HER-2 exon 20 mutation

Single-agent neratinib has limited activity in ERBB2-mutated lung cancers. Combinations with temsirolimus or trastuzumab did not markedly improve overall outcomes, producing durable responses in a limited subset of patients.

She received eight additional cycles (nine in total), resulting in tumor regression without ILD recurrence. Given that T-DXd is currently the only approved HER2-targeted therapy for NSCLC in our country, this case underscores the importance of early detection and appropriate management of ILD to maximize the therapeutic benefits.

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.

In recent years, novel antibody-drug conjugates (ADCs), particularly trastuzumab deruxtecan (T-DXd), have demonstrated groundbreaking efficacy in HER-2-mutant advanced NSCLC patients...The consensus also includes detailed recommendations for screening and managing adverse effects associated with ADCs, such as interstitial lung disease (ILD), emphasizing the crucial role of safety management in ensuring treatment efficacy. The publication of this consensus aims to drive the standardization of molecular diagnosis and treatment pathways for HER-2 variant NSCLC, improve clinical outcomes and quality of life for patients, and facilitate the implementation of personalized precision treatment strategies.

Notably, the presence of HER2 mutations was significantly associated with prolonged PFI in both univariable and multivariable analyses, although no significant association with OST was observed. These findings suggest that HER2 mutation status may serve as a favourable prognostic marker for disease progression in surgically resected cPACs.

Human epidermal growth factor receptor 2 (HER2) mutations are rare in NSCLC and the only FDA approved agent until recently, was trastuzumab deruxtecan in the second line setting. Zongertinib is a HER2 selective tyrosine kinase inhibitor that covalently binds to HER2 receptors, including exon20ins mutations. Zongertinib is safe and effective for patients with HER2-mutated NSCLC based on initial results from preclinical studies and the phase I Beamion LUNG-1 trial showing promising response rates and safety profile ultimately leading to the FDA accelerated approval on August 8, 2025.

In the absence of LMD-specific therapeutic guidelines for HER2-driven NSCLC, treatment was initiated with trastuzumab deruxtecan (Enhertu), based on extrapolated evidence from clinical trials in systemic NSCLC and HER2-positive breast cancer with central nervous system involvement. Other options such as poziotinib and zongertinib were considered but not pursued. This case underscores the urgent need for inclusive clinical trials addressing CNS complications in molecularly defined NSCLC and demonstrates the real-world application of precision oncology beyond trial populations.

Treatment responses varied, with one patient receiving trastuzumab deruxtecan. Our findings highlight the molecular diversity and diagnostic challenges of HER2-mutated NSCLC in underrepresented populations, emphasizing the need for comprehensive molecular profiling and expanded access to targeted therapies.

The patient remained recurrence-free at a 9-month follow-up. This induction targeted-IO strategy enabled surgical conversion in ERBB2-mutant NSCLC with durable remission and acceptable toxicity, warranting investigation in molecular subgroups with limited CRT-IO benefit.

The BM incidence in HER2-mutated NSCLC is high and similar across genetic subtypes. ADC treatments may potentially contribute to prolonged OS for patients with HER2-mutated NSCLC and BM. Besides, brain radiotherapy could confer significant OS benefits.

To the best of our knowledge, this study represents the first reported case demonstrating the promising efficacy of pyrotinib in HER2-altered NSCLC harboring the ra-re exon 12 R456C mutation. Heterogeneous alterations in the HER2 extracellular segment, such as R456C, may be targetable and could confer survival benefits with HER2-targeted inhibitors.

In addition, this case reinforces the importance of molecular profiling in guiding personalized treatment strategies and highlights the need for further research, particularly in overcoming challenges related to central nervous system metastases. Overall, T-DXd represents a promising advancement in HER2-mutant NSCLC management, offering hope for improved outcomes in this underserved patient population.