Foreword
The most common lung cancer One of the common distant metastases is the brain. The prognosis of patients with brain metastases from lung cancer is poor, and the natural average survival time is only 1-2 months. It has been reported that anaplastic lymphoma kinase (ALK)-positive NSCLC patients are more likely to develop brain metastases1-2 than ALK-negative NSCLC patients. In recent years, new discoveries, new theories and new methods have been emerging, making the treatment models of brain metastases increasingly diversified.
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Professor Yao Wenxiu
Chief Physician of Medical Oncology Department of Sichuan Cancer Hospital, Deputy Director of Medical Oncology Center and Director of Thoracic Medical Oncology (presiding over the work of the Medical Oncology Center), doctor of oncology, postgraduate tutor of University of Electronic Science and Technology of China School of Medicine and Chengdu Medical School
Sichuan Anti-Japanese Medicine Chairman of Cancer Pain Committee of Cancer Society
Deputy Chairman of Oncology Branch of Chinese Society of Medical Bioimmunology
Zhonghua Vice-Chairman of Cancer Immunology, Sichuan Branch of the Society of Immunology
Vice-Chairman of the Cancer Treatment Committee of the Sichuan Women’s Physician Association
Business Director of Sichuan Tumor Disease Medical Quality Control Center
Deputy Director of Chengdu Cancer Prevention and Control Special Committee
Excellent experts with outstanding contributions in Sichuan Province
Director of Sichuan International Medical Exchange Promotion Association
Academic Technology of Sichuan Provincial Department of Health Leader
Editorial board member of “Tumor Prevention and Treatment”
Challenges: For ALK-positive NSCLC patients, optimizing treatment strategies for brain metastases is of great significance
Professor Yao introduced, ALK is one of the important driving genes for the occurrence and development of lung cancer, and it is also the “golden target” of current cancer treatment. Studies have shown that 30% of newly diagnosed patients may develop brain metastases, and over time, the cumulative incidence of brain metastases from ALK-positive NSCLC is higher2-3.
Before the advent of targeted drugs, the main treatments for patients with brain metastases were radiotherapy and chemotherapy. Radiotherapy mainly includes whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS). However, these methods all have certain limitations1:
1. Internal subclinical lesions have a certain control effect, but due to the dose limitation of normal brain tissue, it is difficult to cure intracranial lesions. About 1/3 of patients with brain metastases have uncontrolled intracranial lesions after WBRT, which cannot effectively prolong overall survival (OS). ), the therapy may also reduce the quality of life of patients; while a single SRS is difficult to achieve a good local control effect for larger lesions, and the treatment toxicity is significantly increased.
2. Chemotherapy drugs are difficult to penetrate the blood-brain barrier due to their large molecular weight, charge and easy binding to albumin. Metastases play an anti-tumor effect.
Professor Yao pointed out that, the emergence of targeted drugs, the treatment of ALK-positive advanced NSCLC Brain metastases offer new hope. At present, a variety of ALK-TKIs have been used in clinical practice. However, the generation ALK-TKI has a low intracranial remission rate and relatively limited intracranial control effect, while the new generation ALK-TKI brigatinib has a better control effect on brain metastases.
“The magic touch”: Brigatinib sustained and effective control of brain metastases, bringing new hope to patients with ALK positive NSCLC Protein (P-gp) and breast cancer resistance protein (BCRP) can expel small molecules including drugs from the brain, making it difficult for drugs to reach effective concentrations in the brain and unable to exert their due efficacy. It is the main reason for the failure of drug treatment. Professor Yao introduced, the first-generation ALK-TKI crizotinib is a P-gp protein substrate with low brain penetration rate, so it has relatively poor intracranial control< sup>4-5. The efficacy of brigatinib in the treatment of ALK-positive advanced NSCLC patients with brain metastases at baseline is very good! The results of an international multi-center, phase III clinical study (ALTA-1L study) showed that 6-8, the intracranial lesion response rate (iORR) for patients with measurable brain metastases at baseline was close to 80%, and brigatinib had a Duration of Response (DoR) of 27.9 months. Compared with the first generation of crizotinib, the efficacy of brigatinib is very bright.
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Figure 1 iORR and DoR results in patients with brain metastases
So, can the excellent intracranial response of brigatinib also bring durable survival benefits to patients?
