The advent of targeted drugs has opened the door to the era of precision treatment of lung cancer. From "blind bombing" to "precision attack", the average median survival time of lung cancer patients in my country has been greatly improved.

Foreword

Cancer treatment has undergone tremendous changes and innovative developments in the past few decades. The discovery of driver genes is undoubtedly an important "watershed" in this field. The advent of targeted drugs has opened the door to the era of precision treatment of lung cancer. From "blind bombing" to "precision attack", the average median survival time of lung cancer patients in my country has been greatly improved. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of lung cancers. The detection rate of anaplastic lymphoma kinase (ALK) mutations is about 3%-7%. In response to this mutation, a variety of ALK tyrosine kinase inhibitors (ALK-TKI) have been approved for marketing. The treatment outcomes of patients are gradually moving closer to the goal of balancing efficacy and safety, promoting the improvement of the overall treatment value for patients^{1- 2}.

On March 22, 2022, the my country Food and Drug Administration approved the new generation ALK-TKI brigatinib for any line treatment of patients with ALK-positive locally advanced or metastatic NSCLC, bringing more hope to the majority of domestic patients. In this regard, Yimaitong specially invited Professor Zhou Jianying from the First Affiliated Hospital of Zhejiang University to interpret the ALTA-1L research data, share solutions to the unmet needs of ALK, and how to improve the overall therapeutic value of front-line patients.

Expert profile

Professor Zhou Jianying

• Honorary Director of the Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Zhejiang University

• Director of the Pulmonary Disease Diagnosis and Treatment Center

• Director of the first batch of training bases for respiratory specialists in the country

• National Standing Committee Member of the Respiratory Disease Branch of the Chinese Medical Association

• Chinese Medical Doctor Association Member of the Standing Committee of the Respiratory Physician Branch

• Deputy Chairman of the Thoracic Oncology Branch of the China Medical Promotion Association

• President of the Respiratory Physician Branch of the Zhejiang Medical Association

• Former Chairman of the Respiratory Disease Branch of the Zhejiang Medical Association

Powerful brain protection, better survival, and improved overall patient performance Therapeutic value

Professor Zhou introduced . Looking at the research progress of targeted therapy in recent years, the field of ALK-positive NSCLC can be said to be "blooming", providing patients with a variety of first-line treatment options. While achieving long-term survival benefits, there are still some Unmet needs, especially brain metastasis and quality of life issues ³:

• Brain metastasis is highly prevalent and occurs throughout the patient's entire disease course, resulting in poor patient prognosis; and brain metastasis aggravates the deterioration of the quality of life.

• There is a single first-line treatment option. For example, although radiotherapy can alleviate the neurological symptoms of patients with brain metastases, it cannot effectively prolong OS and may reduce the quality of life and damage cognition. Although the benefits of first-generation ALK TKI have improved, the improvement is limited. The progression is still mainly intracranial.

Professor Zhou pointed out that , the launch of brigatinib, provides a new option for this type of patients, the overall population median PFS exceeded the 30-month mark, reducing the risk of disease progression or death by 57%; also focuses on the brain Metastasis and quality of life problems, and improve the overall treatment value of patients⁴.

Excellent intracranial efficacy - the 4-year OS rate of patients with brain metastasis is as high as 71%, and the risk of disease progression or death is reduced by 75%

Regarding the problem of brain metastasis, Professor Zhou pointed out that according to the results of the ALTA-1L study, brigatinib It has a breakthrough effect in the treatment of patients with brain metastases:

• median PFS reached 24 months, compared with 5.6 months in the control group, with an HR value of 0.25 (p<0.0001),>

• Brigatinib is currently the only ALK TKI that provides a benefit in the OS rate of brain metastases. The 34-year OS rate reaches 71%, which means that it helps nearly three-quarters of patients with brain metastases achieve a long survival of 4 years (or more). ⁴. truly realizes the chronicization of patients with ALK-positive brain metastases.

Professor Zhou concluded that the ALTA-1L study showed that brigatinib can provide significant long-term survival benefits for both the overall population and patients with brain metastases.

Better quality of life - brigatinib is the first ALK TKI to significantly improve survival and quality of life, improving the overall therapeutic value of patients

The improvement of the overall therapeutic value of patients, in addition to long-term survival benefits, is also inseparable from safety Improvement in sex and quality of life.

Professor Zhou introduced that brigatinib not only provides significant long-term survival benefits, but also takes into account good safety ^4-5. ALTA-1L shows that the overall safety of brigatinib is good, and adverse reactions are mostly grade 1 to 2, which are controllable and tolerable; adverse reactions of grade 3 and above are mainly increased blood or biochemical indicators and are asymptomatic.

