 events occurred in 2.2 percent, Grade 4 in 0.4 percent and Grade 5 in 1.8 percent of patients. 

Enhertu is a HER2-directed Antibody-Drug Conjugate (ADC) discovered by Daiichi Sankyo and jointly developed and commercialised by Daiichi Sankyo and AstraZeneca. The companies are evaluating Enhertu across multiple HER2-targetable cancers and treatment settings. 

HER2 mutations occur in a subset of non-squamous NSCLC and represent a molecular target associated with disease progression and poor prognosis. DESTINY-Lung04 evaluated whether directly targeting HER2 with Enhertu could improve outcomes when used before other systemic therapies in this patient population.