Method for treating alk-positive or ros1-positive non-small cell lung cancer

Abstract

Provided is a method for treating ALK-positive non-small cell lung cancer in a subject by means of administering a compound A or a pharmaceutically acceptable salt thereof to the subject. Further provided is a method for treating ROS1-positive non-small cell lung cancer in a subject by means of administering compound A or a pharmaceutically acceptable salt thereof to the subject.

Description

Methods for treating ALK-positive or ROS1-positive non-small cell lung cancer Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a method for treating non-small cell lung cancer, such as ALK-positive and / or ROS1-positive non-small cell lung cancer, using a macrocyclic compound (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(methylene bridge)pyrazolo[4,3-h][2,5,11]benzoxadiazatetradecane-3-carbonitrile (Compound A) or a pharmaceutically acceptable salt thereof. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase that belongs to the insulin receptor superfamily. It was first discovered in 1994 by Morris, Shiota, and colleagues as a product of a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). The most common fusion is between the NPM (nucleophosmin) gene on chromosome 5 and the ALK gene on chromosome 2. NPM-ALK fusion protein is detected in approximately 75% of ALK-positive ALCL patients. Subsequent studies have found different ALK fusion forms in a variety of cancers, including inflammatory myofibroblastic tumor and diffuse large B-cell lymphoma. Despite this, the importance of ALK kinase as an effective anticancer drug target has not been fully recognized. It wasn't until 2007, when Soda et al. discovered that the EML4-ALK fusion protein occurs in 5% of non-small-cell lung cancer (NSCLC) cases, that the importance of ALK kinase as an anti-cancer drug target became apparent. This is due to the enormous number of cancer patients worldwide, with lung cancer being the leading cause. Over 8,000 new cases of ALK-positive lung cancer are diagnosed annually in the United States, while China experiences over 65,000 new cases annually. Furthermore, the global five-year survival rate for lung cancer is only 15%. Interestingly, patients with EML4-ALK gene positivity generally do not carry mutations in the epidermal growth factor receptor (EGFR) or the Kirsten rat sarcoma virus (KRAS), making the EML4-ALK fusion gene a unique molecular target for NSCLC. Furthermore, ALK gene amplification or point mutations have been found in neuroblastomas, anaplastic thyroid cancer, and ovarian cancer.

[0003] ROS1 is a proto-oncogene receptor tyrosine kinase belonging to the insulin receptor subfamily and is involved in cell proliferation and differentiation. ROS1 is expressed in epithelial cells of various human tissues. ROS1 expression and / or activation have been found in glioblastoma and tumors of the central nervous system. Genetic alterations of ROS1 that result in abnormal fusion proteins leading to ROS1 kinase include FIG-ROS1 deletion translocation in glioblastoma and non-small cell lung cancer (NSCLC), SLC34A2-ROS1 translocation in NSCLC, and CD74-ROS1 translocation in NSCLC and cholangiocarcinoma. Additional fusions have been found in tumor samples from lung cancer patients, including TPM3-ROS1, SDC4-ROS1, EZR-ROS1, and LRTG3-ROS1.

[0004] SUMMARY OF THE INVENTION

[0005] The present invention provides a use and method of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer, such as ALK-positive and / or ROS1-positive non-small cell lung cancer.

[0006] In one aspect, the present invention discloses the use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer, wherein the Compound A has the following structure:

[0007] In another aspect, the present invention discloses a method for treating non-small cell lung cancer in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A has the following structure:

[0008] In another aspect, the present invention discloses Compound A or a pharmaceutically acceptable salt thereof for use in treating non-small cell lung cancer, wherein the Compound A has the following structure:

[0009] In another aspect, disclosed herein is a method for detecting the concentration of Compound A in the CNS fluid of a subject in ALK-positive and / or ROS1-positive CNS-metastatic non-small cell lung cancer, comprising:

[0010] a. Collect a sample of cerebrospinal fluid; and

[0011] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 shows the growth curves of tumor volume in the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (10 mg / kg), medium-dose (3 mg / kg), and low-dose (1 mg / kg) groups of mice in the Ba / F3 (EML4-ALK L1196M) subcutaneous tumor model.

[0013] Figure 2 shows the body weight change curves of the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (10 mg / kg) group, medium-dose (3 mg / kg) group, and low-dose (1 mg / kg) group over treatment time in the Ba / F3 (EML4-ALK L1196M) subcutaneous tumor model.

[0014] Figure 3 shows the curves of the percentage change in body weight over treatment time in the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (10 mg / kg) group, medium-dose (3 mg / kg) group, and low-dose (1 mg / kg) group in the Ba / F3 (EML4-ALK L1196M) subcutaneous tumor model.

[0015] Figure 4 shows the growth curves of tumor volume in the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (15 mg / kg), medium-dose (5 mg / kg), and low-dose (1.5 mg / kg) groups of mice in the Ba / F3 (EML4-ALK G1202R) subcutaneous tumor model.

[0016] Figure 5 shows the body weight change curves of the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (15 mg / kg) group, medium-dose (5 mg / kg) group, and low-dose (1.5 mg / kg) group over treatment time in the Ba / F3 (EML4-ALK G1202R) subcutaneous tumor model.

[0017] Figure 6 shows the curve of the percentage change in body weight over treatment time for the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (15 mg / kg) group, medium-dose (5 mg / kg) group, and low-dose (1.5 mg / kg) group in the Ba / F3 (EML4-ALK G1202R) subcutaneous tumor model.

[0018] Figure 7 shows the growth curves of tumor volume in the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the experimental drug compound A high-dose (15 mg / kg), medium-dose (5 mg / kg), and low-dose (1.5 mg / kg) groups of mice in the Ba / F3 (SLC34A2-ROS1G2032R) subcutaneous tumor model.

[0019] Figure 8 shows the body weight change curves of the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the experimental drug compound A high-dose (15 mg / kg) group, medium-dose (5 mg / kg) group, and low-dose (1.5 mg / kg) group over treatment time in the Ba / F3 (SLC34A2-ROS1 G2032R) subcutaneous tumor model.

[0020] Figure 9 shows the percentage change curve of body weight over treatment time in the vehicle control group, the positive control group Crizotinib (100 mg / kg), and the test drug compound A high-dose (15 mg / kg) group, medium-dose (5 mg / kg) group, and low-dose (1.5 mg / kg) group in the Ba / F3 (SLC34A2-ROS1 G2032R) subcutaneous tumor model.

[0021] Figure 10 is a waterfall plot of the best percentage change from baseline in the sum of the total tumor diameter among subjects with ALK-positive post-baseline efficacy evaluation in the indication expansion phase – full analysis set (RP2D dose group), of which Figure 10a shows the results for 93 subjects who had previously received second-generation TKI treatment, Figure 10b shows the results for 14 subjects who had previously received crizotinib treatment, and Figure 10c shows the results for 33 ALK TKI-naive patients.

[0022] FIG11a shows the results of systemic progression-free survival in ALK-positive subjects in the indication expansion phase.

[0023] Figure 11b is a Kaplan-Meier plot of ALK-positive progression-free survival in the indication expansion phase – full analysis set (primary analysis).

[0024] Figure 12a shows the results of intracranial progression-free survival in ALK-positive subjects in the indication expansion phase, where Group A Cohort 2 includes 5 subjects with intracranial metastases in the 60 mg group in the dose escalation and expansion phases.

[0025] Figure 12b is a Kaplan-Meier plot of overall survival for ALK-positive patients in the indication expansion phase – full analysis set (primary analysis).

[0026] Figure 12c is a Kaplan-Meier plot of ROS1-positive progression-free survival in the indication expansion phase – full analysis set (primary analysis).

[0027] Figure 12d is a Kaplan-Meier plot of overall survival for ROS1-positive patients in the indication expansion phase – full analysis set (primary analysis).

[0028] Figure 13 shows the PFS of patients with mutant TP53 or wild-type TP53 treated with Compound A in the ALK TKI-resistant subgroup.

[0029] Figure 14 is a waterfall plot of the best percentage change from baseline in the sum of whole-body tumor diameters (IRC assessment results) – full analysis set.

[0030] Figure 15 shows the Kaplan-Meier curve of PFS (IRC assessment results) – full analysis set.

[0031] Figure 16 is a waterfall plot of the best percentage change from baseline in the sum of intracranial tumor diameters (IRC assessment results) – full analysis set.

[0032] Figure 17 shows the Kaplan-Meier curve of IC-PFS (IRC assessment result) – full analysis set.

[0033] Figure 18 is a forest plot of the objective response rate (%) in each subgroup (IRC assessment results) - full analysis set.

[0034] Detailed Description of the Invention

[0035] The present invention has discovered that Compound A can be used to treat ALK-positive and / or ROS1-positive non-small cell lung cancer. Therefore, the present invention discloses the use and method of Compound A or a pharmaceutically acceptable salt thereof in treating ALK-positive and / or ROS1-positive non-small cell lung cancer.

[0036] Abbreviations

[0037] definition

[0038] The present invention may be more readily understood by reference to the following detailed description of embodiments of the invention and the examples included herein. It should be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting. It should be further understood that, unless otherwise specifically defined herein, the terms used herein should be given their ordinary meanings known in the relevant art.

[0039] As used herein, the singular forms "a," "an," and "the" include plural references unless otherwise indicated. For example, "a" compound includes one or more compounds.

[0040] As used herein, the use of "or" means "and / or" unless stated otherwise.

[0041] Use of the term "include," as well as other forms such as "including," "containing," and "having," is not limiting.

[0042] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, guidelines, and treatises, are hereby expressly incorporated herein by reference in their entirety for any purpose.

[0043] "Subject" includes, but is not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0044] "Disease," "disorder," and "condition" are used interchangeably herein.

[0045] As used herein, and unless otherwise indicated, the term "treating" includes actions that occur while a subject has a particular disease, disorder, or condition that reduce the severity of, or delay or slow the development of, the disease, disorder, or condition ("therapeutic treatment"), as well as actions that occur before a subject becomes ill with a particular disease, disorder, or condition ("prophylactic treatment").

[0046] A "therapeutically effective amount" refers to a dose sufficient to prevent, delay progression, or cause regression of a disease, or to reduce symptoms caused by a disease such as cancer, eg, lung cancer (such as NSCLC).

[0047] "Non-small cell lung cancer (NSCLC)" refers to any type of lung cancer that is different from small cell lung cancer. NSCLC includes squamous cell carcinoma (SQCC), adenocarcinoma (ADC) and large cell carcinoma. Both ADC and large cell carcinoma are classified as non-squamous cell types of cancer. ADC can be divided into subclasses, including acinar carcinoma, papillary carcinoma, bronchogenic carcinoma (BAC), solid tumors and mixed subtypes (2004 World Health Organization classification of lung tumors, Beasley et al., Semin. Roentgenol. 40:90-97, 2004). ADC accounts for approximately 40% of all lung cancers and is the most common form of lung cancer among individuals who have never smoked. ADC is classified as a non-squamous cell type of NSCLC. Histologically, ADC shows glandular formation, papillary structure or solid growth with mucin production. Large cell carcinoma includes the subclasses giant cell tumor, clear cell carcinoma, adenosquamous carcinoma and undifferentiated carcinoma.

[0048] A "sample" is a biological specimen obtained from a subject and containing genomic DNA, RNA (including mRNA), protein, or other combinations thereof. Examples include specimens containing at least one NSCLC cell ("NSCLC sample"), such as tissue or tumor biopsy, fine needle aspirate, bronchoalveolar lavage, pleural fluid, sputum, surgical specimen, lymph node, NSCLC metastasis, peripheral blood, or autopsy material. In other examples, the sample includes a control, such as a non-NSCLC cell or tissue sample.

[0049] "ALK" is a transmembrane receptor tyrosine kinase that belongs to the insulin receptor subfamily. The ALK receptor tyrosine kinase (RTK) was initially identified due to its involvement in a subtype of human non-Hodgkin's lymphoma known as anaplastic large cell lymphoma (ALCL). ALK normally has a restricted distribution in mammalian cells and is found at significant levels only in the nervous system during embryonic development, suggesting a role for ALK in brain development.

[0050] In addition to its role in normal development, expression of full-length normal ALK has been detected in cell lines derived from a variety of tumors, such as glioblastoma, neuroectodermal tumors and glioblastoma, as well as breast cancer and melanoma lines.

[0051] As with other RTKs, translocations affect the ALK gene, resulting in the expression of protocellular fusion kinases, the most common of which is NPM-ALK. For example, approximately 60% of anaplastic large cell lymphomas (ALCL) are associated with chromosomal mutations that produce a fusion protein composed of the intracellular domain of nucleolar phosphatidylcholine (NMP) ALK. This mutant protein, NPM-ALK, possesses a constitutively active tyrosine kinase domain that is responsible for its oncogenic properties by activating downstream effectors. Experimental data have demonstrated that aberrant expression of constitutively active ALK is directly involved in the pathogenesis of ALCL and that such inhibition of ALK can significantly impede the growth of ALK-positive lymphoma cells. Constitutively activated chimeric ALK has been shown to be present in approximately 60% of inflammatory myofibroblastic tumors (IMT), a slow-growing sarcoma that primarily affects children and young adults. In addition, recent reports have described the emergence of the variant ALK fusion TPM4-ALK in cases of squamous cell carcinoma (SCC) of the esophagus. Therefore, ALK is one of the few examples of RTK involved in the neoplasia in both non-hematopoietic and hematopoietic malignancies. Recently, it has been shown that inversion within chromosome 2p leads to the formation of a fusion gene comprising a portion of the thorny microtubule-associated protein 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer cells. In non-small cell lung cancer, exemplary ALK fusions include EML4-ALK, KIF5B-ALK, KLC1-ALK, PTPN3-ALK, HIP1-ALK, TPR-ALK, STRN-ALK, PPM1B-ALK, EIF2AK3-ALK, SPDYA-ALK, ASXL2-ALK, BIRC6-ALK, PICALM-ALK, CRIM1-ALK, CUX-ALK, FAM179A-ALK, COL25A1-ALK, BIRC6-ALK and PICALM-ALK, among which EML4-ALK is more common. ALK fusion gene detection can be performed using IHC, FISH, RT-PCR, or HTS methods.

[0052] "ALK-positive" refers to chromosomal rearrangement of the ALK fusion gene and / or ALK overexpression and / or ALK point mutation in the tumor. In some embodiments, ALK-positive requires one of the following test results: FISH, RT-PCR, IHC, or NGS (high-throughput sequencing) as diagnostic evidence.

[0053] ROS1 belongs to the sevenless subfamily of insulin receptor genes, a family of receptor tyrosine kinases. The protein encoded by this gene is a type I integral membrane protein with tyrosine kinase activity. ROS1 shares structural similarity with the ALK protein. Genetic rearrangements involving ROS1 have been identified in various cancers. The small molecule tyrosine kinase inhibitor crizotinib has been approved for the treatment of patients with metastatic NSCLC whose tumors are ROS1-positive or ALK-positive. In non-small cell lung cancer, exemplary ROS1 fusions include SLC34A2-ROS1, CD74-ROS1, TPM3-ROS1, SDC4-ROS1, EZR-ROS1, LRIG3-ROS1, KDELR2-ROS1, CCDC6-ROS1, FIG-ROS1, TPD52L1-ROS1, FYN-ROS1, MKX-ROS1, CLTC-ROS1 and LIMA1-ROS1, among which SLC34A2-ROS1, CD74-ROS1, EZR-ROS1 or SDC4-ROS1 are more common.

[0054] "SLC34A2-ROS1 fusion protein or gene" refers to a somatic gene fusion of the partner SLC34A2 and ROS1. In some embodiments, the SLC34A2-ROS1 fusion protein includes the N-terminal domain of a fusion partner, such as SLC34A2, and the C-terminal kinase domain of the ROS1 protein. The N-terminal domain of the fusion partner can be located at the N-terminus of the fusion protein, and the C-terminal kinase domain of the ROS1 protein can be located at the C-terminus of the fusion protein. The fusion partner can be the N-terminal domain of the SLC34A2 protein located at the N-terminus of the fusion protein. In this case, the fusion protein can be expressed as an SLC34A2-ROS1 protein comprising the N-terminal domain of the SLC34A2 protein at the N-terminus and the C-terminal kinase domain of the ROS1 protein at the C-terminus. In another embodiment, a fusion gene encoding the fusion protein is provided, wherein the gene encoding the N-terminal domain of the fusion partner is located at the 5' end, and the gene encoding the C-terminal kinase domain of the ROS1 protein is located at the 3' end. In some embodiments, a portion of the SLC34A2 protein is fused in frame to a portion of the ROS1 protein comprising a functional kinase domain due to an aberrant chromosomal translocation that produces a ROS1 chromosomal rearrangement in the presence of SLC34A2. In some embodiments, the SLC34A2-ROS1 fusion protein may comprise a fusion of SLC34A2 exon 4 to ROS1 fusion exon 32. In some embodiments, the SLC34A2-ROS1 fusion protein may comprise a fusion of SLC34A2 exon 4 to ROS1 fusion exon 34.

[0055] "ROS1 positive" refers to chromosomal rearrangement of the ROS1 fusion gene and / or ROS1 overexpression in the tumor. In some embodiments, ROS1 positivity requires one of the following test results: FISH, RT-PCR, or NGS as diagnostic evidence.

[0056] "ALK inhibitor" is a molecule that inhibits or reduces ALK activity, such as ALK tyrosine kinase activity. In some examples, ALK inhibitors can be small molecules, proteins (such as antibodies) or nucleic acids (such as antisense molecules). ALK inhibitors can inhibit or reduce the binding of ligands (such as pleiotrophin) to ALK, and thus reduce ALK tyrosine kinase activity. ALK inhibitors can also directly inhibit or reduce ALK tyrosine kinase activity, such as ATP competitive inhibitors (such as crizotinib). Molecules that reduce or inhibit ALK expression, such as antisense molecules, are also ALK inhibitors. In some examples, ALK inhibitors inhibit or reduce the activity of genetically altered ALK, such as ALK gene fusions (including but not limited to ALK-EML4 gene fusions). ALK inhibitors can specifically inhibit ALK tyrosine kinase activity or can inhibit other receptor tyrosine kinase activities (such as c-Met / HGFR activity) outside of inhibiting ALK tyrosine kinase activity. Hua Gao et al., (Synthesis and clinical application of small-molecule inhibitors and PROTACs of anaplastic lymphoma kinase. Bioorganic Chemistry 140 (2023) 106807) discloses small molecule ALK inhibitors that are on the market and in various stages of development in Table 1, which is incorporated herein by reference in its entirety for all purposes.

[0057] "First, second or third generation ALK inhibitor" refers to a first, second or third generation ALK inhibitor.

[0058] For "first-line, second-line, third-line, fourth-line, and fifth-line treatments for ALK-positive or ROS1-positive non-small cell lung cancer," please refer to the "Guidelines for the Diagnosis and Treatment of Primary Lung Cancer" updated in 2022 by the Expert Committee of the Chinese Society of Clinical Oncology (CSCO).

