WO2024222705A1 - Drug for treating patient with pd-l1 expression positive local advanced or metastatic nsclc and use thereof - Google Patents

Abstract

The present invention relates to the field of medicine, and particularly relates to a combined drug for treating a patient with PD-L1 expression positive (TC≥1%) local advanced or metastatic NSCLC and the use thereof. The combined drug comprises a component (i) and a component (ii), wherein the component (i) is selected from an HDAC1 inhibitor, an HDAC2 inhibitor, an HDAC3 inhibitor and/or an HDAC10 inhibitor, and the component (ii) is selected from a PD-1 inhibitor. The present application proves by means of clinical trials that the efficacy of the combination of the HDAC selective inhibitor represented by chidamide and the PD-1 inhibitor represented by tislelizumab provided in the present invention is increased by 1.5 times or more compared with that of the PD-1 inhibitor alone. The combination of the two has a synergistic effect, significantly improves the efficacy of the drug, and has an unexpected technical effect.

Description

Drugs and uses thereof for treating patients with locally advanced or metastatic NSCLC with positive PD-L1 expression Technical Field

The present invention relates to the field of medicine, and in particular to a drug for treating patients with locally advanced or metastatic NSCLC who have positive PD-L1 expression (TC≥1%) and a use thereof.

Background Art

Lung cancer is one of the most common malignant tumors in the world and has become the leading cause of death from malignant tumors in urban populations in my country. Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of lung cancer cases and is the main type of lung cancer. There are no specific clinical manifestations in the early stages, and most patients are already in the middle or late stages when they seek medical treatment, losing the opportunity for radical surgery or chemoradiotherapy. Currently, the first-line drug treatment for locally advanced or metastatic NSCLC mainly includes chemotherapy, molecular targeted therapy, and immunotherapy.

The 2021 NCCN guidelines (National Comprehensive Cancer Network N. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer (Version 5.2021) [Z]. 2021) have divided driver gene-negative NSCLC patients according to PD-L1 expression levels, thereby making different treatment decisions. Currently, the drugs and clinical studies that have differentiated the target patient population of NSCLC by PD-L1 expression levels mainly include: pembrolizumab (single-agent for the treatment of NSCLC with PD-L1 ≥ 1%), cemiplizumab (single-agent for the treatment of NSCLC with PD-L1 ≥ 50%), and atezolizumab monotherapy (single-agent for the treatment of NSCLC with PD-L1 ≥ 50%), all of which have shown that there are differences in efficacy in the target patient population of NSCLC differentiated by PD-L1 expression levels.

Histone deacetylases (HDACs, HDAC) inhibitors are molecular targeted drugs that target tumor epigenetic modifications. As key proteases that regulate genes, the dysfunction of HDAC inhibitors has been shown to be directly related to the occurrence and development of tumors. The purpose of treating tumors can be achieved by inhibiting and regulating the function of HDAC. The mechanism of action of HDAC inhibitors has been widely studied, and various histone deacetylase inhibitors have been developed. According to the structural type, histone deacetylase inhibitors can be roughly divided into: hydroxamic acid compounds, cyclic tetrapeptide compounds, fatty acid salt compounds, benzamide compounds and electrophilic ketone compounds. HDAC inhibitors inhibit the proliferation of tumor cells and induce cell differentiation and (or) apoptosis by increasing the acetylation level of histones in cells and increasing the expression levels of genes such as p21. At present, 18 types of HDAC have been found in the human body, namely: It belongs to four categories (Class I, II, III and IV). Therefore, the corresponding mainstream HDAC inhibitors also have four major categories, namely hydroxamic acids, cyclotetrapeptides, short-chain fatty acids and benzamides. Among them, the first three categories are non-selective HDAC inhibitors, while the last category, benzamides, are selective.

Chidamide is a Class 1.1 new drug developed by Shenzhen Chipscreen Biotech Co., Ltd. It is a selective inhibitor of the 1, 2, and 3 subtypes of Class I HDAC and the 10 subtypes of Class IIb benzamide histone deacetylase (HDAC) subtypes, and has a regulatory effect on abnormal epigenetic functions of tumors. Currently, the approved indications for chidamide include: 1) peripheral T-cell lymphoma; 2) for hormone receptor-positive, human epidermal growth factor receptor-2-negative, postmenopausal, locally advanced or metastatic breast cancer patients who have relapsed or progressed after endocrine therapy.

CN03139760.3 discloses a cedamide compound, specifically a benzamide histone deacetylase inhibitor with differentiation and anti-proliferation activity and a preparation method and application of its pharmaceutical preparation, which discloses a general structural formula and defines substituents. Such compounds, as histone deacetylase inhibitors, can be used to treat diseases related to differentiation and proliferation, such as cancer and psoriasis.

CN201210489178.8 discloses two crystalline forms of Chidamide, i.e., Chidamide Form A and Chidamide Form B, and a method for preparing a new crystalline form of Chidamide. The Chidamide Form A and Chidamide Form B have excellent oral absorbability and inhibition of cell differentiation and proliferation, and have weak toxicity and good storage and handling stability, and can be used to prepare drugs for treating diseases related to cell differentiation and proliferation.

CN201410136761.X discloses an E-configuration benzamide compound and its pharmaceutical preparation and application. The E-configuration benzamide compound is chidamide, and its chemical name is N(2-amino-4-fluorophenyl)-4[N[(E)3(3-pyridine)acryloyl]aminomethyl]benzamide. In its structural formula, the configuration of 3-pyridineacryloyl is E-type. The E-configuration chidamide has subtype selective histone deacetylase inhibitory activity, mainly inhibiting HDAC1, HDAC2, HDAC3 in class I HDAC and HDAC10 in class IIb HDAC. The E-configuration chidamide can be used to treat diseases related to abnormal histone deacetylase activity, such as cancer, including lymphoma, solid tumors and hematological tumors.

PD-1/PD-L1 inhibitors are a new class of anticancer immunotherapy inhibitors that mainly overcome the patient's immune suppression and reactivate the patient's own immune cells to kill tumors, making full use of the body's own immune system to resist and fight cancer. By blocking the PD-1/PD-L1 signaling pathway, cancer cells die. It is a new anti-tumor treatment concept. The status of this therapy has gradually increased, from second-line treatment to first-line treatment, from monotherapy to combination therapy, and rich clinical experience and evidence-based medicine evidence have been accumulated.

Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody. On June 23, 2021, the National Medical Products Administration (NMPA) approved BeiGene's anti-PD-1 antibody Tislelizumab (tislelizumab) is used as the first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC). At the same time, NMPA has conditionally approved Tislelizumab For the treatment of patients with hepatocellular carcinoma (HCC) who have undergone at least one systemic therapy. Currently, Tislelizumab has been approved for five indications, including: 1) relapsed or refractory classical Hodgkin's lymphoma after at least two lines of systemic chemotherapy; 2) locally advanced or metastatic urothelial carcinoma with high PD-L1 expression that has failed platinum-containing chemotherapy, including progression within 12 months of neoadjuvant or adjuvant chemotherapy; 3) combined with paclitaxel and carboplatin for the first-line treatment of locally advanced or metastatic squamous non-small cell lung cancer; 4) Tislelizumab combined with chemotherapy as the first-line treatment for patients with advanced non-squamous non-small cell lung cancer; 5) Tislelizumab for the treatment of previously treated patients with unresectable hepatocellular carcinoma (HCC).

Although tumor immunotherapy has shown remarkable efficacy in clinical use in recent years, the complex process of tumor immunity and the combined effects of multiple mechanisms affect the efficacy of immune checkpoint inhibitors. Therefore, it is of great significance to widely try immunotherapy combination therapy to further improve the applicability and benefit rate of tumor immunotherapy for patients, reduce the dosage of single drugs, improve the incidence and/or severity of adverse events (AE) during treatment, enhance clinical control of tumor symptoms/progression, and prolong the degree and duration of patients' response to drugs. At the same time, this is still a major challenge in the medical field.

Summary of the invention

The purpose of the present invention is to provide a drug and its application for first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer.

The first aspect of the present invention provides the use of component (i) in the preparation of a medicament for use in combination with component (ii) as a first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer; wherein component (i) is selected from HDAC1 inhibitors, HDAC2 inhibitors, HDAC3 inhibitors and/or HDAC10 inhibitors; and component (ii) is selected from PD-1 inhibitors.

In some embodiments, component (i) is selected from a single target inhibitor of HDAC1, HDAC2, HDAC3 and/or HDAC10 or a multi-target selective inhibitor of a combination of two or more thereof. Exemplary "single target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10" include: HDAC1 Single-target inhibitor, HDAC2 single-target inhibitor, HDAC3 single-target inhibitor, HDAC10 single-target inhibitor. Exemplary "multi-target selective inhibitors of two or more combinations of HDAC1, HDAC2, HDAC3 and/or HDAC10" include: HDAC1, HDAC2 dual-target inhibitor, HDAC1, HDAC3 dual-target inhibitor, HDAC1, HDAC10 dual-target inhibitor, HDAC2, HDAC3 dual-target inhibitor, HDAC2, HDAC10 dual-target inhibitor, HDAC3, HDAC10 dual-target inhibitor, HDAC1, HDAC2 and HDAC3 multi-target inhibitor, HDAC1, HDAC2 and HDAC10 multi-target inhibitor, HDAC1, HDAC3 and HDAC10 multi-target inhibitor, HDAC2, HDAC3, HDAC10 multi-target inhibitor, HDAC1, HDAC2, HDAC3 and HDAC10 multi-target inhibitor.

In some embodiments, component (i) is selected from one or a combination of two or more of the following drugs: Chidamide, Entinostat, Vorinostat, Romidepsin, Fingolimod, Lovastatin, Valproic acid, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof.

In some embodiments, component (i) is selected from Chidamide, Entinostat, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof.

In some embodiments, component (i) is selected from Chidamide or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof.

In some embodiments, component (i) is selected from chidamide.

The PD-1 inhibitors of the present invention include small molecule compounds, nucleic acids, peptides, proteins, antibodies, peptibodies, bifunctional antibodies, miniantibodies, single-chain variable fragments (ScFv) or fragments or variants thereof.

In some embodiments, the PD-1 inhibitor is selected from a PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, component (ii) is selected from one or a combination of two or more of the following drugs: tislelizumab, nivolumab, pembrolizumab, cemiplimab, toripalimab, cindilimab, camrelizumab, pidilizumab, zimberelimab, penpulimab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210 or MEDI0680 or an antigen-binding fragment or variant thereof.

In some embodiments, component (ii) is selected from tislelizumab or an antigen-binding fragment or variant thereof.

In some embodiments, component (ii) is tislelizumab.

The second aspect of the present invention provides the use of component (i) in combination with component (ii) in the first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer, and/or in the preparation of a first-line, second-line or third-line medicament for the prevention and/or treatment and/or improvement of non-small cell lung cancer; wherein component (i) is selected from HDAC1 inhibitors, HDAC2 inhibitors, HDAC3 inhibitors and/or HDAC10 inhibitors; component (ii) is selected from PD-1 inhibitors.

In some embodiments, component (i) is selected from single-target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10 or multi-target selective inhibitors of two or more combinations thereof. Exemplary "single-target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10" include: single-target inhibitors of HDAC1, single-target inhibitors of HDAC2, single-target inhibitors of HDAC3, and single-target inhibitors of HDAC10. Exemplary “multi-target selective inhibitors of two or more combinations of HDAC1, HDAC2, HDAC3 and/or HDAC10” include: HDAC1, HDAC2 dual-target inhibitor, HDAC1, HDAC3 dual-target inhibitor, HDAC1, HDAC10 dual-target inhibitor, HDAC2, HDAC3 dual-target inhibitor, HDAC2, HDAC10 dual-target inhibitor, HDAC3, HDAC10 dual-target inhibitor, HDAC1, HDAC2 and HDAC3 multi-target inhibitor, HDAC1, HDAC2 and HDAC10 multi-target inhibitor, HDAC1, HDAC3 and HDAC10 multi-target inhibitor, HDAC2, HDAC3, HDAC10 multi-target inhibitor, HDAC1, HDAC2, HDAC3 and HDAC10 multi-target inhibitor.

