Safe administration of a2a receptor antagonists

Abstract

The present disclosure provides methods of treating lung cancer by administering A2a receptor antagonists. In particular, these methods include monotherapy as well as combination therapy with checkpoint inhibitors and / or radiotherapy.

Description

Technical Field

[0001] This application relates to a method for treating lung cancer, the method comprising administering an A2a receptor antagonist. Specifically, the method comprises monotherapy with an A2a receptor antagonist and combination therapy with checkpoint inhibitors and / or radiotherapy.

[0002] Reference sequence list submitted electronically

[0003] This application contains a sequence list submitted electronically. The electronic sequence list (Sequence Listing_065768-164US3.xml; size: 15KB; creation date: September 6, 2024) is incorporated herein by reference in its entirety. Background Technology

[0004] Lung cancer is the leading cause of cancer-related deaths worldwide, with extremely poor prognosis and a low 5-year survival rate. Furthermore, even when diagnosed with early-stage lung cancer, the cure rate is lower than that of other major cancers causing death.

[0005] Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for advanced lung cancer. The era of lung cancer immunotherapy began after initial phase 3 trials demonstrated that anti-PD-1 antibodies were superior to standard docetaxel chemotherapy in previously treated metastatic NSCLC (Brahmer et al., N. Engl. J. Med. 2015, 373:123-135; Borghaei et al., N. Engl. J. Med. 2015, 373:1627-1639; Herbst et al., Lancet 2016, 387:1540–1550; Rittmeyer et al., Lancet 2017, 389: 255-265). In patients with non-oncogene-driven metastatic NSCLC, immunotherapy with anti-PD-(L)1 agents has induced durable partial and complete remissions. Currently, anti-PD-(L)1 agents constitute the main first-line treatment for non-oncogene-driven metastatic NSCLC (Gadgeel et al., J. Clin. Oncol. 2020, 38:1505; Gandhi et al., N. Engl. J. Med. 2018, 378:2078), and are also used as consolidation therapy for unresectable stage III NSCLC (Antonia et al., N. Engl. J. Med. 2017, 377:1919-1929).

[0006] In the metastatic setting, while ICI therapy may provide durable responses in many patients, clinical data indicate that most patients experience only partial responses (Walsh et al., Ther. Adv. Med. Oncol. 2020, 12:1-22). The benefits offered by approved therapies (such as docetaxel in combination with or in combination with ramucirumab) are also limited after failure of both ICI and chemotherapy (Fossella, Clin. Lung. Cancer. 2002 May, 3 Suppl 2:S23-8). Therefore, there is a need for therapies that can improve current ICI response rates and overcome or prevent resistance to immunotherapy in patients with metastatic NSCLC.

[0007] Based on the success of immunomodulatory inhibitors (ICIs) in cancer treatment, there is considerable interest in evaluating the combination therapy of ICIs with other immunomodulators that have the potential to alter the immunosuppressive characteristics within the tumor microenvironment (TME)—inducing resistance to immunotherapy. Adenosine signaling via the A2a receptor has immunosuppressive effects in the TME. High expression of the A2a receptor has been found on immune cells, particularly T cells, NK cells, myeloid cells, and neutrophils. In key anti-tumor effector cells such as T cells and NK cells, adenosine signaling via the A2a receptor has immunosuppressive effects, significantly reducing proliferation, activation, killing function, cytokine production, and survival. In various syngeneic tumor models, the immunosuppressive effects of adenosine signaling have been demonstrated by significantly improving tumor growth control, metastasis, and survival.

[0008] Therefore, there is a desire to develop A2a receptor antagonists in combination with immunotherapy and / or radiotherapy to treat lung cancer. Summary of the Invention

[0009] This application describes the first human study of an A2a receptor antagonist as a monotherapy or as a combination therapy with checkpoint inhibitors and / or radiation therapy (RT). The primary objective of this study is to determine the safety and tolerable dose of the compound of Formula I for further investigation in combination with cetrelimab and RT. A secondary objective is to determine the pK of the compound of Formula I when administered as a monotherapy and in combination with cetrelimab and / or RT.

