China's New Era of Precision Treatment for Non-Small Cell Lung Cancer

As a seasoned observer in the global pharmaceutical field, DengYueMed has always closely monitored the innovative progress in China's non-small cell lung cancer (NSCLC) treatment landscape. Guided by the mission to promote the cross-border circulation and clinical application of innovative therapies, we have witnessed the full process of a series of highly clinically valuable targeted drugs from research and development to approval. These drugs not only fill treatment gaps for specific patient populations but also reshape the NSCLC treatment paradigm with precise mechanisms of action and significant clinical efficacy. This article focuses on four core drugs: Sheng Ruisha (Gefitinib), An Luoqing (Lorlatinib), Rui Bida (Ceritinib), and Ao Kaile (Afatinib), providing an in-depth analysis of their mechanisms of action, clinical evidence, applicable scenarios, and profound impact on global lung cancer treatment, serving as a reference for clinical practice and industry research.

The Evolution and Reshaping of China's NSCLC Targeted Therapy Landscape

Lung cancer is the malignant tumor with the highest global incidence and mortality rates, with NSCLC accounting for over 85%. Over the past decade, China's NSCLC treatment has achieved a leapfrog transformation from "chemotherapy-dominated" to "precision targeted therapy," driven by continuous optimization of regulatory policies, the popularization of biomarker testing technologies, and collaborative innovation between domestic and international pharmaceutical companies. As of 2025, China has become one of the core markets for NSCLC targeted drug development and application globally, with approved targeted drugs covering multiple key driver genes such as EGFR, ALK, and ROS1. Among them, Sheng Ruisha, An Luoqing, Rui Bida, and Ao Kaile stand out as key treatment options for NSCLC patients at different stages and with different mutation types, thanks to their unique clinical positioning.

The rise of targeted therapy has significantly improved the prognosis of NSCLC patients—the median overall survival (mOS) for EGFR-mutated patients has extended from less than 1 year in the traditional chemotherapy era to over 3 years, and ALK fusion patients have broken through the 5-year survival bottleneck. However, challenges such as the complexity of resistance mechanisms, treatment gaps for rare mutation patients, and regional disparities in drug accessibility still need to be addressed. The clinical application and iteration of these four core drugs vividly illustrate China's NSCLC treatment advancing toward "more precise, longer-lasting, and safer" goals.

Classic Cornerstone: Sheng Ruisha (Gefitinib)—The Pioneer in EGFR-Mutated NSCLC

Sheng Ruisha (generic name: Gefitinib) is a first-generation EGFR tyrosine kinase inhibitor (TKI) and a "milestone drug" in China's NSCLC targeted therapy field. Developed by AstraZeneca, it was approved for the Chinese market in 2005, becoming the first oral targeted drug for treating advanced NSCLC with EGFR-sensitive mutations, fundamentally changing the treatment fate of EGFR-mutated patients.

Mechanism of Action and Development Rationale

EGFR is one of the core driver genes in NSCLC, with a mutation rate of up to about 50% in Asian populations. EGFR-sensitive mutations (primarily exon 19 deletions and exon 21 L858R mutations) lead to sustained activation of EGFR kinase, driving unlimited proliferation of tumor cells. Sheng Ruisha competitively binds to the ATP-binding site in the EGFR tyrosine kinase domain, inhibiting EGFR autophosphorylation and downstream activation of MAPK and PI3K/AKT signaling pathways, thereby blocking tumor cell proliferation and inducing apoptosis.

Compared to traditional chemotherapy, Sheng Ruisha's core advantage lies in "precise targeting"—it primarily affects EGFR-mutated tumor cells with minimal damage to normal cells, fundamentally reducing severe adverse reactions such as bone marrow suppression and gastrointestinal issues associated with chemotherapy, significantly improving patients' treatment tolerance and quality of life.

Clinical Evidence and Value

Sheng Ruisha's approval was based on several key clinical trials, with the IPASS study being a landmark in EGFR targeted therapy. This study enrolled 1,217 patients with advanced NSCLC who had not previously received chemotherapy. Results showed that for patients with EGFR-sensitive mutations, the median progression-free survival (mPFS) in the Sheng Ruisha group was 9.5 months, significantly better than 6.3 months in the chemotherapy group, with an objective response rate (ORR) of 71.2% versus 47.3% in the chemotherapy group.