In some embodiments, component (i) is selected from one or a combination of two or more of the following drugs: Chidamide, Entinostat, Vorinostat, Romidepsin, Fingolimod, Lovastatin, Valproic acid, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof.

In some embodiments, component (i) is selected from Chidamide, Entinostat, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof.

In some embodiments, component (i) is selected from Chidamide or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof.

In some embodiments, component (i) is selected from chidamide.

The PD-1 inhibitors of the present invention include small molecule compounds, nucleic acids, peptides, proteins, antibodies, peptibodies, bifunctional antibodies, miniantibodies, single-chain variable fragments (ScFv) or fragments or variants thereof.

In some embodiments, the PD-1 inhibitor is selected from a PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, component (ii) is selected from one or a combination of two or more of the following drugs: tislelizumab, nivolumab, pembrolizumab, cemiplimab, toripalimab, cindilimab, camrelizumab, pidilizumab, zimberelimab, penpulimab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210 or MEDI0680 or an antigen-binding fragment or variant thereof.

In some embodiments, component (ii) is selected from tislelizumab or an antigen-binding fragment or variant thereof.

In some embodiments, component (ii) is tislelizumab.

The third aspect of the present invention provides a first-line, second-line or third-line pharmaceutical composition for preventing and/or treating and/or improving non-small cell lung cancer, comprising: component (i) and component (ii); wherein component (i) is selected from HDAC1 inhibitors, HDAC2 inhibitors, HDAC3 inhibitors and/or HDAC10 inhibitors; and component (ii) is selected from PD-1 inhibitors.

In some embodiments, component (i) is selected from single-target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10 or multi-target selective inhibitors of two or more combinations thereof. Exemplary "single-target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10" include: single-target inhibitors of HDAC1, single-target inhibitors of HDAC2, single-target inhibitors of HDAC3, and single-target inhibitors of HDAC10. Exemplary “multi-target selective inhibitors of two or more combinations of HDAC1, HDAC2, HDAC3 and/or HDAC10” include: HDAC1, HDAC2 dual-target inhibitor, HDAC1, HDAC3 dual-target inhibitor, HDAC1, HDAC10 dual-target inhibitor, HDAC2, HDAC3 dual-target inhibitor, HDAC2, HDAC10 dual-target inhibitor, HDAC3, HDAC10 dual-target inhibitor, HDAC1, HDAC2 and HDAC3 multi-target inhibitor, HDAC1, HDAC2 and HDAC10 multi-target inhibitor, HDAC1, HDAC3 and HDAC10 multi-target inhibitor, HDAC2, HDAC3, HDAC10 multi-target inhibitor, HDAC1, HDAC2, HDAC3 and HDAC10 multi-target inhibitor wait.

In some embodiments, component (i) is selected from one or a combination of two or more of the following drugs: Chidamide, Entinostat, Vorinostat, Romidepsin, Fingolimod, Lovastatin, Valproic acid, Simvastatin, Pravastatin, Fluvastatin, Atorvastatin, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof.

In some embodiments, component (i) is selected from Chidamide, Entinostat, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof.

In some embodiments, component (i) is selected from Chidamide or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof.

In some embodiments, component (i) is selected from chidamide.

In the present application, the PD-1 inhibitor is a small molecule compound, nucleic acid, peptide, protein, antibody, peptibody, bifunctional antibody, mini antibody, single-chain variable fragment (ScFv) or a fragment or variant thereof.

In some embodiments, the PD-1 inhibitor is a PD-1 antibody or an antigen-binding fragment thereof.

In some embodiments, component (ii) is selected from one or a combination of two or more of the following drugs: tislelizumab, nivolumab, pembrolizumab, cemiplimab, toripalimab, cindilimab, camrelizumab, pidilizumab, zimberelimab, penpulimab, REGN2810 (also known as SAR-439684), PDR001, SHR-1210 or MEDI0680 or an antigen-binding fragment or variant thereof.

In some embodiments, component (ii) is selected from tislelizumab or an antigen-binding fragment or variant thereof.

In some embodiments, component (ii) is tislelizumab.

The fourth aspect of the present invention provides use of the pharmaceutical composition as described above for treating non-small cell lung cancer.

The fifth aspect of the present invention provides a medicine kit comprising the pharmaceutical composition as described above.

The sixth aspect of the present invention provides a drug kit comprising the components (i) and (ii) as described above; the component (i) can be used to prepare a drug for use in combination with the component (ii) as a first-line, second-line or third-line treatment of non-small cell lung cancer. Cancer drugs.

In some embodiments, the non-small cell lung cancer is as defined above.

In some embodiments, in the pharmaceutical kit as described above, the component (i) and the component (ii) are unit preparations with the same or different specifications, and the component (i) and the component (ii) are placed in the same container or in different containers.

In some embodiments, in the pharmaceutical kit as described above, component (i) is a dosage form for gastrointestinal administration, preferably an oral preparation; and component (ii) is a dosage form for parenteral administration, preferably an injection preparation.

In some embodiments, in the drug kit as described above, component (i) is cedamide, and its content is 60-300 mg, preferably, its content is 120-240 mg; its specification is 5 mg/tablet; component (ii) is tilelizumab; its content is 100-400 mg, preferably, its content is 200-300 mg; its specification is 100 mg/10 ml. The content of component (i) and component (ii) in the above scheme is the total content of component (i) and component (ii) respectively used in the same medication cycle. For example, within 3 weeks, the total dosage of cedamide is 60-300 mg, and the total dosage of tilelizumab is 100-400 mg. Component (i) and component (ii) can increase, decrease and adjust the frequency of medication and the single dosage according to clinical symptoms and doctor's advice.

In some embodiments, in the medicine kit as described above, component (i) is cedamide, and its content is 10-50 mg, preferably, its content is 20-40 mg; its specification is 5 mg/tablet; component (ii) is tislelizumab; its content is 100-400 mg, preferably, its content is 200-300 mg; its specification is 100 mg/10 ml. In the aforementioned scheme, the contents of component (i) and component (ii) refer to the dosage of component (i) and component (ii) for a single dose. The total dosage and frequency of medication of component (i) and component (ii) can be set and adjusted according to clinical symptoms and doctor's advice.

