Enhertu significantly improved progression-free survival versus chemotherapy plus pembrolizumab in first-line HER2-mutant NSCLC in the Phase III DESTINY-Lung04 trial.
Written By: Shaik Yasmeen, PharmD
Reviewed By: Pharmacally Editorial Team
AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) significantly improved progression-free survival (PFS) compared with platinum-pemetrexed chemotherapy plus pembrolizumab in previously untreated patients with unresectable, locally advanced or metastatic HER2-mutant non-squamous non-small cell lung cancer (NSCLC), according to topline results from the Phase III DESTINY-Lung04 trial (NCT05048797). The study met its primary endpoint, while overall survival and other secondary endpoints remain under evaluation.
A New First-Line Targeted Approach for HER2-Mutant NSCLC
HER2 mutations occur in approximately 2% to 4% of patients with non-squamous NSCLC and represent a distinct molecular target. These alterations are more frequently reported in younger patients and people with no history of smoking and are associated with aggressive disease and a higher incidence of brain metastases.
The current global first-line standard combines immunotherapy with platinum-based chemotherapy. Although this approach improves outcomes for many patients, a substantial proportion experience disease progression, leaving an unmet need for targeted therapies that can be used earlier in metastatic disease.
DESTINY-Lung04 Shows a PFS Benefit
DESTINY-Lung04 was a global, randomised, open-label Phase III trial that enrolled 454 patients with unresectable, locally advanced or metastatic non-squamous NSCLC carrying HER2 exon 19 or exon 20 mutations. Patients were randomised 1:1 to receive Enhertu at 5.4 mg/kg or platinum-pemetrexed doublet chemotherapy combined with pembrolizumab.
The primary endpoint was PFS assessed by blinded independent central review. Enhertu produced a statistically significant and clinically meaningful improvement in PFS over the chemotherapy-immunotherapy regimen. The trial will continue to assess overall survival, investigator-assessed PFS, objective response rate, duration of response, pharmacokinetics and safety.
The safety profile was generally consistent with the established profile of Enhertu, with no new safety concerns identified in the study.
ADC Technology Supports Earlier-Line Development
Enhertu is a HER2-directed antibody-drug conjugate (ADC) developed using Daiichi Sankyo’s DXd ADC technology. The drug combines a HER2-targeting monoclonal antibody with a topoisomerase I inhibitor payload, DXd, linked through a cleavable tetrapeptide-based linker. This architecture enables delivery of the cytotoxic payload to HER2-expressing tumour cells.
Enhertu is already approved in more than 80 countries for patients with metastatic NSCLC harbouring activating HER2 mutations after prior systemic therapy. The DESTINY-Lung04 findings could therefore support a shift from its established later-line role toward treatment at metastatic diagnosis.
Regulatory Discussions Expected
Susan Galbraith, Executive Vice President of Oncology Haematology R&D at AstraZeneca, said the results make DESTINY-Lung04 the first Phase III trial to demonstrate a PFS benefit over the global standard of care in this first-line setting. Daiichi Sankyo’s John Tsai similarly highlighted the potential for Enhertu to delay disease progression when introduced earlier in metastatic treatment.
The companies plan to present the full DESTINY-Lung04 results at a forthcoming medical meeting and share the data with global regulatory authorities. The ongoing overall survival analysis will be an important next measure of whether the PFS advantage translates into a broader clinical benefit.
If confirmed through the remaining analyses and regulatory review, the findings could establish Enhertu as an earlier-line targeted treatment option for patients with HER2-mutant metastatic NSCLC, expanding the clinical role of HER2-directed ADC therapy beyond the previously treated setting.
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About the Writer
Shaik Yasmeen (LinkedIn) is a Pharm.D graduate with interests in clinical pharmacy, pharmacovigilance, and medical writing. She has gained experience through hospital clinical postings, patient case reviews, case presentations, and literature evaluation. Passionate about evidence-based healthcare, she is committed to creating accurate and engaging medical content while continuously expanding her professional knowledge.