Extended studies in Chinese populations further confirmed its efficacy—for Chinese patients with advanced NSCLC harboring EGFR-sensitive mutations, Sheng Ruisha monotherapy achieved an mPFS of 10.0 months and mOS of 22.9 months, with adverse reactions mainly grade 1-2 rash and diarrhea, and a grade 3 or higher adverse reaction rate of only 10.2%.

As the "pioneer" of EGFR targeted therapy, Sheng Ruisha's clinical value lies not only in its efficacy breakthrough but also in promoting the popularization of EGFR gene testing, laying the foundation for the implementation of precision treatment concepts. Today, Sheng Ruisha remains one of the first-line standard regimens for advanced NSCLC with EGFR-sensitive mutations, particularly suitable for elderly patients, those with poor performance status, or those intolerant to chemotherapy. It has also been included in the national medical insurance catalog, significantly enhancing drug accessibility.

Third-Generation Ace: An Luoqing (Lorlatinib)—The Resistance Breaker in ALK Fusion NSCLC

An Luoqing (generic name: Lorlatinib) is a third-generation ALK tyrosine kinase inhibitor developed by Pfizer, approved for the Chinese market in 2022 for treating ALK-positive locally advanced or metastatic NSCLC patients. As a "rising star" in ALK targeted therapy, An Luoqing has become a core treatment option for ALK fusion patients, especially those with resistance, due to its strong resistance coverage and blood-brain barrier penetration.

Mechanism of Action and Development Rationale

ALK fusion is an important driver gene in NSCLC, with an incidence of about 5%-7%, commonly seen in young, non-smoking adenocarcinoma patients. First-generation ALK-TKIs (such as crizotinib) can significantly improve patient prognosis, but most patients develop resistance after 1-2 years of treatment, with ALK secondary mutations (such as G1202R, L1196M) and central nervous system (CNS) metastases being the main causes.

An Luoqing achieves three core advantages through molecular structure optimization: first, it has highly selective inhibitory effects on ALK fusions and their secondary resistance mutations (including G1202R, L1196M, etc.), with an IC50 value as low as 0.07 nM, effectively overcoming resistance to first- and second-generation ALK-TKIs; second, it has extremely strong blood-brain barrier penetration, with cerebrospinal fluid drug concentrations reaching over 60% of plasma levels, effectively controlling brain metastases; third, it adopts a macrocyclic amide structure design, enhancing drug stability and target specificity while reducing off-target effects.

Second-Generation Mainstay: Rui Bida (Ceritinib)—The Precision Advancement Option for ALK Fusion NSCLC

Rui Bida (generic name: Ceritinib) is a second-generation ALK tyrosine kinase inhibitor developed by Novartis, approved for the Chinese market in 2018, and subsequently for both second-line and first-line treatment of ALK-positive advanced NSCLC. As an important iteration of first-generation ALK-TKIs, Rui Bida has become a key treatment drug for ALK fusion patients with stronger ALK inhibitory activity and broader applicability.

Mechanism of Action and Development Rationale

Compared to the first-generation ALK-TKI crizotinib, Rui Bida's binding affinity to the ALK kinase domain is enhanced by about 20-fold, with an IC50 value as low as 0.2 nM, enabling more effective inhibition of ALK fusion protein phosphorylation. Additionally, Rui Bida has inhibitory effects on certain ALK secondary mutations (such as L1196M, G1269A), making it suitable for treatment after crizotinib resistance.

Furthermore, Rui Bida has high oral bioavailability and is unaffected by food, offering more flexible administration. Its mechanism of action is also through inhibition of downstream MAPK and PI3K/AKT signaling pathways of ALK, blocking tumor cell proliferation and metastasis, while also having certain inhibitory activity against other targets like ROS1 fusions, providing treatment possibilities for multi-target mutation patients.

