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

Treatment methods for ALK-positive or ROS1-positive non-small cell lung cancer Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to a method for treating non-small cell lung cancer, such as ALK-positive and / or ROS1-positive non-small cell lung cancer, with macrocyclic compound (10R)-7-amino-12-fluoro-2-(methyl-d3)-10,16-dimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metamerylbridged)pyrazole[4,3-h][2,5,11]benzoxazadazetatetracyclo-3-carboxynitrile (compound A) or a pharmaceutically acceptable salt thereof. Background Technology

[0002] Anaplastic lymphoma kinase (ALK) is a receptor-type protein tyrosine kinase belonging to the insulin receptor superfamily. It was discovered in 1994 by Morris and Shiota et al. as a product of chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). The most common fusion mode is the fusion of the NPM (Nucleophosmin) gene on chromosome 5 with the ALK gene on chromosome 2. The NPM-ALK fusion protein is detected in nearly 75% of ALK-positive ALCL patients. Subsequent studies have found different ALK fusion forms in many cancers, including inflammatory myofibroblastoma and diffuse large B-cell lymphoma. Nevertheless, the importance of ALK kinase as a target for effective anti-tumor drugs is not fully recognized. It wasn't until 2007, when Soda et al. discovered that the EML4-ALK fusion protein accounted for 5% of non-small-cell lung cancer (NSCLC), that the importance of ALK kinase as a target for anti-tumor drugs became apparent. This is because the number of cancer patients worldwide is enormous, with lung cancer being the most prevalent. The United States sees over 8,000 new cases of ALK-positive lung cancer annually, while China has over 65,000 new cases each year, and the global 5-year survival rate for lung cancer is only 15%. Interestingly, patients with positive EML4-ALK genes generally do not carry epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma virus (KRAS) mutations, making the EML4-ALK fusion gene a unique molecular target for NSCLC. In addition, ALK gene amplification or point mutations have been found in neuroblastoma, 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. Aberrant fusion proteins leading to ROS1 kinase involve genetic alterations to ROS1, including 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. Other fusions have also been found in tumor samples from lung cancer patients, including TPM3-ROS1, SDC4-ROS1, EZR-ROS1, and LRTG3-ROS1.

[0004] Invention Overview

[0005] This invention provides the 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 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 the treatment of non-small cell lung cancer, wherein said compound A has the following structure:

[0009] On the other hand, this article discloses a method for detecting the concentration of compound A in the CNS fluid of subjects with ALK-positive and / or ROS1-positive metastatic non-small cell lung cancer, comprising:

[0010] a. Collecting cerebrospinal fluid samples; and

[0011] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution. Attached Figure Description

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

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

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

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

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

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

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

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

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

[0021] Figure 10 is a waterfall plot of the percentage change in the sum of the total tumor diameters relative to the baseline in subjects evaluated for efficacy after baseline in the indication expansion phase – full analysis set (RP2D dose group). Figure 10a shows the results of 93 subjects who had previously received second-generation TKI treatment, Figure 10b shows the results of 14 subjects who had previously received crizotinib treatment, and Figure 10c shows the results of 33 ALK TKI-naïve patients.

[0022] Figure 11a shows the results of systemic progression-free survival in ALK-positive subjects during the indication expansion phase.

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

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

[0025] Figure 12b shows the Kaplan-Meier plot of ALK-positive overall survival during the indication expansion phase – full analysis set (primary analysis).

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

[0027] Figure 12d shows the Kaplan-Meier plot of ROS1-positive overall survival during the indication expansion phase – full analysis set (primary analysis).

[0028] Figure 13 shows the progression-free survival (PFS) of patients with mutant or wild-type TP53 treated with compound A in the ALK TKI resistance subgroup.

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

[0032] Figure 17 shows the Kaplan-Meier curves of IC-PFS (IRC evaluation results) – full analysis set.

[0033] Figure 18 shows the forest plot of objective remission rate (%) for each subgroup (IRC assessment results) - full analysis set.

[0034] Invention Details

[0035] This invention has discovered that compound A can be used to treat ALK-positive and / or ROS1-positive non-small cell lung cancer. Therefore, this invention discloses the use and methods of compound A or a pharmaceutically acceptable salt thereof in the treatment of ALK-positive and / or ROS1-positive non-small cell lung cancer.

[0036] Abbreviations

[0037] definition

[0038] The invention can be more readily understood by referring to the following detailed description of embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be further understood that, unless specifically defined in the text, the terms used herein should be given their ordinary meanings known in the relevant art.

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

[0040] As used herein, unless otherwise indicated, the use of “or” means “and / or”.

[0041] The term "including" and other forms of use, such as "containing," "containing," and "having," are not restrictive.

[0042] The section headings used herein are for organizational purposes only and are not intended to limit the subject matter described. All documents or parts thereof cited in this application, including but not limited to patents, patent applications, articles, books, guidelines, and discussions, are expressly incorporated herein by reference in their entirety for any purpose.

[0043] "Subject" includes, but is not limited to: humans (i.e., men or women 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, such as mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, 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] The terms “disease,” “disorder,” and “symptom” are used interchangeably in this article.

[0045] Unless otherwise stated, the term “treatment” as used herein includes effects that occur when a subject has a specific disease, disorder, or condition, which reduce the severity of the disease, disorder, or condition, or delay or slow the development of the disease, disorder, or condition (“therapeutic treatment”), and also includes effects that occur before a subject begins to have a specific disease, disorder, or condition (“preventive treatment”).

[0046] "Therapeutic effective dose" refers to a dose that is sufficient to stop, delay progression, or cause disease regression, or that can reduce symptoms caused by a disease such as cancer, such as lung cancer (e.g., NSCLC).

[0047] "Non-small cell lung cancer (NSCLC)" refers to any type of lung cancer that differs 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 carcinoma types. ADC can be further subdivided into subtypes, 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 never-smokers. ADC is a non-squamous cell type of NSCLC. Histologically, ADC shows glandular formation, papillary structures, or solid growth with mucin production. Large cell carcinoma includes subtypes such as giant cell tumor, clear cell carcinoma, adenosquamous carcinoma, and undifferentiated carcinoma.

[0048] A “sample” is a biological specimen obtained from a subject that contains genomic DNA, RNA (including mRNA), proteins, or other combinations thereof. Examples include specimens containing at least one type of NSCLC cell (“NSCLC sample”), such as tissue or tumor biopsies, fine-needle aspirations, bronchoalveolar lavage fluid, pleural fluid, sputum, surgical specimens, lymph nodes, NSCLC metastases, peripheral blood, or autopsy material. In other examples, samples include controls, such as non-NSCLC cell or tissue samples.

[0049] ALK is a transmembrane receptor tyrosine kinase belonging to the insulin receptor subfamily. 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 typically has a restricted distribution in mammalian cells, and its significant presence only in the nervous system during embryonic development suggests a role for ALK in brain development.

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

[0051] Like other RTKs, translocations affect the ALK gene, leading to the expression of protocellular fusion kinases, most commonly NPM-ALK. For example, approximately 60 percent of anaplastic large cell lymphomas (ALCL) are associated with chromosomal mutations producing a fusion protein consisting of the intracellular domain of nucleolar phosphatase (NMP) ALK. This mutant protein, NPM-ALK, possesses a constitutively active tyrosine kinase domain, which 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 impair the growth of ALK-positive lymphoma cells. Constitutively activated chimeric ALK has been shown to be present in approximately 60 percent of inflammatory myofibroblastic tumors (IMT) (a slow-growing sarcoma that primarily affects children and young adults). Furthermore, a variant ALK fusion, TPM4-ALK, has been described in the case of squamous cell carcinoma (SCC) of the esophagus. Therefore, ALK is one of the few instances of RTK involved in tumorigenesis in both non-hematopoietic and hematopoietic malignancies. Recently, an inversion within chromosome 2p has been shown to lead to the formation of a fusion gene in non-small cell lung cancer cells containing a portion of the biceps microtubule-associated protein-4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene. Exemplary ALK fusions in non-small cell lung cancer 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, with EML4-ALK being the most common. ALK fusion gene detection can be performed using IHC, FISH, RT-PCR, or HTS methods.

[0052] "ALK positive" refers to chromosomal rearrangements with ALK fusion genes and / or ALK overexpression and / or ALK point mutations in a tumor. In some implementations, ALK positivity requires a result from one of the following tests: FISH, RT-PCR, IHC, or NGS (high-throughput sequencing) as diagnostic evidence.

[0053] ROS1 belongs to the sevenless subfamily of the insulin receptor gene, a receptor tyrosine kinase. The protein encoded by this gene is a type I membrane-integrated protein with tyrosine kinase activity. ROS1 shares structural similarities with ALK proteins. Gene 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 either 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 conjugate SLC34A2 and ROS1. In some embodiments, the SLC34A2-ROS1 fusion protein includes an N-terminal domain of a fusion conjugate such as SLC34A2 and a C-terminal kinase domain of the ROS1 protein. The N-terminal domain of the fusion conjugate may be located at the N-terminus of the fusion protein, and the C-terminal kinase domain of the ROS1 protein may be located at the C-terminus of the fusion protein. The fusion conjugate may be the N-terminal domain of the SLC34A2 protein located at the N-terminus of the fusion protein. In this case, the fusion protein may be represented as the SLC34A2-ROS1 protein comprising the N-terminal domain of the SLC34A2 protein and the C-terminal kinase domain of the ROS1 protein. In another embodiment, a fusion gene encoding a fusion protein is provided, wherein the gene encoding the N-terminal domain of the fusion conjugate 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 and a portion of the ROS1 protein containing a functional kinase domain are co-fused due to an aberrant chromosomal translocation that results in a ROS1 chromosomal rearrangement in the presence of SLC34A2. In some embodiments, the SLC34A2-ROS1 fusion protein may include fusion exon 4 of SLC34A2 and fusion exon 32 of ROS1. In some embodiments, the SLC34A2-ROS1 fusion protein may include fusion exon 4 of SLC34A2 and fusion exon 34 of ROS1.

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

[0056] An "ALK inhibitor" is a molecule that inhibits or reduces ALK activity, such as ALK tyrosine kinase activity. In some cases, ALK inhibitors can be small molecules, proteins (such as antibodies), or nucleic acids (such as antisense molecules). ALK inhibitors inhibit or reduce the binding of ligands (such as pleiotropic proteins) to ALK, thus reducing 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 cases, 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, in addition to inhibiting ALK tyrosine kinase activity, can inhibit the activity of other receptor tyrosine kinases (such as c-Met / HGFR activity). Hua Gao et al., (Synthesis and clinical application of small-molecule inhibitors and PROTACs of anaplastic lymphoma kinase. Bioorganic Chemistry 140(2023)106807) disclosed marketed and investigational small-molecule ALK inhibitors in Table 1. This article is incorporated herein by reference in its entirety for all purposes.

[0057] "First-generation, second-generation, or third-generation ALK inhibitors" refers to first-generation, second-generation, or third-generation ALK inhibitors.

[0058] For information on "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 by the Chinese Society of Clinical Oncology (CSCO) Expert Committee in 2022.

[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 main pharmacokinetic parameters for a single dose include peak concentration (C0). max Peak time (T) max ), half-life (T)1 / 2 ), total clearance (CL) and volume of distribution (Vd), AUC 0-t AUC 0-∞ The main pharmacokinetic parameters for multiple-dose administration include the area under the steady-state plasma concentration-time curve (AUC). ss Steady-state peak plasma concentration (C) max，ss Steady-state trough concentration of drug in blood (C min，ss ) and steady-state time to peak plasma concentration (T) max，ss )wait.

[0061] Adverse events will be described using MedDRA (Medical Terminology Dictionary). 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] According to RECIST version 1.1, for patients initially evaluated for complete response (CR) or partial response (PR), efficacy must be confirmed after at least 4 weeks. In patients with asymptomatic central nervous system (CNS) metastases, in addition to evaluating 5 extracranial target lesions, up to 5 intracranial target lesions will also be evaluated. Specific indicators are as follows:

[0063] "CR" is 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 below 10 mm.

[0064] "PR" is defined as a reduction of at least 30% in the total diameter of the target lesion, with the total diameter of the baseline as a reference value.

[0065] "PD" is defined as an increase of at least 20% in the total diameter of the target lesions, using the minimum total diameter in the study as a reference (this value may include the total diameter of the baseline). In addition, the absolute value of the total diameter must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

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

[0067] "ORR" includes CR and PR, and is defined as the proportion of patients who achieve a complete or partial response.

[0068] "IC-ORR" includes CR or PR for confirmed intracranial lesions, defined as the proportion of patients with complete or partial remission of intracranial lesions among patients with intracranial lesions.

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

[0070] "IC-DCR" is defined as the proportion of patients with intracranial lesions who achieve 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 initial assessment of CR or PR to disease progression or death, and applies only to patients who have achieved 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 whose intracranial lesions have achieved remission.