[0059] The definition of "advanced non-small cell lung cancer" is non-small cell lung cancer in stages IIIB, IIIC, and IV. Please refer to the "Guidelines for the Diagnosis and Treatment of Primary Lung Cancer" updated in 2022.

[0060] The PK parameters of a single dose mainly include peak concentration (C max ), peak time (T max ), half-life (T1 / 2 ), systemic clearance (CL) and volume of distribution (Vd), AUC 0-t , AUC 0-∞ ; Multiple-dose PK parameters mainly include the area under the steady-state plasma concentration-time curve (AUC ss ), steady-state peak plasma concentration (C max，ss ), steady-state blood trough concentration (C min，ss ) and time to peak blood drug concentration (T max，ss )wait.

[0061] Adverse events will be described using MedDRA (Medical Dictionary for Reproductive Diseases). Analysis of adverse events will be based on treatment-emergent adverse events (TEAEs). TEAEs are defined as adverse events that occur or worsen after treatment / medication.

[0062] Anti-tumor efficacy was evaluated according to RECIST version 1.1. For patients who achieved complete remission (CR) or partial remission (PR) in the initial evaluation, efficacy was confirmed at least 4 weeks later. In patients with asymptomatic central nervous system (CNS) metastases, in addition to evaluating 5 extracranial target lesions, up to 5 intracranial target lesions were also evaluated. Specific indicators are as follows:

[0063] "CR" was defined as the disappearance of all target lesions, and the short-axis diameter of all pathological lymph nodes (whether target or non-target lymph nodes) must be reduced to less than 10 mm.

[0064] “PR” was defined as a reduction of at least 30% in the sum of the diameters of target lesions, based on the baseline sum of the diameters.

[0065] "PD" is defined as an increase of at least 20% in the sum of the diameters of target lesions, using the smallest sum of diameters in the study as the reference value (this value can include the baseline sum of diameters). In addition, an absolute increase of at least 5 mm in the sum of diameters must also be met (the appearance of one or more new lesions is also considered progressive disease).

[0066] "SD" is defined as a state in which the decrease in target lesions is insufficient to achieve partial response and the increase in target lesions is insufficient to achieve disease progression.

[0067] “ORR” includes CR and PR and is defined as the proportion of patients with complete response or partial response.

[0068] “IC-ORR” included CR or PR in patients with confirmed intracranial lesions and was defined as the proportion of patients with complete response or partial response to intracranial lesions among patients with intracranial lesions.

[0069] "DCR" is defined as the proportion of patients who achieved response (PR+CR) and stable disease (SD) after treatment.

[0070] “IC-DCR” is defined as the proportion of patients with intracranial lesions who achieved intracranial remission (PR+CR), intracranial disease stability (SD), and non-target lesion CR / non-target lesion PD after treatment.

[0071] "DOR" is defined as the time from the first assessment of CR or PR to disease progression or death and is only applicable to patients who achieve remission.

[0072] "IC-DOR" is defined as the time from the first assessment of intracranial CR or intracranial PR to disease progression or death, and is only applicable to patients who achieve remission of intracranial lesions.

[0073] "TTR" is defined as the time from patient enrollment (first dose of trial drug) to tumor response (CR / PR) based on patients with an objective response.

[0074] "IC-TTR" is defined as the time from patient enrollment (first dose of trial drug) to intracranial tumor response (IC-CR / PR) based on patients with an intracranial objective response.

[0075] "PFS" is defined as the time from the first dose of trial drug to disease progression (PD) or death from any cause, whichever occurs first.

[0076] “IC-PFS” was defined as the time from the first dose of trial drug to intracranial tumor progression (PD) or death from any cause, whichever occurred first;

[0077] “OS” was defined as the time from the first dose of trial drug to death from any cause.

[0078] Compound A

[0079] The present invention relates to compound A of the following formula:

[0080] or a pharmaceutically acceptable salt thereof.

[0081] Compound A, chemically named (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(methylene-bridged)pyrazolo[4,3-h][2,5,11]benzoxadiazatetradecane-3-carbonitrile, is a third-generation ALK / ROS1 dual tyrosine kinase inhibitor. It disrupts the ALK and ROS1 signaling pathways, inhibiting overexpression of ALK and ROS1 in NSCLC cells and thereby suppressing NSCLC cell proliferation. It is sensitive to most secondary ALK kinase domain mutations, including the G1202R solvent front region mutation, and can cross the blood-brain barrier. Compound A and its preparation were first disclosed in WO2017 / 148325A1, followed by its preparation method in WO2020 / 108522A1, and subsequently its salt form, crystal form and pharmaceutical composition in WO2021 / 233296A1. The full text of these three patents are incorporated herein by reference for all purposes.

[0082] The term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., and are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66: 1-19. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and inorganic and organic bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts formed with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Salts formed using conventional methods in the art, such as ion exchange methods, are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, if appropriate.

[0083] In certain embodiments, in an X-ray powder diffraction pattern obtained using CuKα radiation, Compound A comprises at least characteristic peaks located at the following °2θ: 16.175±0.2, 17.299±0.2, and 21.218±0.2. In a specific embodiment, in the X-ray powder diffraction pattern, Compound A further comprises characteristic peaks located at the following °2θ: 9.637±0.2, 12.555±0.2, 14.343±0.2, and 19.366±0.2. In a specific embodiment, in the X-ray powder diffraction pattern, Compound A further comprises characteristic peaks located at the following °2θ: 7.435±0.2, 10.11±0.2, 11.808±0.2, 14.922±0.2, 18.359±0.2, 19.859±0.2, 23.401±0.2, 23.939±0.2, 25.117±0.2, 25.727±0.2, 26.831±0.2 and 28.862±0.2.

[0084] Pharmaceutical composition

[0085] Compositions of Compound A and methods of preparing the same are described in WO 2021 / 233296 A1, which is incorporated herein by reference in its entirety for all purposes.

[0086] In one aspect, the present invention provides uses and methods of a pharmaceutical composition for treating ALK-positive non-small cell lung cancer, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0087] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating ALK-positive CNS metastatic non-small cell lung cancer, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0088] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating non-small cell lung cancer with EML4-ALK L1196M mutation, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0089] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating CNS-metastatic non-small cell lung cancer with EML4-ALK L1196M mutation, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0090] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating non-small cell lung cancer with EML4-ALK G1202R mutation, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0091] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating CNS-metastatic non-small cell lung cancer with EML4-ALK G1202R mutation, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0092] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating ROS1-positive non-small cell lung cancer, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0093] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating ROS1-positive CNS metastatic non-small cell lung cancer, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0094] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating non-small cell lung cancer with SLC34A2-ROS1 G2032R mutation, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0095] In another aspect, the present invention provides uses and methods of a pharmaceutical composition for treating CNS-metastatic non-small cell lung cancer with RSLC34A2-ROS1 G2032R mutation, wherein the pharmaceutical composition comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0096] In certain embodiments, the pharmaceutical compositions taught by the present invention comprise (i) a pharmaceutically active ingredient: a crystalline form of the free base of Compound A or a crystalline form of a pharmaceutically acceptable salt thereof, (ii) a diluent, (iii) a disintegrant, (iv) a binder, and (v) a lubricant.

[0097] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the crystalline form in the total weight of the pharmaceutical composition is 1-30%, preferably 2-20%, preferably 3-15%, more preferably about 4%, 5%, 6%, 7%, 8%, 9% or 10%, more preferably about 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 15% or 16%, more preferably about 6.25% or 15.38%, based on the free base of the compound. Calculated by weight; preferably, the content of the crystalline form in a unit dose is 1-100 mg, preferably 2-50 mg, preferably 3-40 mg, preferably 5-60 mg, preferably 10-100 mg, preferably about 5, 10, 15, 20, 25, 30, 35 or 40 mg, preferably about 5, 10, 15, 20, 25, 30, 35, 40, 50, 55, 60, 65, 70 or 80 mg, preferably about 5, 20, 25 or 60 mg.

[0098] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the diluent to the total weight of the pharmaceutical composition is 65-95%, preferably 70-90%, preferably about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%; preferably, the content of the diluent in the unit dose is 50-380 mg, preferably 60-360 mg, preferably 70-350 mg, for example about 70 mg or 350 mg.

[0099] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the diluent is selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate and mannitol, such as microcrystalline cellulose 102, mannitol 100SD and mannitol 50C, and mixtures thereof; preferably, when microcrystalline cellulose 102 and mannitol 50C are present at the same time, the weight ratio of microcrystalline cellulose 102 to mannitol 50C is 5:1 to 1:5, preferably 3:1 to 1:2, preferably about 2:1.

[0100] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the disintegrant to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the content of the disintegrant in a unit dose is 1-20 mg, preferably 2-16 mg, preferably about 2, 2.5, 3, 6, 9 or 12 mg.

[0101] In a specific embodiment, the present invention provides the above pharmaceutical composition, wherein the disintegrant is cross-linked carboxymethyl cellulose sodium or cross-linked povidone XL-10, preferably cross-linked carboxymethyl cellulose sodium.

[0102] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the binder to the total weight of the pharmaceutical composition is 1-5%, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the content of the binder in the unit dose is 1-20 mg, preferably 2-16 mg, preferably about 2, 2.5, 3, 6, 9 or 12 mg.

[0103] In a specific embodiment, the present invention provides the above pharmaceutical composition, wherein the binder is hydroxypropylcellulose EXF or povidone K30, preferably hydroxypropylcellulose EXF.

[0104] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the weight percentage of the lubricant to the total weight of the pharmaceutical composition is 0.1-5%, preferably 0.5-2%, preferably about 1%; preferably, the content of the lubricant in the unit dose is 0.1-20 mg, preferably 0.5-8 mg, preferably about 0.5, 1, 2, 3, 4, 5, 6, 7 or 8 mg.

[0105] In a specific embodiment, the present invention provides the above pharmaceutical composition, wherein the lubricant is magnesium stearate or sodium stearyl fumarate PRUV, preferably magnesium stearate.

[0106] In certain embodiments, the present invention provides the above-mentioned pharmaceutical composition, which comprises the following ingredients:

[0107] (i) 1-30% by weight of compound A,

[0108] (ii) 65-95% by weight of microcrystalline cellulose 102 and mannitol 50C (weight ratio of about 2:1),

[0109] (iii) 2-4% by weight of cross-linked sodium carboxymethyl cellulose,

[0110] (iv) 2-4% by weight of hydroxypropylcellulose EXF, and

[0111] (v) 0.1-5% by weight of magnesium stearate.

[0112] In certain embodiments, the present invention provides the above-described pharmaceutical composition, wherein the unit dose comprises the following components:

[0113] (i) about 5 mg of Compound A,

[0114] (ii) about 46.2 mg microcrystalline cellulose 102 and about 23.2 mg mannitol 50C,

[0115] (iii) about 2.4 mg croscarmellose sodium,

[0116] (iv) about 2.4 mg of hydroxypropylcellulose EXF, and

[0117] (v) about 0.8 mg magnesium stearate.

[0118] In certain embodiments, the present invention provides the above-described pharmaceutical composition, wherein the unit dose comprises the following components:

[0119] (i) about 25 mg of Compound A,

[0120] (ii) about 231 mg of Avicel 102 and about 116 mg of Mannitol 50C,

[0121] (iii) about 12 mg croscarmellose sodium,

[0122] (iv) about 12 mg of hydroxypropylcellulose EXF, and

[0123] (v) about 4 mg magnesium stearate.

[0124] In a specific embodiment, Compound A in the pharmaceutical composition comprises at least characteristic peaks at the following °2θ in an X-ray powder diffraction pattern obtained using CuKα radiation: 16.175±0.2, 17.299±0.2, and 21.218±0.2. In another embodiment, in the X-ray powder diffraction pattern, Compound A further comprises characteristic peaks at the following °2θ: 9.637±0.2, 12.555±0.2, 14.343±0.2, and 19.366±0.2. In certain embodiments, in the X-ray powder diffraction pattern, Compound A further comprises characteristic peaks located at the following °2θ: 7.435±0.2, 10.11±0.2, 11.808±0.2, 14.922±0.2, 18.359±0.2, 19.859±0.2, 23.401±0.2, 23.939±0.2, 25.117±0.2, 25.727±0.2, 26.831±0.2 and 28.862±0.2.

[0125] In certain embodiments, the present invention provides the above pharmaceutical composition, which is a tablet, preferably a coated tablet; preferably, the coating agent is Opadry II 85F620077.

[0126] The pharmaceutical compositions provided herein can be administered by a variety of routes, including but not limited to oral (enteral) administration, parenteral (by injection), rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC), intravenous (IV), intramuscular (IM) and intranasal administration. In one embodiment, the pharmaceutical compositions disclosed herein are administered orally.

[0127] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, for example, for the remainder of the subject's life. In one embodiment, chronic administration is intended to provide a constant level of the compound in the blood, for example, within a therapeutic window over an extended period of time.

[0128] The pharmaceutical compositions provided herein can be presented in unit dosage form for the purpose of accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.

[0129] In another embodiment, the pharmaceutical compositions provided herein are administered to a subject in a solid dosage form. In a specific embodiment, the solid dosage form is a tablet.

[0130] In another embodiment, the compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.

[0131] Use and treatment methods

[0132] ALK-positive non-small cell lung cancer

[0133] In certain embodiments, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ALK-positive non-small cell lung cancer. In a specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In a specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer to the CNS, bone, liver, adrenal, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, and the disease has progressed or is intolerant. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, and the disease has progressed or is intolerant. In another specific embodiment, the subject has previously progressed on or is intolerant to a second-generation ALK inhibitor after continuous treatment. In another specific embodiment, the second-generation ALK inhibitor is selected from Ceritinib, Alectinib, Brigatinib, Ensartinib, Iruplinalkib, or Entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from Alectinib, Ceritinib, Ensartinib, or Brigatinib. In another specific embodiment, the subject has not previously been treated with an ALK inhibitor. In another specific embodiment, the subject has not previously been treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to a first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed on or is intolerant to a first-line, second-line, third-line, fourth-line, or fifth-line treatment. In another specific embodiment, the subject has previously progressed on or is intolerant to a first-line or second-line treatment. In another embodiment, the non-small cell lung cancer has an EML4-ALK L1196M mutation or an EML4-ALK G1202R mutation. In another embodiment, the dose of Compound A is about 5 mg / day to about 180 mg / day. In another embodiment, the dose of Compound A is about 5 mg / day to about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0134] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ALK-positive non-small cell lung cancer, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiotherapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucizumab, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not been previously treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to one or more lines of therapy.In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line or second-line treatment. In another specific embodiment, the non-small cell lung cancer has an EML4-ALK L1196M mutation or an EML4-ALK G1202R mutation. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0135] ALK-positive CNS metastatic non-small cell lung cancer

[0136] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ALK-positive CNS metastatic non-small cell lung cancer. In one embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is adenocarcinoma. In another embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, followed by disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, followed by disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, followed by disease progression or intolerance. In another embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluorazolidone, or entrectinib. In another embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another embodiment, the subject has not previously been treated with an ALK inhibitor. In another embodiment, the subject has not previously been treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the non-small cell lung cancer has an EML4-ALK L1196M mutation or an EML4-ALK G1202R mutation. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day.In another embodiment, Compound A is administered until disease progression, unacceptable toxicity, or death.

[0137] In another embodiment, the present invention relates to a method for treating ALK-positive CNS metastatic non-small cell lung cancer with Compound A or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiotherapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the subject has previously progressed on or is intolerant to crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject has previously received at least a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the subject has previously received a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluorazolidone, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously been treated with an ALK inhibitor. In another specific embodiment, the subject has not previously been treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously received one or more lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one, two, three, four, or five lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one or two lines of treatment for disease progression or intolerance. In another embodiment, the non-small cell lung cancer has an EML4-ALK L1196M mutation or an EML4-ALK G1202R mutation. In another embodiment, the dose of Compound A is about 5 mg / day to about 180 mg / day. In another embodiment, the dose of Compound A is about 5 mg / day to about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death or individual choice.

[0138] In another embodiment, the present invention relates to a method for detecting the concentration of Compound A in the CNS fluid of a subject in ALK-positive CNS-metastatic non-small cell lung cancer, comprising:

[0139] a. Collect a sample of cerebrospinal fluid; and

[0140] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid.

[0141] Non-small cell lung cancer with EML4-ALK L1196M mutation

[0142] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with the EML4-ALK L1196M mutation. In one specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously experienced disease progression or intolerance after continuous treatment with crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject has previously experienced disease progression or intolerance after continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluaco or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib or brigatinib. In another specific embodiment, the subject has not been previously treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / days to about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / days, about 10 mg / days, about 20 mg / days, about 40 mg / days, about 60 mg / days, about 80 mg / days, about 100 mg / days or about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / days, about 60 mg / days, about 80 mg / days, about 100 mg / days or about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / days, about 60 mg / days or about 80 mg / days.In another embodiment, the dose of Compound A is about 60 mg / day. In another embodiment, Compound A is administered orally. In another embodiment, Compound A is administered orally on an empty stomach. In another embodiment, Compound A is administered orally once a day, twice a day, or three times a day. In another embodiment, Compound A is administered orally once a day. In another embodiment, Compound A is administered orally until disease progression, intolerable toxicity, or death.

[0143] In one embodiment, the present invention relates to uses and methods of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with the EML4-ALK L1196M mutation, wherein the non-small cell lung cancer has progressed after another therapy. In one specific embodiment, the other therapy is radiation therapy, drug therapy, or surgery. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucizumab, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not been previously treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor.In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line or second-line treatment. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0144] EML4-ALK L1196M mutation in CNS-metastatic non-small cell lung cancer

[0145] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating CNS metastatic non-small cell lung cancer with the EML4-ALK L1196M mutation. In one embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is adenocarcinoma. In another embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, resulting in disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, resulting in disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, resulting in disease progression or intolerance. In another embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucazide, or entrectinib. In another embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another embodiment, the subject has not previously been treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0146] In another embodiment, the present invention relates to uses and methods of treating CNS-metastatic non-small cell lung cancer with an EML4-ALK L1196M mutation using an effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer has progressed after another therapy. In one embodiment, the other therapy is radiation therapy, drug therapy, or surgery. In another embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the subject has previously progressed on or is intolerant to crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject has previously received at least a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the subject has previously received a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluorazolidone, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously been treated with an ALK inhibitor. In another specific embodiment, the subject has not previously been treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously received one or more lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one, two, three, four, or five lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one or two lines of treatment for disease progression or intolerance. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0147] In another embodiment, the present invention relates to a method for detecting the concentration of Compound A in the CNS fluid of a subject with CNS-metastatic non-small cell lung cancer harboring the EML4-ALK L1196M mutation, comprising:

[0148] a. Collect a sample of cerebrospinal fluid; and

[0149] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid.