The seventh aspect of the present invention provides a method for first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer, comprising administering an effective amount of the pharmaceutical composition as described above to a patient in need thereof.

The eighth aspect of the present invention provides a method for first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of components (i) and (ii) as described above.

In some embodiments, the component (i) and the component (ii) are administered simultaneously, separately or sequentially.

In some embodiments, the component (i) is taken 1-4 times per week, preferably twice per week; and the component (ii) is taken once every 2-5 weeks, preferably once every 3 weeks.

In some embodiments, the non-small cell lung cancer described herein is non-small cell lung cancer squamous cell carcinoma.

In some embodiments, the non-small cell lung cancer described herein is non-small cell lung cancer non-squamous cell carcinoma.

In some embodiments, the non-small cell lung cancer described herein is locally advanced or metastatic non-small cell lung cancer.

In some embodiments, the non-small cell lung cancer described herein is locally advanced or metastatic non-small cell lung cancer.

In some embodiments, the non-small cell lung cancer described herein is locally advanced or metastatic non-small cell lung cancer.

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression.

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer squamous cell carcinoma with positive PD-L1 expression.

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer non-squamous carcinoma with positive PD-L1 expression.

In some embodiments, the locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression described in the present application is the determination of the PD-L1 expression level in the patient's cancer cells, and the expression level can be any value greater than 1%, for example, PD-L1 expression TC≥1%, TC≥5%, TC≥10%, TC≥15%, TC≥20%, TC≥25%, TC≥30%, TC≥35%, TC≥40%, TC≥45%, TC≥50%, TC≥55%, TC≥60%, TC≥65%, TC≥70%, TC≥75%, TC≥80%, TC≥85%, TC≥90%, TC≥95%, TC≥99%.

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 1%).

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer squamous cell carcinoma with positive PD-L1 expression (TC ≥ 1%).

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 1%). In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 50%);

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer squamous cell carcinoma with positive PD-L1 expression (TC ≥ 50%).

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer (NSCLC) that is positive for PD-L1 expression (TC ≥ 50%).

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC=1-49%).

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer squamous cell carcinoma with positive PD-L1 expression (TC=1-49%).

In some embodiments, the non-small cell lung cancer described in the present application is locally advanced or metastatic non-small cell lung cancer non-squamous carcinoma with positive PD-L1 expression (TC=1-49%). In some preferred embodiments, the non-small cell lung cancer non-squamous carcinoma described in the present application is non-small cell lung cancer adenocarcinoma.

illustrate:

In this application, "squamous cell carcinoma of non-small cell lung cancer" is equivalent to "squamous non-small cell lung cancer" and "squamous cell carcinoma", "non-squamous cell carcinoma of non-small cell lung cancer" is equivalent to "non-squamous non-small cell lung cancer" and "non-squamous carcinoma", and "adenocarcinoma of non-small cell lung cancer" is equivalent to "adenoid non-small cell lung cancer" and "adenocarcinoma", which are several different types of non-small cell lung cancer.

In the present application, the "HDAC1 inhibitor, HDAC2 inhibitor, HDAC3 inhibitor and/or HDAC10 inhibitor" in component (i) should be understood as a single target inhibitor of HDAC1, HDAC2, HDAC3, HDAC10, a multi-target inhibitor of two or more combinations, or a combination of two or more single-target or multi-target inhibitors.

Exemplary “single target inhibitors of HDAC1, HDAC2, HDAC3, HDAC10” include single target inhibitors of HDAC1, single target inhibitors of HDAC2, single target inhibitors of HDAC3, and single target inhibitors of HDAC10.

Exemplary "multi-target inhibitors in combination of two or more" include, but are not limited to: HDAC1, HDAC2 dual-target inhibitors, HDAC1, HDAC3 dual-target inhibitors, HDAC2, HDAC3 dual-target inhibitors, HDAC1, HDAC2 and HDAC3 multi-target inhibitors, HDAC1, HDAC2 and HDAC10 multi-target inhibitors, HDAC1, HDAC3 and HDAC10 multi-target inhibitors, HDAC1, HDAC2, HDAC3 and HDAC10 multi-target inhibitors.

Exemplary “combinations of two or more single-target or multi-target inhibitors” include, but are not limited to: a combination of an HDAC1 single-target inhibitor and an HDAC2 single-target inhibitor, a combination of an HDAC1 single-target inhibitor and an HDAC3 single-target inhibitor, a combination of an HDAC2 single-target inhibitor and an HDAC3 single-target inhibitor, Combination, a combination of an HDAC1 single-target inhibitor, an HDAC2 single-target inhibitor and an HDAC3 single-target inhibitor, a combination of an HDAC1 single-target inhibitor, an HDAC2 single-target inhibitor and an HDAC10 single-target inhibitor, a combination of an HDAC1 single-target inhibitor, an HDAC3 single-target inhibitor and an HDAC10 single-target inhibitor, a combination of an HDAC10 single-target inhibitor, an HDAC2 single-target inhibitor and an HDAC3 single-target inhibitor, a combination of an HDAC1 single-target inhibitor, an HDAC2 single-target inhibitor, an HDAC3 single-target inhibitor and an HDAC10 single-target inhibitor, a combination of an HDAC1, HDAC2, HDAC3 and HDAC10 multi-target inhibitor and an HDAC1 single-target inhibitor, a combination of an HDAC1, HDAC2, HDAC3 and HDAC10 multi-target inhibitor and an HDAC1 single-target inhibitor, and the like.

Definition of terms:

In the present invention, the crystal form includes a non-solvated crystal form, a solvated crystal form and an amorphous structure.

In the present invention, the isomers include conformational isomers, enantiomers and diastereomers.

The "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" of the present invention refers to an acid addition salt or a base addition salt obtained by reacting chidamide with a pharmaceutically acceptable acid or base. The pharmaceutically acceptable acid is preferably selected from inorganic acids (such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, etc.), and organic acids (such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or benzoic acid, etc.); the pharmaceutically acceptable base is preferably selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate, ammonia water or ammonium bicarbonate, etc.

