Hyrnuo (sevabertinib)

NSCLCs harboring ECD-ERBB2 mutations are associated with a unique clinico-genomic phenotype and improved outcomes with first-line chemoimmunotherapy. These findings have implications for optimizing treatment strategies in this disease.

P3, N=444, Recruiting, Bayer | N=177 --> 444

In November 2025, sevabertinib was approved under accelerated approval in the USA for use in adults with locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC) whose tumours have HER2 (ERBB2) TK domain (TKD) activating mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This article summarizes the milestones in the development of sevabertinib leading to this first approval for the treatment of locally advanced or metastatic NSCLC with HER2 (ERBB2) activating mutations.

In the past few years, targeted therapeutic modalities such as antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (the first agent to be granted FDA approval for HER2-mutant NSCLC), alongside selective tyrosine kinase inhibitors (TKIs), including zongertinib and sevabertinib, have demonstrated robust systemic efficacy and notable intracranial penetration. This comprehensive review delineates the molecular landscape and clinical phenotypes of HER2-altered NSCLC, synthesizes interim and mature data from ongoing clinical trials evaluating anti-HER2 therapies, and critically examines efficacy and safety results from different classes of targeted agents. Further research is crucial to uncover potential mechanisms of resistance in NSCLC with HER2 mutations and define sequencing or combinatorial strategies pertinent to optimizing individualized patient management.

A number of drugs are in development for the treatment of ERBB2(HER2)-mutated NSCLC, including antibody-drug conjugates such as trastuzumab-deruxtecan and tyrosine kinase inhibitors such as zongertinib and sevabertinib. Herein, we report a case of relapsed advanced ERBB2-mutant NSCLC with acquired resistance to zongertinib potentially mediated through ERBB2 amplification and HER2 3+ immunohistochemistry overexpression with subsequent durable response to fifth-line trastuzumab-deruxtecan. We propose this as a mechanism for zongertinib resistance, one that may underpin a biological rationale for future ERBB2 tyrosine kinase inhibitor-antibody-drug conjugate combination therapy.

P1, N=18, Completed, Bayer | Recruiting --> Completed

P3, N=278, Recruiting, Bayer | Trial primary completion date: Apr 2027 --> Oct 2027

P1/2, N=370, Active, not recruiting, Bayer | Trial primary completion date: Dec 2025 --> Nov 2026

Sevabertinib showed antitumor activity in patients with locally advanced or metastatic HER2-mutant NSCLC. Diarrhea was the most common adverse event. (Funded by Bayer; SOHO-01 ClinicalTrials.gov number, NCT05099172.).

We furthermore demonstrate the activity of sevabertinib in a cancer cell line dependent on a fusion of NRG1, a ligand for the HER2 family member and heterodimerization partner, HER3. Finally, we report patient responses to sevabertinib from a Phase 1/2 clinical trial, indicating potential benefit for patients with HER2-mutant lung cancer.