Professor Yao’s introduction, via Bugatti BIRC-assessed median progression-free survival (PFS) of 24 months (HR=0.25, p<0.0001), 75% lower risk of disease progression and death. In terms of OS rate, the 4-year OS rate of patients with baseline brain metastases treated with brigatinib was as high as 71%6-8. It fully reflects the good survival benefit of brigatinib in patients with brain metastases.
Professor Yao added, brigatinib can break the bottleneck in the treatment of brain metastases , bringing lasting intracranial protection to patients with brain metastases is inseparable from its unique molecular structure and mechanism of action9. Brigatinib has a unique DMPO structure (dimethylphosphorus oxide), which ensures high selectivity and enhances drug activity. At the same time, its characteristics of high solubility and high permeability, and balanced water solubility and lipid solubility create very favorable objective conditions for penetrating the blood-brain barrier and maintaining the concentration of drugs in the brain. Appropriate drug concentration can not only achieve continuous and effective relief of intracranial symptoms, but also will not cause excessive intracranial adverse events due to excessive concentration. At present, brigatinib has been approved for marketing in China. It is believed that there will be better development in the future. At the same time, it is hoped that brigatinib can bring better benefits to more Chinese patients.
“Tailored”: Precision therapy helps lung cancer achieve “chronic disease management”
With the rapid development of basic and clinical research, people gradually recognize tumors According to some characteristics of the tumor, the tumor can be reclassified from clinical classification to pathological classification, and then to molecular classification. Molecular typing is an indispensable therapeutic basis in the field of targeted therapy. Professor Yao said , in the era of precision medicine, clinicians not only need to know the patient’s pathological type, but also need to know whether the patient has gene mutation, PD- L1 expression level, the patient’s physical condition and the state of organ function, so that individualized diagnosis and treatment can be carried out for each patient. Among them, for the presence of driver genesPatients with mutations (such as EGFR-positive, ALK-positive, etc.) are usually treated with targeted therapy, so that patients can achieve long-term survival. At present, in addition to common EGFR mutations and ALK mutations, there are also targeted drugs for some rare mutations, such as ROS1, BRAF, RET, NTRK, MET exon 14 skipping mutations, etc., and have achieved good curative effect. . If the patient has no driver gene mutation, single-agent immunotherapy, immunotherapy combined with chemotherapy, or immunotherapy combined with antiangiogenic therapy can be selected according to PD-L1 expression level, TMB level, or other clinical characteristics. The purpose is to improve patient survival. Improve patients’ quality of life.
In addition, multidisciplinary diagnosis and treatment (MDT) is also very important. Professor Yao introduced, a single department often has limited treatment, and multi-disciplinary (internal medicine, radiotherapy, surgery, pathology, imaging, etc.) Help provide patients with individualized “tailor-made” treatment plans to help patients benefit more. As early as ten years ago, Sichuan Cancer Hospital established a lung cancer MDT team. “We will select patients with controversial treatment and bring them up for discussion. Through multidisciplinary diagnosis and treatment, the overall 5-year survival rate of lung cancer patients in our center has been significantly improved, especially for patients with ALK-positive NSCLC, which has basically achieved chronic disease. management.”Professor Yao added.
References:
1 . Oncologists Branch of Chinese Medical Doctor Association. Chinese guidelines for the treatment of brain metastases from lung cancer (2021 edition). Chinese Journal of Oncology. 2021.43(3):269-281.
2. Zou Z, Xing P, Hao X, et al. Intracranial efficacy of alectinib in ALK-positive NSCLC patients with CNS metastases-a multicenter retrospective study. BMC Med. 2022 Jan 18;20(1 ): 12.
3. Zhang Xuchao, Lu Shun, Zhang Li et al. Guidelines for the diagnosis and treatment of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer in China[J]. Zhonghua Disease Journal of Science. 2015,44(10):696-703.
4. Cheng H, Perez-Soler R. Leptomeningeal metastases in non-small-cell lung cancer.Lancet Oncol . 2018 Jan;19(1):e43-e55.
5. Costa DB, Kobayashi S, Pandya SS, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011 May 20;29(15):e443-5.
6. 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.< /span>
7. 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.
8. Camidge DR, et al. Brigatinib vs Crizotinib in ALK Inhibitor–Naïve Advanced ALK+ NSCLC: Updated Results From the Phase 3 ALTA-1L Trial.ALTA-1L 2019 ESMO ASIA.
9. 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.
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Approval code: C-APROM/CN/ALUN/0173
Approval date: July 2022
Editor: Dayuan
Typesetting: Yami
Execution: Xiaoyuan