[0150] Non-small cell lung cancer with EML4-ALK G1202R mutation

[0151] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with the EML4-ALK G1202R mutation. In one embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is adenocarcinoma. In another embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another embodiment, the subject has previously experienced disease progression or intolerance after continuous treatment with crizotinib as the sole ALK inhibitor. In another embodiment, the subject has previously experienced disease progression or intolerance after continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluaco or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib or brigatinib. In another specific embodiment, the subject has not been previously treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / days to about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / days, about 10 mg / days, about 20 mg / days, about 40 mg / days, about 60 mg / days, about 80 mg / days, about 100 mg / days or about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / days, about 60 mg / days, about 80 mg / days, about 100 mg / days or about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / days, about 60 mg / days or about 80 mg / days.In another embodiment, the dose of Compound A is about 60 mg / day. In another embodiment, Compound A is administered orally. In another embodiment, Compound A is administered orally on an empty stomach. In another embodiment, Compound A is administered orally once a day, twice a day, or three times a day. In another embodiment, Compound A is administered orally once a day. In another embodiment, Compound A is administered orally until disease progression, intolerable toxicity, or death.

[0152] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with the EML4-ALK G1202R mutation, wherein the non-small cell lung cancer has progressed after another therapy. In one embodiment, the other therapy is radiation therapy, drug therapy, or surgery. In another embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucizumab, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not been previously treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to one or more lines of therapy.In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line or second-line treatment. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another embodiment, the dose of Compound A is about 60 mg / day. In another embodiment, Compound A is administered orally. In another embodiment, Compound A is administered orally on an empty stomach. In another embodiment, Compound A is administered orally once a day, twice a day, or three times a day. In another embodiment, Compound A is administered orally once a day. In another embodiment, Compound A is administered orally until disease progression, intolerable toxicity, or death.

[0153] EML4-ALK G1202R mutation in CNS-metastatic non-small cell lung cancer

[0154] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating CNS metastatic non-small cell lung cancer with the EML4-ALK G1202R mutation. In one embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is adenocarcinoma. In another embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, followed by disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, followed by disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, followed by disease progression or intolerance. In another embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucazide, or entrectinib. In another embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another embodiment, the subject has not previously been treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0155] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating CNS metastatic non-small cell lung cancer with the EML4-ALK G1202R mutation, wherein the non-small cell lung cancer has progressed after another therapy. In one embodiment, the other therapy is radiation therapy, drug therapy, or surgical therapy. In another embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the subject has previously progressed on or is intolerant to crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject has previously received at least a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the subject has previously received a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluorazolidone, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously been treated with an ALK inhibitor. In another specific embodiment, the subject has not previously been treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously received one or more lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one, two, three, four, or five lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one or two lines of treatment for disease progression or intolerance. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day.In another specific embodiment, the dose of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dose of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dose of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dose of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0156] In another embodiment, the present invention relates to a method for detecting the concentration of Compound A in the CNS fluid of a subject with CNS metastatic non-small cell lung cancer harboring the EML4-ALK G1202R mutation, comprising:

[0157] a. Collect a sample of cerebrospinal fluid; and

[0158] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid.

[0159] TP53-positive ALK-positive non-small cell lung cancer

[0160] In certain embodiments, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating TP53-positive ALK-positive non-small cell lung cancer. In a specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In a specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor and the disease has progressed or is intolerant. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor and the disease has progressed or is intolerant. In another specific embodiment, the subject has previously received or had disease progression or intolerance after continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucella, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously received or had an ALK inhibitor. In another specific embodiment, the subject has not previously received or had a third-generation ALK inhibitor. In another specific embodiment, the subject has previously received or had disease progression or intolerance after one or more lines of therapy. In another specific embodiment, the subject has previously received or had disease progression or intolerance after one, two, three, four, or five lines of therapy. In another specific embodiment, the subject has previously received or had disease progression or intolerance after one or two lines of therapy. In another specific embodiment, the non-small cell lung cancer has an EML4-ALK L1196M mutation or an EML4-ALK G1202R mutation. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0161] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating TP53-positive ALK-positive non-small cell lung cancer, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiotherapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib as the sole ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucizumab, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not been previously treated with an ALK inhibitor. In another specific embodiment, the subject has not been previously treated with a third-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to one or more lines of therapy.In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line or second-line treatment. In another specific embodiment, the non-small cell lung cancer has an EML4-ALK L1196M mutation or an EML4-ALK G1202R mutation. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0162] ROS1-positive non-small cell lung cancer

[0163] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ROS1-positive non-small cell lung cancer. In one specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib or has had disease progression or intolerance. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor or has had disease progression or intolerance. In another specific embodiment, the subject has previously received or is intolerant to a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucella, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously received a ROS1 inhibitor. In another specific embodiment, the subject has not previously received a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously received or is intolerant to a first-line or higher-line therapy. In another specific embodiment, the subject has previously received or is intolerant to a first-line, second-line, third-line, fourth-line, or fifth-line therapy. In another specific embodiment, the subject has previously received or is intolerant to a first-line or second-line therapy. In another specific embodiment, the non-small cell lung cancer has the SLC34A2-ROS1 G2032R mutation. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0164] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ROS1-positive non-small cell lung cancer, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiation therapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib or has been intolerant to the disease. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor or has been intolerant to the disease. In another specific embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor or has been intolerant to the disease. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucizumab, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not been previously treated with a ROS1 inhibitor. In another specific embodiment, the subject has not been previously treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to one or more lines of therapy.In another embodiment, the subject has previously progressed on or is intolerant to first-line, second-line, third-line, fourth-line or fifth-line therapy. In another embodiment, the subject has previously progressed on or is intolerant to first-line or second-line therapy. In another embodiment, the non-small cell lung cancer has an SLC34A2-ROS1 G2032R mutation. In another embodiment, the dose of Compound A is from about 5 mg / day to about 180 mg / day. In another embodiment, the dose of Compound A is from about 5 mg / day to about 125 mg / day. In another embodiment, the dose of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another embodiment, the dose of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dose of Compound A is selected from about 40 mg / day, about 60 mg / day, or about 80 mg / day.

[0165] day. In another embodiment, the dose of Compound A is about 60 mg / day. In another embodiment, Compound A is administered orally. In another embodiment, Compound A is administered orally on an empty stomach. In another embodiment, Compound A is administered orally once a day, twice a day, or three times a day. In another embodiment, Compound A is administered orally once a day. In another embodiment, Compound A is administered orally until disease progression, intolerable toxicity, or death.

[0166] ROS1-positive CNS metastatic non-small cell lung cancer

[0167] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ROS1-positive CNS metastatic non-small cell lung cancer. In one embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is adenocarcinoma. In another embodiment, the subject has previously undergone continuous treatment with crizotinib for disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor for disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor for disease progression or intolerance. In another embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucazide or entrectinib. In another embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib or brigatinib. In another embodiment, the subject has not previously been treated with a ROS1 inhibitor. In another embodiment, the subject has not previously been treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to first-line or more treatment. In another specific embodiment, the subject has previously progressed on or is intolerant to first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed on or is intolerant to first-line or second-line treatment. In another specific embodiment, the non-small cell lung cancer has an SLC34A2-ROS1 G2032R mutation. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dose of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0168] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating ROS1-positive CNS metastatic non-small cell lung cancer, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiation therapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the subject has previously progressed on or is intolerant to crizotinib. In another specific embodiment, the subject has previously received at least a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the subject has previously received a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluorazolidone, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously been treated with a ROS1 inhibitor. In another specific embodiment, the subject has not previously been treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously received one or more lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one, two, three, four, or five lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one or two lines of treatment for disease progression or intolerance. In another embodiment, the non-small cell lung cancer has a SLC34A2-ROS1 G2032R mutation. In another embodiment, the dose of Compound A is about 5 mg / day to about 180 mg / day. In another embodiment, the dose of Compound A is about 5 mg / day to about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0169] In another embodiment, the present invention relates to a method for detecting the concentration of Compound A in the CNS fluid of a subject with ROS1-positive CNS metastatic non-small cell lung cancer, comprising:

[0170] a. Collect a sample of cerebrospinal fluid; and

[0171] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid.

[0172] Non-small cell lung cancer with SLC34A2-ROS1 G2032R mutation

[0173] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with the SLC34A2-ROS1 G2032R mutation. In one specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously experienced disease progression or intolerance after continuous treatment with crizotinib. In another specific embodiment, the subject has previously experienced disease progression or intolerance after continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluaco or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib or brigatinib. In another specific embodiment, the subject has not previously been treated with a ROS1 inhibitor. In another specific embodiment, the subject has not previously been treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / days to about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / days, about 10 mg / days, about 20 mg / days, about 40 mg / days, about 60 mg / days, about 80 mg / days, about 100 mg / days or about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / days, about 60 mg / days, about 80 mg / days, about 100 mg / days or about 125 mg / days. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / days, about 60 mg / days or about 80 mg / days.In another embodiment, the dose of Compound A is about 60 mg / day. In another embodiment, Compound A is administered orally. In another embodiment, Compound A is administered orally on an empty stomach. In another embodiment, Compound A is administered orally once a day, twice a day, or three times a day. In another embodiment, Compound A is administered orally once a day. In another embodiment, Compound A is administered orally until disease progression, intolerable toxicity, or death.

[0174] In another embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating non-small cell lung cancer with the SLC34A2-ROS1 G2032R mutation, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiation therapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the non-small cell lung cancer is metastatic non-small cell lung cancer. In another specific embodiment, the metastatic non-small cell lung cancer is CNS metastatic non-small cell lung cancer, bone metastatic non-small cell lung cancer, liver metastatic non-small cell lung cancer, adrenal metastatic non-small cell lung cancer, or other metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject has previously undergone continuous treatment with crizotinib or has been intolerant to the disease. In another specific embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor or has been intolerant to the disease. In another specific embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor or has been intolerant to the disease. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucizumab, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not been previously treated with a ROS1 inhibitor. In another specific embodiment, the subject has not been previously treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously progressed on or is intolerant to one or more lines of therapy.In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed with disease or is intolerant after first-line or second-line treatment. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another embodiment, the dose of Compound A is about 60 mg / day. In another embodiment, Compound A is administered orally. In another embodiment, Compound A is administered orally on an empty stomach. In another embodiment, Compound A is administered orally once a day, twice a day, or three times a day. In another embodiment, Compound A is administered orally once a day. In another embodiment, Compound A is administered orally until disease progression, intolerable toxicity, or death.

[0175] SLC34A2-ROS1 G2032R mutation in CNS-metastatic non-small cell lung cancer

[0176] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating CNS metastatic non-small cell lung cancer with the SLC34A2-ROS1 G2032R mutation. In one embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another embodiment, the non-small cell lung cancer is adenocarcinoma. In another embodiment, the subject has previously undergone continuous treatment with crizotinib for disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with at least a second-generation ALK inhibitor for disease progression or intolerance. In another embodiment, the subject has previously undergone continuous treatment with a second-generation ALK inhibitor for disease progression or intolerance. In another embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucazide, or entrectinib. In another embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another embodiment, the subject has not previously been treated with a ROS1 inhibitor. In another specific embodiment, the subject has not been previously treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or more first-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line, second-line, third-line, fourth-line or fifth-line treatment. In another specific embodiment, the subject has previously progressed or is intolerant to the disease after first-line or second-line treatment. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 180 mg / day. In another specific embodiment, the dose of Compound A is from about 5 mg / day to about 125 mg / day. In another specific embodiment, the dose of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death or individual choice.

[0177] In one embodiment, the present invention relates to the use and method of Compound A or a pharmaceutically acceptable salt thereof for treating CNS metastatic non-small cell lung cancer with SLC34A2-ROS1 G2032R mutation, wherein the non-small cell lung cancer has progressed after another therapy. In a specific embodiment, the other therapy is radiation therapy, drug therapy, or surgical therapy. In another specific embodiment, the drug therapy is chemotherapy, targeted therapy, or immunotherapy. In another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody. In another specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is adenocarcinoma. In another specific embodiment, the subject has previously progressed on or is intolerant to crizotinib. In another specific embodiment, the subject has previously received at least a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the subject has previously received a second-generation ALK inhibitor for continuous treatment, followed by disease progression or intolerance. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iluorazolidone, or entrectinib. In another specific embodiment, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific embodiment, the subject has not previously been treated with a ROS1 inhibitor. In another specific embodiment, the subject has not previously been treated with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has previously received one or more lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one, two, three, four, or five lines of treatment for disease progression or intolerance. In another specific embodiment, the subject has previously received one or two lines of treatment for disease progression or intolerance. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 180 mg / day. In another embodiment, the dosage of Compound A is from about 5 mg / day to about 125 mg / day.In another specific embodiment, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day. In another specific embodiment, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day. In another specific embodiment, the dosage of Compound A is about 60 mg / day. In another specific embodiment, Compound A is administered orally. In another specific embodiment, Compound A is administered orally on an empty stomach. In another specific embodiment, Compound A is administered orally once a day, twice a day or three times a day. In another specific embodiment, Compound A is administered orally once a day. In another specific embodiment, Compound A is administered until disease progression, intolerable toxicity or death.

[0178] In another embodiment, the present invention relates to a method for detecting the concentration of Compound A in the CNS fluid of a subject with CNS-metastatic non-small cell lung cancer harboring the SLC34A2-ROS1 G2032R mutation, comprising:

[0179] a. Collect a sample of cerebrospinal fluid; and

[0180] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid.

[0181] More specifically, the present invention relates to the following technical solutions:

[0182] 1. Use of Compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer, wherein the Compound A has the following structure:

[0183] 2. A method for treating non-small cell lung cancer in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein Compound A has the following structure:

[0184] 3. Compound A or a pharmaceutically acceptable salt thereof for use in treating non-small cell lung cancer, wherein the compound A has the following structure:

[0185] 4. The use according to Technical Scheme 1 or the method according to Technical Scheme 2 or the use of the compound according to Technical Scheme 3, wherein the non-small cell lung cancer is ALK-positive non-small cell lung cancer; preferably, wherein the non-small cell lung cancer is advanced ALK-positive non-small cell lung cancer; preferably, wherein the ALK is ALK L1196M or ALK G1202R mutation; preferably, wherein the non-small cell lung cancer is TP53-positive (including mutations and wild-type) ALK-positive non-small cell lung cancer; preferably, the non-small cell lung cancer is TP53-mutated ALK-positive non-small cell lung cancer.

[0186] 5. The use, method or compound according to any one of technical solutions 1 to 4, wherein the non-small cell lung cancer is adenocarcinoma.

[0187] 6. The use, method or compound according to any one of technical solutions 1 to 5, wherein the non-small cell lung cancer is metastatic non-small cell lung cancer; preferably, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer (e.g., intracranial metastatic non-small cell lung cancer).

[0188] 7. The use, method or compound according to any one of technical solutions 1 to 6, wherein the non-small cell lung cancer has not been treated.

[0189] 8. The use, method or compound according to any one of technical solutions 1 to 6, wherein the non-small cell lung cancer progresses after treatment with another therapy;

[0190] Preferably, the other therapy is selected from radiotherapy, drug therapy or surgical therapy; preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy;

[0191] Preferably, the drug therapy is chemotherapy;

[0192] Preferably, the drug therapy is targeted therapy;

[0193] Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

[0194] 9. The use, method or compound according to technical solution 8, wherein the non-small cell lung cancer progresses after treatment with an ALK inhibitor.

[0195] 10. The use, method or compound according to technical solution 9, wherein the ALK inhibitor is a first-generation or second-generation ALK inhibitor; preferably, the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, ensartinib or brigatinib.

[0196] 11. The use, method or compound according to any one of technical solutions 1 to 10, wherein the non-small cell lung cancer is in clinical stage III or IV.

[0197] 12. The use, method or compound according to any one of technical solutions 1 to 11, wherein the patient has received first-line or more treatment; preferably, wherein the patient has received second-line or more treatment; preferably, the patient has received first-line, second-line, third-line, fourth-line or fifth-line treatment.

[0198] 13. The use, method or compound according to technical solution 12, wherein the patient has disease progression or intolerance after receiving one or more lines of treatment; preferably, wherein the patient has disease progression or intolerance after receiving one or two lines of treatment.

[0199] 14. The use, method or compound according to technical solution 12 or 13, wherein the first-line or more first-line treatment is selected from radiotherapy, drug therapy or surgical therapy;

[0200] Preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy;

[0201] Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

[0202] 15. The use, method or compound according to technical solution 14, wherein the patient has previously received chemotherapy; preferably, the chemotherapy drug is selected from carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate or pyridoxine, preferably carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, docetaxel, endostatin, sodium cantharidate or pyridoxine.

[0203] 16. The use, method or compound according to technical solution 14, wherein the patient has previously received targeted therapy; preferably, the patient has previously received ALK inhibitor treatment; preferably, the patient has previously received second-generation ALK inhibitor treatment, such as alectinib, ceritinib, ensartinib or brigatinib; preferably, the patient has previously received crizotinib as the only ALK inhibitor treatment.

[0204] 17. The use, method or compound according to technical solution 14, wherein the patient has not previously received treatment with an ALK inhibitor (e.g., a third-generation ALK inhibitor).

[0205] 18. The use, method or use of any one of technical solutions 1 to 17, wherein the dosage of compound A is about 5 mg / day to about 180 mg / day;

[0206] Preferably, the dosage of Compound A is about 5 mg / day to about 125 mg / day;

[0207] Preferably, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day;

[0208] Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day;

[0209] Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day;

[0210] Preferably, the dosage of Compound A is about 60 mg / day.

[0211] 19. The use, method or use of any one of technical solutions 1 to 18, wherein the compound A is administered orally.

[0212] 20. The use, method or compound according to any one of technical solutions 1 to 19, wherein the compound A is orally administered once a day, twice a day or three times a day;

[0213] Preferably, the compound A is administered orally once a day.

[0214] 21. The use, method or use of any one of technical solutions 1 to 20, wherein the compound A is administered until disease progression, intolerable toxicity or death.

[0215] 22. The use, method or use of any one of technical solutions 1 to 21, wherein the patient has a CSF / plasma concentration ratio of Compound A of greater than about 40% after administration of Compound A; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 50%; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 60%.

[0216] 23. The use according to Technical Solution 1, the method according to Technical Solution 2, or the use of the compound according to Technical Solution 3, wherein the non-small cell lung cancer is ROS1-positive non-small cell lung cancer; preferably, the non-small cell lung cancer is advanced ROS1-positive non-small cell lung cancer; preferably, the ROS1 is a ROS1 G2032R mutation.