[0010] In a general sense, this article provides a method for administering a compound of formula (I) to a human subject in need:

[0011] Or a method of treating lung cancer in human subjects with a pharmaceutically acceptable salt thereof.

[0012] In another general aspect, this document provides a method for treating lung cancer in a human subject by administering to a human subject in need a compound of Formula I or a pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier, wherein the total dose of the compound of Formula I administered is from about 1 mg to about 200 mg daily, such as from 1 mg to 150 mg daily, from 1 mg to 120 mg daily, or from 1 mg to 90 mg daily, and in some embodiments, it is administered orally. In another general aspect, this document provides a method for treating lung cancer in a human subject by administering to a human subject in need a compound of Formula I or a pharmaceutically acceptable salt thereof, along with a pharmaceutically acceptable carrier, orally, wherein the total dose of the compound of Formula I administered is from about 5 mg to about 200 mg daily, such as from 5 mg to 150 mg daily, from 5 mg to 120 mg daily, or from 5 mg to 90 mg daily.

[0013] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises:

[0014] a. Heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and light chain complementarity-determining regions (LCDRs) 1, LCDR2, and LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively; and / or

[0015] b. The heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8; and / or

[0016] c. Heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and light chain (LC) containing the amino acid sequence of SEQ ID NO: 10.

[0017] In some embodiments, an effective dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every 2 to 6 weeks, such as every 2, 3, 4, 5, or 6 weeks, particularly every 3 weeks. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment is administered subcutaneously.

[0018] In some implementations, a loading dose of the anti-PD-1 antibody or its antigen-binding fragment is administered before the effective dose. As used herein, the loading dose is a predetermined initial amount of the pharmaceutical compound administered to the patient, which is typically higher than subsequent doses. Specifically, the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously at a loading dose of about 600 mg to 1200 mg, followed by an effective dose of about 300 mg to about 900 mg every two to four weeks.

[0019] In some implementations, the method also includes administering radiotherapy (RT) to the subject.

[0020] In some implementations, radiotherapy is administered in doses of approximately 3 to 8 Gy over 1 day to 2 weeks, or in doses of 1.8 to 3 Gy over 3 to 7 weeks, or in a total dose of 5 to 100 Gy over 1 day to 8 weeks, such as 8 to 30 Gy or 30 to 70 Gy.

[0021] In some embodiments, radiotherapy is initiated after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, specifically, radiotherapy is initiated about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0022] In some implementations, the administration of anti-PD-1 antibody or its antigen-binding fragment is initiated after radiotherapy, particularly about 3 to 10 days after radiotherapy, preferably about 5 to 7 days.

[0023] In some implementation schemes, human subjects need to be treated for cancer.

[0024] In one implementation, this document provides a method for treating lung cancer in a human subject of need, the method comprising:

[0025] (1) Administering a compound of formula I or a pharmaceutically acceptable salt thereof to a subject, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and

[0026] (2) The subject was given an anti-PD-1 antibody or its antigen-binding fragment, wherein the anti-PD-1 antibody or its antigen-binding fragment was administered subcutaneously at a loading dose of about 900 mg, followed by subcutaneous administration every three weeks at an effective dose of about 600 mg.