The prodrug in the present invention, also known as prodrug, drug precursor, prodrug, etc., refers to a compound that is obtained after the drug is chemically modified and has no activity or low activity in vitro, and releases active drugs through enzymatic or non-enzymatic conversion in vivo to exert its efficacy.

The metabolites in the present invention refer to the intermediate metabolites and final metabolites obtained after the compounds are metabolized in the body of an animal individual.

In the present invention, the "effective amount" in the effective amount for prevention/treatment/improvement refers to a dose between the minimum limit amount and the maximum amount, which can produce a significant effect on the body without causing toxic reactions.

In the present invention, the "subject" in the subject in need refers to a vertebrate. In certain embodiments, the vertebrate refers to a mammal. Mammals include, but are not limited to, livestock (such as cattle), pets (such as cats, dogs, and horses), primates, mice and rats. In certain embodiments, the mammal refers to a human.

Beneficial effects of the present invention:

Tislelizumab monotherapy for locally advanced or metastatic NSCLC with PD-L1 expression positive (TC ≥ 1%) The ORR of the patient is 25%. In the preliminary experiment, the ORR of the chidamide combined with tislelizumab provided by the present invention for the treatment of patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥1%) is 66.6%, which is more than 1.5 times higher than the efficacy of tislelizumab alone. The combination of the two has a synergistic effect, significantly improves the efficacy of the drug, and has unexpected technical effects. In addition, the objective response rate (ORR) of tislelizumab combined with chidamide for the treatment of patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥50%) reached 100%; compared with the chidamide combined with tislelizumab for the treatment of locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥1%), it has an unexpectedly better efficacy.

DETAILED DESCRIPTION

The present invention discloses drugs and uses for NSCLC patients, especially for treating patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC ≥ 1%). Those skilled in the art can refer to the content of this article and appropriately improve the medication parameters to achieve it. It should be pointed out in particular that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The drugs and uses for treating patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC ≥ 1%) described in the present invention have been described through preferred embodiments. Relevant personnel can obviously modify or appropriately change and combine the applications and pharmaceutical compositions described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.

Example 1 Efficacy trial of chidamide combined with tislelizumab as first-line treatment for patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC ≥ 1%)

1. Purpose of the test

The main experimental purpose of the present invention is to evaluate the preliminary efficacy of HDAC1, HDAC2, HDAC3 and/or HDAC10 subtype selective inhibitors represented by chidamide combined with PD-1 antibodies represented by tislelizumab compared with tislelizumab as first-line treatment for patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥1%).

2. Experimental Drugs:

Chidamide tablets, specification: 5 mg/tablet; produced and provided by ChipScan Biopharma.

Placebo, chidamide dummy tablets; provided by ChipStone Biopharm.

Tislelizumab injection, specifications; 10ml: 100mg; produced and provided by BeiGene.

3. Experimental design:

The study was divided into two stages: pre-test and formal test.

Pre-test :

Three subjects were enrolled to preliminarily evaluate the safety of the combination of cedabenb and tislelizumab. The pilot subjects received the standard doses of cedabenb and tislelizumab, i.e. 30 mg BIW of cedabenb combined with 200 mg Q3W of tislelizumab. The number of subjects with adverse events (AEs) within 3 weeks after the first dose was observed to be ≤ 1 among the 3 evaluable subjects, and the formal trial enrollment began.

The above-mentioned AEs are limited to those judged to be related to any drug in the combination regimen, including four situations: definitely related, very likely related, possibly related, and unable to be evaluated.

For subjects enrolled in the pre-trial phase, except that they were not allowed to reduce the dose of chidamide within 3 weeks after the first dose and did not participate in the blinding and randomization, the other trial procedures were the same as those of the subjects enrolled in the formal trial phase.

Formal test:

A randomized, double-blind, controlled, multicenter phase II design was adopted, and approximately 114 subjects were planned to be enrolled. Two groups were set up, namely, the tucidinostat plus tislelizumab group (TT group) and the placebo plus tislelizumab group (PT group).

Screening period: Qualified subjects were randomly assigned to the TT group or the PT group at a ratio of 1:1. Randomization stratification factors were: PD-L1 expression level (≥50% vs. 1-49%), tissue type (squamous cell carcinoma vs. non-squamous cell carcinoma).

Treatment period: TT group received cedabenb 30 mg BIW combined with tislelizumab 200 mg Q3W, and PT group received placebo combined with tislelizumab 200 mg Q3W. All subjects received trial treatment until disease progression, death, intolerable toxicity, loss to follow-up, withdrawal of informed consent, or end of the study (whichever occurred first). From the first day of medication, both groups were evaluated for efficacy every 6 weeks and safety every 3 weeks.

Follow-up period: The follow-up period begins after the treatment is completed. Safety follow-up: 28 days (±7 days) after the last medication or before starting a new anti-tumor treatment (whichever occurs first). Efficacy follow-up: For subjects who end the trial drug treatment for reasons other than disease progression (ICPD according to iRECIST standards), tumor assessments should continue as planned until disease progression (ICPD according to iRECIST standards), death, loss to follow-up, withdrawal of consent, receipt of new anti-tumor treatment, or end of the study (whichever occurs first). Survival follow-up begins after the efficacy follow-up. Survival follow-up: Visit: Starting from the earliest imaging examination date of the last efficacy evaluation, the subjects' survival status and subsequent anti-tumor treatment will be recorded every 12 weeks (±7 days) through field visits or telephone follow-up until the subjects die, are lost to follow-up, withdraw informed consent, or the study is terminated.

End of the trial:

The last subject in the group completed 6 cycles of treatment, disease progression (ICPD according to iRECIST standards), death, intolerable toxicity, loss to follow-up, or withdrawal of informed consent (whichever occurred first).

IV. Inclusion and Exclusion Criteria

Subjects must meet all of the following conditions to be included:

1. Aged ≥ 18 years old, both male and female.

2. Patients with locally advanced or metastatic (stage IIIB-IV) NSCLC confirmed by histology or cytology (diagnosed according to the 8th edition or the latest version of AJCC) who are not amenable to surgery and/or radical radiotherapy (with or without concurrent chemotherapy).

