Enhertu Extends Progression-Free Survival by Six Months in First-Line HER2-Mutant NSCLC

AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) significantly improved progression-free survival compared with pembrolizumab plus platinum-based chemotherapy in patients with previously untreated, unresectable locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC). The Phase III DESTINY-Lung04 results, presented at the IASLC 2026 World Conference on Lung Cancer in Seoul, position Enhertu for potential expansion into the first-line setting.

Six-month PFS advantage over standard care

Enhertu reduced the risk of disease progression or death by 37% versus pembrolizumab plus chemotherapy (hazard ratio [HR], 0.63; 95% CI, 0.50-0.79; p<0.0001). Median progression-free survival reached 14.3 months with Enhertu compared with 8.3 months with pembrolizumab plus chemotherapy, extending median PFS by six months.

The PFS benefit remained favorable across key prespecified subgroups, including patients with brain or liver metastases, different smoking histories, HER2 exon 19 or exon 20 mutations, and de novo or recurrent disease.

Enhertu also produced a higher objective response rate, with 70.0% of patients responding compared with 44.5% with pembrolizumab plus chemotherapy. Median duration of response was 13.4 months with Enhertu versus 9.7 months with standard care.

Directly targeting HER2-mutant lung cancer

HER2 mutations occur in approximately 2%-4% of patients with non-squamous NSCLC and represent a distinct molecular alteration associated with tumor growth and poor prognosis. Patients with these mutations also have an increased incidence of brain metastases.

In the metastatic first-line setting, the global standard of care has been immunotherapy combined with platinum-based doublet chemotherapy. However, many patients experience disease progression after initial treatment, highlighting the need for targeted approaches in molecularly defined NSCLC.

Enhertu is a HER2-directed antibody-drug conjugate (ADC) that combines a HER2 monoclonal antibody with DXd, a topoisomerase I inhibitor payload, through a cleavable tetrapeptide-based linker. This ADC technology is intended to deliver the cytotoxic payload through HER2-directed binding and internalization.

Phase III trial and safety profile

DESTINY-Lung04 enrolled 454 patients with unresectable, locally advanced or metastatic non-squamous NSCLC carrying a HER2 exon 19 or exon 20 mutation across sites in Asia, Europe and North America. Patients were randomized 1:1 to Enhertu 5.4 mg/kg or pembrolizumab plus platinum-pemetrexed chemotherapy.

The primary endpoint was PFS assessed by blinded independent central review. Secondary endpoints included objective response rate, duration of response, PFS2, overall survival, pharmacokinetics and safety.

Enhertu’s safety profile remained consistent with its established profile, with no new safety concerns identified. Despite longer median treatment exposure with Enhertu, Grade 3 or higher treatment-related adverse events were similar between groups, occurring in 34.1% of Enhertu-treated patients and 33.6% of patients receiving pembrolizumab plus chemotherapy. Neutropenia was the most common Grade 3 or higher adverse event in both arms.

Interstitial lung disease (ILD) or pneumonitis occurred in 20.8% of patients receiving Enhertu. Importantly, most events were low-grade, with 3.1% classified as Grade 1 and 13.3% as Grade 2. Ten patients (4.4%) experienced Grade 3-5 ILD events, including five Grade 3 cases, one Grade 4 case and four fatal Grade 5 events.

 Overall survival remains immature

Median overall survival was 29.3 months with Enhertu versus 33.1 months with pembrolizumab plus chemotherapy (HR, 1.15; 95% CI, 0.88-1.52). However, the OS analysis was only 46.9% mature, and no formal hypothesis testing had been performed at the data cutoff.

Interpretation is further complicated by differences in subsequent treatment. HER2-directed therapies were used more frequently after progression in the control arm than in the Enhertu arm, while subsequent immunotherapy plus chemotherapy was used less frequently after Enhertu. These treatment imbalances may affect the current OS comparison.

First-line expansion could broaden Enhertu’s role

Julia Rotow, MD, lead investigator of DESTINY-Lung04, said the 70% response rate and 14.3-month median PFS indicate that trastuzumab deruxtecan could become an important first-line treatment option for patients with this aggressive form of NSCLC.

The findings also strengthen the case for moving HER2-directed therapy earlier in the treatment sequence. Enhertu is already approved for previously treated metastatic NSCLC with activating HER2 mutations, making DESTINY-Lung04 a potential basis for expanding its use into the first-line setting.

AstraZeneca and Daiichi Sankyo will now face the regulatory next steps associated with the Phase III result. The key clinical question will be whether the substantial PFS and response advantages translate into a first-line treatment benefit that ultimately improves longer-term outcomes as the OS analysis matures.

 Reference

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 III trial, Astra Zeneca, 14 September 2026

A Study to Investigate the Efficacy and Safety of Trastuzumab Deruxtecan as the First Treatment Option for Unresectable, Locally Advanced/​Metastatic Non-Small Cell Lung Cancer With HER2 Mutations, ClinicalTrials.gov ID NCT05048797