[0027] In one implementation, this document provides a method for treating lung cancer in a human subject of need, the method comprising:

[0028] (1) Administering a compound of formula I or a pharmaceutically acceptable salt thereof to a subject, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and

[0029] (2) The subject is given radiotherapy, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8 Gy for about 2 to 7 days, and the radiotherapy is initiated about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0030] In one implementation, this document provides a method for treating lung cancer in a human subject of need, the method comprising:

[0031] (1) Administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a subject, wherein the total dose of the compound of Formula I or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day;

[0032] (2) Administering radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8 Gy for about 2 to 7 days, and the radiotherapy begins about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of the compound of Formula I or a pharmaceutically acceptable salt thereof; and

[0033] (3) The subject is given an anti-PD-1 antibody or its antigen-binding fragment, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously at a loading dose of about 900 mg, followed by an effective dose of about 600 mg every three weeks, and the administration of the anti-PD-1 antibody or its antigen-binding fragment begins after radiotherapy is completed, particularly about 3 to 10 days after radiotherapy is completed, preferably about 5 to 7 days.

[0034] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof is administered as a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable carrier.

[0035] In some implementations, the compound of formula I or its pharmaceutical salt is administered orally once or twice daily.

[0036] In some embodiments, a compound of formula I or a pharmaceutical salt thereof is administered once or twice daily in the form of a pharmaceutical composition comprising a compound of formula I or a pharmaceutical salt thereof and a pharmaceutically acceptable carrier.

[0037] In some implementations, the pharmaceutical composition is administered orally once daily or twice daily.

[0038] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg, or any dose in between.

[0039] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg or 60 mg.

[0040] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 60 mg, or any dose in between.

[0041] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 15 mg or 30 mg.

[0042] In some embodiments, the pharmaceutical composition comprises a compound of formula I.

[0043] In some implementations, radiotherapy is administered at a dose of about 6 Gy for about 3 to 7 days, preferably about 5 days.

[0044] In some implementations, radiotherapy is administered at a dose of about 8 Gy for about 2 to 4 days, preferably about 3 days.

[0045] In some implementation schemes, radiation therapy is administered once daily or every other day.

[0046] In some implementation schemes, lung cancer is non-small cell lung cancer.

[0047] In some implementation schemes, lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0048] In some implementations, the pharmaceutical composition is a tablet.

[0049] In some implementations, the human subject has received at least one prior therapy.

[0050] In some implementations, the prior therapy is selected from the group consisting of immune checkpoint inhibitor therapy and chemotherapy, preferably anti-PD-1 / PD-L1 therapy, docetaxel therapy and platinum-based chemotherapy.

[0051] In some implementation schemes, non-small cell lung cancer has gene mutations, preferably EGFR, ALK, ROS1, and BRAF mutations.

[0052] In some implementations, human subjects have an ECOG fitness level of 0 or 1.

[0053] In some implementations, human subjects had a creatinine clearance rate of >50 mL / min calculated using the Cockcroft-Gault method during the screening period and within 72 hours of starting administration of the method.

[0054] In some implementation schemes, the human subjects had good liver function.

[0055] In some implementations, this method does not lead to serious adverse effects.

[0056] In some implementations, serious adverse effects are selected from the group consisting of: death, life-threatening events, hospitalization or prolongation of existing hospitalization, persistent or severe disability / loss of ability, congenital abnormalities / birth defects, suspected transmission of any infectious agent through the pharmaceutical product, and medically significant events.

[0057] In some implementations, the method does not result in clinically significant changes from pre-drug baseline in physical examination, Eastern Cooperative Oncology Group (ECOG) performance status score, vital signs, echocardiography (ECHO) scan, multi-gated acquisition (MUGA) scan, electrocardiogram (ECG), laboratory assessment, or pregnancy testing.

[0058] In some implementations, the method does not induce dose-limiting toxicity (DLT) in subjects.

[0059] In some implementations, the DLT rate does not exceed 30% in a cohort of at least 3 subjects.

[0060] In some embodiments, DLT is a hematologic toxicity or a non-hematologic toxicity, and hematologic toxicity is preferably a decrease in neutrophil count, a decrease in platelet count, or any grade 5 hematologic toxicity, and non-hematologic toxicity is preferably any grade 3 or higher non-hematologic toxicity.

[0061] In some implementations, iRECIST confirmed that human subjects did not experience disease progression.