Professor Zhou added that due to the dose lead-in period designed in the ALTA-1L study, the incidence of pulmonary-related adverse events was significantly reduced. The ALTA-1L study showed that the incidence of early-onset pulmonary events in the brigatinib group was 3% (2% for ALK TKI overall), the incidence is not high and can be managed through dose adjustment or symptomatic treatment.

At the same time, brigatinib is currently the first ALK-TKI to achieve significant benefits in both long-term survival and quality of life. It has significantly improved the time to deterioration in multiple dimensions, especially intracranial functions of clinical concern such as cognition. Functional and emotional functions also have certain clinical benefits ^4-5.

Ingenious spirit, the precise structure of brigatinib brings broad clinical benefits

Excellent data are inseparable from the characteristics of the mechanism, and the structure determines performance. Brigatinib starts from the molecular structure and focuses on the control of intracranial symptoms.

• improves the selectivity and drug activity of brigatinib for ALK by adding DMPO (dimethylphosphorus oxide) structure to the molecular structure;

• introduces the hydrophilic group (weakly basic solubilizing group) to improve It improves the water solubility of brigatinib and improves the balance between water solubility and fat solubility, so that brigatinib has both high solubility and high permeability, which is conducive to brigatinib better penetrating the blood-brain barrier and achieving cranial The accumulation of intracranial drug concentration can effectively improve intracranial symptoms without causing obvious intracranial adverse events. The

ALTA-1L study also confirmed that the unique structure has indeed translated into significant clinical benefits - powerful brain protection, lasting benefits, and better survival. To improve the overall therapeutic value of first-line patients, brigatinib has also been listed as the first-line preferred drug in the "NCCN Oncology Clinical Practice Guidelines" ⁷. The future of

is here! With the deepening of the concept of precision treatment, the era of "chronic disease" of lung cancer will eventually come.

One of the visions of " Healthy China 2030" is to promote precision treatment of major diseases and chronic disease management. As the deputy leader of the lung cancer group of the Respiratory Branch of the Chinese Medical Association, Professor Zhou said that the development of precision cancer medicine is changing with each passing day, and new drug research data are emerging one after another. In order to benefit more patients, relevant departments have accelerated the approval process for new drug launches and expanded indications. At present, cancer research is gradually "getting rid of" chemotherapy and making great strides into the era of targeted and immunotherapy. Among them, in terms of accurate diagnosis and treatment of lung cancer, NGS gene detection technology provides new means and basis for clinical screening of target-sensitive groups, immune-beneficial groups, and analysis and tracking of drug resistance mechanisms. Combined with TKI, it can be used to identify patients with rare targets in lung cancer. Provide precise treatment to help make lung cancer a chronic disease. In this regard, focusing on unmet needs and solving them is the key to improving the overall treatment value for patients. In addition, oncologists also need to constantly learn about the latest developments so that they can keep up with the pace of medical development and use drugs more scientifically, standardizedly, and accurately in clinical practice.

With the advancement of science and technology and the development of medicine, lung cancer patients will have more and more treatment options. Lung cancer treatment will gradually become more precise and personalized. We have reason to believe that lung cancer will become controllable in the near future. chronic".

References:

1. Chinese Society of Clinical Oncology Working Committee. Chinese Society of Clinical Oncology (CSCO) Non-small cell cancer diagnosis and treatment guidelines 2021[M]. People's Medical Publishing House, 2021: 107-110.

2. Zhang Xuchao, Lu Shun, Zhang Li et al. Guidelines for diagnosis and treatment of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer in China[J]. Chinese Journal of Pathology. 2015,44(10):696-703.

3. Oncologist Branch of Chinese Medical Doctor Association. Lung cancer brain metastasis Chinese Treatment Guidelines (2021 Edition). Chinese Journal of Oncology. 2021.43(3):269-281.

4. Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib Versus Crizotinib in ALK Inhibitor-Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial[J]. J Thorac Oncol . 2021 Dec;16(12):2091-2108.

5. Camidge DR, Kim HR, Ahn MJ, et al.Brigatinib versus Crizotinib in ALK-Positive Non -Small-Cell Lung Cancer[J].N Engl J Med . 2018 Nov 22;379(21):2027-2039.

6. Huang WS, Liu S, Zou D,et al. Discovery of Brigatinib (AP26113), a Phosphine Oxide-Containing, Potent, Orally Active Inhibitor of Anaplastic Lymphoma Kinase. J Med Chem. 2016 May 26;59(10):4948-64.

7. NCCN Clinical Practice Guidelines In Oncology: Non⁃Small Cell Lung Cancer (2022 Version 2).

statement: This information is for medical and health professionals only. This information cannot replace professional medical guidance in any way, and should not be regarded as diagnosis and treatment advice. If such information is used for purposes other than obtaining information, this site and the author do not assume any relevant responsibility.

Approval number: C-APROM/CN/ALUN/0140

Approval time: 2022.6

Editor: Dayuan

Typesetting: Uni

Execution: Youshi

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