[0217] 24. The use, method or compound according to any one of technical solutions 1-3 and 23, wherein the non-small cell lung cancer is adenocarcinoma.

[0218] 25. The use, method or compound according to any one of technical solutions 1-3 and 23-24, wherein the non-small cell lung cancer is metastatic non-small cell lung cancer; preferably, wherein the non-small cell lung cancer is CNS metastatic non-small cell lung cancer (e.g., intracranial metastatic non-small cell lung cancer).

[0219] 26. The use, method or compound according to any one of technical solutions 1-3 and 23-25, wherein the non-small cell lung cancer has not been treated.

[0220] 27. The use, method or compound according to any one of technical solutions 1-3 and 23-26, wherein the non-small cell lung cancer progresses after treatment with another therapy;

[0221] Preferably, the other therapy is selected from radiotherapy, drug therapy or surgical therapy; preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy;

[0222] Preferably, the drug therapy is chemotherapy;

[0223] Preferably, the drug therapy is targeted therapy;

[0224] Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

[0225] 28. The use, method or compound according to technical solution 27, wherein the non-small cell lung cancer progresses after treatment with a ROS1 inhibitor.

[0226] 29. The use, method or compound according to technical solution 28, wherein the ROS1 inhibitor is a first-generation ROS1 inhibitor; preferably, the ROS1 inhibitor is selected from crizotinib, alectinib, ceritinib, ensartinib or brigatinib.

[0227] 30. The use, method or compound according to any one of technical solutions 1-3 and 23-29, wherein the non-small cell lung cancer is in clinical stage III or IV, preferably clinical stage IV.

[0228] 31. The use, method or compound according to any one of technical solutions 1-3 and 23-30, wherein the patient has received first-line or more treatment; preferably, wherein the patient has received second-line treatment.

[0229] 32. The use, method or compound according to technical solution 31, wherein the patient has disease progression or intolerance after receiving one or more first-line treatments; preferably, wherein the patient has disease progression or intolerance after receiving second-line treatments.

[0230] 33. The use, method or compound according to technical solution 31 or 32, wherein the first-line or more first-line treatment is selected from radiotherapy, drug therapy or surgical therapy;

[0231] Preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy;

[0232] Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

[0233] 34. The use, method or compound of technical solution 33, wherein the patient has previously received chemotherapy; preferably, the chemotherapy drug is selected from carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, Brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate or pyridoxine, preferably carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, docetaxel, endostatin, sodium cantharidate or pyridoxine.

[0234] 35. The use, method or compound of claim 33, wherein the patient has previously received targeted therapy; preferably, the patient has previously received a ROS1 inhibitor, such as alectinib, ceritinib, ensartinib or brigatinib; preferably, the patient has previously received crizotinib as the sole ROS1 inhibitor.

[0235] 36. The use, method or compound according to technical solution 33, wherein the patient has not previously received treatment with a ROS1 inhibitor (eg, a second-generation ROS1 inhibitor).

[0236] 37. The use, method or use of any one of technical solutions 1-3 and 23-36, wherein the dosage of compound A is about 5 mg / day to about 180 mg / day;

[0237] Preferably, the dosage of Compound A is about 5 mg / day to about 125 mg / day;

[0238] Preferably, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day;

[0239] Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day;

[0240] Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day;

[0241] Preferably, the dosage of Compound A is about 60 mg / day.

[0242] 38. The use, method or use of a compound according to any one of technical solutions 1-3 and 23-37, wherein the compound A is administered orally.

[0243] 39. The use, method or compound according to any one of technical solutions 1-3 and 23-38, wherein the compound A is orally administered once a day, twice a day or three times a day;

[0244] Preferably, the compound A is administered orally once a day.

[0245] 40. The use, method or use of any one of technical solutions 1-3 and 23-39, wherein the compound A is administered until disease progression, intolerable toxicity or death.

[0246] 41. The use, method or compound of any one of technical solutions 1-3 and 23-40, wherein the patient has a CSF / plasma concentration ratio of Compound A of greater than about 40% after administration of Compound A; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 50%; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 60%.

[0247] 42. A method for detecting the concentration of Compound A in the CNS fluid of a subject with ALK-positive or ROS1-positive CNS-metastatic non-small cell lung cancer, comprising:

[0248] a. Collect a sample of cerebrospinal fluid; and

[0249] b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid. Example

[0250] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages are by weight.

[0251] Example 1 Anti-tumor effect of Ba / F3 (EML4-ALK L1196M) cell line in a female NOD-SCID mouse model subcutaneously transplanted.

[0252] Experimental animals: 50 female NOD-SCID mice, 7-8 weeks old (age at time of tumor cell inoculation), weighing 16.0-22.0 g (with 32 surplus mice), purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2017-0006, animal qualification certificate number: 1103301911000908. Housing environment: SPF grade.

[0253] Animal housing: All animals were housed in individually ventilated boxes at a constant temperature and humidity of 20-26°C, 40-70% humidity, 10-20 air changes per hour, and a 12-hour light / dark cycle. They were provided with a continuous supply of cobalt-60-irradiated complete mouse pellets, with ad libitum access. Tap water (autoclaved) was also available, and water was supplied via a continuous water bottle. The boxes were autoclaved polysulfone boxes, measuring 325 mm × 210 mm × 180 mm. The bedding consisted of autoclaved corn cobs. Five animals were housed per box. Cage cards were labeled with the IACUC approval number, experiment number, experiment start date, project leader, experimenter, animal source, group, and animal number. Animals were identified with ear tags or ear tags.

[0254] Cell Culture: Ba / F3 (EML4-ALK L1196M) cells (cell number: TC-00136) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and 2 μg / mL blasticidin. Ba / F3 (EML4-ALK L1196M) cells were harvested during the exponential growth phase, resuspended in PBS to the appropriate concentration, and then subcutaneously inoculated into nude mice.

[0255] Experimental method: Female NOD / SCID mice were subcutaneously inoculated on the right side with 5×10 6 Ba / F3 (EML4-ALK L1196M) cells were used to establish a subcutaneous tumor transplant model. The experiment was divided into five groups, including a high-dose Compound A (10 mg / kg) group, a medium-dose Compound A (3 mg / kg) group, a low-dose Compound A (1 mg / kg) group, a Crizotinib positive control group (100 mg / kg), and a vehicle control group, with 10 animals in each group. Oral administration was performed by gavage once daily. Efficacy was evaluated based on relative tumor inhibition rate (TGI), and safety was evaluated based on animal weight changes and mortality.

[0256] The experimental protocols for this animal study were reviewed and approved by the International Animal Care and Research Committee (IACUC) of CrownBio. All animal procedures complied with the requirements of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All procedures, including dosing, tumor measurement, and body weight, were performed in a biosafety cabinet or clean bench.

[0257] The relative tumor growth rate (T / C%) is the percentage of the relative tumor volume of the treatment group and the control group at a certain time point, or the percentage of the tumor weight of the treatment group and the control group. The calculation formula is: T / C% = T RTV / C RTV ×100%(T RTV : Average RTV of treatment group; C RTV : Average RTV of the vehicle control group; RTV = Vt / V0, V0 is the tumor volume of the animal at the time of grouping, V t is the tumor volume of the animal after treatment); or T / C% = T TW / C TW ×100%(T TW : Average tumor weight of the treatment group at the end of the experiment; C TW : average tumor weight at the end of the experiment in the vehicle control group).

[0258] The relative tumor inhibition rate (TGI%) was calculated as follows: TGI%=1-T / C%.

[0259] Statistical Analysis: To compare tumor volumes on a given day across treatment groups, we first used the Bartlett test to verify the assumption of homogeneity of variance among all groups. When the p-value from the Bartlett test was ≥0.05, one-way ANOVA was used to test the equality of the means across all groups. If the p-value from the one-way ANOVA was less than 0.05, we used the Tukey HSD test for pairwise comparisons between all groups or the Dunnett's t-test for pairwise comparisons between each treatment group and the control group. When the p-value from the Bartlett test was less than 0.05, the Kruskal-Wallis test was used to test the equality of the medians across all groups. If the p-value from the Kruskal-Wallis test was less than 0.05, we used the Conover test for pairwise comparisons between all groups or between each treatment group and the control group, with p-values ​​adjusted for multiple testing. All statistical analyses and figures were performed in the R language environment (version 3.3.1). Unless otherwise specified, all tests were two-tailed, and p-values ​​less than 0.05 were considered statistically significant.

[0260] Experimental results:

[0261] On the 17th day after administration (i.e., the end of the experiment: administration started on the 7th day and ended on the 24th day), the average tumor volume of mice in the vehicle control group was 2222.44 mm 3 In contrast, the average tumor volume of the test compound A at 10 mg / kg, 3 mg / kg and 1 mg / kg, once a day, was 0 mm 3 , 0mm 3 and 1125.94mm 3 The relative tumor inhibition rates (TGI) were 100%, 100% and 49.53% respectively, which were statistically significantly different from those of the vehicle control group (P<0.001). At the end of the experiment, in the compound A 10 mg / kg and 3 mg / kg treatment groups, the tumor volume of all (10 / 10, 10 / 10) tumor-bearing mice was reduced to 0 and completely disappeared. The positive control drug Crizotinib had an average tumor volume of 1965.17 mm at a dosage of up to 100 mg / kg, po once a day. 3 The relative tumor inhibition rate (TGI) was 12.00%, which was not statistically significantly different from the vehicle control group (P>0.05), and the therapeutic effect was worse than that of the 1 mg / kg dose group of compound A. The tumor growth of each treatment group and the control group is shown in Figure 1.

[0262] During the experiment, no animals died in any treatment group, and no significant drug toxicity was observed. Treatment was well tolerated. The changes in body weight after administration in the treatment and control groups are shown in Figures 2 and 3.

[0263] Example 2 Anti-tumor effect of Ba / F3 (EML4-ALK G1202R) cell line in a female NOD-SCID mouse model subcutaneously transplanted.

[0264] Experimental animals: 50 female NOD-SCID mice, 7-8 weeks old (age at time of tumor cell inoculation), weighing 16.0-20.3 g (with 30 surplus mice), purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2017-0006, animal qualification certificate number: 1103301911000914. Housing environment: SPF grade.

[0265] Animal housing: All animals were housed in individually ventilated boxes at a constant temperature and humidity of 20-26°C, 40-70% humidity, 10-20 air changes per hour, and a 12-hour light / dark cycle. They were provided with a continuous supply of cobalt-60-irradiated complete mouse pellets, with ad libitum access. Tap water (autoclaved) was also available, and water was supplied via a continuous water bottle. The boxes were autoclaved polysulfone boxes, measuring 325 mm × 210 mm × 180 mm. The bedding consisted of autoclaved corn cobs. Five animals were housed per box. Cage cards were labeled with the IACUC approval number, experiment number, experiment start date, project leader, experimenter, animal source, group, and animal number. Animals were identified with ear tags or ear tags.

[0266] Cell Culture: Ba / F3 (EML4-ALK G1202R) cells (Cell ID: ECL-00031) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. Ba / F3 (EML4-ALK G1202R) cells were harvested during the exponential growth phase and resuspended in PBS to an appropriate concentration before subcutaneous tumor inoculation.

[0267] Experimental method: Female NOD / SCID mice were subcutaneously inoculated with 2×10 6Ba / F3 (EML4-ALK G1202R) cells were used to establish a subcutaneous tumor transplantation model. The experiment was divided into 5 groups, including a high-dose Compound A (15 mg / kg) group, a medium-dose Compound A (5 mg / kg) group, a low-dose Compound A (1.5 mg / kg) group, a Crizotinib positive control group (100 mg / kg), and a vehicle control group, with 10 animals in each group. Oral administration was performed by gavage once a day. Efficacy was evaluated based on relative tumor inhibition rate (TGI), and safety was evaluated based on animal weight changes and mortality.

[0268] The experimental protocols for this animal study were reviewed and approved by the CrownBio IACUC Committee. Animal experimental procedures adhered to AAALAC standards. All procedures, including drug administration, tumor measurement, and body weight, were performed in a biosafety cabinet or clean bench.

[0269] The relative tumor growth rate (T / C%) is the percentage of the relative tumor volume of the treatment group and the control group at a certain time point, or the percentage of the tumor weight of the treatment group and the control group. The calculation formula is: T / C% = T RTV / C RTV ×100%(T RTV : Average RTV of treatment group; C RTV : Average RTV of vehicle control group; RTV = V t / V0, V0 is the tumor volume of the animal when grouped, V t is the tumor volume of the animal after treatment); or T / C% = T TW / C TW ×100%(T TW : Average tumor weight of the treatment group at the end of the experiment; C TW : average tumor weight at the end of the experiment in the vehicle control group).

[0270] The relative tumor inhibition rate (TGI%) was calculated as follows: TGI%=1-T / C%.

[0271] Statistical Analysis: To compare tumor volumes on a given day across treatment groups, we first used the Bartlett test to verify the assumption of homogeneity of variance among all groups. When the p-value from the Bartlett test was ≥0.05, one-way ANOVA was used to test the equality of the means across all groups. If the p-value from the one-way ANOVA was less than 0.05, we used the Tukey HSD test for pairwise comparisons between all groups or the Dunnett's t-test for pairwise comparisons between each treatment group and the control group. When the p-value from the Bartlett test was less than 0.05, the Kruskal-Wallis test was used to test the equality of the medians across all groups. If the p-value from the Kruskal-Wallis test was less than 0.05, we used the Conover test for pairwise comparisons between all groups or between each treatment group and the control group, with p-values ​​adjusted for multiple testing. All statistical analyses and figures were performed in the R language environment (version 3.3.1). Unless otherwise specified, all tests were two-tailed, and p-values ​​less than 0.05 were considered statistically significant.

[0272] Experimental results:

[0273] On the 16th day after administration (i.e., the end of the experiment: administration started on the 6th day and ended on the 22nd day), the average tumor volume of the mice in the vehicle control group was 2723.66 mm 3 In contrast, the average tumor volume of the test drug compound A at 15 mg / kg, 5 mg / kg and 1.5 mg / kg, once a day, was 0.25 mm 3 、576.11mm 3 and 2139.18mm 3 The relative tumor inhibition rates (TGI) were 99.99%, 79.17% and 21.50% respectively, which were statistically significantly different from the vehicle control group (P<0.001 for both the 15mg / kg and 5mg / kg treatment groups, and P<0.05 for the 1.5mg / kg treatment group). At the end of the experiment, the tumor volume of 9 / 10 tumor-bearing mice in the compound A 15mg / kg treatment group was reduced to 0, completely disappearing. The positive control drug Crizotinib had an average tumor volume of 2275.28mm at a dosage of up to 100mg / kg, po once a day. 3 The relative tumor inhibition rate (TGI) was 17.32%, which was statistically significantly different from the vehicle control group (P<0.05), and the therapeutic effect was worse than that of the 1.5 mg / kg dose group of compound A. The tumor growth of each treatment group and the control group is shown in Figure 4.

[0274] During the experiment, no animals died in any treatment group, no significant drug toxicity was observed, and the treatment was well tolerated. The changes in body weight after administration in the treatment and control groups are shown in Figures 5 and 6.

[0275] Example 3 Anti-tumor effect of Ba / F3 (SLC34A2-ROS1 G2032R) cell line in a female NOD-SCID mouse model subcutaneously transplanted.

[0276] Experimental animals: 50 female NOD-SCID mice, 7-8 weeks (age at time of tumor cell inoculation), weighing 13.4-20.2 g (with 30 surplus mice) were purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2017-0006, animal qualification certificate number: 1103301911000909. Housing environment: SPF grade.

[0277] Animal housing: All animals were housed in individually ventilated boxes at a constant temperature and humidity of 20-26°C, 40-70% humidity, 10-20 air changes per hour, and a 12-hour light / dark cycle. They were provided with a continuous supply of cobalt-60-irradiated complete mouse pellets, with ad libitum access. Tap water (autoclaved) was also available, and water was supplied via a continuous water bottle. The boxes were autoclaved polysulfone boxes, measuring 325 mm × 210 mm × 180 mm. The bedding consisted of autoclaved corn cobs. Five animals were housed per box. Cage cards were labeled with the IACUC approval number, experiment number, experiment start date, project leader, experimenter, animal source, group, and animal number. Animals were identified with ear tags or ear tags.

[0278] Cell Culture: Ba / F3 (SLC34A2-ROS1 G2032R) cells (cell number ECL-00019) were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. Ba / F3 (SLC34A2-ROS1 G2032R) cells were harvested during the exponential growth phase, resuspended in PBS to an appropriate concentration, and then subcutaneously inoculated into nude mice.

[0279] Experimental method: Female NOD / SCID mice were subcutaneously inoculated with 2×10 6A subcutaneous tumor model was established using Ba / F3 (SLC34A2-ROS1 G2032R) cells. The study was divided into five groups, including a high-dose Compound A (15 mg / kg) group, a medium-dose Compound A (5 mg / kg) group, a low-dose Compound A (1.5 mg / kg) group, a crizotinib positive control group (100 mg / kg), and a vehicle control group, with 10 animals in each group. The drug was administered orally by gavage once daily. Efficacy was evaluated based on relative tumor inhibition (TGI), and safety was assessed based on changes in animal body weight and mortality.

[0280] The experimental protocols for this animal study were reviewed and approved by the CrownBio IACUC Committee. Animal experimental procedures adhered to AAALAC standards. All procedures, including drug administration, tumor measurement, and body weight, were performed in a biosafety cabinet or clean bench.

[0281] The relative tumor growth rate (T / C%) is the percentage of the relative tumor volume of the treatment group and the control group at a certain time point, or the percentage of the tumor weight of the treatment group and the control group. The calculation formula is: T / C% = T RTV / C RTV ×100%(T RTV : Average RTV of treatment group; C RTV : Average RTV of vehicle control group; RTV = V t / V0, V0 is the tumor volume of the animal when grouped, V t is the tumor volume of the animal after treatment); or T / C% = T TW / C TW ×100%(T TW : Average tumor weight of the treatment group at the end of the experiment; C TW : average tumor weight at the end of the experiment in the vehicle control group).

[0282] The relative tumor inhibition rate (TGI%) was calculated as follows: TGI%=1-T / C%.

[0283] Statistical Analysis: To compare tumor volumes on a given day across treatment groups, we first used the Bartlett test to verify the assumption of homogeneity of variance among all groups. When the p-value from the Bartlett test was ≥0.05, one-way ANOVA was used to test the equality of the means across all groups. If the p-value from the one-way ANOVA was less than 0.05, we used the Tukey HSD test for pairwise comparisons between all groups or the Dunnett's t-test for pairwise comparisons between each treatment group and the control group. When the p-value from the Bartlett test was less than 0.05, the Kruskal-Wallis test was used to test the equality of the medians across all groups. If the p-value from the Kruskal-Wallis test was less than 0.05, we used the Conover test for pairwise comparisons between all groups or between each treatment group and the control group, with p-values ​​adjusted for multiple testing. All statistical analyses and figures were performed in the R language environment (version 3.3.1). Unless otherwise specified, all tests were two-tailed, and p-values ​​less than 0.05 were considered statistically significant.

