Hyrnuo (sevabertinib)

Concerning treatment, in advanced HER2-positive, Non-Squamous NSCLC tumors, the first-line treatment is Platinum-based + Pemetrexed chemotherapy, with or without immunotherapy, because no HER2-targeted antibody therapy has yet been approved for initial treatment. After progression, HER2-targeted antibody-drug conjugates like Trastuzumab-Deruxtecan and Ado Trastuzumab-Emtansine may offer patients clinical benefits. New HER2-selective tyrosine kinase inhibitors, such as zongertinib and sevabertinib, have shown promising results, including patients previously treated with antibody-drug conjugates (ADCs). Recent advances, including next-generation ADCs such as SHR-A1811 and A166, and bispecific antibodies, such as zenocutuzumab for NRG1 fusion-positive disease, which are also expanding treatment options. Overall, advances in diagnostics and new targeted therapies are changing how HER2-altered NSCLC is treated and are helping to make care more personalized.

P1/2, N=400, Recruiting, Bayer | Trial completion date: Dec 2026 --> Jun 2029 | Active, not recruiting --> Recruiting

Trastuzumab deruxtecan, zongertinib and sevabertinib have been approved in the United States for the treatment of patients with advanced metastatic HER2 mutated non-small-cell lung cancer (NSCLC). Unfortunately, tumor progression is inevitable in many cases. In this case report, we share our experience with a patient with HER2 mutated NSCLC who responded to the combination of trastuzumab deruxtecan and zongertinib after progressing on each agent when given alone, highlighting the potential for such combinations.

Three such agents have gained accelerated US Food and Drug Administration (FDA) approval for use in previously treated HER2-mutant NSCLC: the antibody-drug conjugate, trastuzumab deruxtecan; the HER2-specific tyrosine kinase inhibitor (TKI), zongertinib; and the HER2/EGFR TKI, sevabertinib. Zongertinib has also been granted accelerated FDA approval in a first-line setting. The emergence of multiple treatment options highlights the importance of early HER2 mutation testing to guide treatment sequencing and maximize patient benefit.

Trastuzumab deruxtecan (T-DXd) was the first targeted therapy approved for patients with HER2-mutant NSCLC, demonstrating robust and durable responses in about 50% of these patients...On the other hand, novel orally available TKIs with higher specificity and inhibitory potency against HER2 over wild type EGFR such as sevabertinib (a dual HER2/EGFR mutant-selective reversible TKI) or zongertinib (an irreversible HER2-selective TKI that spares EGFR, including mutant EGFR) have further demonstrated deep and durable responses in this disease...In this review, we first describe the molecular landscape and clinical features of HER2-mutant NSCLC. Then, we summarize the clinical and preclinical evidence of HER2-targeted therapies and provide a forward-looking perspective of the treatment landscape of HER2-mutant NSCLC.

P3, N=444, Recruiting, Bayer | N=174 --> 444

Following the 2022 approval of the antibody-drug conjugate fam-trastuzumab deruxtecan (T-DXd), the therapeutic landscape of HER2-mutant NSCLC further expanded in 2025 with the regulatory approval of two highly selective oral HER2 tyrosine kinase inhibitors, zongertinib and sevabertinib. We also outline ongoing trials that may further shift first-line standards. In summary, recent breakthroughs in HER2-targeted TKIs and ADCs are transforming outcomes in this rare NSCLC subset, though optimizing sequencing, managing resistance, and improving patient selection through biomarker development remain priorities for future research.

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.