Emerging Oral HER2-Targeted TKIs (Zongertinib and Sevabertinib): Efficacy and Safety in HER2-Mutated NSCLC

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Zongertinib represents a breakthrough HER2-selective tyrosine kinase inhibitor (TKI) that spares EGFR, avoiding common rash and diarrhea adverse effects associated with dual-target inhibitors. Phase 1 data presented at AACR and published in the New England Journal of Medicine demonstrate robust response rates exceeding 70% with progression-free survival of 12.9 months. The drug's selectivity profile offers improved tolerability compared to antibody-drug conjugates, with minimal fatigue, nausea, or hematologic toxicity, and notably no interstitial lung disease risk.

Sevabertinib (formerly BAY 2927088) functions as a dual HER2/EGFR exon 20 inhibitor, showing equally impressive 60% response rates in recent ASCO 2025 data. While less HER2-specific than zongertinib, this agent has been filed with the FDA for second-line approval. The dual inhibition profile results in higher gastrointestinal toxicity rates, particularly diarrhea, due to EGFR-mediated effects. Both agents represent significant advances in oral targeted therapy options for patients with HER2-mutated non–small cell lung cancer (NSCLC).

Three phase 3 frontline trials are currently evaluating these novel HER2 inhibitors against standard chemotherapy: Beamion LUNG-1 and LUNG-2 studying zongertinib, and SOHO-2 investigating sevabertinib. These studies may revolutionize first-line treatment by moving effective targeted therapies earlier in the treatment sequence. The oral formulation offers significant quality-of-life advantages over intravenous chemotherapy, potentially transforming the treatment experience for patients with HER2-mutated NSCLC while maintaining or improving efficacy outcomes.