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

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

[0075] “PFS” is defined as the time from the first administration of the investigational drug to disease progression (PD) or death from any cause, whichever comes first.

[0076] "IC-PFS" is defined as the time from the first administration of the investigational drug to intracranial tumor progression (PD) or death from any cause, whichever comes first.

[0077] "OS" is defined as the time from the first administration of the experimental drug to death from any cause.

[0078] Compound A

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

[0080] Or its pharmaceutically acceptable salt.

[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-(methylbridged)pyrazole[4,3-h][2,5,11]benzoxazadiaceta-mannone-3-carboxynitrile, is a potent third-generation ALK / ROS1 dual tyrosine kinase inhibitor. It inhibits the overexpression of ALK and ROS1 in NSCLC cells by disrupting ALK and ROS1-mediated signaling pathways, thereby suppressing NSCLC cell proliferation. It is sensitive to secondary mutations in most ALK kinase domains, including mutations in the G1202R solvant front region, 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 then its salt form, crystal form and pharmaceutical composition in WO2021 / 233296A1. The full text of these three patents is incorporated herein by reference for all purposes.

[0082] The term "pharmaceutically acceptable salt" refers to those salts that, within the bounds of reliable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. 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 this 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 methods conventional in the art are also included, such as ion exchange methods. Other pharmaceutically acceptable salts include: adipic acid salts, alginate salts, ascorbate salts, aspartate salts, benzenesulfonate salts, benzoate salts, bisulfate salts, borate salts, butyrate salts, camphorate salts, camphor sulfonate salts, citrate salts, cyclopentylpropionate salts, diglucuronate salts, dodecyl sulfate salts, ethanesulfonate salts, formate salts, fumarate salts, gluconate salts, glyceryl phosphate salts, glucuronate salts, hemisulfate salts, heptarate salts, hexanoate salts, hydroiodate salts, 2-hydroxy-ethanesulfonate salts, lactobionate salts, lactate salts, laurate salts, lauryl sulfate salts, malate salts, maleate salts, malonate salts, methanesulfonate salts, 2-naphthalenesulfonate salts, nicotinate salts, nitrate salts, oleate salts, oxalate salts, palmitate salts, dihydroxynaphthalate salts, pectin ester salts, persulfate salts, 3-phenylpropionate salts, phosphate salts, picrate salts, p-pentanoate salts, propionate salts, stearate salts, succinate salts, sulfate salts, tartrate salts, thiocyanate salts, p-toluenesulfonate salts, undecanoate salts, valerate salts, etc. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts, if appropriate, include non-toxic ammonium salts, quaternary ammonium salts, and amine cations that form with counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonates, and aryl sulfonates.

[0083] In some embodiments, in the X-ray powder diffraction pattern obtained using CuKα radiation, compound A includes at least the characteristic peaks represented by the following °2θ values: 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 includes the characteristic peaks represented by the following °2θ values: 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 includes characteristic peaks located at the following °2θ values: 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 for preparing said compositions are described in WO2021 / 233296A1, the entire contents of which are incorporated herein by reference for all purposes.

[0086] In one aspect, the present invention provides the use and method of a pharmaceutical composition for treating ALK-positive non-small cell lung cancer, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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

[0088] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating EML4-ALK L1196M-mutant non-small cell lung cancer, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0089] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating metastatic non-small cell lung cancer of the CNS with an EML4-ALK L1196M mutation, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0090] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating EML4-ALK G1202R-mutated non-small cell lung cancer, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0091] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating metastatic non-small cell lung cancer of the CNS with an EML4-ALK G1202R mutation, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0092] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating ROS1-positive non-small cell lung cancer, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0093] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating ROS1-positive metastatic non-small cell lung cancer in the CNS, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0094] In another aspect, the present invention provides the use and method of a pharmaceutical composition for treating SLC34A2-ROS1 G2032R-mutated non-small cell lung cancer, the pharmaceutical composition comprising compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

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

[0096] In some embodiments, the pharmaceutical compositions taught in this invention comprise (i) a pharmaceutically active ingredient: a crystal form of the free base of compound A or a crystal 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-described pharmaceutical composition, wherein the crystal form accounts for 1-30% of the total weight of the pharmaceutical composition, 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%, with the free base of the compound accounting for... Weight calculation; preferably, the content of the crystal 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-described pharmaceutical composition, wherein the diluent accounts for 65-95% of the total weight of the pharmaceutical composition, preferably 70-90%, and more preferably about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90%; preferably, the diluent is present in a dose of 50-380 mg, preferably 60-360 mg, and more 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 simultaneously, the weight ratio of microcrystalline cellulose 102 to mannitol 50C is 5:1 to 1:5, preferably 3:1 to 1:2, and more preferably about 2:1.

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

[0101] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the disintegrant is croscarmellose sodium or croscarmellose XL-10, preferably croscarmellose sodium.

[0102] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the adhesive accounts for 1-5% of the total weight of the pharmaceutical composition, preferably 2-4%, preferably about 2%, 2.5%, 3%, 3.5% or 4%; preferably, the adhesive content in a 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-mentioned pharmaceutical composition, wherein the binder is hydroxypropyl cellulose EXF or povidone K30, preferably hydroxypropyl cellulose EXF.

[0104] In a specific embodiment, the present invention provides the above-mentioned pharmaceutical composition, wherein the lubricant accounts for 0.1-5% of the total weight of the pharmaceutical composition, preferably 0.5-2%, preferably about 1%; preferably, the content of the lubricant in a 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-mentioned pharmaceutical composition, wherein the lubricant is magnesium stearate or sodium stearate fumarate (PRUV), preferably magnesium stearate.

[0106] In some embodiments, the present invention provides the above-described pharmaceutical composition comprising the following components:

[0107] (i) Compound A, in the weight percentage of 1-30%,

[0108] (ii) Microcrystalline cellulose 102 and mannitol 50C, with a weight percentage of 65-95% (weight ratio of approximately 2:1),

[0109] (iii) 2-4% by weight of croscarmellose sodium,

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

[0111] (v) Magnesium stearate in a weight percentage of 0.1-5%.

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

[0113] (i) Approximately 5 mg of compound A,

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

[0115] (iii) Approximately 2.4 mg of croscarmellose sodium,

[0116] (iv) Approximately 2.4 mg of hydroxypropyl cellulose EXF, and

[0117] (v) Approximately 0.8 mg of magnesium stearate.

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

[0119] (i) Approximately 25 mg of compound A,

[0120] (ii) Approximately 231 mg of microcrystalline fiber 102 and approximately 116 mg of mannitol 50C,

[0121] (iii) Approximately 12 mg of croscarmellose sodium,

[0122] (iv) Approximately 12 mg of hydroxypropyl cellulose EXF, and

[0123] (v) Approximately 4 mg of magnesium stearate.

[0124] In a specific embodiment, the X-ray powder diffraction pattern of compound A in the pharmaceutical composition, obtained using CuKα radiation, includes at least the characteristic peaks represented by the following °2θ values: 16.175±0.2, 17.299±0.2, and 21.218±0.2. In another embodiment, the X-ray powder diffraction pattern of compound A further includes the characteristic peaks represented by the following °2θ values: 9.637±0.2, 12.555±0.2, 14.343±0.2, and 19.366±0.2. In some embodiments, in the X-ray powder diffraction pattern, compound A further includes characteristic peaks located at the following °2θ values: 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 some embodiments, the present invention provides the above-described pharmaceutical composition as a tablet, preferably a coated tablet; preferably, the coating agent is Opadry II 85F620077.

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

[0127] The pharmaceutical compositions described herein can also be administered long-term (“long-term administration”). Long-term administration means that the compound or pharmaceutical composition thereof is administered for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, for example, for the remainder of the subject's life. In one embodiment, long-term administration aims to provide a constant level of the compound in the blood, for example, within a therapeutic window during the extended period of time.

[0128] The pharmaceutical compositions described herein are presented in unit dosage forms to facilitate precise administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for use in human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect when combined with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-quantitative ampoules or syringes of liquid compositions, or, in the case of solid compositions, pills, tablets, capsules, etc.

[0129] In another embodiment, the pharmaceutical composition provided in this text is administered to the subject in a solid dosage form. In one specific embodiment, the solid dosage form is a tablet.

[0130] In another embodiment, the compounds provided in this text may be administered as a single active agent, or they may be administered in combination with other active agents.

[0131] Use and treatment methods

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

[0133] In some embodiments, the present invention relates to the use and methods of treating ALK-positive non-small cell lung cancer with compound A or a pharmaceutically acceptable salt thereof. In a specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In one 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 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 implementation, the subject experienced disease progression or intolerance after prior continuous treatment with a second-generation ALK inhibitor. In another specific implementation, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, iruplinalkib, or entrectinib. In another specific implementation, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific implementation, the subject has not previously received ALK inhibitor treatment. In another specific implementation, the subject has not previously received third-generation ALK inhibitor treatment. In another specific implementation, the subject experienced disease progression or intolerance after prior first-line or higher-level treatment. In another specific implementation, the subject experienced disease progression or intolerance after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific implementation, the subject experienced disease progression or intolerance after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 treating ALK-positive 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 one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 specific embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another specific 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 experienced 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, irucalb, or entrectinib. In another specific implementation, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific implementation, the subject has not previously received ALK inhibitor treatment. In another specific implementation, the subject has not previously received third-generation ALK inhibitor treatment. In another specific implementation, the subject has experienced disease progression or intolerance after first-line or higher therapy.In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

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

[0136] In one embodiment, the present invention relates to the use and method of treating ALK-positive metastatic non-small cell lung cancer (NSCLC) with compound A or a pharmaceutically acceptable salt thereof. In one specific embodiment, the NSCLC is advanced NSCLC. In another specific embodiment, the NSCLC is adenocarcinoma. 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 experienced 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, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily.In another specific implementation, compound A is administered until disease progression, intolerable toxicity, or death.

[0137] In another embodiment, the present invention relates to a method of 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 one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 experienced disease progression or intolerance after prior continuous treatment with crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, 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. Collecting cerebrospinal fluid samples; and

[0140] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution.

[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 EML4-ALK L1196M-mutant 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 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 experienced disease progression or intolerance after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irulac, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-line or higher-level treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first- 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 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 approximately 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

[0143] In one embodiment, the present invention relates to the use and method of treating EML4-ALK L1196M-mutant non-small cell lung cancer (NSCLC) with a pharmaceutically acceptable salt thereof, wherein the NSCLC has progressed after another therapy. In one specific embodiment, the other therapy is radiotherapy, pharmacotherapy, or surgical therapy. In another specific embodiment, the pharmacotherapy is chemotherapy, targeted therapy, or immunotherapy. In yet another specific embodiment, the pharmacotherapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 specific embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another specific 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 experienced 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, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment.In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-line or higher-level treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

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

[0145] In one embodiment, the present invention relates to the use and method of compound A or a pharmaceutically acceptable salt thereof for treating metastatic non-small cell lung cancer (NSCLC) with an EML4-ALK L1196M mutation in the CNS. In one specific embodiment, the NSCLC is advanced NSCLC. In another specific embodiment, the NSCLC is adenocarcinoma. 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 experienced 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, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received treatment with a third-generation ALK inhibitor. In another specific embodiment, the subject has experienced disease progression or intolerance after first-line or later-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

[0146] In another embodiment, the present invention relates to the use and method of treating metastatic non-small cell lung cancer with an EML4-ALK L1196M mutation in the CNS, wherein the non-small cell lung cancer has progressed after another therapy. In one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy is selected from one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contatinib, 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. 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 experienced disease progression or intolerance after prior continuous treatment with crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 in metastatic non-small cell lung cancer with an EML4-ALK L1196M mutation, comprising:

[0148] a. Collecting cerebrospinal fluid samples; and

[0149] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution.

[0150] EML4-ALK G1202R mutant non-small cell lung cancer

[0151] In one embodiment, the present invention relates to the use and method of compound A or a pharmaceutically acceptable salt thereof for treating EML4-ALK G1202R-mutated 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 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 experienced disease progression or intolerance after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irulac, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-line or higher-level treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first- 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 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 approximately 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered 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 EML4-ALK G1202R-mutant non-small cell lung cancer, wherein the non-small cell lung cancer has progressed after another therapy. In one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 specific embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another specific 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 experienced 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, irucalb, or entrectinib. In another specific implementation, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific implementation, the subject has not previously received ALK inhibitor treatment. In another specific implementation, the subject has not previously received third-generation ALK inhibitor treatment. In another specific implementation, the subject has experienced disease progression or intolerance after first-line or higher therapy.In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 approximately 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

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

[0154] In one embodiment, the present invention relates to the use and method of compound A or a pharmaceutically acceptable salt thereof for treating metastatic non-small cell lung cancer with an EML4-ALK G1202R mutation in the CNS. 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 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 experienced 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, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received treatment with a third-generation ALK inhibitor. In another specific embodiment, the subject has experienced disease progression or intolerance after first-line or later-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 metastatic non-small cell lung cancer with an EML4-ALK G1202R mutation in the CNS, wherein the non-small cell lung cancer has progressed after another therapy. In one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 experienced disease progression or intolerance after prior continuous treatment with crizotinib as the sole ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 in metastatic non-small cell lung cancer with an EML4-ALK G1202R mutation, comprising:

[0157] a. Collecting cerebrospinal fluid samples; and

[0158] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution.