3. Patients who have not received systemic treatment for locally advanced or metastatic NSCLC. Patients who have received neoadjuvant therapy, adjuvant therapy, radiotherapy, or chemoradiotherapy for non-metastatic disease with curative intent must have a disease-free interval of at least 6 months from the last treatment to the first medication.

4. Tumor tissue PD-L1 expression ≥ 1% (TC ≥ 1%), detected by the kit VENTANA PD-L1 (SP263). If there is no previous test report that meets the requirements, archived tumor tissue or fresh biopsy tissue is required for prospective detection of PD-L1 expression.

5. ECOG score is 0 or 1.

6. According to RECIST v1.1 criteria, there is at least one measurable lesion. The target lesion can be located in an area that has been previously radiotherapy, but imaging examinations are required to confirm that the site has disease progression during the screening period.

7. Laboratory examinations meet the following criteria (without blood transfusion or hematopoietic stimulating factor medication within 14 days):

(1) Routine blood examination: hemoglobin (Hb) ≥ 90 g/L, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count (PLT) ≥ 90 × 109/L;

(2) Biochemical examination: serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN); total bilirubin (TBIL) ≤ 1.5 × ULN (for subjects with Gilbert syndrome: ≤ 3 × ULN); alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 × ULN (for subjects with liver metastasis: ≤ 5 × ULN);

(3) Coagulation function: international normalized ratio (INR) ≤ 1.5 × ULN; prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN; (For subjects receiving anticoagulant therapy, The investigator judged that both INR and aPTT were within the safe and effective therapeutic range);

8. Expected survival ≥12 weeks.

9. Understand and voluntarily sign the informed consent form.

If any of the following criteria are met, they will be excluded from this study:

1. Confirmation of EGFR or ALK-related mutations, indicating that targeted therapy should be used as the primary treatment.

2. Patients who have received targeted therapy for driver genes in the past, such as gefitinib, alectinib, etc.

3. Patients who have received HDAC inhibitors before, including but not limited to chidamide and entinostat.

4. Patients who have received immunotherapy or participated in clinical trials of immunotherapy, including but not limited to PD-1, PD-L1, PD-L2, CTLA-4 inhibitors (such as Ipilimumab) or other drugs that specifically target T cell co-stimulatory pathways or immune checkpoint pathways.

5. Participated in clinical trials of drugs or devices within 28 days before the first use of the drug.

6. Patients who have received radiotherapy within 2 weeks before the first use of the drug, or received lung radiotherapy of >30Gy within 6 months before the first use of the drug; when enrolled, the subjects must also meet the requirement that the remaining radiation toxicity does not require steroid treatment, and have never had radiation pneumonitis, and are not expected to require palliative radiotherapy within at least 4 weeks after the first use of the drug.

7. Systemic immunosuppressive drugs have been used within 28 days before the first medication, including but not limited to glucocorticoids, cyclophosphamide, azathioprine, methotrexate, thalidomide, etc.; excluding local treatment by nasal spray, inhalation or other routes, or physiological doses of systemic steroid hormones (i.e. no more than 10 mg/day of prednisone or equivalent drugs).

8. Systemic immunostimulatory drugs have been used within 28 days before the first use of the drug, including but not limited to interferon, interleukin-2, BCG, etc.

9. Received live vaccines within 28 days before the first dose or planned during the study. Seasonal influenza vaccine or new coronavirus vaccine that does not contain live vaccine is allowed.

10. Patients who have undergone major surgical procedures (craniotomy, thoracotomy, or laparotomy) within 28 days before the first medication, or who still have serious, unhealed wounds, ulcers, or fractures as determined by the investigator at the time of screening.

11. The patient had toxicity caused by previous treatment that had not recovered to CTCAE grade ≤1 before the first use of the drug, excluding alopecia, or abnormal laboratory test values that the investigator assessed to be clinically insignificant.

12. Known untreated central nervous system metastasis and/or meningeal metastasis. Patients who have received treatment for brain metastasis (such as surgery, radiotherapy, etc.) and whose condition is stable can participate in this study and must meet the following conditions: (1) Neurological symptoms have recovered to CTCAE ≤ 1 more than 2 weeks before the first dose; (2) There was no imaging evidence of new brain metastases or enlargement of brain metastases more than 4 weeks before the first dose.

13. Patients with obvious clinical symptoms or pleural effusion, ascites, pericardial effusion requiring drainage, or those who have received drainage for treatment within 1 month before the first use of the drug, except for those with only a small amount of pleural effusion, a small amount of ascites, or a small amount of pericardial effusion without clinical symptoms shown in imaging;

14. Uncontrolled or serious cardiovascular and cerebrovascular diseases, including:

(1) Congestive heart failure of New York Heart Association (NYHA) grade II or above, unstable angina, myocardial infarction within 6 months before the first use of the drug, or arrhythmia requiring treatment and left ventricular ejection fraction (LVEF) <50% at screening;

(2) Primary cardiomyopathy (such as dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy);

(3) symptomatic coronary heart disease requiring drug treatment during the screening period;

(4) A history of clinically significant QTcF interval prolongation, or a QTcF interval >470ms (female) and >450ms (male) during the screening period;

(5) Cerebrovascular accident (including cerebral hemorrhage, cerebral infarction, transient ischemic attack, etc.) occurred within 6 months before the first use of the drug;

(6) Inadequate blood pressure control during the screening period (regardless of whether antihypertensive drugs are being taken): systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg, or a record of changes in the dosage and composition of antihypertensive drugs within 14 days before the first medication;

(7) Other cardiovascular and cerebrovascular diseases judged by the researchers to be unsuitable for inclusion in the study.

15. Clinically significant hemoptysis (at least 0.5 teaspoon of fresh blood) or tumor bleeding occurred within 2 weeks before the first medication; or significant clinically significant active bleeding (such as gastrointestinal bleeding, etc.) occurred within 2 months before the first medication; or anticoagulants (such as warfarin, phenprocoumon, preventive use of low-dose aspirin and low-molecular-weight heparin) were being taken during the screening period; or the investigators judged that there was a clear high-risk bleeding tendency during the screening period, such as esophageal varices with bleeding risk, local active ulcer lesions, positive stool occult blood that could not rule out gastrointestinal bleeding, and imaging evidence of tumor invasion/infiltration of large blood vessels.

