Trastuzumab deruxtecan (Enhertu) has become the first HER2-directed therapy to demonstrate a progression-free survival (PFS) benefit over the global standard of care in a Phase III trial for first-line HER2-mutant advanced non-small cell lung cancer (NSCLC), according to AstraZeneca and Daiichi Sankyo. The DESTINY-Lung04 result could move the antibody-drug conjugate (ADC) earlier in the treatment pathway as competition intensifies for this molecularly defined lung cancer population.
DESTINY-Lung04 enrolled 454 patients with unresectable, locally advanced or metastatic non-squamous NSCLC harboring HER2 exon 19 or 20 mutations. Patients were randomized 1:1 to trastuzumab deruxtecan at 5.4 mg/kg or platinum-pemetrexed chemotherapy plus Merck's Keytruda (pembrolizumab), the current global standard of care. The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS by blinded independent central review, the companies said.
No hazard ratio, median PFS values, or p-values were disclosed in the top-line announcement, with full results due at a forthcoming medical meeting. The safety profile was consistent with trastuzumab deruxtecan's known profile, with no new safety concerns identified. Overall survival continues to be assessed as a secondary endpoint.
Trastuzumab deruxtecan is a HER2-directed ADC carrying a topoisomerase I inhibitor payload. The drug already has accelerated US FDA approval for previously treated HER2-mutant metastatic NSCLC, based on single-arm clinical data. DESTINY-Lung04 provides randomized Phase III evidence that could support expansion into first-line treatment while also adding confirmatory evidence for its existing lung cancer indication.
HER2 mutations occur in approximately 2–4% of non-squamous NSCLC and have historically lacked targeted first-line treatment options. That landscape is now changing rapidly. Boehringer Ingelheim's Hernexeos (zongertinib), an oral HER2-selective tyrosine kinase inhibitor (TKI), received accelerated US FDA approval in February 2026 for previously untreated HER2-mutant advanced NSCLC, becoming the first targeted therapy approved in this setting. Bayer's Hyrnuo (sevabertinib), already approved for previously treated disease, is also under US FDA Priority Review for first-line use.