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

[0160] In some embodiments, the present invention relates to the use and methods of treating TP53-positive ALK-positive non-small cell lung cancer with compound A or a pharmaceutically acceptable salt thereof. In a specific embodiment, the non-small cell lung cancer is advanced non-small cell lung cancer. In one 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 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's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ALK inhibitor treatment. In another specific embodiment, the subject has not previously received third-generation ALK inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 treating TP53-positive ALK-positive non-small cell lung cancer with a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer has progressed after another therapy. In one specific embodiment, the other therapy is radiotherapy, pharmacotherapy, or surgical therapy. In another specific embodiment, the pharmacotherapy is chemotherapy, targeted therapy, or immunotherapy. In yet another specific embodiment, the pharmacotherapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 specific embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another specific 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 experienced 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, irucalb, or entrectinib. In another specific implementation, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific implementation, the subject has not previously received ALK inhibitor treatment. In another specific implementation, the subject has not previously received third-generation ALK inhibitor treatment. In another specific implementation, the subject has experienced disease progression or intolerance after first-line or higher therapy.In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 treating ROS1-positive non-small cell lung cancer with compound A or a pharmaceutically acceptable salt thereof. 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's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ROS1 inhibitor treatment. In another specific embodiment, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 treating ROS1-positive 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 one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 specific embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with crizotinib. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, or entrectinib. In another specific implementation, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific implementation, the subject has not previously received ROS1 inhibitor treatment. In another specific implementation, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific implementation, the subject has experienced disease progression or intolerance after first-line or higher therapy.In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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] In another specific embodiment, the dose of compound A is approximately 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

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

[0167] In one embodiment, the present invention relates to the use and method of treating ROS1-positive metastatic non-small cell lung cancer (NSCLC) with compound A or a pharmaceutically acceptable salt thereof. In one specific embodiment, the NSCLC is advanced NSCLC. In another specific embodiment, the NSCLC is adenocarcinoma. 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 experienced 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, irucalb, 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 ROS1 inhibitor treatment. In another specific embodiment, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 treating ROS1-positive metastatic non-small cell lung cancer of compound A or a pharmaceutically acceptable salt thereof, wherein the non-small cell lung cancer has progressed after another therapy. In one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimidacil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 experienced disease progression or intolerance after prior continuous treatment with crizotinib. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ROS1 inhibitor treatment. In another specific embodiment, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 in ROS1-positive metastatic non-small cell lung cancer, comprising:

[0170] a. Collecting cerebrospinal fluid samples; and

[0171] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution.

[0172] SLC34A2-ROS1 G2032R mutant non-small cell lung cancer

[0173] In one embodiment, the present invention relates to the use and method of compound A or a pharmaceutically acceptable salt thereof for treating SLC34A2-ROS1 G2032R-mutated 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 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 experienced disease progression or intolerance after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irulac, 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 ROS1 inhibitor treatment. In another specific embodiment, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-line or higher-level treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after prior first- 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 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 approximately 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered 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 SLC34A2-ROS1 G2032R-mutant non-small cell lung cancer, wherein the non-small cell lung cancer has progressed after another therapy. In one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 specific embodiment, the non-small cell lung cancer is CNS metastatic non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is metastatic advanced non-small cell lung cancer. In another specific embodiment, the non-small cell lung cancer is CNS metastatic advanced non-small cell lung cancer. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with crizotinib. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, or entrectinib. In another specific implementation, the second-generation ALK inhibitor is selected from alectinib, ceritinib, ensartinib, or brigatinib. In another specific implementation, the subject has not previously received ROS1 inhibitor treatment. In another specific implementation, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific implementation, the subject has experienced disease progression or intolerance after first-line or higher therapy.In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 approximately 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, or death.

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

[0176] In one embodiment, the present invention relates to the use and method of compound A or a pharmaceutically acceptable salt thereof for treating SLC34A2-ROS1 G2032R-mutated metastatic non-small cell lung cancer in the CNS. 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 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 experienced 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, irucalb, 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 ROS1 inhibitor treatment. In another specific embodiment, the subject has not previously received treatment with a second-generation ROS1 inhibitor. In another specific embodiment, the subject has experienced disease progression or intolerance after first-line or later-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject has experienced disease progression or intolerance after first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. In another specific embodiment, compound A is administered until disease progression, intolerable toxicity, 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 SLC34A2-ROS1 G2032R-mutated metastatic non-small cell lung cancer in the CNS, wherein the non-small cell lung cancer has progressed after another therapy. In one 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 yet another specific embodiment, the drug therapy is chemotherapy. In another specific embodiment, the drug therapy comprises one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimidacil, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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. 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 experienced disease progression or intolerance after prior continuous treatment with crizotinib. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with at least a second-generation ALK inhibitor. In another specific embodiment, the subject's disease progressed or became intolerant after prior continuous treatment with a second-generation ALK inhibitor. In another specific embodiment, the second-generation ALK inhibitor is selected from ceritinib, alectinib, brigatinib, ensartinib, irucalb, 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 ROS1 inhibitor treatment. In another specific embodiment, the subject has not previously received second-generation ROS1 inhibitor treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-line or higher-level treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first-, second-, third-, fourth-, or fifth-line treatment. In another specific embodiment, the subject's disease progressed or became intolerant after prior first- 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 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 daily, twice daily, or three times daily. In another specific embodiment, compound A is administered orally once daily. 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 in CNS metastatic non-small cell lung cancer with an SLC34A2-ROS1 G2032R mutation, comprising:

[0179] a. Collecting cerebrospinal fluid samples; and

[0180] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution.

[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 said compound A has the following structure:

[0183] 2. A method of 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 the treatment of non-small cell lung cancer, wherein said compound A has the following structure:

[0185] 4. According to the use of technical solution 1, the method of technical solution 2, or the use of the compound of technical solution 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 mutant and wild-type) ALK-positive non-small cell lung cancer; preferably, the non-small cell lung cancer is TP53-mutant ALK-positive non-small cell lung cancer.

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

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

[0188] 7. The use, method, or compound according to any one of the technical solutions 1-6, wherein the non-small cell lung cancer is untreated.

[0189] 8. The use, method, or compound according to any one of the technical solutions 1-6, 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 a targeted therapy;

[0193] Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

[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- 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 the technical solutions 1-10, 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 1-11, wherein the patient has received first-line or higher treatment; preferably, wherein the patient has received second-line or higher treatment; preferably, the patient has received first-line, second-line, third-line, fourth-line, or fifth-line treatment.

[0198] 13. According to the use, method or compound of technical solution 12, wherein the patient has disease progression or intolerance after receiving first-line or higher treatment; preferably, wherein the patient has disease progression or intolerance after receiving first-line or second-line treatment.

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

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

[0201] Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

[0202] 15. The use, method, or compound according to technical 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, croton, gimidacil, 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 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 sole ALK inhibitor.

[0204] 17. The use, method, or compound according to claim 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 compound according to any one of the technical claims 1-17, wherein the dose of said 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 compound according to any one of technical claims 1-18, wherein said compound A is administered orally.

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

[0213] Preferably, compound A is administered orally once daily.

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

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

[0216] 23. According to the use of technical solution 1, the method of technical solution 2, or the use of the compound of technical solution 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 the 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 is untreated.

[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 a targeted therapy;

[0224] Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

[0225] 28. The use, method, or compound of claim 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 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 higher treatment; preferably, wherein the patient has received second-line treatment.

[0229] 32. According to the use, method or compound of technical solution 31, wherein the patient has disease progression or intolerance after receiving first-line or higher treatment; preferably, wherein the patient has disease progression or intolerance after receiving second-line treatment.

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

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

[0232] Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

[0233] 34. The use, method, or compound according to technical 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, croton, gimidacil, 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 according to claim 33, wherein the patient has previously received targeted therapy; preferably, the patient has previously received ROS1 inhibitor therapy, 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 of claim 33, wherein the patient has not previously received treatment with a ROS1 inhibitor (e.g., a second-generation ROS1 inhibitor).

[0236] 37. The use, method, or compound according to any one of technical solutions 1-3 and 23-36, wherein the dosage of said 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 compound according to any one of technical claims 1-3 and 23-37, wherein said 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 administered orally once daily, twice daily, or three times daily;

[0244] Preferably, compound A is administered orally once daily.

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

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

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

[0248] a. Collecting cerebrospinal fluid samples; and

[0249] b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution. Example

[0250] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percentages.

[0251] Example 1: Antitumor effect of Ba / F3 (EML4-ALK L1196M) cell line subcutaneously transplanted into a female NOD-SCID mouse animal model.

[0252] Experimental animals: NOD-SCID mice, female, 7 - 8 weeks old (age of mice at the time of tumor cell inoculation), body weight 16.0 - 22.0 g, 50 mice (另有32只富余小鼠). Purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK(Beijing)2017 - 0006, animal certificate number: 1103301911000908. Feeding environment: SPF level.

[0253] Environmental conditions of the experimental animal breeding room: All experimental animals were housed in independent ventilated boxes with constant temperature and humidity. The temperature of the breeding room was 20 - 26 °C, the humidity was 40 - 70%, the air exchange rate was 10 - 20 times / hour, and the day-night light-dark cycle was 12 h / 12 h; irradiated mouse complete pellet feed sterilized by cobalt-60 was continuously supplied, and the animals could freely ingest it without limit. Tap water (used after high-pressure steam sterilization) was provided for drinking, and the water bottles were continuously supplied with water for free intake. The breeding mouse boxes were polysulfone mouse boxes, used after high-pressure sterilization, with a specification of 325 mm × 210 mm × 180 mm; the bedding was high-pressure sterilized corncobs, with 5 animals in each box. The cage cards were marked with the IACUC approval number, experimental number, start time of the experiment, project leader, experimental personnel, animal source, group and animal number, etc.; the experimental animals were marked by ear punching or ear tags.

[0254] Cell culture: Ba / F3(EML4-ALK L1196M) cells (cell number: TC-00136) were cultured in RPMI1640 medium containing 10% fetal bovine serum and 2 μg / mL blasticidin. Ba / F3(EML4-ALK L1196M) cells in the exponential growth phase were collected, resuspended in PBS to a suitable concentration, and then used for subcutaneous tumor inoculation in nude mice.

[0255] Experimental method: 5×10 6 Ba / F3(EML4-ALK L1196M) cells were subcutaneously inoculated into the right side of female NOD / SCID mice to establish a subcutaneous transplanted tumor model. The experiment was divided into 5 groups, including the high-dose (10 mg / kg) group of compound A, the medium-dose (3 mg / kg) group of compound A, the low-dose (1 mg / kg) group of compound A, the Crizotinib positive control group (100 mg / kg), and the vehicle control group, with 10 mice in each group. Oral gavage was performed once a day. The efficacy was evaluated according to the relative tumor inhibition rate (TGI), and the safety was evaluated according to the changes in animal body weight and death.

[0256] All experimental protocols for these animal studies were reviewed and approved by the Animal Ethics Committee (IACUC) of Crown Bioscience. During the experiments, all animal procedures complied with the requirements of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All procedures, including drug administration, tumor measurement, and weight measurement, were performed in biosafety cabinets or clean benches.

[0257] Relative tumor proliferation rate (T / C%) is the percentage of tumor volume in the treatment group compared to the control group at a given time point, or the percentage of tumor weight in the treatment group compared to the control group. The calculation formula is: T / C% = T RTV / C RTV ×100% (T) RTV : Mean RTV of the treatment group; C RTV : Mean RTV of the solvent control group; RTV = Vt / V0, where V0 is the tumor volume of the animal at the time of grouping, V t (This refers to the tumor volume in the animal after treatment); or T / C% = T TW / C TW ×100% (T) TW : Average tumor weight at the end of the trial in the treatment group; C TW (The average tumor weight at the end of the experiment in the solvent control group).

[0258] The relative tumor inhibition rate (TGI%) is calculated using the formula: TGI% = 1 - T / C%.

[0259] Statistical Analysis: To compare tumor volume on a given day across different treatment groups, we first used the Bartlett test to verify the hypothesis of homogeneity of variance among all groups. When the p-value of the Bartlett test is not less than 0.05, one-way ANOVA was used to test whether the means of all groups were equal. If the p-value of the one-way ANOVA was less than 0.05, we used the Tukey HSD test for pairwise comparisons between all groups, or Dunnett's t-test for pairwise comparisons between each treatment group and the control group. When the p-value of the Bartlett test was less than 0.05, the Kruskal-Wallis test was used to test whether the medians of all groups were equal. If the p-value of the Kruskal-Wallis test was less than 0.05, we used the Conover test for pairwise comparisons between all groups or pairwise comparisons between each treatment group and the control group, and adjusted the p-value accordingly based on the number of groups in the multiple tests. All statistical analyses and graphs were performed in the R language environment (version 3.3.1). Unless otherwise specified, all tests are two-tailed tests, and a p-value less than 0.05 is considered statistically significant.