[0284] Experimental results:

[0285] On the 21st day after administration (i.e., the end of the experiment: administration started on the 15th day and ended on the 36th day), the average tumor volume of the mice in the vehicle control group was 2177.24 mm 3 In contrast, the average tumor volume of the test compound A at 15 mg / kg, 5 mg / kg and 1.5 mg / kg, once a day, was 0 mm 3 、305.46mm 3 and 1334.38mm 3 The relative tumor inhibition rates (TGI) were 100%, 85.78% and 38.05% respectively, which were statistically significantly different from those of the vehicle control group (P<0.001 for both the 15 mg / kg and 5 mg / kg treatment groups, and P<0.05 for the 1.5 mg / kg treatment group). At the end of the experiment, the tumor volume of all (10 / 10) tumor-bearing mice in the compound A 15 mg / kg treatment group was reduced to 0 and completely disappeared. The positive control drug Crizotinib had an average tumor volume of 1651.66 mm at a dosage of up to 100 mg / kg, po once a day. 3 The relative tumor inhibition rate (TGI) was 25.52%, which was not statistically significantly different from the vehicle control group (P>0.05), and the therapeutic effect was worse than that of the 1.5 mg / kg dose group of compound A. The tumor growth of each treatment group and the control group is shown in Figure 7.

[0286] During the experiment, no animals died in any treatment group, no significant drug toxicity was observed, and the treatment was well tolerated. The changes in body weight after administration in the treatment and control groups are shown in Figures 8 and 9.

[0287] Example 4 A Phase I clinical trial evaluating the safety, tolerability, pharmacokinetics and preliminary efficacy of Compound A in the treatment of patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer

[0288] Study objectives:

[0289] Main Purpose:

[0290] To evaluate the safety and tolerability of compound A in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer (NSCLC) and to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).

[0291] Secondary objectives:

[0292] 1) Evaluate the pharmacokinetic (PK) characteristics of Compound A in patients with ALK-positive or ROS1-positive advanced NSCLC;

[0293] 2) Evaluate the preliminary efficacy of compound A in patients with ALK-positive or ROS1-positive advanced NSCLC.

[0294] Exploratory purpose:

[0295] To explore the blood-brain barrier permeability of compound A in patients with ALK-positive or ROS1-positive advanced NSCLC.

[0296] Overall design

[0297] This trial is a multicenter, single-arm, open-label Phase I clinical trial, divided into three phases: dose escalation phase, dose expansion phase and indication expansion phase. It is used to explore the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of compound A in patients with ALK-positive or ROS1-positive advanced NSCLC.

[0298] The dose-escalation and dose-expansion phases plan to enroll patients with ALK-positive advanced NSCLC whose disease has progressed or is intolerant after continuous treatment with at least a second-generation ALK inhibitor (including second-generation ALK inhibitors that are already on the market or in clinical trials) and patients with ROS1-positive advanced NSCLC who have failed crizotinib treatment.

[0299] The dose-escalation phase included approximately eight dose groups: 5 (starting dose), 10, 20, 40, 60, 80, 100, and 125 mg. Subjects in all dose groups received a single dose on Day 1 (D1), and blood samples were collected for pharmacokinetic (PK) testing and tolerability monitoring. If no Grade 2 or higher adverse events related to the investigational drug occurred during the single-dose phase (5-7 days) (if any, dose adjustments based on toxicity were made according to the protocol), the subject entered the multiple-dose phase (i.e., treatment period) 5-7 days later (for subjects in the first dose group, a 7-day interval followed the first dose [i.e., multiple dosing starting on Day 8]; for subjects in subsequent dose groups, the intervals were determined based on available tolerability and PK data). Subjects in the first dose group were initially dosed once daily (QD) during the multiple-dose phase (if PK data from the single-dose phase were available, the dosing frequency in the multiple-dose phase could be determined based on these data). For subjects in subsequent dose groups, the dosing frequency after entering the multiple-dose phase was determined based on available PK and tolerability data. For all subjects in this trial, dosing frequency adjustments are permitted throughout the trial based on evolving safety and PK data. The four lower dose cohorts (5mg, 10mg, 20mg, and 40mg) will be administered using an accelerated titration design, with one subject enrolled in each dose cohort. If any Grade 2 or higher adverse event related to the investigational drug occurs, the dose will be escalated to a "3+3" approach. The 60mg and subsequent dose cohorts will follow a "3+3" approach, and the maximum dose tolerance (MTD) will be determined. After evaluation of the eighth dose cohort, if the investigator and sponsor agree that a higher dose cohort may demonstrate improved efficacy and a manageable safety profile, further dose exploration may be pursued (e.g., dose cohorts 9 and 10, 150mg and 180mg, respectively). During the dose-escalation process, if a dose cohort demonstrates preliminary antitumor efficacy and a manageable safety profile (e.g., no DLTs in three subjects or only one DLT in six subjects), dose expansion at that level may be considered after discussion between the investigator and sponsor.

[0300] The dose expansion phase is expected to be conducted in multiple dose groups, and each dose group is expected to be expanded to a total of approximately 10 cases (including the dose escalation phase and the dose expansion phase) to determine the appropriate dosing regimen for the subsequent indication expansion phase.

[0301] The indication expansion phase will determine the appropriate dosing regimen based on the safety, tolerability, PK, and efficacy data from the dose escalation and dose expansion phases, and expand the target population. Based on the patient's previous treatment and genetic mutation status, the subjects in the expansion group will be assigned to the following different populations, with the sample size initially determined as follows:

[0302] Group A: Patients with ALK-positive advanced NSCLC who have failed one or more lines of therapy (including disease progression or intolerance after previous treatment with crizotinib or other ALK inhibitors). At least 20 patients will be enrolled.

[0303] Cohort 1: Patients with ALK-positive advanced NSCLC whose disease has progressed or failed after continuous treatment with crizotinib as the sole ALK inhibitor;

[0304] Cohort 2: Patients with ALK-positive advanced NSCLC whose disease has progressed or is intolerant after continuous treatment with at least a second-generation ALK inhibitor (including second-generation ALK inhibitors that are marketed or in clinical trials) (regardless of whether they have previously received crizotinib) (including such subjects who use the target dose level in the dose escalation and dose expansion phases);

[0305] Group B: Patients with ROS1-positive advanced NSCLC whose disease has progressed on or is intolerant to crizotinib. Approximately 20 patients will be enrolled (including those in the target dose cohorts during the dose-escalation and dose-expansion phases);

[0306] Group C: Patients with ALK-positive advanced NSCLC who have not received ALK inhibitor treatment. A total of approximately 25 patients will be enrolled.

[0307] After obtaining preliminary efficacy data from Group A, the Safety Monitoring Committee (SMC) will comprehensively consider the risk-benefit assessment and decide whether to initiate enrollment of subjects in Group C.

[0308] All subjects in the dose escalation phase and dose expansion phase of this study need to undergo intensive blood sampling PK study of Compound A, and all subjects need to undergo population PK study of Compound A.

[0309] Descriptive statistical methods were used to analyze and compare the drug concentrations in cerebrospinal fluid and blood at the same time points after administration.

[0310] Inclusion criteria:

[0311] Patients who meet all of the following criteria may be considered for inclusion:

[0312] 1) Agree to follow the trial treatment plan and visit plan, voluntarily enroll, and sign the written informed consent;

[0313] 2) Aged ≥ 18 years old on the day of signing the informed consent form, regardless of gender;

[0314] 3) Patients with the following advanced NSCLC who are ALK-positive or ROS1-positive as confirmed by histopathology or cytology. The treatment line requirements for subjects at different stages of the study are as follows:

[0315] Dose escalation and dose expansion phase: Patients with ALK-positive advanced NSCLC whose disease has progressed after or is intolerant to at least a second-generation ALK inhibitor (including second-generation ALK inhibitors that are marketed or in clinical trials) and patients with ROS1-positive advanced NSCLC who have failed crizotinib.

[0316] Indication expansion phase: Group A: Patients with ALK-positive advanced NSCLC who have failed one or more lines of treatment (including disease progression or intolerance after previous continuous treatment with crizotinib or other ALK inhibitors), including: Cohort 1: Patients with ALK-positive advanced NSCLC whose disease has progressed or failed after continuous treatment with crizotinib as the only ALK inhibitor; Cohort 2: Patients with ALK-positive advanced NSCLC who have progressed or become intolerant after continuous treatment with at least a second-generation ALK inhibitor (including second-generation ALK inhibitors that are already on the market or in clinical trials) (regardless of whether they have previously used crizotinib); Group B: Patients with ROS1-positive advanced NSCLC whose disease has progressed or become intolerant after continuous treatment with crizotinib; Group C: Patients with ALK-positive advanced NSCLC who have not received prior ALK inhibitor treatment.

[0317] 4) Subjects must be able to provide archived tissue samples and / or fresh tumor tissue samples obtained during the screening period for biomarker testing (subjects with previous biomarker test results may be exempt from this test); or have previous high-throughput sequencing (NGS) results. If a subject is unable to provide a tumor tissue sample (e.g., due to exhaustion from previous diagnostic testing, or a higher clinical risk associated with re-puncture), the patient may only participate in this study after obtaining the consent of the medical monitor. If a fresh tissue sample is available or a previous tissue sample is available, it must still be sent to a third-party central laboratory for retesting, and the test results will not affect the previous exemption.

[0318] 5) Central nervous system metastases are allowed if the following conditions are met: a. Asymptomatic: currently not requiring corticosteroid treatment or the dose is stable or the dose has been reduced by ≤10mg QD prednisone or equivalent; or b. Diagnosed in the past, treatment has been completed, the acute effects of radiation therapy or surgery before the first dose have fully recovered, corticosteroid treatment for these metastases has been stopped for at least 4 weeks, and the neurological system is stable;

[0319] 6) Before the first administration of the trial drug, patients who have previously received targeted therapy (specifically ALK or ROS1 inhibitors) must stop the drug for ≥ 5 half-lives;

[0320] 7) According to the RECIST version 1.1 criteria, there must be at least one measurable target lesion (non-lymph node longest diameter ≥10 mm, lymph node shortest diameter ≥15 mm). Lesions that have been previously radiotherapy cannot be used as target lesions unless the lesion has significantly progressed;

[0321] 8) Eastern Cooperative Oncology Group (ECOG) performance status (PS), dose escalation and dose expansion phase: score 0-1 points; indication expansion phase: score 0-2 points;

[0322] 9) Adequate bone marrow, liver, kidney, coagulation, and pancreatic function (refer to the upper limit of normal values ​​of each clinical trial center):

[0323] Bone marrow (no blood transfusion or use of drugs to increase white blood cells, platelets, hemoglobin, or red blood cells within 2 weeks before the screening test):

[0324] Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L;

[0325] √Platelets≥100×10 9 / L;

[0326] √Hemoglobin ≥90g / L;

[0327] Liver function:

[0328] √ Serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN);

[0329] √ In the absence of liver metastasis, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) ≤ 2.5 times ULN; in the presence of liver metastasis, ALT, AST, or ALP ≤ 5 times ULN;

[0330] Renal function: serum creatinine ≤1.5 times ULN;

[0331] Coagulation function: international normalized ratio (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0332] Pancreatic function:

[0333] √ Serum total amylase ≤ 1.5 times ULN;

[0334] √ Serum lipase ≤ 1.5 times ULN;

[0335] 10) Expected survival period ≥ 3 months;

[0336] 11) Men of childbearing potential and women of childbearing age are willing to use effective contraceptive measures from the time they sign the informed consent form until 6 months after the last dose of the trial drug; women of childbearing age include premenopausal women and women within 2 years of postmenopause. Women of childbearing age must have a negative pregnancy test result within 7 days before the first dose of the trial drug.

[0337] Exclusion criteria:

[0338] Patients who meet any of the following criteria are not eligible for inclusion:

[0339] 1) Subjects who have previously received other third-generation ALK inhibitors or second-generation ROS1 inhibitors other than Compound A;

[0340] 2) Patients who are known to be allergic to any active ingredient or excipient of Compound A, or have a clear history of allergy to protein drugs, a history of atopic allergic reactions (asthma, rheumatism, eczematous dermatitis), or have experienced other severe allergic reactions and are determined by the investigator to be unsuitable for treatment with Compound A;

[0341] 3) Patients with another malignant tumor other than lung cancer, excluding malignant tumors such as cervical cancer in situ and non-melanoma skin cancer that have received curative treatment and have not recurred within 5 years;

[0342] 4) Subjects who underwent major surgery within 4 weeks before the first dose. Minor surgical procedures (such as IV tube implantation) are not exclusion criteria, but sufficient time is required for the wound to fully heal;

[0343] 5) Spinal cord compression, unless the subject achieves good pain control through treatment and the neurological function is fully recovered within 4 weeks before the first dose;

[0344] 6) Gastrointestinal dysfunction, mainly including inability to take oral medications, need for intravenous nutrition, previous surgical procedures (including total gastrectomy or gastric banding) that affect absorption, active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease, treatment of active peptic ulcer disease or malabsorption syndrome in the past 6 months, etc.;

[0345] 7) Patients with active pneumonia or a history of clinically significant interstitial lung disease, or radiation-induced or drug-induced lung disease requiring treatment. Patients with radiation pneumonitis who are asymptomatic 3 months after radiotherapy can be enrolled;

[0346] 8) Patients with heart failure, including but not limited to left ventricular ejection fraction (LVEF) <50%, history of congestive heart failure or ventricular arrhythmia requiring treatment, hypokalemia, hereditary long QT syndrome, myocardial infarction or unstable angina within 6 months before screening; patients with New York Heart Association heart failure grade ≥2;

[0347] 9) Patients with clinically significant abnormal QTc in electrocardiogram (ECG) examination (QTc>450msec [male] or QTc>470msec [female] in the resting state); concomitant use of any drug known to prolong the QT interval and cause torsades de pointes;

[0348] 10) Hypertension that is not controlled after drug treatment (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);

[0349] 11) Uncontrolled hyperglycemia, acute cholelithiasis, and those with susceptible features to acute pancreatitis;

[0350] 12) Patients who, according to the investigator's judgment, have severe or uncontrollable systemic diseases (such as unstable or uncompensated respiratory, cardiac, liver or kidney diseases) and are expected to be unable to tolerate the trial drug treatment;

[0351] 13) Patients who have used the following drugs within 14 days before the first dose or need to use the following drugs during treatment: drugs that may cause QTc interval prolongation and / or ventricular tachycardia;

[0352] 14) Previous anti-tumor treatment: (1) Any systemic anti-tumor treatment used within 28 days before the first administration of the trial drug (if the drug has been discontinued for more than 5 half-lives and the investigator assesses that Compound A can be used within 28 days after the end of systemic anti-tumor treatment, the patient can be included in the trial), including systemic chemotherapy, immunotherapy (physiological replacement doses of glucocorticoids [prednisone or equivalent <10 mg / day] are allowed), large molecule monoclonal antibodies, small molecule targeted drugs, etc.; (2) Radiotherapy or treatment with Chinese herbal medicine or Chinese patent medicine approved for anti-tumor treatment within 14 days before the first administration of the trial drug; (3) Received antibodies or drugs targeting T cell co-stimulation or immune checkpoint pathways within the past 28 days, including but not limited to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibodies; There is no limit on the washout period of systemic anti-tumor treatment before the trial drug is given again for subjects who have been discharged from the lower dose group due to disease progression and then received a higher dose level;

[0353] 15) Toxic reactions related to previous surgical procedures and previous anti-tumor treatments have not recovered and have been assessed by the investigator to affect the safety of the subject;

[0354] 16) Patients with clinically significant active bacterial, fungal, or viral infections, including those with positive hepatitis B surface antigen and HBV DNA ≥ ULN (only in patients with positive hepatitis B surface antigen), or hepatitis C (patients with positive hepatitis C antibody but negative HCV RNA polymerase chain reaction (PCR) test are eligible), any one or more of the Treponema pallidum antibody or human immunodeficiency virus antibody test results are positive, or those with any uncontrolled infection;

[0355] 17) Patients who have taken strong inducers or inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic window within two weeks before the first dose of the trial drug;

[0356] 18) Female subjects who are pregnant or lactating;

[0357] 19) Women of childbearing age who are unwilling or unable to use acceptable contraceptive methods during the entire treatment period of this trial and within 6 months after the last dose of the trial drug (women of childbearing age include: anyone who has had menarche and has not undergone successful artificial sterilization surgery [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or is premenopausal); male patients of childbearing potential who are unwilling or unable to take effective contraceptive measures if their partner is a woman of childbearing age;

[0358] 20) Subjects who are currently participating in other clinical studies or whose first medication time is less than 4 weeks from the end of the previous clinical study or 5 half-lives of the study drug, whichever is shorter;

[0359] 21) Any mental or cognitive disorder that may limit their understanding and execution of the informed consent form; other conditions that the researcher deems unsuitable for participation in this study, such as poor compliance, etc.

[0360] Test results:

[0361] 1) As of July 1, 2023, a total of 268 subjects were screened in the dose-escalation and expansion phases and the indication-expansion phase. 198 subjects were successfully screened, while 69 failed screening due to ineligibility criteria or exclusion criteria. Among these 198 subjects, 171 were ALK-positive and 27 were ROS1-positive. 114 subjects had brain metastases at enrollment, and 192 subjects had their most recent tumor stage at enrollment as stage IV. Baseline disease characteristics of the subjects are detailed in Tables 1 and 2.

[0362] Table 1: Baseline characteristics of patients in the dose escalation and expansion phases and the indication expansion phase

[0363] *: One subject in the 60 mg group was missing

[0364] Table 2 Baseline characteristics of patients in the dose escalation and expansion phases

[0365] 2) Among the 42 subjects in the dose-escalation and expansion phases, 11 (26.2%) had previously received radiotherapy, all for NSCLC. All 42 subjects had previously received anticancer drug therapy, primarily alectinib, crizotinib, and pemetrexed (see Table 3). Eleven subjects (26.2%) had previously received first-line therapy, 14 (33.3%) second-line therapy, 9 (21.4%) third-line therapy, 6 (14.3%) fourth-line therapy, and 2 (4.8%) fifth-line therapy. Six (14.3%) subjects had previously received anticancer surgery.

[0366] Table 3 Previous anticancer drugs in the dose escalation and expansion phases

[0367] A total of 97 subjects in the 60 mg dose group had previously received at least one second-generation ALK inhibitor, including 85 subjects in Cohort 2 of the indication expansion phase A and 12 subjects in the 60 mg dose group in the dose escalation and expansion phases. Among these 97 subjects, 59 (60.8%), 40 (41.2%), 25 (25.8%), 13 (13.4%), and 30 (30.9%) had previously received alectinib, crizotinib, ceritinib, ensartinib, and other ALK tyrosine kinase inhibitors, respectively.