16. Previous severe thromboembolic events (such as arterial thrombotic events, pulmonary embolism or deep vein thrombosis, etc.). Thrombosis caused by implanted venous infusion ports or catheters, or superficial venous thrombosis, or thromboembolism that is assessed by the investigator to be stable and not expected to require emergency medical intervention during the study is not considered "severe" thromboembolism.

17. Chest imaging during the screening period shows suspected interstitial lung disease (ILD) or pulmonary fibrosis or requires treatment or a history of lung disease treated with oral or intravenous steroids within 6 months before first use of the drug.

18. There are obvious gastrointestinal abnormalities during the screening period, which may affect the intake, transportation or absorption of drugs according to the judgment of the researchers (such as inability to swallow, chronic diarrhea, intestinal obstruction, small bowel resection or total gastrectomy, etc.).

19. During the screening period, if urine protein is ≥2+ in routine urine examination, a 24-hour urine protein quantitative test should be performed. If the quantitative urine protein is ≥1g/24h, the patient cannot be included in the group. If the urine protein is ≥2+ and no quantitative test is performed, the patient cannot be included in the group. However, if the urine protein is ≥2+ and the quantitative test is <1g/24h, the patient can be included in the group.

20. Active infection requiring intravenous treatment during the screening period. Severe infection within 28 days before the first medication (including but not limited to hospitalization due to infection, bacteremia or severe pneumonia complications). Patients receiving prophylactic antibiotic treatment (such as to prevent urinary tract infection or chronic obstructive pulmonary disease) can be included in the group.

21. Known to have active pulmonary tuberculosis, currently receiving anti-tuberculosis treatment or having received anti-tuberculosis treatment within 1 year before the first use of medication.

22. Active hepatitis B (HBsAg positive with positive viral replication) or hepatitis C (HCV antibody positive with positive viral replication).

23. HIV/AIDS or other serious infectious diseases.

24. History of other primary malignant tumors, except: carcinoma in situ, non-melanoma skin cancer or lentigo maligna that has been adequately treated and has no evidence of disease recurrence, and has been in complete remission for at least 2 years before the first medication and is not expected to require treatment during the study.

25. Active autoimmune disease during the screening period and received systemic treatment within 2 years before the first medication. Patients who only need hormone replacement therapy (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency, etc.) can be included in the group.

26. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation.

27. Contraindications to any of the study drug ingredients.

28. History of hypersensitivity reaction to monoclonal antibodies, chidamide, or any known excipients of the study drug.

29. Have a history of alcoholism or drug abuse.

30. Any mental or cognitive impairment that may limit the understanding, execution, and compliance with the informed consent form and the study.

31. Unwilling or unable to use effective contraceptive methods during the entire treatment period of this trial and within 12 weeks after the last use of cedabenb or within 5 months after the last use of tislelizumab (whichever is the latest). Female patients of childbearing age or spouses of male patients [women of childbearing age include: anyone who has had menarche and has not undergone successful artificial sterilization surgery (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or has not reached menopause]; pregnant or lactating women.

32. Other circumstances that the researcher considers unsuitable for participation in this trial.

5. Dosage regimen:

Preliminary study : Chidamide tablets, 30 mg/time (6 tablets), taken twice a week, the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.), taken 30 minutes after meals. Tislelizumab injection, 200 mg/time, once every 3 weeks, on the first day of each cycle (21 days), intravenous infusion.

Formal test :

TT group: Chidamide tablets, 30 mg/time (6 tablets), twice a week, the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.), taken 30 minutes after meals. Tislelizumab injection, 200 mg/time, once every 3 weeks, on the first day of each cycle (21 days), intravenous infusion.

PT group: Chidamide analog tablets (placebo), 6 tablets/time, twice a week, the interval between two doses should not be less than 3 days (such as Monday and Thursday, Tuesday and Friday, Wednesday and Saturday, etc.), taken 30 minutes after meals. Tislelizumab injection, 200 mg/time, once every 3 weeks, on the first day of each cycle (21 days), intravenous infusion.

Suspension, delay, termination of treatment, or other dosage adjustments of any study drug will not affect the continued use of the other study drug as planned.

6. Experimental results:

(1) Preliminary experimental results

A total of 3 subjects were actually enrolled, and their basic information is shown in Table 1:

Table 1: Basic information of 3 pilot subjects

After administration of cedabenb combined with tislelizumab, the tumors of two patients (i.e., subject 2 and subject 3) showed partial remission (PR), and the tumor of one patient (i.e., subject 1) remained stable (SD), that is, the objective response rate (ORR) of tislelizumab combined with cedabenb in the treatment of patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥1%) reached 66.6%, and the objective response rate (ORR) of tislelizumab combined with cedabenb in the treatment of patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥50%) reached 100%. The objective response rate (ORR) of tislelizumab monotherapy in patients with locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥1%) was 25%. Therefore, the efficacy of chidamide combined with tislelizumab was more than 1.5 times higher than that of tislelizumab monotherapy, proving that chidamide combined with tislelizumab has a good synergistic effect in the treatment of locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥1%); and in comparison, chidamide combined with tislelizumab has an unexpectedly better efficacy in the treatment of locally advanced or metastatic NSCLC with positive PD-L1 expression (TC≥50%).

The present invention has been introduced in detail above. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core ideas, including the best mode, and also enable any technician in the field to practice the present invention, including making and using any device or system, and implementing any combined method. It should be pointed out that for ordinary technicians in this technical field, without departing from the principle of the present invention, the present invention can also be improved and modified in several ways, and these improvements and modifications also fall within the scope of protection of the claims of the present invention. The scope of patent protection of the present invention is defined by the claims and may include other embodiments that can be thought of by those skilled in the art. If these other embodiments have structural elements that are not different from the textual expression of the claims, or if they include equivalent structural elements that are not substantially different from the textual expression of the claims, then these other embodiments should also be included in the scope of the claims.