[0260] Experimental results:

[0261] In the solvent control group, the average tumor volume was 2222.44 mm on day 17 after drug administration (i.e., at the end of the experiment: drug administration started on day 7 and ended on day 24). 3 In contrast, the mean tumor volume of test drug compound A was 0 mmHg when administered once daily at doses of 10 mg / kg, 3 mg / kg, and 1 mg / kg. 3 0mm 3 and 1125.94mm 3 The relative tumor inhibition rates (TGI%) were 100%, 100%, and 49.53%, respectively, all of which were statistically significant compared to the solvent control group (P<0.001). At the end of the experiment, in the compound A treatment groups of 10 mg / kg and 3 mg / kg, the tumor volume of all (10 / 10, 10 / 10) tumor-bearing mice shrank to 0 and completely disappeared. The positive control drug Crizotinib, administered at a dose up to 100 mg / kg once daily orally, resulted in an average tumor volume of 1965.17 mm. 3 The relative tumor inhibition rate (TGI) was 12.00%, which was not statistically significant compared to the solvent control group (P>0.05), indicating a worse therapeutic effect than the 1 mg / kg dose group of compound A. Tumor growth in each treatment group and the control group is shown in Figure 1.

[0262] During the experiment, no animals died in each treatment group, no obvious drug toxicity was shown, and they tolerated well during the treatment period. The changes in body weight after administration in the treatment group and the control group are shown in Figure 2 and Figure 3.

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

[0264] Experimental animals: NOD-SCID mice, female, 7 - 8 weeks old (mouse age at the time of tumor cell inoculation), body weight 16.0 - 20.3 g, 50 animals (another 30 surplus mice). Purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK (Beijing) 2017 - 0006, animal certificate number: 1103301911000914. Breeding environment: SPF level.

[0265] Environmental conditions of the experimental animal breeding room: All experimental animals are raised in independent ventilated boxes with constant temperature and humidity. The temperature of the breeding room is 20 - 26 °C, the humidity is 40 - 70%, the air exchange is 10 - 20 times per hour, and the day-night light-dark cycle time is 12 h / 12 h; continuously supply cobalt-60 irradiated sterilized complete pellet feed for mice, freely ingested without limit, drink tap water (used after high-pressure steam sterilization), and the water bottle supplies water continuously, freely ingested. The breeding mouse box is a polysulfone mouse box, used after high-pressure sterilization, with a specification of 325 mm × 210 mm × 180 mm; the bedding is high-pressure sterilized corncob, 5 animals per box, and the cage card indicates the IACUC approval number, experimental number, start time of the experiment, project leader, experimental personnel, animal source, group, and animal number, etc.; the experimental animals are marked with ear tags or ear marks.

[0266] Cell culture: Ba / F3 (EML4-ALK G1202R) cells (cell number: ECL-00031) are cultured in RPMI1640 culture medium containing 10% fetal bovine serum. Collect Ba / F3 (EML4-ALK G1202R) cells in the exponential growth phase, resuspend them with PBS to a suitable concentration, and then perform subcutaneous tumor inoculation.

[0267] Experimental method: Subcutaneously inoculate 2×10 6A subcutaneous tumor transplantation model was established using Ba / F3 (EML4-ALK G1202R) cells. The experiment was divided into five groups: a high-dose (15 mg / kg) compound A group, a medium-dose (5 mg / kg) compound A group, a low-dose (1.5 mg / kg) compound A group, a crizotinib positive control group (100 mg / kg), and a solvent control group, with 10 animals in each group. Administered orally via gavage once daily. Efficacy was evaluated based on the tumor inhibition ratio (TGI), and safety was evaluated based on changes in animal body weight and mortality.

[0268] The experimental protocols for this animal study were reviewed and approved by the Crown Bio IACUC committee. During the experiments, all animal procedures complied with AAALAC requirements. All procedures, including drug administration, tumor measurement, and weight measurement, were performed in a biosafety cabinet or clean bench.

[0269] Relative tumor proliferation rate (T / C%) is the percentage of tumor volume in the treatment group compared to the control group at a given time point, or the percentage of tumor weight in the treatment group compared to the control group. The calculation formula is: T / C% = T RTV / C RTV ×100% (T) RTV : Mean RTV of the treatment group; C RTV : The mean RTV of the solvent control group; RTV = V t / V0, where V0 is the tumor volume of the animal at the time of grouping, V t (This refers to the tumor volume in the animal after treatment); or T / C% = T TW / C TW ×100% (T) TW : Average tumor weight at the end of the trial in the treatment group; C TW (The average tumor weight at the end of the experiment in the solvent control group).

[0270] The relative tumor inhibition rate (TGI%) is calculated using the formula: TGI% = 1 - T / C%.

[0271] Statistical Analysis: To compare tumor volume on a given day across different treatment groups, we first used the Bartlett test to verify the hypothesis of homogeneity of variance among all groups. When the p-value of the Bartlett test is not less than 0.05, one-way ANOVA was used to test whether the means of all groups were equal. If the p-value of the one-way ANOVA was less than 0.05, we used the Tukey HSD test for pairwise comparisons between all groups, or Dunnett's t-test for pairwise comparisons between each treatment group and the control group. When the p-value of the Bartlett test was less than 0.05, the Kruskal-Wallis test was used to test whether the medians of all groups were equal. If the p-value of the Kruskal-Wallis test was less than 0.05, we used the Conover test for pairwise comparisons between all groups or pairwise comparisons between each treatment group and the control group, and adjusted the p-value accordingly based on the number of groups in the multiple tests. All statistical analyses and graphs were performed in the R language environment (version 3.3.1). Unless otherwise specified, all tests are two-tailed tests, and a p-value less than 0.05 is considered statistically significant.

[0272] Experimental results:

[0273] In the solvent control group, the average tumor volume of mice on day 16 after drug administration (i.e., at the end of the experiment: drug administration started on day 6 and ended on day 22) was 2723.66 mm. 3 In contrast, the mean tumor volume of test drug compound A, administered once daily at doses of 15 mg / kg, 5 mg / kg, and 1.5 mg / kg, 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, all of which were statistically significant compared to the solvent control group (P<0.001 for 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, in the compound A 15 mg / kg treatment group, 9 / 10 of the tumor-bearing mice had their tumor volume reduced to 0 and completely disappeared. The positive control drug Crizotinib, administered at a dose up to 100 mg / kg once daily orally, resulted in an average tumor volume of 2275.28 mm. 3 The relative tumor inhibition rate (TGI) was 17.32%, which was statistically significant compared to the solvent control group (P<0.05), indicating a poorer therapeutic effect than the 1.5 mg / kg dose group of compound A. Tumor growth in each treatment group and the control group is shown in Figure 4.

[0274] During the experiment, no animals died in each treatment group, no obvious drug toxicity was shown, and they tolerated well during the treatment period. The changes in body weight after administration in the treatment group and the control group are shown in Figure 5 and Figure 6.

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

[0276] Experimental animals: NOD-SCID mice, female, 7 - 8 weeks old (mouse age at the time of tumor cell inoculation), body weight 13.4 - 20.2 g, 50 mice (another 30 surplus mice). Purchased from Beijing Ankai Yibo Biotechnology Co., Ltd., production license number: SCXK(Beijing)2017 - 0006, animal certificate number: 1103301911000909. Feeding environment: SPF level.

[0277] Environmental conditions of the experimental animal breeding room: All experimental animals were raised in independent ventilated boxes with constant temperature and humidity. The temperature of the breeding room was 20 - 26 °C, the humidity was 40 - 70%, the air exchange was 10 - 20 times / hour, and the day-night light-dark cycle was 12 h / 12 h; irradiated sterilized mouse complete pellet feed by cobalt 60 was continuously supplied, and they could freely ingest it without limit. Tap water (used after high-pressure steam sterilization) was provided for drinking, and the water bottles were continuously supplied with water for free ingestion. The breeding mouse boxes were polysulfone mouse boxes, used after high-pressure sterilization, with a specification of 325 mm × 210 mm × 180 mm; the bedding was high-pressure sterilized corncobs, with 5 animals in each box, and the cage cards were marked with IACUC approval number, experiment number, experiment start time, project leader, experiment personnel, animal source, group and animal number, etc.; the experimental animals were marked by ear punching or ear tags.

[0278] Cell culture: Ba / F3 (SLC34A2-ROS1 G2032R) cells (cell number ECL-00019) were cultured in RPMI1640 culture medium containing 10% fetal bovine serum. Ba / F3 (SLC34A2-ROS1 G2032R) cells in the exponential growth phase were collected, resuspended in PBS to a suitable concentration, and then used for subcutaneous tumor inoculation in nude mice.

[0279] Experimental method: Subcutaneously inoculate 2×10 6A subcutaneous tumor transplantation model was established using Ba / F3 (SLC34A2-ROS1 G2032R) cells. The experiment was divided into five groups: a high-dose (15 mg / kg) compound A group, a medium-dose (5 mg / kg) compound A group, a low-dose (1.5 mg / kg) compound A group, a crizotinib positive control group (100 mg / kg), and a solvent control group, with 10 animals in each group. Administered orally via gavage once daily. Efficacy was evaluated based on the tumor growth index (TGI), and safety was evaluated based on changes in animal body weight and mortality.

[0280] The experimental protocols for this animal study were reviewed and approved by the Crown Bio IACUC committee. During the experiments, all animal procedures complied with AAALAC requirements. All procedures, including drug administration, tumor measurement, and weight measurement, were performed in a biosafety cabinet or clean bench.

[0281] Relative tumor proliferation rate (T / C%) is the percentage of tumor volume in the treatment group compared to the control group at a given time point, or the percentage of tumor weight in the treatment group compared to the control group. The calculation formula is: T / C% = T RTV / C RTV ×100% (T) RTV : Mean RTV of the treatment group; C RTV : The mean RTV of the solvent control group; RTV = V t / V0, where V0 is the tumor volume of the animal at the time of grouping, V t (This refers to the tumor volume in the animal after treatment); or T / C% = T TW / C TW ×100% (T) TW : Average tumor weight at the end of the trial in the treatment group; C TW (The average tumor weight at the end of the experiment in the solvent control group).

[0282] The relative tumor inhibition rate (TGI%) is calculated using the formula: TGI% = 1 - T / C%.

[0283] Statistical Analysis: To compare tumor volume on a given day across different treatment groups, we first used the Bartlett test to verify the hypothesis of homogeneity of variance among all groups. When the p-value of the Bartlett test is not less than 0.05, one-way ANOVA was used to test whether the means of all groups were equal. If the p-value of the one-way ANOVA was less than 0.05, we used the Tukey HSD test for pairwise comparisons between all groups, or Dunnett's t-test for pairwise comparisons between each treatment group and the control group. When the p-value of the Bartlett test was less than 0.05, the Kruskal-Wallis test was used to test whether the medians of all groups were equal. If the p-value of the Kruskal-Wallis test was less than 0.05, we used the Conover test for pairwise comparisons between all groups or pairwise comparisons between each treatment group and the control group, and adjusted the p-value accordingly based on the number of groups in the multiple tests. All statistical analyses and graphs were performed in the R language environment (version 3.3.1). Unless otherwise specified, all tests are two-tailed tests, and a p-value less than 0.05 is considered statistically significant.

[0284] Experimental results:

[0285] In the solvent control group, the average tumor volume of mice on day 21 after drug administration (i.e., at the end of the experiment: drug administration started on day 15 and ended on day 36) was 2177.24 mm. 3 In contrast, the mean tumor volume of test drug compound A was 0 mmHg when administered once daily at doses of 15 mg / kg, 5 mg / kg, and 1.5 mg / kg. 3 305.46mm 3 and 1334.38mm 3 The relative tumor inhibition rates (TGI%) were 100%, 85.78%, and 38.05%, respectively, all of which were statistically significant compared to the solvent control group (P<0.001 for 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 shrank to 0 and completely disappeared. The positive control drug Crizotinib, administered at a dose up to 100 mg / kg once daily orally, resulted in an average tumor volume of 1651.66 mm². 3 The relative tumor inhibition rate (TGI) was 25.52%, which was not statistically significant compared to the solvent control group (P>0.05), indicating a poorer therapeutic effect than the 1.5 mg / kg dose group of compound A. Tumor growth in each treatment group and the control group is shown in Figure 7.

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

[0287] Example 4: A dose-escalation and expansion phase I clinical trial evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy of compound A in patients with ALK-positive or ROS1-positive advanced non-small cell lung cancer.

[0288] Research objective:

[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 the recommended dose for phase II (RP2D).