[0368] 3) Cerebrospinal fluid concentration

[0369] During the dose-escalation phase, cerebrospinal fluid (CSF) concentrations of Compound A were analyzed in four subjects. Because the protein concentration in cerebrospinal fluid is low, the plasma concentration of Compound A was used as the free concentration when calculating blood-brain barrier permeability. The results are shown in Table 4.

[0370] Table 4 Analysis of cerebrospinal fluid concentration of compound A

[0371] 4) Effectiveness Analysis

[0372] ① The overall response and intracranial response results of the subjects in the dose escalation and expansion phases are shown in Tables 5 and 6 below.

[0373] Table 5 Analysis of whole-body BOR, ORR, DCR, DOR and TTR in the dose escalation and expansion phases

[0374] Table 6 Analysis of intracranial BOR, ORR, DCR, DOR and TTR in the dose escalation and expansion phases

[0375] ② The overall remission and intracranial remission results of the subjects in the indication expansion phase are shown in Tables 7 and 8 below.

[0376] Table 7 Analysis of whole body BOR, ORR, DCR, DOR and TTR in the indication expansion phase

[0377] *: Includes 85 subjects in Cohort 2 of the Indication Expansion Phase A and 12 subjects in the 60 mg dose group in the Dose Escalation and Expansion Phases.

[0378] Table 8 Analysis of BOR, ORR, DCR, DOR and TTR in patients with measurable intracranial lesions during the indication expansion phase

[0379] Among 14 patients who had previously received crizotinib with or without chemotherapy, the ORR was 71.4% (95% CI: 41.9% to 91.6%); 10 patients (71.4%) achieved a confirmed PR, and 4 patients (28.6%) had SD. The median DOR was not reached (95% CI: 5.585 to [NR]), and the median TTR was 2.71 months (range: 1.25–9.66). The best percentage change from baseline in disease status after Compound A treatment is shown in Figure 10b. Among these patients, 4 had measurable central nervous system lesions at baseline, and the intracranial ORR was 50.0% (1 CR and 1 PR). The median intracranial DOR was not reached, and the median TTR was 1.36 months.

[0380] Among 97 patients previously treated with a second-generation TKI, the overall ORR was 39.2% (95% CI: 29.4%-49.6%), the median DOR was 12.48 months (95% CI: [12.45] to [NE]), and the median TTR was 1.38 months (range: 1.28–9.72). The best percentage change from baseline in disease status after Compound A treatment is shown in Figure 10a. Among 27 patients with measurable central nervous system lesions at baseline, 5 achieved a CR and 14 achieved a PR. The IC-ORR was 70.4% (95% CI: 49.8%-86.2%). The median intracranial DOR was 17.97 months (95% CI: 6.64 to [NR]), and the median intracranial TTR was 1.41 months (range: 1.31–9.72).

[0381] A total of 33 ALK TKI-naive patients were analyzed, with an ORR of 84.8% (95% CI: 68.1%-94.9%), including 28 PRs and 4 SDs. At a median follow-up of 10.45 months, the median DOR was not reached (95% CI: [9.69] to [NR]), and the median TTR was 1.35 months (range: 1.12–4.21). The best percentage change from baseline in disease status after Compound A treatment is shown in Figure 10c. Among the eight patients with measurable central nervous system lesions at baseline, the intracranial ORR was 75% (95% CI, 34.9%-96.8%), with six achieving a confirmed PR. The median intracranial DOR was not reached (95% CI, 4.17 to [NR]), and the median TTR was 1.41 months (range: 1.35–1.45).

[0382] In 24 patients with ROS1-positive NSCLC who had previously received crizotinib, the ORR was 29.2% (95% CI: 12.6% to 51.1%). The median DOR was not reached (95% CI: 4.370 to [NR]), and the median TTR was 1.41 months (range: 1.31–7.03). Among these patients, 6 had measurable central nervous system lesions at baseline, and the intracranial ORR was 50.0% (3PR). The median intracranial DOR was not reached, and the median TTR was 1.41 months.

[0383] The results of systemic progression-free survival and intracranial progression-free survival in ALK-positive subjects in the indication expansion phase are shown in Figures 11 and 12, respectively.

[0384] As of April 17, 2024, based on FAS, the median PFS in Cohort 2 of Group A was 6.87 months (95% CI: 4.14, 9.76), and the median PFS in Group B was 8.36 months (95% CI: 1.71, -). The results of systemic progression-free survival and overall survival in ALK-positive subjects in the indication expansion phase are shown in Figures 11b and 12b, respectively, and the results of systemic progression-free survival and overall survival in ROS1-positive subjects in the indication expansion phase are shown in Figures 12c and 12d, respectively.

[0385] ③ The overall remission results of subjects in Group A Cohort 2 who had previously been treated with one, two, and more than or equal to three second-generation ALK inhibitors and were administered Compound A of the present invention are shown in Table 9 below.

[0386] Table 9 Analysis of BOR, ORR, DCR, DOR and TTR in Cohort 2 of Group A

[0387] 6) The PK parameters of the subjects after single and multiple administration of five dose levels of Compound A (40 mg, 60 mg, 80 mg, 100 mg, and 125 mg) are shown in Table 10 below:

[0388] Table 10 PK parameters of single and multiple oral administration of 40 mg, 60 mg, 80 mg, 100 mg and 125 mg of Compound A and 100 mg of lorlatinib

[0389] Note: a indicates that the data in this column are from the third column of Table 4 on page 1322 of Joseph Chen et al., Pharmacokinetics of Lorlatinib After Single and Multiple Dosing in Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: Results from a Global Phase I / II Study. Clinical Pharmacokinetics (2021) 60: 1313–1324 (Asian subjects);

[0390] *[n] represents n subjects.

[0391] 7) Adverse events related to the trial drug during treatment are shown in Table 11, and adverse events related to the CNS are shown in Table 12.

[0392] Table 11 Summary of TRAEs in the safety analysis

[0393] Table 12 CNS-related AEs

[0394] A total of 198 patients were enrolled, of whom 184 (92.9%) experienced treatment-related adverse events (TRAEs), with hypercholesterolemia, hypertriglyceridemia, or weight gain being the most common. Grade 3 or higher treatment-related central nervous system (CNS) AEs occurred in 1.0% of patients; no dose interruptions or dose reductions were observed. No DLTs were observed, and the MTD was not reached. Compound A was well tolerated, with a low incidence of grade 3 or higher TRAEs and CNS AEs.

[0395] 8) MTD and RP2D

[0396] Compound A did not experience dose-limiting toxicity in the dose escalation phase, and was also safe and tolerable in the dose expansion phase and indication expansion phase, indicating that Compound A is well-tolerated.

[0397] Based on the PK, safety, and efficacy data from the dose-escalation and dose-expansion phases of Compound A, the incidence of other AEs in the 60mg group was significantly lower than in the 80mg group. Following discussion and resolution at the SRC meeting, the recommended dose for the expanded indication was determined to be 60mg.

[0398] Biomarker analysis

[0399] Twenty-six subjects who had previously received at least one ALK inhibitor were included in the biomarker analysis (Table 13), including 24 subjects who had previously received second-generation ALK-TKI treatment and 2 subjects whose disease progressed after crizotinib treatment.

[0400] There were 11 PRs among the 26 subjects, with ORRs of 33.3% (2 / 6) and 62.5% (5 / 8) for subjects with variant 1 and variant 3, respectively. Compound A was effective for subjects with common resistance mutations in ALK fusions, with ORRs of 50% (3 / 6), 100% (1 / 1), and 50% (1 / 2) for subjects with G1202R, V1180L, and L1196M mutations, respectively. There was no difference in PFS between subjects with mutant TP53 or wild-type TP53 (P=0.235) (Figure 13, which shows the PFS of patients with mutant TP53 or wild-type TP53 treated with Compound A in the ALK TKI-resistant subgroup).

[0401] Table 13 Biomarker Analysis of 26 Subjects Previously Treated with at Least One ALK Inhibitor

[0402] Example 5 A Phase II, multicenter, single-arm clinical trial to evaluate the efficacy and safety of Compound A as a monotherapy in the treatment of advanced ALK-positive non-small cell lung cancer that has failed treatment with second-generation ALK inhibitors

[0403] Main objectives and main estimated targets:

[0404] Main Purpose:

[0405] The objective response rate (ORR) assessed by an independent imaging review committee (IRC) was used as the endpoint to evaluate the clinical efficacy of Compound A monotherapy in patients with ALK-positive advanced NSCLC whose disease progressed after or was intolerant to second-generation ALK inhibitors.

[0406] Main estimation objectives:

[0407] Target population: Patients with ALK-positive advanced NSCLC whose disease has progressed or is intolerant to second-generation ALK inhibitors;

[0408] Treatment: 60 mg / time, once a day (QD), 3 weeks as a dosing cycle.

[0409] Study variables: Whether the subject achieved objective response (CR / PR) during treatment as assessed by an independent radiographic review committee (IRC).

[0410] Population-level summary: ORR during treatment.

[0411] Secondary purpose

[0412] Other efficacy endpoints were used to evaluate the clinical efficacy of Compound A as a monotherapy in patients with ALK-positive advanced NSCLC;

[0413] To evaluate the safety of Compound A in the treatment of patients with ALK-positive advanced NSCLC;

[0414] To evaluate the population pharmacokinetic (PK) characteristics of Compound A in patients with ALK-positive advanced NSCLC;

[0415] To evaluate the effect of compound A on the PK characteristics of simvastatin tablets in patients with ALK-positive advanced NSCLC.

[0416] Study Design

[0417] The study is divided into four phases: screening phase, treatment phase, safety follow-up phase, and survival follow-up phase.

[0418] Screening period

[0419] After signing the informed consent form, the subjects will enter the screening period, which will be from Day -28 to Day -1. Subjects participating in the DDI study will be screened from Day -28 to Day -4. All subjects will need to complete relevant examinations or observations during the screening period before enrollment to determine their disease status and treatment history. Relevant examinations include vital signs, physical examinations, laboratory tests, pregnancy tests, ECOG scores, tumor imaging evaluations, electrocardiograms, echocardiograms, etc. During the screening period, routine blood tests, blood biochemistry, coagulation function, routine urine tests, 12-lead electrocardiograms, and pregnancy tests must be completed within 1 week before the first dose of the trial drug.

[0420] Treatment period

[0421] Subjects who meet the screening requirements will enter the treatment phase. During the treatment phase, all subjects will receive long-term treatment with Compound A, administered orally on an empty stomach at a dose of 60 mg once daily (QD) for three weeks, until disease progression, unacceptable toxicity, death, withdrawal of informed consent, or study termination (whichever occurs first) as assessed by the IRC. During the treatment phase (starting from C1D1), all subjects will undergo imaging studies and anti-tumor efficacy assessment every 6 weeks / 12 weeks (every 6 weeks from C1 to C17, every 12 weeks thereafter). Laboratory tests, vital signs, and physical examinations will be performed every 6 weeks / 12 weeks (every 6 weeks from C1 to C17, every 12 weeks thereafter) to assess treatment safety. During treatment, investigators may conduct additional examinations based on the subject's clinical symptoms or condition. The researchers judged the disease status according to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) and evaluated and recorded AEs according to CTCAE 5.0.

[0422] In addition, approximately 12 subjects will be selected for a DDI assessment of the effect of Compound A on simvastatin. Subjects will take a single oral dose of 40 mg simvastatin tablets in a fasting state on Cycle 1 (C1) D-2 (C1D-2), and PK sampling will be performed until 32 hours after administration (C1D-1). Subjects will begin taking Compound A according to the dosing regimen established during the treatment period on C1D1. After taking Compound A orally in a fasting state on C1D15, subjects will simultaneously take a single oral dose of 40 mg simvastatin tablets, and PK sampling will be performed until 32 hours after administration (C1D16). Subjects will continue to take Compound A according to the dosing regimen established during the treatment period until disease progression, intolerable toxicity, death, withdrawal of informed consent, or termination of the study as assessed by the IRC occurs, whichever occurs first.

[0423] This study conducted a population PK study to investigate the PK characteristics and potential influencing factors in patients with ALK-positive NSCLC.

[0424] This study sets up an independent imaging review committee (IRC), which evaluates all tumor imaging data to determine objective response and tumor progression. After the researcher determines that the subject's disease has progressed, the IRC confirms the subject's tumor imaging examination data. If the IRC assesses that the subject's disease has progressed, the subject will terminate treatment. If the researcher judges that the disease has progressed and the IRC judges that the disease has not progressed, the sponsor and the researcher need to discuss and reach a consensus to evaluate whether the subject should continue to receive study treatment from the perspective of the subject's risk and benefit. If the subject continues to receive study treatment, the researcher will continue to perform tumor assessments on the subject according to the protocol (unplanned tumor assessments may be added when clinically indicated) until the IRC judges that the patient's disease has progressed. The evaluation results of the IRC will be used for the analysis of effectiveness indicators, and the evaluation results based on the IRC will also be used to guide treatment decisions for the subjects.

[0425] The subject will be treated until they meet the criteria for termination / withdrawal of treatment, at which time the subject will terminate the study treatment. The subject needs to complete the last treatment visit within 7 days of terminating the study treatment, and will enter the safety follow-up period after completing the last treatment visit. If the IRC assesses the subject's disease progression, the researcher will assess that the subject will benefit from continuing to take the trial drug based on the subject's condition. After discussion with the sponsor, the subject may continue the trial treatment. If the subject experiences any adverse events or uses any concomitant medications or treatments during the continued medication period, they must report to the researcher in a timely manner. If necessary, they may come to the hospital for necessary examinations or treatments. The researcher will follow up based on the subject's disease status.

[0426] Safety follow-up period

[0427] After the subject meets the criteria for discontinuation / withdrawal of treatment and stops taking the drug, they will enter a 4-week safety follow-up period. If other anti-cancer treatments are used during the safety follow-up period, safety follow-up visits need to be completed before starting other anti-cancer treatments. For unresolved adverse events or laboratory abnormalities, follow-up will be carried out until the event is resolved, the patient returns to baseline, the patient's condition is stable, a reasonable explanation is obtained, the patient is lost to follow-up, or the patient dies.

[0428] Survival follow-up period

[0429] Starting from the last study dose, survival follow-up (telephone follow-up) will be conducted every 3 months ± 7 days to collect all subsequent anti-tumor treatment and patient survival information until the end of the trial, survival is obtained, or follow-up is refused, whichever occurs first. Unless the subject stops the drug or starts a new anti-tumor treatment due to disease progression or death, during the long-term follow-up period, the subject will need to visit the hospital for a tumor imaging examination every 12 weeks (calculated from the first dose) as originally planned and undergo an efficacy assessment according to RECIST version 1.1 until disease progression, initiation of new anti-tumor treatment, death, refusal to come to the hospital for follow-up, or the end of the trial. The IRC will evaluate the tumor imaging data to determine tumor progression.

[0430] Inclusion criteria

[0431] Patients who meet all of the following criteria may be considered for inclusion:

[0432] 1) Agree to follow the trial treatment plan and visit plan, voluntarily enroll, and sign the written informed consent;

[0433] 2) Aged ≥ 18 years old on the day of signing the informed consent form, regardless of gender;

[0434] 3) Patients with advanced (stage IIIB, IIIC, or IV) ALK-positive, inoperable NSCLC whose disease has progressed after continuous treatment with or is intolerant to second-generation ALK inhibitors (regardless of whether they have previously used crizotinib, those using experimental second-generation drugs are also eligible for inclusion);

[0435] 4) Previous test results (ALK-positive test reports confirmed by nationally approved Ventana D5F3 immunohistochemistry, FISH, PCR, or high-throughput sequencing (NGS)) are acceptable for screening. If no previous test report is available, tissue specimens are required for ALK gene confirmation. Fresh tissue samples or archived tumor tissue paraffin blocks or pathological biopsy sections within the past 6 months are recommended, but sample availability does not affect enrollment.

[0436] 5) Patients with central nervous system metastases at screening who meet the following conditions are eligible for inclusion in this trial: a. Asymptomatic: no need for corticosteroid treatment, or the dose of prednisone / equivalent drugs has been reduced to ≤10 mg QD and has been treated stably for at least 2 weeks; or b. Patients who have previously received treatment for central nervous system metastases (radiotherapy or surgery) have fully recovered from the acute effects of radiotherapy or surgery and have stopped corticosteroid treatment for metastases for at least 4 weeks before the first dose, and their neurological symptoms and signs are stable;

[0437] 6) Before the first administration of the trial drug, patients who had previously received ALK inhibitor treatment must have discontinued the drug for ≥ 5 half-lives;

[0438] 7) According to the RECIST version 1.1 criteria, there is at least one measurable lesion. Lesions that have been previously radiotherapy cannot be used as target lesions unless the lesion has clearly progressed;

[0439] 8) Eastern Cooperative Oncology Group (ECOG) performance status (PS), score 0-2 (Appendix 2);

[0440] 9) Adequate bone marrow, liver, kidney, coagulation, and pancreatic function (refer to the upper limit of normal values ​​of each clinical trial center):

[0441] Bone marrow [no blood transfusion or granulocyte colony-stimulating factor (G-CSF) or other cytokine-based corrective therapy within 2 weeks before the examination]:

[0442] Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L;

[0443] Platelets≥100×10 9 / L;

[0444] Hemoglobin ≥90 g / L;

[0445] Liver function:

[0446] Serum total bilirubin ≤1.5 times the upper limit of normal (ULN);

[0447] In the absence of liver metastasis, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 2.5 times ULN; in the presence of liver metastasis, ALT, AST, and ALP ≤ 5 times ULN;

[0448] Renal function: serum creatinine ≤1.5 times ULN;

[0449] Coagulation function: international normalized ratio (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0450] Pancreatic function:

[0451] Serum total amylase ≤1.5 times ULN;

[0452] Serum lipase ≤1.5 times ULN;

[0453] 10) Expected survival period ≥ 3 months;

[0454] 11) Men of childbearing potential and women of childbearing age are willing to take effective contraceptive measures from the time they sign the informed consent form to 6 months after the last dose of the trial drug; women of childbearing age include premenopausal women and women within 2 years of postmenopause.

