Zongertinib

Trastuzumab deruxtecan (Enhertu) cut the risk of disease progression or death by 37% compared with pembrolizumab plus platinum-pemetrexed chemotherapy as first-line therapy in patients with HER2-mutant advanced non-small cell lung cancer (NSCLC). The drug is jointly developed by AstraZeneca and Daiichi Sankyo, with the DESTINY-Lung04 Phase III results presented at the IASLC 2026 World Conference on Lung Cancer in Seoul. Median progression-free survival (PFS) was 14.3 months with trastuzumab deruxtecan monotherapy versus 8.3 months with the chemoimmunotherapy comparator (hazard ratio 0.63; 95% CI 0.50–0.79; p<0.0001), as assessed by blinded independent central review. The objective response rate (ORR) was 70.0% versus 44.5%, with a median duration of response of 13.4 months versus 9.7 months. The PFS benefit was consistent across prespecified subgroups including brain metastases, liver metastases, smoking status, HER2 mutation type (exon 19 or exon 20), and de novo or recurrent disease. Overall survival (OS) data were 46.9% mature at the data cut-off of June 9, 2026, and no formal hypothesis testing was performed. Median OS was 29.3 months with trastuzumab deruxtecan versus 33.1 months with chemoimmunotherapy (HR 1.15; 95% CI 0.88–1.52). AstraZeneca and Daiichi Sankyo noted that imbalanced use of subsequent HER2-directed therapies — 48.0% in the control arm versus 23.3% in the trastuzumab deruxtecan arm — could complicate interpretation of the immature OS findings. Formal OS testing is planned at later analyses. Despite longer median treatment exposure with trastuzumab deruxtecan, Grade 3 or higher treatment-related adverse events were similar between arms at 34.1% and 33.6%. ILD or pneumonitis remained a notable toxicity, occurring in 20.8% of trastuzumab deruxtecan-treated patients; most events were Grade 1 or 2, but four Grade 5 events were reported, corresponding to a 1.8% fatal ILD rate. Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate (ADC) that delivers the topoisomerase I inhibitor DXd directly to HER2-expressing tumor cells, inducing DNA double-strand breaks. The drug is already approved in the US for previously treated HER2-mutant NSCLC under accelerated approval, based on single-arm data from DESTINY-Lung02. DESTINY-Lung04 evaluates trastuzumab deruxtecan in the first-line setting and could support expansion of the label into previously untreated disease. The competitive landscape in HER2-mutant NSCLC has shifted materially over the past year. Boehringer Ingelheim's Hernexeos (zongertinib), a selective HER2 tyrosine kinase inhibitor, received FDA accelerated approval in February 2026 for treatment-naive patients with HER2-mutant advanced non-squamous NSCLC, based on single-arm Phase II data. Sevabertinib, another HER2 kinase inhibitor, received accelerated approval in November 2025 for the previously treated setting and is being evaluated in the first-line Phase III SOHO-02 trial. DESTINY-Lung04 provides the first randomized Phase III PFS data in the first-line setting for this molecularly defined population, though cross-trial comparisons between the ADC and oral TKI approaches are constrained by differing trial designs, patient populations, and data maturity. HER2 mutations occur in approximately 2–4% of NSCLC cases and have historically been associated with poor responses to chemoimmunotherapy, with median PFS on pembrolizumab-based regimens typically under nine months in this subgroup. The 14.3-month median PFS reported in DESTINY-Lung04 represents a six-month improvement over the control arm. AstraZeneca and Daiichi Sankyo said they intend to share the data with regulatory authorities globally to support potential label expansions into the first-line setting. Spot something wrong? Report an issue with this article