[0291] Secondary objective:

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

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

[0294] Exploratory purpose:

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

[0296] Overall Design

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

[0298] The dose escalation and dose expansion phases plan to enroll ALK-positive advanced NSCLC patients whose disease has progressed or who are intolerant to at least one second-generation ALK inhibitor (including marketed or clinically tested second-generation ALK inhibitors) and ROS1-positive advanced NSCLC patients who have failed crizotinib treatment.

[0299] The dose escalation phase consisted of 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) assays and tolerability monitoring. If no Grade 2 or higher adverse events related to the investigational drug occurred during the single-dose period (5–7 days) (if such events occurred, dose adjustments were made based on toxicity according to the protocol), the subject entered the multiple-dose period (i.e., treatment period) 5–7 days later (7 days after the first dose in the first dose group [i.e., starting multiple-dose treatment on Day 8], and the interval for subsequent dose groups was determined based on obtained tolerability and PK data). Subjects in the first dose group initially received the drug once daily (QD) during the multiple-dose period (if PK data for the single-dose period was available, the dosing frequency for the multiple-dose period could be determined based on the PK data), and the dosing frequency for subsequent dose groups was determined based on obtained PK and tolerability data. In this trial, the dosing frequency for all subjects can be adjusted throughout the trial based on continuously acquired safety and pharmacokinetic (PK) data. The four lower dose groups (5 mg, 10 mg, 20 mg, and 40 mg) will use an accelerated titration design, with one subject enrolled in each dose group. If any grade 2 or higher adverse event related to the investigational drug occurs, the dose will be increased to a "3+3" dose escalation method. The 60 mg dose group and subsequent dose groups will follow a "3+3" dose escalation method, and the mean time to treatment (MTD) will be determined. After the evaluation of the 8th dose group, if the investigator and sponsor agree that higher dose groups may have better efficacy and manageable safety, higher doses can be explored (e.g., the 9th and 10th dose groups, at 150 mg and 180 mg, respectively). During dose escalation, if a dose group is found to have a preliminary antitumor effect and manageable safety (e.g., no DLT in 3 subjects or only 1 in 6 subjects), the dose level can be expanded after discussion and approval by the investigator and sponsor.

[0300] The dose expansion phase is expected to be conducted in multiple dose groups, with each dose group expected to expand to approximately 10 cases in total (including the dose escalation phase and the dose expansion phase), thereby determining an appropriate dosing regimen for the subsequent indication expansion phase.

[0301] The indication expansion phase will determine an appropriate dosing regimen based on safety, tolerability, pharmacokinetic (PK), and efficacy data from the dose escalation and dose expansion phases, and will be expanded within the target population. Based on patients' prior treatments and gene mutation status, participants in the expansion group will be assigned to the following different populations, with initial sample sizes as follows:

[0302] Group A: At least 20 patients with ALK-positive advanced NSCLC who failed first-line or higher therapy (including those whose disease progressed or were intolerant to previous continuous therapy with crizotinib or other ALK inhibitors) were enrolled.

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

[0304] Cohort 2: ALK-positive advanced NSCLC patients whose disease has progressed or who are intolerant to at least one second-generation ALK inhibitor (including those already marketed or in clinical trials) (regardless of whether they have previously used crizotinib) (including subjects using the target dose level during dose escalation and dose extension phases);

[0305] Group B: ROS1-positive advanced NSCLC patients whose disease progressed or were intolerant to crizotinib after continuous treatment were enrolled, totaling approximately 20 patients (including those in the target dose group during dose escalation and dose extension phases);

[0306] Group C: ALK-positive advanced NSCLC patients who had not received ALK inhibitor therapy, totaling approximately 25 patients.

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

[0308] All subjects in the dose escalation and dose expansion phases of this study will undergo intensive blood pharmacokinetic studies of compound A, and all subjects will undergo population pharmacokinetic studies of compound A.

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

[0310] Selection criteria:

[0311] Patients meeting all of the following criteria may be considered for enrollment:

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

[0313] 2) Must be at least 18 years old on the day the informed consent form is signed, regardless of gender;

[0314] 3) For the following advanced NSCLC patients who are confirmed to be ALK-positive or ROS1-positive by histopathological or cytological examination, the treatment line requirements for subjects in different study phases are as follows:

[0315] • Dosage escalation and expansion phase: ALK-positive advanced NSCLC patients whose disease has progressed or who are intolerant to at least second-generation ALK inhibitors (including those already marketed or in clinical trials) and ROS1-positive advanced NSCLC patients who have failed crizotinib treatment.

[0316] • Indication Expansion Phase: Group A: ALK-positive advanced NSCLC patients who have failed first-line or higher therapy (including those whose disease has progressed or who are intolerant to previous continuous therapy with crizotinib or other ALK inhibitors), including: Cohort 1: ALK-positive advanced NSCLC patients whose disease has progressed or failed after continuous therapy with crizotinib as the sole ALK inhibitor; Cohort 2: ALK-positive advanced NSCLC patients whose disease has progressed or who are intolerant to at least one second-generation ALK inhibitor (including those already marketed or in clinical trials) (regardless of whether they have previously used crizotinib); Group B: ROS1-positive advanced NSCLC patients whose disease has progressed or who are intolerant to continuous therapy with crizotinib; Group C: ALK-positive advanced NSCLC patients who have not received ALK inhibitor therapy.

[0317] 4) Subjects must be able to provide archived tissue samples and / or fresh tumor tissue samples obtained during the screening period for biomarker detection (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 of previous diagnostic tests, or high clinical risk of re-puncture), the patient may participate in this study only with 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 permitted if the following conditions are met: a. Asymptomatic: currently not requiring corticosteroid treatment or with a stable dose or a dose reduction of ≤10 mg QD prednisone or equivalent; or b. a previous diagnosis, completed treatment, complete recovery from the acute effects of radiation therapy or surgery prior to the first dose, corticosteroid treatment for these metastases has been discontinued for at least 4 weeks, and the nervous system is stable;

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

[0320] 7) According to RECIST version 1.1 criteria, there must be at least one measurable target lesion (longest diameter of non-lymph node ≥10mm, shortest diameter of lymph node ≥15mm). Lesions previously treated with 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 phases: score 0-1; Indication expansion phase: score 0-2;

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

[0323] Bone marrow (no blood transfusions or use of medications that increase white blood cells, platelets, hemoglobin, or red blood cells within 2 weeks prior to screening):

[0324] √ Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 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] Kidney 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 ≥ 3 months;

[0336] 11) Men of reproductive age and women of reproductive age who are willing to use effective contraception from the date of signing the informed consent form until 6 months after the last dose of the investigational drug; women of reproductive age include premenopausal women and women within 2 years after menopause. Pregnancy tests conducted ≤7 days prior to the first dose of the investigational drug must be negative for women of reproductive age.

[0337] Exclusion criteria:

[0338] Patients meeting any of the following criteria are ineligible for enrollment:

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

[0340] 2) Individuals with known allergies to any active ingredient or excipient of Compound A, or those with a clear history of allergy to protein drugs, a history of specific allergic reactions (asthma, rheumatism, eczema dermatitis), or who have experienced other severe allergic reactions and are deemed unsuitable for treatment with Compound A by the investigator;

[0341] 3) Those suffering from another malignant tumor besides lung cancer; except for 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 have undergone major surgery within 4 weeks prior to the first dose. Minor surgical procedures (e.g., IV line insertion) are not an exclusion criterion, but sufficient time must be allowed for the wound to heal fully;

[0343] 5) Spinal cord compression, unless the subject achieves good pain control through treatment and neurological function fully recovers within 4 weeks prior to 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 surgery) affecting absorption, active inflammatory gastrointestinal diseases, chronic diarrhea, symptomatic diverticulosis, treatment of active peptic ulcer disease or malabsorption syndrome in the past 6 months, etc.

[0345] 7) Patients with a history of active pneumonia or clinically significant interstitial lung disease, or radiation or drug-induced lung disease requiring treatment, or radiation-induced pneumonia patients who have been treated for 3 months and have no clinical symptoms can be enrolled.

[0346] 8) Individuals with heart failure, including but not limited to those with a left ventricular ejection fraction (LVEF) <50%, a history of congestive heart failure or a history of ventricular arrhythmias requiring treatment, hypokalemia, hereditary long QT syndrome, a history of myocardial infarction or unstable angina within 6 months prior to screening; and those with a New York Heart Association heart failure class ≥2.

[0347] 9) Abnormal and clinically significant QTc on electrocardiogram (ECG) examination (QTc > 450 msec [male] or QTc > 470 msec [female] on ECG examination at rest); or concomitant use of any medication known to prolong the QT interval and cause torsades de pointes ventricular tachycardia.

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

[0349] 11) Uncontrolled hyperglycemia, acute cholelithiasis, and individuals with predisposition to acute pancreatitis;

[0350] 12) Individuals who, in the investigator’s judgment, have a serious or uncontrollable systemic disease (such as unstable or uncompensated respiratory, cardiac, liver or kidney disease) and are not expected to tolerate the investigational drug treatment.

[0351] 13) Patients who have used or need to use the following medications within 14 days prior to the first dose or during treatment: medications that pose a risk of QTc interval prolongation and / or ventricular tachycardia;

[0352] 14) Previous antitumor treatment: (1) Any systemic antitumor treatment used within 28 days prior to the first administration of the investigational drug (compound A may be included in the trial if the drug has been discontinued for more than 5 half-lives and the investigator has assessed that compound A may be used within 28 days after the end of systemic antitumor treatment), including systemic chemotherapy, immunotherapy (physiological replacement doses of glucocorticoids [prednisone or equivalent <10 mg / day] are permitted), large molecule monoclonal antibodies, small molecule targeted drugs, etc.; (2) Radiotherapy or Chinese herbal medicine or proprietary Chinese medicine approved for antitumor treatment received within 14 days prior to the first administration; (3) Antibody or drug treatment targeting T cell co-stimulation or immune checkpoint pathway received within the previous 28 days, including but not limited to anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibodies; For subjects in the lower dose group who were removed from the group due to disease progression and then received a higher dose level again, there is no limit to the washout period of systemic antitumor treatment before the investigational drug is administered again;

[0353] 15) Previous surgical procedures and previous antitumor treatment-related toxicities have not recovered and, as assessed by the investigator, affect the safety of the subject;

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

[0355] 17) The patient had taken a strong inducer or inhibitor of CYP3A4, or a CYP3A4 substrate with a narrow therapeutic window, within two weeks prior to the first administration of the investigational drug.

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

[0357] 19) Women of reproductive age who are unwilling or unable to use an acceptable method of contraception throughout the entire treatment period of this trial and for 6 months after the last dose of the investigational drug (women of reproductive age include: any woman who has had menarche and has not undergone successful artificial sterilization [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or is not menopausal); and fertile male patients whose partners are women of reproductive age who are unwilling or unable to use effective contraception.

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

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

[0360] Experimental results:

[0361] 1) As of July 1, 2023, a total of 268 subjects were screened during the dose escalation and expansion phases, as well as the indication expansion phase. Of these, 198 were successfully screened, and 69 failed. The reasons for failure were either not meeting the inclusion criteria or meeting the 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 a most recent tumor stage of IV at enrollment. Baseline disease information for the subjects is detailed in Tables 1 and 2.

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

[0363] *: One participant was missing from the 60mg group.

[0364] Table 2 Baseline characteristics of patients during dose escalation and extension phases

[0365] 2) Among the 42 subjects in the dose escalation and expansion phases, 11 (26.2%) had previously received radiotherapy for NSCLC. All 42 subjects had previously received anti-tumor drug therapy, mainly alectinib, crizotinib, and pemetrexed (see Table 3). Of the subjects, 11 (26.2%) had 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 subjects (14.3%) had undergone anti-tumor surgery.

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

[0367] A total of 97 subjects were included in the 60 mg dose group who 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 during the dose escalation and expansion phases. Among these 97 subjects, 59 (60.8%) had previously received alectinib, 40 (41.2%), 25 (25.8%), 13 (13.4%), and 30 (30.9%) other ALK tyrosine kinase inhibitors, respectively.

[0368] 3) Cerebrospinal fluid concentration

[0369] During the dose escalation phase, cerebrospinal fluid concentration analysis was performed on 4 subjects. Due to the low protein concentration in cerebrospinal fluid, 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. Cerebrospinal fluid analysis of compound A

[0371] 4) Validity analysis

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

[0373] Table 5. Analysis of systemic BOR, ORR, DCR, DOR, and TTR during dose escalation and extension phases.

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

[0375] ②The 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 systemic BOR, ORR, DCR, DOR, and TTR during 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 for measurable intracranial lesions during the indication expansion phase.