[0455] Exclusion criteria

[0456] Patients who meet any of the following criteria are not eligible for inclusion:

[0457] 1) Subjects who have previously received other third-generation ALK inhibitors except Compound A;

[0458] 2) Patients who are known to be allergic to any active ingredient or excipient of Compound A, or have a history of specific allergic reactions (asthma, rheumatism, eczematous dermatitis), or have experienced other severe allergic reactions and are judged by the investigator to be unsuitable for treatment with Compound A;

[0459] 3) Patients with another malignant tumor other than lung cancer, excluding malignant tumors such as cervical cancer in situ and non-melanoma skin cancer that have received curative treatment and have not recurred within 5 years;

[0460] 4) Subjects who underwent major surgery within 4 weeks before the first dose. Minor surgical procedures (such as IV tube implantation) are not exclusion criteria, but sufficient time is required for the wound to fully heal;

[0461] 5) Spinal cord compression (caused by tumor), unless the subject achieves good pain control through treatment and the neurological function is fully recovered within 4 weeks before the first dose;

[0462] 6) Gastrointestinal dysfunction, mainly including inability to take oral medications, need for intravenous nutrition, previous surgical procedures (including total gastrectomy or gastric banding) that affect absorption, active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease, treatment of active peptic ulcer disease or malabsorption syndrome in the past 6 months, etc.;

[0463] 7) Patients with active pneumonia or a history of clinically significant interstitial lung disease, or radiation-induced or drug-induced lung disease requiring treatment. Patients with radiation pneumonitis who are asymptomatic 3 months after radiotherapy can be enrolled;

[0464] 8) Patients with heart failure, including but not limited to left ventricular ejection fraction (LVEF) <50%, history of congestive heart failure or ventricular arrhythmia requiring treatment, hypokalemia, hereditary long QT syndrome, myocardial infarction or unstable angina within 6 months before screening; patients with New York Heart Association heart failure grade ≥2;

[0465] 9) Patients with clinically significant abnormalities in corrected QTc on electrocardiogram (ECG) examination (QTc>450msec [male] or QTc>470msec [female] under resting conditions) or those taking any medications known to prolong the QT interval and cause torsades de pointes (such medications also need to be discontinued before the first dose; see Appendix 6 for specific medications and discontinuation time requirements);

[0466] 10) Hypertension that is not controlled after drug treatment (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);

[0467] 11) Uncontrolled hyperglycemia, acute cholelithiasis, and those with susceptible features to acute pancreatitis;

[0468] 12) Patients who, according to the investigator's judgment, have severe or uncontrollable systemic diseases (such as unstable or uncompensated respiratory, cardiac, liver or kidney diseases) and are expected to be unable to tolerate the trial drug treatment;

[0469] 13) Patients who have used the following drugs within 14 days before the first dose or need to use the following drugs during treatment: drugs that may cause QTc interval prolongation and / or ventricular tachycardia;

[0470] 14) Previous anti-tumor treatment: (1) Any systemic anti-tumor treatment used within 28 days before the first administration of the trial drug (if the drug has been discontinued for more than 5 half-lives and the investigator assesses that compound A can be used within 28 days after the end of systemic anti-tumor treatment, the patient can be included in the trial), including systemic chemotherapy, immunotherapy (physiological replacement dose of glucocorticoids [prednisone or equivalent <10 mg / day] is allowed), large molecule monoclonal antibodies, small molecule targeted drugs, etc.; (2) Radiotherapy or treatment with Chinese herbal medicine or Chinese patent medicine approved for anti-tumor treatment within 14 days before the first administration; (3) Received antibody or drug treatment targeting T cell co-stimulation or immune checkpoint pathways within the past 28 days, including but not limited to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibodies;

[0471] 15) Toxic reactions related to previous surgical procedures and previous anti-tumor treatments have not recovered and have been assessed by the investigator to affect the safety of the subject;

[0472] 16) Patients with clinically significant active bacterial, fungal, or viral infections, including those with positive hepatitis B surface antigen and HBV DNA ≥ ULN (ULN defined as 2000 IU / ml) (only in patients with positive hepatitis B surface antigen), or hepatitis C (patients with positive hepatitis C antibody but HCV RNA polymerase chain reaction (PCR) < ULN are eligible), any one or more positive results of human immunodeficiency virus antibody tests, or any uncontrolled infection;

[0473] 17) Patients who have taken strong inducers or inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic window within two weeks before the first dose of the trial drug;

[0474] 18) Female subjects who are pregnant or lactating;

[0475] 19) Women of childbearing age who are unwilling or unable to use acceptable contraceptive methods during the entire treatment period of this trial and within 6 months after the last dose of the trial drug (women of childbearing age include: anyone who has had menarche and has not undergone successful artificial sterilization surgery [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or is premenopausal); male patients of childbearing potential who are unwilling or unable to take effective contraceptive measures if their partner is a woman of childbearing age;

[0476] 20) Subjects who are currently participating in other clinical studies (excluding the non-intervention phase of interventional clinical studies, such as the survival follow-up period) or whose first medication time is less than 4 weeks from the end of receiving other study drugs or 5 half-lives of the study drug, whichever is shorter;

[0477] 21) Any mental or cognitive disorder that may limit their understanding and execution of the informed consent form; other conditions that the researcher deems unsuitable for participation in this study, such as poor compliance, etc.

[0478] Test results

[0479] A total of 204 subjects were screened in this trial, of which 164 subjects were successfully screened and enrolled, 163 subjects (99.4%) received compound A treatment, and 40 subjects failed screening, the main reason for failure was not meeting the inclusion criteria or meeting the exclusion criteria (37 subjects, 18.1%).

[0480] ① Demographic data

[0481] Based on the full analysis set that met the key inclusion and exclusion criteria, among the 158 subjects with a history of anti-NSCLC tumor drug treatment, the pathological types were adenocarcinoma in 151 cases (95.6%), squamous cell carcinoma in 3 cases (1.9%), other types of cancer in 3 cases (1.9%), and large cell carcinoma in 1 case (0.6%); 2 cases (1.3%) of the subjects had clinical tumor stage III B, III There were 3 cases (1.9%) in stage C, 151 cases (95.6%) in stage IV, and 2 cases in other stages; all subjects were ALK-positive; 153 cases (96.8%) had metastases at enrollment, with the following metastatic sites: intracranial metastasis in 86 cases (56.2%), bone metastasis in 73 cases (47.7%), liver metastasis in 28 cases (18.3%), adrenal metastasis in 20 cases (13.1%), and metastasis in other sites in 130 cases (85.0%); ECOGPS score was 0 in 28 cases (17.7%), 1 in 127 cases (80.4%), and 2 in 3 cases (1.9%).

[0482] The treatment types for the 158 subjects were: targeted therapy (158 cases, 100.0%), other treatments (55 cases, 34.8%), and chemotherapy (43 cases, 27.2%). Classified by preferred name, the most common anti-cancer drugs used were alectinib (89 cases, 56.3%), crizotinib (55 cases, 34.8%), and pemetrexed (49 cases, 31.0%). The usage of second-generation ALK inhibitors was: alectinib in 89 cases (56.3%), ensartinib in 39 cases (24.7%), ceritinib in 20 cases (12.7%), and brigatinib in 7 cases (4.4%). The usage of second-generation ALK inhibitors in clinical trials was: XZP-3621 tablets in 10 cases (6.3%), TQ-B3139 capsules in 10 cases (6.3%), and WX-0593 tablets in 7 cases (4.4%).

[0483] Among them, XZP-3621 is an ALK inhibitor independently developed by Xuanzhu Bio for the treatment of non-small cell lung cancer and is currently in Phase III clinical research. TQ-B3139 is also known as Yifeng Ake, and WX-0593 is also known as Yilu Ake. Their structures are shown below:

[0484] ②Effectiveness results

[0485] a) Systemic tumor efficacy

[0486] As of the data cutoff date (May 20, 2024), based on the full analysis set of 158 subjects, 67 subjects (42.4%) achieved a best objective response (PR) as assessed by IRC, with an ORR of 67 (42.4%, 95% CI: 34.59, 50.51). The median DOR was not yet available, the median TTR was 1.38 months (95% CI: 1.38, 1.41), and the median PFS was 11.14 months (95% CI: 8.41, -). Details of the IRC-assessed whole-body BOR, ORR, and DCR analyses are shown in Table 14. A waterfall plot of the best percentage change from baseline in the sum of whole-body tumor diameters is shown in Figure 14, and the Kaplan-Meier curve (survival curve) for PFS is shown in Figure 15.

[0487] Table 14 Whole-body BOR, ORR and DCR analysis (IRC assessment results) Full analysis set

[0488] The above results show that compound A has good efficacy in subjects after failure of second-generation ALK-TKI treatment, achieves tumor remission in a shorter time, can better control disease progression, and is expected to prolong the subjects' progression-free survival.

[0489] b) Efficacy of intracranial tumors

[0490] As of the data cutoff date (May 20, 2024), based on the full analysis set of 158 subjects, there were 44 subjects with measurable intracranial lesions. No subject achieved CR in the best objective response assessed by IRC, and 24 subjects (54.5%) achieved PR. Their IC-ORR was 24 (54.5%, 95% CI: 38.85, 69.61), and their IC-DCR was 37 (84.1%, 95% CI: 69.93, 93.36). The median IC-DOR was 9.76 months (95% CI: 8.28, -), the median IC-TTR was 1.41 months (95% CI: 1.35, 1.41), and the median IC-PFS was 9.66 months (95% CI: 6.83, -). The detailed analysis of the subjects' IC-BOR, IC-ORR, and IC-DCR is shown in Table 15, the waterfall plot of the change in the sum of intracranial tumor diameters relative to baseline is shown in Figure 16, and the Kaplan-Meier curve of IC-PFS is shown in Figure 17.

[0491] Table 15 Intracranial BOR, ORR and DCR analysis (IRC evaluation results) Full analysis set

[0492] The above results show that compound A has good efficacy in patients who have failed second-generation ALK-TKI treatment and have intracranial target lesions, achieves tumor remission in a shorter time, and can better control the progression of intracranial disease.

[0493] c) ORR of subjects in the “efficacy subgroup”

[0494] The ORR of subjects assessed by IRC based on the FAS is shown in Figure 18. Data showed that there was little difference in ORR among the following subgroups: age < or ≥ 65 years (ORR: 43.0% vs. 40.0%), male or female (ORR: 41.9% vs. 42.9%), and with or without a smoking history (ORR: 38.6% vs. 39.4%). However, the ORR was slightly higher in subjects with a baseline ECOGPS score of 0 compared to those with a baseline ECOGPS score of 1-2 (50.0% vs. 40.8%), slightly higher in subjects with baseline brain metastases compared to those without (45.3% vs. 38.9%), and slightly higher in subjects who had not previously received chemotherapy compared to those who had (45.4% vs. 37.7%). The ORR in subjects with the G1202R mutation was 62.5% (95% CI: 24.5%, 91.5%).

[0495] The results of subgroup analysis showed that compound A was more effective in subjects with a baseline ECOGPS score of 0, baseline brain metastases, and no previous chemotherapy; it was also more effective in subjects with G1202R mutations, with an ORR of 62.5%.

[0496] ③Safety analysis

[0497] Common TRAEs of compound A include hypercholesterolemia, hypertriglyceridemia, weight gain, anemia, and peripheral edema. Most subjects experienced TRAEs of grade 1-2, and the incidence of TRAEs leading to dose reduction, temporary discontinuation, or permanent discontinuation was low. For subjects with TRAEs of grade 3 or above, most recovered through measures such as dosing suspension, dose reduction, or symptomatic treatment. The adverse event classification was similar to that of similar drugs, the safety risks were controllable, and the overall safety profile was good.

[0498] Example 6 A multicenter, randomized, controlled, open-label phase III study comparing the efficacy and safety of Compound A and crizotinib in the treatment of patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC)

[0499] This trial is a multicenter, randomized, open-label, active-controlled Phase III clinical trial, primarily evaluating the clinical efficacy and safety of Compound A compared with crizotinib in the treatment of patients with advanced or metastatic ALK-positive NSCLC. The primary objective is to compare the clinical efficacy of Compound A tablets and crizotinib capsules in the treatment of patients with ALK-positive advanced or metastatic NSCLC, using progression-free survival (PFS) assessed by an independent imaging review committee (IRC) as the endpoint. Secondary objectives are to evaluate the clinical efficacy of Compound A tablets and crizotinib capsules in the treatment of patients with ALK-positive advanced or metastatic NSCLC using other efficacy endpoints; and to compare the safety of Compound A tablets and crizotinib capsules in the treatment of patients with ALK-positive advanced or metastatic NSCLC.

[0500] This study is divided into four phases: screening phase, treatment phase, safety follow-up phase, and survival follow-up phase.

[0501] Screening period

[0502] After signing the informed consent form, the subjects will enter the screening period, which is from Day -28 to Day -1. All subjects need to complete relevant examinations or observations during the screening period before enrollment to determine their disease status, treatment history, etc. Relevant examinations include vital signs, physical examinations, laboratory tests, pregnancy tests, ECOG scores, tumor imaging evaluations, electrocardiograms, echocardiograms, etc. Among them, routine blood tests, blood biochemistry, coagulation function, routine urine tests, 12-lead electrocardiograms, and pregnancy tests during the screening period need to be completed within 1 week before the first dose of the trial drug.

[0503] Treatment period

[0504] Eligible subjects were randomly assigned to an experimental group (Compound A) or a control group (crizotinib) in a 2:1 ratio. This study employed stratified randomization, with stratification based on the presence of central nervous system metastases at baseline and prior chemotherapy for advanced NSCLC. All subjects in the experimental group received long-term treatment with Compound A, 60 mg orally once daily (QD) on an empty stomach, for a 28-day cycle. Subjects in the control group received the active control drug, crizotinib, 250 mg twice daily (BID), for a 28-day cycle. All subjects continued treatment according to their randomized group until IRC-assessed disease progression, unacceptable toxicity, death, withdrawal of informed consent, or study discontinuation, whichever occurred first.

[0505] During the treatment period (starting from C1D1), all subjects underwent imaging examinations and anti-tumor efficacy assessments every 8 weeks and 12 weeks (every 8 weeks for C1-C17 and every 12 weeks thereafter). During the treatment period, all subjects underwent laboratory tests, vital signs, and physical examinations to assess treatment safety every 4 weeks, 8 weeks, and 12 weeks (every 4 weeks for C1-C3, every 8 weeks for C4-C17, and every 12 weeks thereafter). During treatment, the investigator may add additional safety assessments based on the subject's clinical symptoms or status. Disease status was assessed by the investigator according to RECIST v1.1 and adverse events were assessed and recorded according to CTCAE v5.0. A population PK study and exposure-response relationship study of Compound A were conducted in all trial groups to explore the population pharmacokinetic characteristics and potential influencing factors of Compound A in subjects with ALK-positive NSCLC.

[0506] For subjects in the crizotinib group who have disease progression as assessed by the IRC, after discontinuation of crizotinib (crossover is not permitted for subjects who receive other anti-cancer treatments after discontinuation of crizotinib treatment), crossover to the Compound A group for treatment and clinical efficacy and safety follow-up is allowed after investigator assessment and subject consent. Crossover from the Compound A group to the crizotinib group is not permitted. For subjects who cross over to Compound A, the imaging assessment results of disease progression assessed by the IRC will serve as the baseline for the crossover treatment period. After starting to take Compound A tablets, patients will undergo imaging examinations and anti-tumor efficacy evaluation every 8 weeks / 12 weeks (once every 8 weeks for C1-C17, and every 12 weeks after C17), and laboratory tests, vital signs and physical examinations to evaluate treatment safety every 4 / 8 / 12 weeks (once every 4 weeks for C1-C3, once every 8 weeks for C4-C17, and every 12 weeks after C17). The investigator may increase the safety assessment examinations of the subjects according to the clinical symptoms or status of the subjects until disease progression, intolerable toxicity, death, withdrawal of informed consent, or termination of the study, whichever occurs first.

[0507] This study includes an IRC, which evaluates all tumor imaging data during the randomized phase to determine objective response and tumor progression. After the investigator determines that a subject's disease has progressed, the IRC confirms the subject's tumor imaging data. If the investigator determines that the disease has progressed but the IRC determines that it has not, the subject continues to receive study treatment, and the investigator continues to assess the subject's tumor according to the protocol (unplanned tumor assessments may be added as clinically indicated) until the IRC determines that the subject's disease has progressed. The IRC's assessment results will be used to analyze efficacy indicators and guide treatment decisions for the subjects based on the IRC's assessment results.

[0508] The subject will be treated until they meet the termination / withdrawal criteria, at which point the subject will terminate the study treatment. The subject needs to complete the last treatment visit within 7 days of terminating the study treatment, and will enter the safety follow-up period after completing the termination visit. If the IRC assesses the subject's disease progression, the researcher will assess that the subject will benefit from continuing to take the trial drug based on the subject's condition. After discussion with the sponsor, the subject may continue the trial treatment. Follow-up will be based on the previous visit cycle during continued medication. If the subject experiences any adverse events or uses any concomitant medications or treatments during the medication period, they must report to the researcher in a timely manner. If necessary, they may come to the hospital for necessary examinations or treatments. The researcher will follow up based on the subject's disease status.

[0509] Safety follow-up period

[0510] After the subject meets the termination / exit criteria and stops the drug, he / she will enter a safety follow-up period of 4 weeks ± 7 days starting from the last study dose; if other anti-tumor treatments are used during the safety follow-up period, the safety follow-up visit needs to be completed before starting other anti-tumor treatments. For unresolved adverse events or laboratory abnormalities, follow-up will be carried out until the event is resolved, the patient returns to baseline, the condition is stable, and a reasonable explanation is obtained. 、 Lost to follow-up or died.

[0511] Survival follow-up period

[0512] If a subject withdraws from treatment due to disease progression, survival follow-up (telephone follow-up) will be conducted every 12 weeks (±14 days) starting from the last study administration. All subsequent anti-tumor treatment and subject survival status will be collected until the end of the trial, survival is obtained, or follow-up is refused, whichever occurs first.

[0513] Unless the subject stops taking the drug due to disease progression or death, during the long-term follow-up period, the subject needs to come to the hospital for a tumor imaging examination and efficacy evaluation according to RECIST v1.1 once every 12 weeks (±14 days) (calculated from the first dose) as originally planned until disease progression or death or refusal to come to the hospital for follow-up or the end of the trial.

[0514] Patients who meet all of the following criteria may be considered for inclusion:

[0515] 1) Agree to follow the trial treatment plan and visit plan, voluntarily enroll, and sign the written informed consent;

[0516] 2) Aged ≥ 18 years old on the day of signing the informed consent form, regardless of gender;

[0517] 3) NSCLC patients diagnosed with stage IIIB-IV ALK-positive disease by histology or cytology and unable to be cured (surgery, radiotherapy) (International Association for the Study of Lung Cancer, 8th edition lung cancer staging);

[0518] 4) The patient's previous local examination results (nationally approved Ventana D5F3 immunohistochemistry, FISH or PCR, next-generation sequencing (NGS)) are acceptable at screening. If no previous test report is available, a tissue specimen must be provided for central confirmation of the ALK gene before randomization.