Claims (10)

Use of component (i) in the preparation of a medicament for use in combination with component (ii) for the first-line, second-line or third-line treatment of non-small cell lung cancer; wherein component (i) is selected from HDAC1 inhibitors, HDAC2 inhibitors, HDAC3 inhibitors and/or HDAC10 inhibitors; and component (ii) is selected from PD-1 inhibitors; Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer; Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 1%); Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 50%); Or preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC=1-49%); Preferably, the non-small cell lung cancer is selected from non-small cell lung cancer squamous cell carcinoma or non-small cell lung cancer non-squamous cell carcinoma; the non-small cell lung cancer non-squamous cell carcinoma is preferably non-small cell lung cancer adenocarcinoma; Preferably, component (i) is selected from single-target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10 or multi-target selective inhibitors of a combination of two or more thereof; Preferably, component (i) is selected from one or a combination of two or more of the following drugs: cedamide, entinostat, vorinostat, romidepsin, fingolimod, lovastatin, valproic acid, simvastatin, pravastatin, fluvastatin, atorvastatin, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof; Further preferably, component (i) is selected from chidamide, entinostat or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof; Further preferably, component (i) is selected from chidamide or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof; Most preferably, component (i) is chidamide; Preferably, component (ii) is selected from a PD-1 antibody or an antigen-binding fragment thereof; Preferably, component (ii) is selected from one or a combination of two or more of the following drugs: tislelizumab, nivolumab, pembrolizumab, cemiplizumab, toripalimab, sintilimab, carrelizumab, pilizumab, sepalizumab, penpulimab, REGN2810, PDR001, SHR-1210 or MEDI0680 or an antigen-binding fragment or variant thereof; Preferably, component (ii) is selected from tislelizumab or an antigen-binding fragment or variant thereof; Preferably, component (ii) is tislelizumab. Use of component (i) in combination with component (ii) in the first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer, and/or in the preparation of a first-line, second-line or third-line medicament for the prevention and/or treatment and/or improvement of non-small cell lung cancer; wherein component (i) is selected from HDAC1 inhibitors, HDAC2 inhibitors, HDAC3 inhibitors and/or HDAC10 inhibitors; component (ii) is selected from PD-1 inhibitors; Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer; Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 1%); Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 50%); Or preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC=1-49%); Preferably, the non-small cell lung cancer is selected from non-small cell lung cancer squamous cell carcinoma or non-small cell lung cancer non-squamous cell carcinoma; the non-small cell lung cancer non-squamous cell carcinoma is preferably non-small cell lung cancer adenocarcinoma; Preferably, component (i) is selected from single-target inhibitors of HDAC1, HDAC2, HDAC3 and/or HDAC10 or multi-target selective inhibitors of a combination of two or more thereof; Preferably, component (i) is selected from one or a combination of two or more of the following drugs: cedamide, entinostat, vorinostat, romidepsin, fingolimod, lovastatin, valproic acid, simvastatin, pravastatin, fluvastatin, atorvastatin, or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof; Further preferably, component (i) is selected from chidamide, entinostat or pharmaceutically acceptable salts, crystal forms, isomers, prodrugs or metabolites thereof; Further preferably, component (i) is selected from chidamide or a pharmaceutically acceptable salt, crystal form, isomer, prodrug or metabolite thereof; Most preferably, component (i) is chidamide; Preferably, component (ii) is selected from a PD-1 antibody or an antigen-binding fragment thereof; Preferably, component (ii) is selected from one or a combination of two or more of the following drugs: tislelizumab, nivolumab, pembrolizumab, cemiplizumab, toripalimab, sintilimab, carrelizumab, pilizumab, sepalizumab, penampalimab, REGN2810, PDR001, SHR-1210 or MEDI0680, or an antigen-binding fragment or variant thereof; Preferably, component (ii) is selected from tislelizumab or an antigen-binding fragment or variant thereof; Preferably, component (ii) is tislelizumab. A drug kit, characterized in that it comprises component (i) and component (ii); the component (i) can be used to prepare a drug for first-line, second-line or third-line treatment of non-small cell lung cancer in combination with component (ii); The components (i) and (ii) are as defined in claim 1; The non-small cell lung cancer is as defined in claim 1. The medicine kit according to claim 3, characterized in that the component (i) and the component (ii) are unit preparations with the same or different specifications, and the component (i) and the component (ii) are placed in the same container or in different containers. The medicine kit according to claim 3, characterized in that component (i) is a dosage form for gastrointestinal administration, preferably an oral preparation; and component (ii) is a dosage form for parenteral administration, preferably an injection preparation. The medicine box according to claim 3, characterized in that: Component (i) is chidamide, and its content is 60-300 mg, preferably, its content is 120-240 mg; its specification is 5 mg/tablet; component (ii) is tislelizumab; its content is 100-400 mg, preferably, its content is 200-300 mg; its specification is 100 mg/10 ml. The medicine box according to claim 3, characterized in that: Component (i) is chidamide, and its content is 10-50 mg, preferably, its content is 20-40 mg; its specification is 5 mg/tablet; component (ii) is tislelizumab; its content is 100-400 mg, preferably, its content is 200-300 mg; its specification is 100 mg/10 ml. A method for first-line, second-line or third-line prevention and/or treatment and/or improvement of non-small cell lung cancer, comprising administering to a patient in need thereof an effective amount of component (i) and component (ii); The components (i) and (ii) are as defined in claim 1; Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer; Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 1%); Preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC ≥ 50%); Or preferably, the non-small cell lung cancer is locally advanced or metastatic non-small cell lung cancer with positive PD-L1 expression (TC=1-49%); Preferably, the non-small cell lung cancer is selected from non-small cell lung cancer squamous cell carcinoma or non-small cell lung cancer non-squamous cell carcinoma; the non-small cell lung cancer non-squamous cell carcinoma is preferably non-small cell lung cancer adenocarcinoma. The method according to claim 8, characterized in that the component (i) and the component (ii) are administered simultaneously, separately or sequentially. The method according to claim 9, characterized in that component (i) is taken 1-4 times a week, preferably twice a week; and component (ii) is taken once every 2-5 weeks, preferably once every 3 weeks.