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

[0380] In 97 patients who had previously received second-generation TKI therapy, 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 in disease status from baseline after treatment with compound A is shown in Figure 10a. In 27 patients with measurable central nervous system lesions at baseline, 5 achieved CR and 14 achieved 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-naïve patients were analyzed, with an ORR of 84.8% (95% CI: 68.1%–94.9%), of whom 28 achieved PR and 4 achieved SD. 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 in disease status from baseline after compound A treatment is shown in Figure 10c. For 8 patients with measurable central nervous system lesions at baseline, the intracranial ORR was 75% (95% CI, 34.9%–96.8%), and 6 achieved 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 ROS1-positive NSCLC patients 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). Six of these patients had baseline measurable central nervous system lesions, with an intracranial ORR of 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 during 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 progression-free survival and overall survival results for ALK-positive subjects in the indication expansion phase are shown in Figures 11b and 12b, respectively, and the progression-free survival and overall survival results for ROS1-positive subjects in the indication expansion phase are shown in Figures 12c and 12d, respectively.

[0385] ③The overall remission results of subjects in Group A, Cohort 2 who had previously received one, two, or more than three second-generation ALK inhibitors, after being given compound A of the present invention are shown in Table 9 below.

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

[0387] 6) The pharmacokinetic parameters of compound A (40 mg, 60 mg, 80 mg, 100 mg, 125 mg) after single and multiple administrations to subjects are shown in Table 10 below:

[0388] Table 10. PK parameters for single and multiple oral administrations of compound A at doses of 40 mg, 60 mg, 80 mg, 100 mg, and 125 mg, as well as 100 mg of lorlatinib.

[0389] Note: 'a' indicates that the data in this column comes from column 3 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 investigational 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 Security Analysis

[0393] Table 12 AEs related to CNS

[0394] A total of 198 patients were included, of whom 184 (92.9%) experienced treatment-related adverse events (TRAEs), with hypercholesterolemia, hypertriglyceridemia, or weight gain being the most common. 1.0% of patients experienced grade ≥3 treatment-related central nervous system (CNS) AEs; no dose interruption or dose reduction was observed. No dose-limiting events (DLTs) were observed, therefore the mean time to treatment (MTD) was not reached. Compound A was well tolerated, with a low incidence of grade ≥3 TRAEs and CNS AEs.

[0395] 8) MTD and RP2D

[0396] No dose-limiting toxicity was observed in compound A during the dose escalation phase, and it was also shown to be safe and well-tolerated during the dose extension and indication extension phases, indicating that compound A has good safety and tolerability.

[0397] Based on the pharmacokinetic, safety, and efficacy data of compound A during dose escalation and dose extension phases, the incidence of other adverse events was significantly lower in the 60 mg dose group than in the 80 mg dose group. Following discussion and resolution at the SRC meeting, it was decided that the recommended dose for indication extension would be 60 mg.

[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 therapy and 2 subjects whose disease progressed after crizotinib treatment.

[0400] Of the 26 subjects, 11 achieved partial response (PR). The objective responses (ORRs) for subjects with variant 1 and variant 3 were 33.3% (2 / 6) and 62.5% (5 / 8), respectively. Compound A was effective in 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 progression-free survival (PFS) between subjects with mutant TP53 and 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 resistance subgroup).

[0401] Table 13 Biomarker analysis of 26 subjects who had previously received at least one ALK inhibitor.

[0402] Example 5: A phase II, multicenter, single-arm clinical trial evaluating the efficacy and safety of compound A as monotherapy in advanced ALK-positive non-small cell lung cancer that has failed second-generation ALK inhibitor therapy.

[0403] Main objectives and key estimation targets:

[0404] Main purpose:

[0405] The clinical efficacy of compound A monotherapy in patients with ALK-positive advanced NSCLC who had progressed or were intolerant to prior therapy with second-generation ALK inhibitors was evaluated using objective response rate (ORR) as the endpoint, as assessed by an independent imaging review committee (IRC).

[0406] Main estimation target:

[0407] Target population: ALK-positive advanced NSCLC patients whose disease has progressed or who are intolerant to previous continuous treatment with second-generation ALK inhibitors;

[0408] Treatment: 60 mg once daily (QD), for a total of 3 weeks as one treatment cycle.

[0409] Study variable: Whether the subjects achieved objective response (CR / PR) during treatment, as assessed by an independent imaging review committee (IRC).

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

[0411] Secondary objective

[0412] The clinical efficacy of compound A monotherapy in patients with ALK-positive advanced NSCLC was evaluated using other efficacy endpoints.

[0413] Evaluate the safety of compound A in treating patients with ALK-positive advanced NSCLC;

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

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

[0416] Research Design

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

[0418] Screening period

[0419] After signing the informed consent form, participants enter the screening period, which lasts from day -28 to day -1. Participants in the DDI study are screened from day -28 to day -4. All participants 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 examination, laboratory tests, pregnancy tests, ECOG score, tumor imaging evaluation, electrocardiogram, and echocardiogram. Among these, complete blood count, blood biochemistry, coagulation function, urinalysis, 12-lead electrocardiogram, and pregnancy tests during the screening period must be completed within one week before the first administration of the investigational drug.

[0420] Treatment period

[0421] Subjects meeting the screening criteria will enter the treatment period. During the treatment period, all subjects will receive long-term treatment with Compound A, administered orally on an empty stomach, 60 mg once daily (QD), for 3 weeks per dosing cycle, until disease progression, intolerable toxicity, death, withdrawal of informed consent, or termination of the study as determined by the IRC, whichever occurs first. During the treatment period (starting from C1D1), all subjects will undergo imaging examinations and antitumor efficacy assessments every 6 / 12 weeks (every 6 weeks for C1–C17, and every 12 weeks thereafter). During the treatment period, all subjects will undergo laboratory tests, vital signs, and physical examinations every 6 / 12 weeks (every 6 weeks for C1–C17, and every 12 weeks thereafter) to assess treatment safety. During the treatment period, the investigator may increase the number of tests performed on subjects based on their clinical symptoms or condition. The researchers assessed the disease status according to the Evaluation Criteria for Treatment of Solid Tumors (RECIST version 1.1) and evaluated and recorded adverse events (AEs) according to CTCAE 5.0.

[0422] In addition, approximately 12 subjects will be selected for a disease-inhibiting dose (DDI) assessment of the effect of compound A on simvastatin. Subjects will receive a single oral dose of 40 mg simvastatin on an empty stomach on cycle 1 (C1D-2), and PK sampling will be performed up to 32 hours post-dose (C1D-1). Subjects will begin taking compound A on C1D1 according to the treatment-assured dosing regimen. On C1D15, after oral administration of compound A on an empty stomach, subjects will simultaneously receive a single oral dose of 40 mg simvastatin, and PK sampling will be performed up to 32 hours post-dose (C1D16). Subjects will continue taking compound A according to the treatment-assured dosing regimen until disease progression, intolerable toxicity, death, withdrawal of informed consent, or termination of the study as determined by the IRC, whichever occurs first.

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

[0424] This study established an independent Imaging Review Committee (IRC). The IRC evaluated all tumor imaging data to determine objective response and tumor progression. After the investigator determined disease progression in a participant, the IRC reviewed the participant's tumor imaging data. If the IRC assessed disease progression, the participant discontinued treatment. If the investigator determined disease progression, but the IRC determined it had not, the sponsor and investigator needed to discuss and reach a consensus on whether the participant should continue treatment from a risk-benefit perspective. If the participant continued treatment, the investigator continued tumor assessment according to the protocol (and additional unplanned tumor assessments may be added when clinically indicated) until the IRC assessed disease progression. The IRC's assessment results will be used for efficacy endpoint analysis, and the IRC-based assessment results will also guide treatment decisions for participants.

[0425] Subjects will be treated until they meet the criteria for discontinuation / withdrawal from treatment, at which point the study treatment will be terminated. Subjects must complete their last treatment visit within 7 days of termination, after which they will enter a safety follow-up period. If the IRC assesses disease progression and the investigator determines that continued use of the investigational drug will benefit the subject, the subject may continue treatment after discussion with the sponsor. During continued treatment, any adverse events or concomitant medications or treatments must be reported to the investigator immediately. If necessary, the subject may come to the hospital for necessary examinations or treatments. The investigator will follow up based on the subject's disease status.

[0426] Safety follow-up period

[0427] Once a subject meets the criteria for treatment termination / withdrawal and discontinues medication, a 4-week safety follow-up period will begin. If other anti-tumor therapies are used during the safety follow-up period, a safety follow-up visit must be completed before starting the other anti-tumor therapy. For unresolved adverse events or abnormal laboratory tests, follow-up will continue until the event is resolved, the subject returns to baseline, the condition stabilizes, a reasonable explanation is obtained, or the subject is lost to follow-up or dies.

[0428] Survival follow-up period

[0429] Starting from the last study dose, survival follow-up (by telephone) will be conducted every 3 months ± 7 days to collect data on all subsequent anti-tumor treatments and patient survival until the end of the trial, or if the patient achieves survival or refuses follow-up, whichever occurs first. Unless the subject discontinues treatment or starts a new anti-tumor therapy due to disease progression or death, the subject must come to the hospital every 12 weeks (calculated from the first dose) for tumor imaging and efficacy evaluation according to RECIST version 1.1 during the long-term follow-up period, until disease progression, initiation of a new anti-tumor therapy, death, refusal to come for follow-up, or end of the trial. The IRC will evaluate tumor imaging data to determine tumor progression.

[0430] Selection criteria

[0431] Patients meeting all of the following criteria may be considered for enrollment:

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

[0433] 2) Must be at least 18 years old on the day the informed consent form is signed, regardless of gender;

[0434] 3) Patients with advanced (stage IIIB, IIIC, IV) unresectable NSCLC who have progressed or are intolerant to second-generation ALK inhibitors after continuous treatment (regardless of whether they have previously used crizotinib, they may also be enrolled if they are using second-generation drugs that are currently in the trial phase).

[0435] 4) During screening, previous test results of subjects are acceptable (test reports confirmed as ALK positive by nationally approved Ventana D5F3 immunohistochemistry, FISH, PCR, or high-throughput sequencing (NGS); if there is no previous test report, tissue specimens must be provided for confirmation of the ALK gene; fresh tissue samples or paraffin blocks or pathological biopsy sections of tumor tissue archived within the past 6 months should be obtained as much as possible, but whether or not samples can be obtained will not affect enrollment;

[0436] 5) Individuals with central nervous system metastases at the time of screening who meet the following criteria are eligible for this trial: a. Asymptomatic: do not require corticosteroid treatment, or have received stable treatment with a dose of prednisone / equivalent to ≤10 mg QD for at least 2 weeks; or b. have previously received treatment for central nervous system metastases (radiotherapy or surgery), have fully recovered from the acute effects of radiotherapy or surgery before the first dose, have stopped corticosteroid treatment for metastases for at least 4 weeks, and have stable neurological symptoms and signs;

[0437] 6) Patients who have previously received ALK inhibitor therapy must have discontinued the drug for ≥5 half-lives before the first administration of the investigational drug;

[0438] 7) According to RECIST version 1.1 criteria, there must be at least one measurable lesion. Previously radiotreated lesions cannot be used as target lesions unless the lesion has significantly 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 ​​at each clinical trial center):

[0441] Bone marrow [without blood transfusion or cytokine therapy such as granulocyte colony-stimulating factor (G-CSF) within 2 weeks prior to the examination]:

[0442] Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L;

[0443] Platelets≥100×10 9 / L;

[0444] Hemoglobin ≥90g / 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 the ULN; in the presence of liver metastasis, ALT, AST, and ALP ≤ 5 times the ULN.

[0448] Kidney 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 ≥ 3 months;

[0454] 11) Men of reproductive age and women of reproductive age who are willing to use effective contraception from the time they sign the informed consent form until 6 months after the last dose of the investigational drug; women of reproductive age include premenopausal women and women within 2 years after menopause.

[0455] Exclusion criteria

[0456] Patients meeting any of the following criteria are ineligible for enrollment:

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

[0458] 2) Individuals with known hypersensitivity to any active ingredient or excipient of compound A, or those with a history of specific allergic reactions (asthma, rheumatism, eczema dermatitis), or those who have experienced other severe allergic reactions and are deemed unsuitable for treatment with compound A by the investigator;

[0459] 3) Those suffering from another malignant tumor besides lung cancer; except for 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 have undergone major surgery within 4 weeks prior to the first dose. Minor surgical procedures (e.g., IV line insertion) are not an exclusion criterion, but sufficient time must be allowed for the wound to heal fully;

[0461] 5) Spinal cord compression (caused by a tumor), unless the subject achieves good pain control through treatment and neurological function fully recovers within 4 weeks prior to 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 surgery) affecting absorption, active inflammatory gastrointestinal diseases, chronic diarrhea, symptomatic diverticulosis, treatment of active peptic ulcer disease or malabsorption syndrome in the past 6 months, etc.

[0463] 7) Patients with a history of active pneumonia or clinically significant interstitial lung disease, or radiation or drug-induced lung disease requiring treatment, or radiation-induced pneumonia patients who have been treated for 3 months and have no clinical symptoms can be enrolled.