Irreversible Inhibition: Ao Kaile (Afatinib)—The Potent Treatment Option for EGFR-Mutated NSCLC

Ao Kaile (generic name: Afatinib) is a second-generation EGFR tyrosine kinase inhibitor developed by Boehringer Ingelheim, approved for the Chinese market in 2017 for treating advanced NSCLC with EGFR-sensitive mutations. As the first irreversible EGFR-TKI, Ao Kaile provides a more potent treatment option for EGFR-mutated patients with its unique mechanism, particularly suitable for patients with certain rare mutations.

Mechanism of Action and Development Rationale

Unlike the reversible binding of first-generation EGFR-TKIs (such as Sheng Ruisha), Ao Kaile forms covalent bonds with cysteine residues in the EGFR tyrosine kinase domain, achieving irreversible inhibition and more persistently blocking EGFR signaling pathway activation. Additionally, Ao Kaile has a broader inhibitory spectrum against EGFR, covering not only sensitive mutations like exon 19 deletions and exon 21 L858R but also certain rare mutations (such as G719X, L861Q, S768I), providing precision treatment options for rare mutation patients.

Its mechanism of action is also through inhibiting EGFR autophosphorylation, blocking downstream MAPK and PI3K/AKT signaling pathways, thereby inhibiting tumor cell proliferation and inducing apoptosis, while also having certain inhibitory effects on other ErbB family members like HER2 and HER4, further enhancing antitumor effects.

Clinical Positioning and Global Treatment Strategies of the Four Drugs

Although Sheng Ruisha, An Luoqing, Rui Bida, and Ao Kaile belong to different generations and target different points, they form a complementary and synergistic pattern in NSCLC clinical treatment, providing full-cycle precision treatment options for patients:

In clinical practice, physicians need to develop individualized treatment plans based on patients' genetic testing results, treatment history, performance status, presence of brain metastases, and other factors: For newly diagnosed EGFR-sensitive mutation patients, Sheng Ruisha or Ao Kaile can be selected; for EGFR rare mutation patients, Ao Kaile is preferred; for newly diagnosed ALK fusion patients, Rui Bida or An Luoqing can be chosen (with An Luoqing prioritized for patients with brain metastases); for ALK-TKI resistant patients, An Luoqing is the core choice.

Challenges and Future Directions

Although Sheng Ruisha, An Luoqing, Rui Bida, and Ao Kaile have significantly improved the prognosis of NSCLC patients, they still face many challenges: first, resistance issues, with most patients developing secondary resistance after treatment, such as EGFR T790M mutations and ALK G1202R mutations, requiring continued development of next-generation targeted drugs or combination therapies; second, insufficient coverage of rare targets, with some low-frequency mutations (such as EGFR exon 20 insertion mutations) still lacking effective treatments; third, disparities in drug accessibility, with some drugs included in medical insurance but still needing improved availability in grassroots medical institutions; fourth, insufficient accumulation of real-world data, with efficacy and safety in special populations (such as elderly or those with liver/kidney impairment) needing further validation.

In the future, the development direction of NSCLC targeted therapy will focus on three cores: first, optimization of combination therapy strategies, such as combining targeted drugs with immunotherapy and anti-angiogenic drugs to delay resistance and enhance efficacy; second, research and development of next-generation drugs targeting known resistance mutations with more precise inhibitors; third, popularization of dynamic monitoring technologies like liquid biopsy to achieve resistance early warning and regimen adjustments during treatment.

Conclusion

The clinical application and iteration of Sheng Ruisha, An Luoqing, Rui Bida, and Ao Kaile are a microcosm of the development of precision treatment in China's NSCLC field. These drugs not only bring survival hope to countless patients with excellent efficacy and safety but also drive the complete transformation of lung cancer treatment from "empirical therapy" to "precision therapy." As a promoter of the innovative therapy ecosystem, DengYueMed believes that with the continuous advancement of genetic testing technologies, breakthroughs in drug research and development, and deepening interdisciplinary collaborations, NSCLC will gradually become a manageable chronic disease. In the future, we look forward to working hand in hand with global industry peers to continue promoting the development and popularization of innovative therapies, bringing higher-quality and more accessible treatment options to NSCLC patients worldwide.