AstraZeneca and Daiichi Sankyo’s Enhertu Delivers 14.3-Month PFS in HER2-Mutant NSCLC

Seoul, South Korea, September 14, 2026

DESTINY-Lung04 Delivers Significant PFS Benefit

The randomized Phase III DESTINY-Lung04 trial enrolled patients with HER2-mutant, non-squamous NSCLC who had not previously received systemic therapy for advanced disease. The primary endpoint analysis showed that ENHERTU reduced the risk of progression or death compared with the global first-line standard of care, with a hazard ratio of 0.63 (95% CI, 0.50–0.79; P<0.0001). Median PFS was 14.3 months (95% CI, 12.4–16.5) in the ENHERTU arm versus 8.3 months (95% CI, 7.0–9.9) with pembrolizumab plus chemotherapy. The PFS benefit was observed across key prespecified subgroups, including patients with brain metastases, liver metastases, different smoking statuses, HER2 exon 19 or exon 20 mutations, and de novo or recurrent disease. The trial also demonstrated a higher objective response rate (ORR) with ENHERTU. Approximately 70.0% of patients responded to ENHERTU compared with 44.5% receiving pembrolizumab plus chemotherapy. The median duration of response was 13.4 months with ENHERTU versus 9.7 months with the comparator regimen. Median PFS2, an exploratory measure assessing time to second progression or death, was 22.7 months with ENHERTU compared with 17.3 months with pembrolizumab plus chemotherapy.

HER2-Directed Therapy Advances in First-Line NSCLC

The DESTINY-Lung04 findings are significant because ENHERTU is the first HER2-directed therapy to demonstrate superior PFS against the global first-line standard of care in a Phase III trial for patients with HER2-mutant advanced NSCLC. ENHERTU is a specifically engineered HER2-directed antibody-drug conjugate (ADC) discovered by Daiichi Sankyo and jointly developed and commercialized with AstraZeneca. The therapy combines a HER2-targeting antibody with a topoisomerase I inhibitor payload, enabling targeted delivery of the cytotoxic component to HER2-expressing cancer cells. ENHERTU is already approved for previously treated metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations. The DESTINY-Lung04 results now provide evidence supporting its potential movement into the first-line treatment setting, where delaying progression is a major objective for patients with advanced disease. However, the current results concern the clinical-trial setting and do not by themselves establish a new regulatory indication.

Safety Profile Remains Consistent With ENHERTU

The safety profile observed in DESTINY-Lung04 was generally consistent with the established profile of ENHERTU, with no new safety concerns identified. Grade 3 or higher treatment-related adverse events occurred in 34.1% of patients receiving ENHERTU and 33.6% of those receiving pembrolizumab plus chemotherapy. Neutropenia was the most common Grade 3 or higher adverse event occurring in at least 5% of patients in both treatment groups, reported in 11.1% and 14.1%, respectively. An important safety consideration was interstitial lung disease (ILD) or pneumonitis, which occurred in 20.8% of patients treated with ENHERTU according to independent adjudication. Most events were Grade 1 or Grade 2, while Grade 3, Grade 4 and Grade 5 events were also reported. These findings reinforce the importance of continued safety monitoring as the therapy is evaluated in earlier lines of treatment. At the current data cutoff, overall survival data were immature, with 46.9% maturity, and no formal hypothesis testing had been performed. The median OS was 29.3 months with ENHERTU versus 33.1 months with pembrolizumab plus chemotherapy, with an HR of 1.15. Therefore, the key established finding from this analysis is the statistically significant PFS benefit, rather than an overall survival advantage.

Source: AstraZeneca, Daiichi Sankyo press release