[0464] 8) Individuals with heart failure, including but not limited to those with a left ventricular ejection fraction (LVEF) <50%, a history of congestive heart failure or a history of ventricular arrhythmias requiring treatment, hypokalemia, hereditary long QT syndrome, a history of myocardial infarction or unstable angina within 6 months prior to screening; and those with a New York Heart Association heart failure class ≥2.

[0465] 9) Patients whose QTc abnormalities are corrected and are clinically significant (QTc > 450 msec [male] or QTc > 470 msec [female] in the resting state) or who need to use any medication known to prolong the QT interval and cause torsades de pointes ventricular tachycardia (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 by medication (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg);

[0467] 11) Uncontrolled hyperglycemia, acute cholelithiasis, and individuals with predisposition to acute pancreatitis;

[0468] 12) Individuals who, in the investigator’s judgment, have a serious or uncontrollable systemic disease (such as unstable or uncompensated respiratory, cardiac, liver or kidney disease) and are not expected to tolerate the investigational drug treatment.

[0469] 13) Patients who have used or need to use the following medications within 14 days prior to the first dose or during treatment: medications that pose a risk of QTc interval prolongation and / or ventricular tachycardia;

[0470] 14) Previous anti-tumor treatment: (1) Any systemic anti-tumor treatment used within 28 days prior to the first administration of the test drug (compound A may be included in the trial if it has been discontinued for more than 5 half-lives and the investigator has assessed that it may be used within 28 days after the end of systemic anti-tumor treatment), including systemic chemotherapy, immunotherapy (physiological replacement dose of glucocorticoids [prednisone or equivalent <10mg / day] is allowed), large molecule monoclonal antibodies, small molecule targeted drugs, etc.; (2) Radiotherapy or Chinese herbal medicine or proprietary Chinese medicine approved for anti-tumor treatment received within 14 days prior to the first administration; (3) Antibody or drug treatment targeting T cell co-stimulation or immune checkpoint pathway received within the previous 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) Previous surgical procedures and previous antitumor treatment-related toxicities have not recovered and, as assessed by the investigator, affect the safety of the subject;

[0472] 16) Clinically significant active bacterial, fungal, or viral infection, including hepatitis B surface antigen positive and HBV DNA ≥ ULN (ULN defined as 2000 IU / ml) (only in hepatitis B surface antigen positive patients), or hepatitis C (hepatitis C antibody positive but HCV RNA polymerase chain reaction (PCR) < ULN can be included), positive for any one or more of the human immunodeficiency virus antibody test results, or any uncontrolled infection.

[0473] 17) The patient had taken a strong inducer or inhibitor of CYP3A4, or a CYP3A4 substrate with a narrow therapeutic window, within two weeks prior to the first administration of the investigational drug.

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

[0475] 19) Women of reproductive age who are unwilling or unable to use an acceptable method of contraception throughout the entire treatment period of this trial and for 6 months after the last dose of the investigational drug (women of reproductive age include: any woman who has had menarche and has not undergone successful artificial sterilization [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or is not menopausal); and fertile male patients whose partners are women of reproductive age who are unwilling or unable to use effective contraception.

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

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

[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 the screening. The main reasons for failure were not meeting the inclusion criteria or meeting the exclusion criteria (37 cases, 18.1%).

[0480] ① Demographic data

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

[0482] The treatment types for the 158 subjects were as follows: targeted therapy in 158 cases (100.0%), other treatments in 55 cases (34.8%, mainly including chemotherapy combined with targeted therapy and / or immunotherapy, chemotherapy combined with targeted therapy combined with traditional Chinese medicine, targeted therapy combined with traditional Chinese medicine, traditional Chinese medicine or traditional Chinese medicine treatment and adjuvant therapy), and chemotherapy in 43 cases (27.2%). Classified by preferred name, the most commonly used antitumor drugs 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 as follows: 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 as follows: 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] XZP-3621 is an ALK inhibitor independently developed by Xuanzhu Biotechnology for the treatment of non-small cell lung cancer, and it is currently in Phase III clinical trials; TQ-B3139 is also known as Ifonak, and WX-0593 is also known as Iruak, and their structures are shown below:

[0484] ② Validity results

[0485] a) Therapeutic effects on systemic tumors

[0486] As of the data cutoff date (May 20, 2024), based on the full analysis set of 158 subjects, 67 subjects (42.4%) achieved best objective response (PR) as assessed by IRC, with an ORR of 67 subjects (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, -). Detailed analyses of whole-body BOR, ORR, and DCR for subjects assessed by IRC are shown in Table 14. A waterfall plot of the percentage change in the sum of whole-body tumor diameters relative to baseline 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 indicate that compound A is effective in subjects who have failed second-generation ALK-TKI treatment, achieving tumor remission in a shorter time, effectively controlling disease progression, and is expected to prolong progression-free survival.

[0489] b) Treatment of intracranial tumors

[0490] As of the data cutoff date (May 20, 2024), based on the full analysis set of 158 subjects, 44 subjects had measurable intracranial lesions. No subjects achieved complete remission (CR) according to IRC assessment, and 24 subjects (54.5%) achieved partial remission (PR). The IC-ORR for these 24 subjects was 54.5% (95% CI: 38.85, 69.61), and the IC-DCR for these 37 subjects was 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, -). For detailed analysis of subjects’ IC-BOR, IC-ORR and IC-DCR, see Table 15. The waterfall plot of the sum of intracranial tumor diameters relative to baseline is shown in Figure 16. The Kaplan-Meier curve of IC-PFS is shown in Figure 17.

[0491] Table 15. Analysis of Intracranial BOR, ORR, and DCR (IRC Assessment Results) - Full Analysis Set

[0492] The above results indicate that compound A is effective in patients who have failed second-generation ALK-TKI treatment and have intracranial target lesions, achieving tumor remission in a shorter time and effectively controlling intracranial disease progression.

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

[0494] Figure 18 shows the ORR of subjects assessed by IRC in each subgroup based on FAS. Data shows that there was essentially no 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 of subjects with a baseline ECOGPS score of 0 was slightly higher than that of subjects with a baseline ECOGPS score of 1-2 (50.0% vs. 40.8%), the ORR of subjects with baseline brain metastases was slightly higher than that of subjects without baseline brain metastases (45.3% vs. 38.9%), and the ORR of subjects who had never received chemotherapy was slightly higher than that of subjects who had previously received chemotherapy (45.4% vs. 37.7%). The ORR in subjects with the G1202R mutation was 62.5% (95% CI: 24.5%, 91.5%).

[0495] Subgroup analysis showed that compound A was more effective in subjects with a baseline ECOGPS score of 0, baseline brain metastases, and no prior chemotherapy; it was also significantly effective in subjects with the G1202R mutation, with an ORR of 62.5%.

[0496] ③ Security Analysis

[0497] Common adverse events associated with compound A include hypercholesterolemia, hypertriglyceridemia, weight gain, anemia, and peripheral edema. Most subjects experienced grade 1-2 adverse events, and the incidence of adverse events leading to dose reduction, temporary discontinuation, or permanent discontinuation was low. For subjects with grade 3 or higher adverse events, most recovered by pausing administration, reducing the dose, or symptomatic treatment. The adverse event classification was similar to that of similar drugs, the safety risks were manageable, and the overall safety profile was good.

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

[0499] This is a multicenter, randomized, open-label, active-controlled phase III clinical trial primarily evaluating the clinical efficacy and safety of compound A versus crizotinib in patients with advanced or metastatic ALK-positive NSCLC. The primary objective was to compare the clinical efficacy of compound A tablets versus crizotinib capsules in treating patients with ALK-positive advanced or metastatic NSCLC, using progression-free survival (PFS) as assessed by an independent imaging review committee (IRC). Secondary objectives included evaluating the clinical efficacy of compound A tablets versus crizotinib capsules in treating patients with ALK-positive advanced or metastatic NSCLC on other efficacy endpoints, and comparing the safety of compound A tablets versus crizotinib capsules in treating patients with ALK-positive advanced or metastatic NSCLC.

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

[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 examination, laboratory tests, pregnancy tests, ECOG score, tumor imaging evaluation, electrocardiogram, echocardiogram, etc. Among them, blood routine, blood biochemistry, coagulation function, urinalysis, 12-lead electrocardiogram and pregnancy test during the screening period need to be completed within 1 week before the first administration of the investigational drug.

[0503] Treatment period

[0504] Eligible participants were randomly assigned to either the experimental group (compound A) or the control group (crizotinib) in a 2:1 ratio. Stratified randomization was employed, based on the presence of central nervous system metastases at baseline and prior chemotherapy for advanced NSCLC. All participants in the experimental group received long-term treatment with compound A, orally at 60 mg once daily (QD) for 28 days. Participants in the control group received crizotinib, a positive control, at 250 mg twice daily (BID) for 28 days. All participants continued treatment according to their randomization until disease progression, intolerable toxicity, death, withdrawal of informed consent, or termination of the study, as determined by the IRC, whichever occurred first.

[0505] During the treatment period (starting from C1D1), all subjects underwent imaging examinations and antitumor efficacy assessments every 8 / 12 weeks (every 8 weeks for C1–C17, and every 12 weeks thereafter). During the treatment period, all subjects underwent laboratory tests, vital signs assessments, and physical examinations every 4 / 8 / 12 weeks (every 4 weeks for C1–C3, every 8 weeks for C4–C17, and every 12 weeks thereafter) to assess treatment safety. During medication, investigators may add additional safety assessments based on the subjects' clinical symptoms or status. Disease status was assessed by investigators according to the Recognition of Efficacy in Solid Tumors (RECIST v1.1), and adverse events (AEs) were assessed and recorded according to CTCAE v5.0. A population pharmacokinetic study and exposure-effect relationship study of compound A were conducted in all experimental groups to explore the population pharmacokinetic characteristics and potential influencing factors of compound A in ALK-positive NSCLC subjects.

[0506] For subjects in the crizotinib group whose disease has progressed according to IRC assessment, crossover to compound A group is permitted after discontinuation of crizotinib (crossover is not allowed for subjects who receive other anti-tumor therapies after discontinuation of crizotinib treatment, subject to investigator evaluation and subject consent, with follow-up on clinical efficacy and safety. Crossover from compound A group to crizotinib group is not permitted. For subjects crossing over to compound A, the imaging assessment result indicating disease progression according to IRC assessment is used as the baseline for the crossover treatment period. After starting compound A tablets, subjects will undergo imaging examinations and antitumor efficacy assessments every 8 / 12 weeks (every 8 weeks for C1–C17, and every 12 weeks thereafter). Treatment safety will be assessed every 4 / 8 / 12 weeks (every 4 weeks for C1–C3, every 8 weeks for C4–C17, and every 12 weeks thereafter) including laboratory tests, vital signs, and physical examinations. Investigators may add further safety assessments based on the subjects' clinical symptoms or status until disease progression, intolerable toxicity, death, informed consent withdrawal, or the end of the study, whichever occurs first.

[0507] This study established an IRC (Internal Responsibility Controller) to evaluate all tumor imaging data during the randomization phase to determine objective response and tumor progression. After the investigator determines disease progression in a participant, the IRC confirms the participant's tumor imaging data. If the investigator determines disease progression but the IRC determines it has not, the participant continues study treatment, and the investigator continues to evaluate the participant's tumor according to the protocol (unplanned tumor evaluations may be added when clinically indicated) until the IRC assesses disease progression. The IRC evaluation results will be used for efficacy indicator analysis, and the evaluation results based on the IRC will also guide treatment decisions for the participants.

[0508] Subjects will be treated until they meet the criteria for discontinuation / withdrawal, at which point they will cease treatment in the study. Subjects must complete their last treatment visit within 7 days of treatment termination, after which they will begin the safety follow-up period. If the IRC assesses disease progression and the investigator determines that continued use of the investigational drug would be beneficial, the subject may continue treatment after discussion with the sponsor. Follow-up during continued treatment will follow the previous visit schedule. If any adverse events occur or any concomitant medications or treatments are used during treatment, the subject must report to the investigator immediately. If necessary, the subject may come to the hospital for necessary examinations or treatments. The investigator will follow up based on the subject's disease status.

[0509] Safety follow-up period

[0510] After subjects meet the criteria for treatment termination / withdrawal and discontinue medication, a safety follow-up period of 4 weeks ± 7 days will begin, starting from the last study dose. If other anti-tumor therapies are used during the safety follow-up period, a safety follow-up visit must be completed before starting the other anti-tumor therapy. For unresolved adverse events or abnormal laboratory tests, follow-up will continue until the event is resolved, returns to baseline status, stabilizes, and is reasonably explained. 、 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 (by telephone) will be conducted every 12 weeks (±14 days) from the date of the last study dose. All subsequent anti-tumor treatments and subject survival information will be collected until the end of the trial, or the subject achieves survival or refuses follow-up, whichever occurs first.