[0519] 5) No previous experience with ALK inhibitors; at most, progression or intolerance after first-line chemotherapy;

[0520] 6) Patients with asymptomatic brain metastases at screening can be enrolled. Patients with untreated brain metastases do not require the use of corticosteroids. If patients develop neurological symptoms or signs due to CNS metastases, they are required to complete whole-brain radiotherapy or gamma knife treatment at least 14 days before the first dose and achieve symptom stability (fixed-dose or dose-decreasing corticosteroids at baseline);

[0521] 7) According to the RECIST version 1.1 criteria, there must be at least one measurable target lesion (non-lymph node longest diameter ≥10 mm, lymph node shortest diameter ≥15 mm). Lesions that have been previously radiotherapy cannot be used as target lesions unless the lesion has significantly progressed;

[0522] 8) Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-2;

[0523] 9) Adequate bone marrow, liver, kidney, coagulation, and pancreatic function:

[0524] Bone marrow [no blood transfusion or corrective treatment with cytokine drugs such as granulocyte colony-stimulating factor (G-CSF) within 2 weeks before the screening test]:

[0525] Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L;

[0526] Platelets≥100×10 9 / L;

[0527] Hemoglobin ≥90 g / L;

[0528] Liver function:

[0529] Serum total bilirubin ≤1.5 times the upper limit of normal (ULN);

[0530] In the absence of liver metastasis, alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase (ALP) ≤ 2.5 times ULN; in the presence of liver metastasis, ALT, AST, or ALP ≤ 5 times ULN;

[0531] Renal function: serum creatinine ≤1.5 times ULN;

[0532] Coagulation function: international normalized ratio (INR) ≤ 1.5 × ULN, activated partial thromboplastin time (APTT) ≤ 1.5 × ULN;

[0533] Pancreatic function:

[0534] Serum total amylase ≤1.5 times ULN;

[0535] Serum lipase ≤1.5 times ULN;

[0536] 10) Expected survival period ≥ 3 months;

[0537] 11) Males and females of childbearing potential are willing to use effective contraceptive measures from the time they sign the informed consent form until 6 months after the last dose of the trial drug; females of childbearing age include premenopausal women and women within 1 year of postmenopausal women. Females of childbearing age must have a negative blood pregnancy test result ≤ 7 days before the first dose of the trial drug.

[0538] Patients who meet any of the following criteria are not eligible for inclusion:

[0539] 1) Patients with known allergies to Compound A and any active ingredient or excipient of crizotinib capsules, or with a clear history of specific allergic reactions (asthma, rheumatism, eczematous dermatitis), or who have had other severe allergic reactions;

[0540] 2) In addition to lung cancer, patients have had other malignant tumors in the past 5 years (except for basal cell carcinoma of the skin, carcinoma in situ of the cervix, or other curable cancers that have no effect on the PFS and OS of the current NSCLC);

[0541] 3) received radiotherapy within 14 days before the first dose;

[0542] 4) Received other systemic anti-tumor drug treatment within 4 weeks before the first dose, or is still within 5 half-lives of the drug. Received Chinese herbal medicine or Chinese patent medicine for anti-tumor treatment within 14 days before the first dose;

[0543] 5) Underwent major surgery within 4 weeks before the first dose;

[0544] 6) Spinal cord compression (caused by tumor), unless the subject achieves good pain control through treatment and the neurological function is fully recovered within 4 weeks before the first dose;

[0545] 7) Gastrointestinal dysfunction, including inability to take oral medications, need for intravenous nutrition, previous surgical procedures (including total gastrectomy or gastric banding) that affect absorption, active inflammatory gastrointestinal disease, chronic diarrhea, symptomatic diverticular disease, active peptic ulcer requiring treatment within the past 6 months, or malabsorption syndrome;

[0546] 8) Patients with active pneumonia or a history of clinically significant interstitial lung disease, or radiation-induced or drug-induced lung disease requiring interventional treatment. Patients with radiation pneumonitis who are asymptomatic 3 months after radiotherapy can be enrolled;

[0547] 9) Patients with heart failure, including but not limited to left ventricular ejection fraction (LVEF) <50%, history of congestive heart failure or ventricular arrhythmia requiring treatment, hypokalemia, hereditary long QT syndrome, myocardial infarction or unstable angina within 6 months before screening; patients with New York Heart Association heart failure grade ≥2;

[0548] 10) The patient has a clinically significant abnormal QTc on electrocardiogram (ECG) examination (QTc>450msec [male] or QTc>470msec [female] at rest) or is taking any drug known to prolong the QT interval and cause torsades de pointes;

[0549] 11) Hypertension that is poorly controlled after drug treatment (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);

[0550] 12) Uncontrolled hyperglycemia, acute cholelithiasis, and those with susceptible features to acute pancreatitis;

[0551] 13) Patients who, according to the investigator's judgment, have severe or uncontrollable systemic diseases (such as unstable or uncompensated respiratory, cardiac, liver or kidney diseases) and are expected to be unable to tolerate the trial drug treatment;

[0552] 14) Toxic reactions related to previous surgical procedures and previous anti-tumor treatments have not recovered and have been assessed by the investigator to affect the safety of the subject;

[0553] 15) Patients with clinically significant active bacterial, fungal, or viral infections, including those with positive hepatitis B surface antigen and HBV DNA ≥ 2000 IU / ml (only in patients with positive hepatitis B surface antigen), or hepatitis C (patients with positive hepatitis C antibody but HCV RNA polymerase chain reaction (PCR) test < ULN are eligible), those with positive human immunodeficiency virus antibody test results, or those with any uncontrolled infection;

[0554] 16) Patients who have taken strong inducers or inhibitors of CYP3A4 or CYP3A4 substrates with a narrow therapeutic window within two weeks before the first dose of the trial drug;

[0555] 17) Female subjects who are pregnant or breastfeeding;

[0556] 18) Women of childbearing age who are unwilling or unable to use acceptable contraceptive methods during the entire treatment period of this trial and within 6 months after the last dose of the trial drug (women of childbearing age include: anyone who has had menarche, and has not successfully undergone artificial sterilization surgery [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or is not in menopause); male patients of childbearing potential who are unwilling or unable to take effective contraceptive measures if their partner is a woman of childbearing age;

[0557] 19) Subjects who are currently participating in other clinical studies or whose first medication time is less than 4 weeks from the end of receiving other study drugs or 5 half-lives of the study drug, whichever is shorter;

[0558] 20) Suffering from any mental illness or cognitive impairment that may limit their understanding and implementation of the informed consent form;

[0559] 21) Other circumstances that the researcher deems unsuitable for participation in this study.

[0560] Criteria for discontinuation of treatment

[0561] In any of the following situations, the researcher may terminate the treatment of the subject:

[0562] The subject voluntarily requested to stop treatment;

[0563] The researcher believes that the subject should terminate the trial drug treatment for safety reasons (such as intolerable adverse events);

[0564] The subject is pregnant;

[0565] die;

[0566] The subject has a serious protocol violation, and the investigator believes that the protocol violation seriously affects the evaluation of the primary endpoint of this trial;

[0567] If the investigator assesses a subject to have disease progression, the IRC will conduct a rapid review of the disease progression. If the IRC assesses the subject to have disease progression, the subject will discontinue treatment. If the IRC assesses the subject to have no disease progression, the sponsor and investigator will discuss and reach a consensus on whether the subject should continue with the study treatment based on the risk-benefit ratio.

[0568] Exit criteria for the study:

[0569] The following reasons may cause subjects to withdraw from the study:

[0570] 1. Death of the subject;

[0571] 2. The subject requests to withdraw from the study;

[0572] 3. The subject is lost to follow-up;

[0573] 4. The sponsor terminates the study;

[0574] Subjects can withdraw from the study at any stage according to their own wishes.

[0575] A clear distinction should be made between subjects permanently discontinuing the study drug (i.e., terminating treatment) and withdrawing from the study. Subjects who permanently discontinue the study drug should remain in the study to complete safety visits and survival follow-up. Subjects who withdraw from the study are encouraged to complete the appropriate examinations and survival follow-up within 7 days of the decision to withdraw, referring to the end-of-term visit (EOT) visit, as shown in the trial flow chart. Subject withdrawal from the study should be recorded on the corresponding page of the eCRF and in the subject's medical record, and the reason for withdrawal should be recorded.

[0576] Exit criteria for the study:

[0577] The following reasons may cause subjects to withdraw from the study:

[0578] 1. Death of the subject;

[0579] 2. The subject requests to withdraw from the study;

[0580] 3. The subject is lost to follow-up;

[0581] 4. The sponsor terminates the study;

[0582] Subjects can withdraw from the study at any stage according to their own wishes.

[0583] A clear distinction should be made between subjects permanently discontinuing the study drug (i.e., terminating treatment) and withdrawing from the study. Subjects who permanently discontinue the study drug should remain in the study to complete safety visits and survival follow-up. Subjects who withdraw from the study are encouraged to complete the appropriate examinations and survival follow-up within 7 days of the decision to withdraw, referring to the end-of-term visit (EOT) visit, as shown in the trial flow chart. Subject withdrawal from the study should be recorded on the corresponding page of the eCRF and in the subject's medical record, and the reason for withdrawal should be recorded.

[0584] The above content is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention should not be considered to be limited to these descriptions. For those skilled in the art to which the present invention belongs, several simple deductions or substitutions can be made without departing from the concept of the present invention, and all of these should be considered to fall within the scope of protection of the present invention.

Claims

1. Use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer, wherein the compound A has the following structure:

2. A method for treating non-small cell lung cancer in a patient, comprising administering to the patient a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein the Compound A has the following structure:

3. Compound A or a pharmaceutically acceptable salt thereof for use in treating non-small cell lung cancer, wherein the compound A has the following structure:

4. The use according to claim 1 or the method according to claim 2 or the use of the compound according to claim 3, wherein the non-small cell lung cancer is ALK-positive non-small cell lung cancer; preferably, wherein the non-small cell lung cancer is advanced ALK-positive non-small cell lung cancer; preferably, wherein the ALK is ALK L1196M or ALK G1202R mutation; preferably, wherein the non-small cell lung cancer is TP53-positive (including mutations and wild-type) ALK-positive non-small cell lung cancer; preferably, the non-small cell lung cancer is TP53-mutated ALK-positive non-small cell lung cancer.

5. The use, method or use of a compound according to any one of claims 1 to 4, wherein the non-small cell lung cancer is an adenocarcinoma.

6. The use, method or use of a compound according to any one of claims 1 to 5, wherein the non-small cell lung cancer is metastatic non-small cell lung cancer; preferably, wherein the non-small cell lung cancer is CNS metastatic non-small cell lung cancer (eg, intracranial metastatic non-small cell lung cancer).

7. The use, method or use of a compound according to any one of claims 1 to 6, wherein the non-small cell lung cancer is not treatment-naive.

8. The use, method or use of a compound according to any one of claims 1 to 6, wherein the non-small cell lung cancer has progressed after treatment with another therapy; Preferably, the other therapy is selected from radiotherapy, drug therapy or surgical therapy; preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy; Preferably, the drug therapy is chemotherapy; Preferably, the drug therapy is targeted therapy; Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, brucea brucei, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

9. The use, method or use of a compound according to claim 8, wherein the non-small cell lung cancer progresses after treatment with an ALK inhibitor.

10. The use, method or use of a compound according to claim 9, wherein the ALK inhibitor is a first-generation or second-generation ALK inhibitor; preferably, the ALK inhibitor is selected from crizotinib, alectinib, ceritinib, ensartinib or brigatinib.

11. The use, method or use of a compound according to any one of claims 1 to 10, wherein the non-small cell lung cancer is clinical stage III or IV.

12. The use, method or use of a compound according to any one of claims 1 to 11, wherein the patient has received one or more lines of treatment; preferably, wherein the patient has received two or more lines of treatment; preferably, the patient has received one, two, three, four or five lines of treatment.

13. The use, method or use of a compound according to claim 12, wherein the patient has disease progression or intolerance after receiving one or more lines of treatment; preferably, wherein the patient has disease progression or intolerance after receiving one or two lines of treatment.

14. The use, method or use of a compound according to claim 12 or 13, wherein the first line or more than one line of treatment is selected from radiotherapy, drug therapy or surgical therapy; Preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy; Preferably, the drug of the drug therapy is selected from carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, brucea brucei, gimeracil, oteracil, tegafur, tadalafil, tadalafil, tegra, tadalafil ... One or more of fluorine, sodium cantharides, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitors, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

15. The use, method or use of a compound according to claim 14, wherein the patient has previously received chemotherapy; preferably, wherein the chemotherapy drug is selected from carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate or pyridoxine, preferably carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, docetaxel, endostatin, sodium cantharidate or pyridoxine.

16. The use, method or use of a compound according to claim 14, wherein the patient has previously received targeted therapy; preferably, the patient has previously received ALK inhibitor therapy; preferably, the patient has previously received second-generation ALK inhibitor therapy, such as alectinib, ceritinib, ensartinib or brigatinib; preferably, the patient has previously received crizotinib as the only ALK inhibitor therapy.

17. The use, method or use of a compound according to claim 14, wherein the patient has not been previously treated with an ALK inhibitor (eg, a third generation ALK inhibitor).

18. The use, method or use of a compound according to any one of claims 1 to 17, wherein the dose of Compound A is from about 5 mg / day to about 180 mg / day; Preferably, the dosage of Compound A is about 5 mg / day to about 125 mg / day; Preferably, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day; Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day; Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day; Preferably, the dosage of Compound A is about 60 mg / day.

19. The use, method or use of a compound according to any one of claims 1 to 18, wherein the compound A is administered orally.

20. The use, method or use of a compound according to any one of claims 1 to 19, wherein the compound A is orally administered once a day, twice a day or three times a day; Preferably, the compound A is orally administered once a day.

21. The use, method or use of a compound according to any one of claims 1 to 20, wherein the compound A is administered until disease progression, intolerable toxicity or death.

22. The use, method or use of a compound according to any one of claims 1 to 21, wherein the patient has a CSF / plasma concentration ratio of Compound A of greater than about 40% after administration of Compound A; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 50%; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 60%.

23. The use according to claim 1 or the method according to claim 2 or the use of the compound according to claim 3, wherein the non-small cell lung cancer is ROS1-positive non-small cell lung cancer; preferably, wherein the non-small cell lung cancer is advanced ROS1-positive non-small cell lung cancer; preferably, wherein the ROS1 is a ROS1 G2032R mutation.

24. The use, method or use of a compound according to any one of claims 1 to 3 and 23, wherein the non-small cell lung cancer is an adenocarcinoma.

25. The use, method or use of a compound according to any one of claims 1-3 and 23-24, wherein the non-small cell lung cancer is metastatic non-small cell lung cancer; preferably, wherein the non-small cell lung cancer is CNS metastatic non-small cell lung cancer (eg, intracranial metastatic non-small cell lung cancer).

26. The use, method or use of a compound according to any one of claims 1-3 and 23-25, wherein the non-small cell lung cancer is not treatment-naive.

27. The use, method or use of a compound according to any one of claims 1-3 and 23-26, wherein the non-small cell lung cancer has progressed following treatment with another therapy; Preferably, the other therapy is selected from radiotherapy, drug therapy or surgical therapy; preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy; Preferably, the drug therapy is chemotherapy; Preferably, the drug therapy is targeted therapy; Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, brucea brucei, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

28. The use, method or use of a compound according to claim 27, wherein the non-small cell lung cancer progresses after treatment with a ROS1 inhibitor.

29. The use, method or use of a compound according to claim 28, wherein the ROS1 inhibitor is a first generation ROS1 inhibitor; preferably, the ROS1 inhibitor is selected from crizotinib, alectinib, ceritinib, ensartinib or brigatinib.

30. The use, method or use of a compound according to any one of claims 1-3 and 23-29, wherein the non-small cell lung cancer is clinical stage III or IV, preferably clinical stage IV.

31. The use, method or use of a compound according to any one of claims 1-3 and 23-30, wherein the patient has received one or more lines of treatment; preferably, wherein the patient has received two lines of treatment.

32. The use, method or use of a compound according to claim 31, wherein the patient has disease progression or intolerance after receiving one or more lines of treatment; preferably, wherein the patient has disease progression or intolerance after receiving a second line of treatment.

33. The use, method or use of a compound according to claim 31 or 32, wherein the first line or more than one line of treatment is selected from radiotherapy, drug therapy or surgical therapy; Preferably, the drug therapy is chemotherapy, targeted therapy or immunotherapy; Preferably, the drug of the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, brucea brucei, gimeracil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contertinib, ALK inhibitor, APG2499, bevacizumab, sintilimab, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-CD137 antibody or anti-CTLA-4 antibody.

34. The use, method or use of a compound according to claim 33, wherein the patient has previously received chemotherapy; preferably, wherein the chemotherapy drug is selected from carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, brucea javanica, gimeracil, oteracil, tegafur, sodium cantharidate or pyridoxine, preferably carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, docetaxel, endostatin, sodium cantharidate or pyridoxine.

35. The use, method or use of a compound according to claim 33, wherein the patient has previously received targeted therapy; preferably, the patient has previously received ROS1 inhibitor treatment, such as alectinib, ceritinib, ensartinib or brigatinib; preferably, the patient has previously received crizotinib as the only ROS1 inhibitor treatment.

36. The use, method or use of a compound according to claim 33, wherein the patient has not been previously treated with a ROS1 inhibitor (eg a second generation ROS1 inhibitor).

37. The use, method or use of a compound according to any one of claims 1-3 and 23-36, wherein the dose of Compound A is from about 5 mg / day to about 180 mg / day; Preferably, the dosage of Compound A is about 5 mg / day to about 125 mg / day; Preferably, the dosage of Compound A is selected from about 5 mg / day, about 10 mg / day, about 20 mg / day, about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day; Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day, about 80 mg / day, about 100 mg / day or about 125 mg / day; Preferably, the dosage of Compound A is selected from about 40 mg / day, about 60 mg / day or about 80 mg / day; Preferably, the dosage of Compound A is about 60 mg / day.

38. The use, method or use of a compound according to any one of claims 1-3 and 23-37, wherein the compound A is administered orally.

39. The use, method or use of a compound according to any one of claims 1-3 and 23-38, wherein the compound A is orally administered once a day, twice a day or three times a day; Preferably, the compound A is orally administered once a day.

40. The use, method or use of a compound according to any one of claims 1-3 and 23-39, wherein the compound A is administered until disease progression, intolerable toxicity or death.

41. The use, method or use of a compound according to any one of claims 1-3 and 23-40, wherein the patient has a CSF / plasma concentration ratio of Compound A of greater than about 40% after administration of Compound A; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 50%; preferably, a CSF / plasma concentration ratio of Compound A of greater than about 60%.

42. A method for detecting the concentration of Compound A in the CNS fluid of a subject in ALK-positive or ROS1-positive CNS metastatic non-small cell lung cancer, comprising: a. Collect cerebrospinal fluid samples; and b. Measuring the concentration of Compound A in the CSF sample to determine the concentration of Compound A present in the CNS fluid.

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