Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases, and its treatment has evolved from traditional chemotherapy to a precision medicine era based on molecular subtyping. Epidermal growth factor receptor (EGFR) mutations, as a key driver gene, have propelled the rapid development of targeted therapy. In this process, the approval of the third-generation EGFR tyrosine kinase inhibitor (TKI) Limertinib marks a new era in NSCLC treatment.

EGFR mutations are prevalent in NSCLC patients, especially in Asian populations. This discovery has driven the development of EGFR-TKIs from first to third generation. While traditional TKIs have achieved significant clinical success, challenges remain, such as insufficient control of brain metastases and drug resistance. Limertinib was developed to address these unmet clinical needs, with its unique molecular design aimed at improving efficacy while optimizing safety.

Limertinib employs an innovative naphthylamine backbone structure with a chlorine substituent introduced at the ortho position. This design significantly enhances the drug's lipophilicity and conformational stability. Unlike mainstream indole modification strategies, this structural optimization strategy not only improves the drug's penetration across the blood-brain barrier, thus achieving efficient control of central nervous system (CNS) metastases, but also reduces the potential risk of hepatotoxicity. This differentiated molecular design approach provides a superior treatment option for patients at high risk of brain metastases.

Based on the pivotal Phase III ASK-LC-120067-F-III study, Limertinib was approved in April 2025 for the treatment of patients with advanced NSCLC harboring EGFR-sensitive mutations (Ex19del/L858R). Study data showed that patients treated with Limertinib achieved a median progression-free survival (PFS) of 20.7 months, a significant prolongation compared to the control group, with a 56% reduction in the risk of disease progression. Furthermore, its objective response rate (ORR) and disease control rate (DCR) reached 88.1% and 96.4%, respectively, fully demonstrating its superior systemic antitumor activity.

Limertinib performed particularly well in patients with CNS metastases, achieving a median intracranial progression-free survival (iPFS) of 20.7 months, significantly reducing the risk of intracranial progression by 72%. Its high blood-brain barrier penetration enabled a central nervous system objective response rate (CNS ORR) of 88.9%, providing an effective solution to this traditional treatment challenge. This significant advantage stems directly from its molecular structure's optimization of blood-brain barrier penetration.

In terms of safety, limertinib performed well, with adverse reactions primarily being grade 1-2 diarrhea, rash, and anemia. The incidence of ≥ grade 3 adverse events was low, and the permanent discontinuation rate due to adverse reactions was only 1.8%. This favorable safety profile not only significantly improves patient adherence to treatment but also effectively safeguards their quality of life, laying a solid foundation for long-term treatment.

In the 2025 "Chinese Expert Consensus on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer," Limertinib was recommended as a Class I first-line treatment option for EGFR-sensitive mutation-positive advanced NSCLC. This consensus fully recognizes its comprehensive evidence-based medicine, covering multiple dimensions such as efficacy, CNS control, and safety. This recommendation has powerfully promoted the standardization and homogenization of clinical diagnosis and treatment. As clinical expert Professor Wu Lin pointed out, Limertinib provides a new option for precision treatment of NSCLC, especially suitable for patients at high risk of brain metastases.

The successful approval of Limertinib has opened a new chapter in NSCLC treatment, and its structural innovation provides a new paradigm for subsequent drug development. With the accumulation of more clinical data and in-depth research, Limertinib is expected to play a greater role in combination therapy and overcoming drug resistance mechanisms, thereby further extending patient survival and optimizing treatment strategies. This significant advancement not only significantly improves patient prognosis but also fully demonstrates the strong competitiveness of domestically developed original drugs in the global lung cancer treatment field.

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