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

[0514] Patients meeting all of the following criteria may be considered for enrollment:

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

[0516] 2) Must be at least 18 years old on the day the informed consent form is signed, regardless of gender;

[0517] 3) NSCLC patients who are diagnosed with stage IIIB-IV ALK-positive disease by histology or cytology and are not eligible for radical treatment (surgery, radiotherapy) (International Association for the Study of Lung Cancer 8th Edition Lung Cancer Staging);

[0518] 4) Patients' previous test results in the local area are acceptable during screening (nationally approved Ventana D5F3 immunohistochemistry, FISH or PCR, next-generation high-throughput sequencing (NGS)); if there is no previous test report, tissue specimens must be provided for central confirmation of the ALK gene before randomization.

[0519] 5) Has never received ALK inhibitor therapy before; has progressed or is intolerant to the most recent first-line chemotherapy regimen;

[0520] 6) Patients with asymptomatic brain metastases at the time of screening can be included. The brain metastases are untreated and do not require the use of corticosteroids. If the patient has neurological symptoms or signs due to CNS metastases, the patient needs to complete whole brain radiotherapy or Gamma Knife treatment at least 14 days before the first dose and achieve symptom stability (using a fixed dose or dose-reducing corticosteroid at baseline).

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

[0522] 8) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score: 0–2;

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

[0524] Bone marrow [without blood transfusion or corrective therapy with cytokine drugs such as granulocyte colony-stimulating factor (G-CSF) within 2 weeks prior to screening]:

[0525] Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L;

[0526] Platelets≥100×10 9 / L;

[0527] Hemoglobin ≥90g / 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 the ULN; in the presence of liver metastasis, ALT, AST, or ALP ≤ 5 times the ULN.

[0531] Kidney 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 ≥ 3 months;

[0537] 11) Men of reproductive age and women of reproductive age who are willing to use effective contraception from the date of signing the informed consent form until 6 months after the last dose of the investigational drug; women of reproductive age include premenopausal women and women within 1 year of menopause. Women of reproductive age must have a negative blood pregnancy test result within ≤7 days prior to the first dose of the investigational drug.

[0538] Patients meeting any of the following criteria are ineligible for enrollment:

[0539] 1) Individuals with known hypersensitivity to any active ingredient or excipient of compound A and crizotinib capsules, or with a clear history of specific allergic reactions (asthma, rheumatism, eczema dermatitis), or who have experienced other severe allergic reactions;

[0540] 2) In addition to lung cancer, patients have had other malignant tumors in the past 5 years (excluding basal cell carcinoma of the skin, cervical carcinoma in situ that has been cured, or other cancers that are curable and do not affect the PFS and OS of the current NSCLC).

[0541] 3) Received radiation therapy within 14 days prior to the first dose;

[0542] 4) The patient has received other systemic antitumor drug treatment within 4 weeks prior to the first dose, or is still within 5 half-lives of the drug. The patient has received traditional Chinese medicine or proprietary Chinese medicine treatment for antitumor purposes within 14 days prior to the first dose;

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

[0544] 6) Spinal cord compression (caused by a tumor), unless the subject achieves good pain control through treatment and neurological function fully recovers within 4 weeks prior to 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 diverticulosis, active peptic ulcer or malabsorption syndrome that requires treatment within the past 6 months, etc.

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

[0547] 9) Individuals with heart failure, including but not limited to those with a left ventricular ejection fraction (LVEF) <50%, a history of congestive heart failure or a history of ventricular arrhythmias requiring treatment, hypokalemia, hereditary long QT syndrome, a history of myocardial infarction or unstable angina within 6 months prior to screening; and those with a New York Heart Association heart failure class ≥2.

[0548] 10) An abnormal and clinically significant QTc on an electrocardiogram (ECG) (QTc > 450 msec [male] or QTc > 470 msec [female] on an ECG at rest) or the need for concomitant use of any medication known to prolong the QT interval and cause torsades de pointes ventricular tachycardia;

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

[0550] 12) Uncontrolled hyperglycemia, acute cholelithiasis, and individuals with predisposition to acute pancreatitis;

[0551] 13) Individuals who, in the investigator’s judgment, have a serious or uncontrollable systemic disease (such as unstable or uncompensated respiratory, cardiac, liver or kidney disease) and are not expected to tolerate the investigational drug treatment.

[0552] 14) Previous surgical procedures and previous antitumor treatment-related toxicities have not recovered and, as assessed by the investigator, affect the safety of the subject;

[0553] 15) Clinically significant active bacterial, fungal, or viral infection, including hepatitis B surface antigen positive and HBV DNA ≥2000 IU / ml (only in hepatitis B surface antigen positive patients), or hepatitis C (hepatitis C antibody positive but HCV RNA polymerase chain reaction (PCR) test <ULN can be included), positive human immunodeficiency virus antibody test result, or any uncontrolled infection.

[0554] 16) The patient had taken a strong inducer or inhibitor of CYP3A4, or a CYP3A4 substrate with a narrow therapeutic window, within two weeks prior to the first administration of the investigational drug.

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

[0556] 18) Women of reproductive age who are unwilling or unable to use an acceptable method of contraception throughout the entire treatment period of this trial and for 6 months after the last dose of the investigational drug (women of reproductive age include: any woman who has had menarche and has not undergone successful artificial sterilization [hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or is not menopausal); and fertile male patients whose partners are women of reproductive age who are unwilling or unable to use effective contraception.

[0557] 19) Subjects who are participating in other clinical studies or whose first dose was less than 4 weeks after the end of other investigational drug treatment or 5 half-lives of the investigational drug, whichever is shorter;

[0558] 20) Having any mental illness or cognitive impairment may limit their understanding and compliance with informed consent forms;

[0559] 21) Other situations in which the researchers deem it unsuitable for participation in this study.

[0560] Criteria for Termination of Treatment

[0561] Researchers may terminate treatment for a subject if any of the following occurs:

[0562] The subject voluntarily requested to stop treatment;

[0563] Researchers may decide to discontinue treatment with the investigational drug for safety reasons (e.g., if the subject experiences an intolerable adverse event).

[0564] Subject pregnancy;

[0565] die;

[0566] The participant exhibited serious protocol violation, and the investigator believed that the protocol violation significantly affected the evaluation of the primary endpoint of the trial;

[0567] If the investigator assesses that a subject has experienced disease progression, the IRC needs to conduct a rapid review of the disease progression. If the IRC assesses that the subject has experienced disease progression, the subject should discontinue treatment. If the IRC assesses that the subject has not experienced disease progression, the sponsor and the investigator need to discuss and reach a consensus, and should assess whether the subject should continue to receive study treatment from the perspective of the subject's risk and benefit.

[0568] Exit from research criteria:

[0569] Participants may withdraw from the study for the following reasons:

[0570] 1. The subject died;

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

[0572] 3. Loss to follow-up of participants;

[0573] 4. The sponsor terminates the research;

[0574] Participants may withdraw from the study at any stage of the study at their own discretion.

[0575] It is important to clearly distinguish between permanent discontinuation of the study drug (i.e., termination of treatment) and withdrawal from the study. Subjects who permanently discontinue the study drug should remain in the study to complete safety visits and survival follow-ups. Subjects who withdraw from the study are encouraged to complete the necessary examinations and survival follow-ups within 7 days of deciding to withdraw, as per the trial flowchart. Subject withdrawal should be recorded on the relevant page of the eCRF and in the subject's medical record, along with the reason for withdrawal.

[0576] Exit from research criteria:

[0577] Participants may withdraw from the study for the following reasons:

[0578] 1. The subject died;

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

[0580] 3. Loss to follow-up of participants;

[0581] 4. The sponsor terminates the research;

[0582] Participants may withdraw from the study at any stage of the study at their own discretion.

[0583] It is important to clearly distinguish between permanent discontinuation of the study drug (i.e., termination of treatment) and withdrawal from the study. Subjects who permanently discontinue the study drug should remain in the study to complete safety visits and survival follow-ups. Subjects who withdraw from the study are encouraged to complete the necessary examinations and survival follow-ups within 7 days of deciding to withdraw, as per the trial flowchart. Subject withdrawal should be recorded on the relevant page of the eCRF and in the subject's medical record, along with the reason for withdrawal.

[0584] The above description, in conjunction with specific preferred embodiments, provides a further detailed explanation of the present invention. It should not be construed that the specific implementation of the present invention is limited to these descriptions. For those skilled in the art, various simple deductions or substitutions can be made without departing from the concept of the present invention, and all such modifications and substitutions should be considered 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 said compound A has the following structure:

2. A method of 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:

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

4. The use according to claim 1, the method of claim 2, or the use of the compound of 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 mutant and wild-type) ALK-positive non-small cell lung cancer; preferably, the non-small cell lung cancer is TP53-mutant ALK-positive non-small cell lung cancer.

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

6. The use, method, or compound according to any one of claims 1-5, 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 (e.g., intracranial metastatic non-small cell lung cancer).

7. The use, method, or compound according to any one of claims 1-6, wherein the non-small cell lung cancer is untreated.

8. The use, method, or compound according to any one of claims 1-6, wherein the non-small cell lung cancer progresses 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 a targeted therapy; Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

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

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

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

12. The use, method, or compound according to any one of claims 1-11, wherein the patient has received first-line or higher treatment; preferably, wherein the patient has received second-line or higher treatment; preferably, the patient has received first-line, second-line, third-line, fourth-line, or fifth-line treatment.

13. The use, method, or compound according to claim 12, wherein the patient has experienced disease progression or intolerance after receiving first-line or higher treatment; preferably, wherein the patient has experienced disease progression or intolerance after receiving first-line or second-line treatment.

14. The use, method, or compound according to claim 12 or 13, wherein the first-line or higher treatment is selected from radiotherapy, pharmacotherapy, or surgical therapy; Preferably, the drug therapy is chemotherapy, targeted therapy, or immunotherapy; Preferably, the drug used in the drug therapy is selected from carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton seed, gimeracil, otetracil, and tegacil. Fluorine, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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, or one or more of these.

15. The use, method, or 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, croton, gimidacil, oteracil, tegafur, sodium cantharidate, or pyridoxine, more preferably carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, docetaxel, endostatin, sodium cantharidate, or pyridoxine.

16. The use, method, or 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 sole ALK inhibitor.

17. The use, method, or compound of claim 14, wherein the patient has not previously received treatment with an ALK inhibitor (e.g., a third-generation ALK inhibitor).

18. The use, method, or use of the compound according to any one of claims 1-17, wherein the dose of said 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 1-18, wherein said compound A is administered orally.

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

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

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

23. The use according to claim 1, 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 the ROS1 G2032R mutation.

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

25. The use, method, or 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 (e.g., intracranial metastatic non-small cell lung cancer).

26. The use, method, or compound according to any one of claims 1-3 and 23-25, wherein the non-small cell lung cancer is untreated.

27. The use, method, or compound according to any one of claims 1-3 and 23-26, wherein the non-small cell lung cancer progresses 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 a targeted therapy; Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

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

29. The use, method, or 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 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 compound according to any one of claims 1-3 and 23-30, wherein the patient has received first-line or higher treatment; preferably, wherein the patient has received second-line treatment.

32. The use, method, or compound according to claim 31, wherein the patient has experienced disease progression or intolerance after receiving first-line or higher treatment; preferably, wherein the patient has experienced disease progression or intolerance after receiving second-line treatment.

33. The use, method, or compound according to claim 31 or 32, wherein the first-line or higher treatment is selected from radiotherapy, pharmacotherapy, or surgical therapy; Preferably, the drug therapy is chemotherapy, targeted therapy, or immunotherapy; Preferably, the drug used in the drug therapy is selected from one or more of the following: carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, paclitaxel, docetaxel, gemcitabine, endostatin, croton, gimbalimidine, oteracil, tegafur, sodium cantharidate, pyridoxine, crizotinib, ceritinib, alectinib, ensartinib, brigatinib, anlotinib, gefitinib, contetinib, 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.

34. The use, method, or 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, croton, gimidacil, oteracil, tegafur, sodium cantharidate, or pyridoxine, preferably carboplatin, cisplatin, nedaplatin, lobaplatin, pemetrexed, docetaxel, endostatin, sodium cantharidate, or pyridoxine.

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

36. The use, method, or compound of claim 33, wherein the patient has not previously received treatment with a ROS1 inhibitor (e.g., a second-generation ROS1 inhibitor).

37. The use, method, or use of the compound according to any one of claims 1-3 and 23-36, wherein the dose of said 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 said 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 administered orally once daily, twice daily, or three times daily; Preferably, compound A is administered orally once daily.

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

41. The use, method, or use of the compound according to any one of claims 1-3 and 23-40, wherein the patient has a CSF / plasma concentration ratio of compound A greater than about 40% after administration of compound A; preferably, a CSF / plasma concentration ratio of compound A greater than about 50%; preferably, a CSF / plasma concentration ratio of compound A 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 metastatic non-small cell lung cancer, comprising: a. Collect cerebrospinal fluid samples; and b. Measure the concentration of compound A in the CSF sample to determine the concentration of compound A present in the CNS solution.

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