[0062] In some implementations, the method provides one or more efficacy events selected from a group consisting of objective response rate (ORR), complete response rate (CRR), duration of response (DOR), and disease control rate (DCR), wherein ORR is defined according to RECIST v1.1 and iRECIST.

[0063] In another general aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the method of any one of the foregoing embodiments.

[0064] In another general aspect, the present invention provides checkpoint inhibitors for use in the methods of any of the foregoing embodiments, particularly anti-PD-1 antibodies or antigenic fragments thereof.

[0065] In another general aspect, the present invention provides radiotherapy for use in any of the foregoing embodiments.

[0066] Details of one or more embodiments of the present invention are shown in the following description. Other features and advantages will become apparent from the following detailed description and the appended claims. Attached Figure Description

[0067] The foregoing and other objects, aspects, features and advantages of the exemplary embodiments will become more apparent and better understood by referring to the following description in conjunction with the accompanying drawings.

[0068] Figure 1A and Figure 1B This is the average blood concentration-time curve of the compound of formula I. Figure 1A Day 1 of the first cycle; Figure 1B Day 8 of Cycle 1. All participants received a loading dose of 900 mg cilimab subcutaneously (SC) on Day 1 of Cycle 2, followed by 600 mg every 3 weeks (Q3W) starting on Day 1 of Cycle 3. Error bars represent standard deviation. Detailed Implementation

[0069] The methods of this disclosure can be readily understood by referring to the following specific embodiments that form a part of this disclosure. It should be understood that the methods disclosed herein are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for illustrative purposes only and is not intended to limit the methods protected by the claims.

[0070] The background and description throughout this specification reference or describe various publications, articles, and patents; the full text of each of these references is incorporated herein by reference. Discussions of documents, actions, materials, devices, articles, etc., included in this specification are intended to provide context for the invention. Such discussions are not an admission that any or all of these matters constitute prior art with respect to any invention disclosed or protected by the claims.

[0071] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings set forth in this specification. All patents, published patent applications, and publications cited herein are incorporated herein by reference as if fully set forth herein.

[0072] definition

[0073] It should be noted that, unless the context clearly indicates otherwise, the singular forms “a” and “the” as used herein and in the appended claims include plural references.

[0074] When a list is provided, unless otherwise indicated, it should be understood that each individual element in the list and each combination of the list is a separate implementation. For example, a list of implementations presented as “A, B or C” will be understood to include implementations “A”, “B”, “C”, “A or B”, “A or C”, “B or C”, or “A, B or C”.

[0075] To provide a more concise description, some of the quantitative expressions given herein are not modified by the term "approximately". It should be understood that, whether or not the term "approximately" is explicitly used, each quantity given herein is intended to refer to an actual given value, and also to an approximation of such given values ​​that can be reasonably inferred by one of ordinary skill in the art, including approximations of such given values ​​caused by experimental and / or measurement conditions.

[0076] Furthermore, for the sake of brevity, unless otherwise stated, the term "at least" preceding a series of elements should be understood to define each element in the series. Those skilled in the art will recognize, or can determine, various equivalents of the specific embodiments of the invention described herein using only conventional experiments. Such equivalents are intended to be covered by this invention.

[0077] Throughout this specification and the following claims, unless the context otherwise requires, the word “comprising” and variations such as “including” and “containing” shall be understood to imply inclusion of the stated integers or steps or groups of integers or steps, but not to exclude any other integers or steps or groups of integers or steps. When used herein, the term “comprising” may be replaced by the terms “containing” or “including”, or sometimes by the term “having”.

[0078] When used herein, "composed of" excludes any element, step, or component not specified in the elements of the claims. When used herein, "substantially composed of" does not exclude materials or steps that do not substantially affect the essential and novel features of the claims. Whenever used herein in the context of an aspect or embodiment of the invention, any of the foregoing terms "comprising," "containing," "including," and "having" may be replaced by the terms "composed of" or "substantially composed of" to change the scope of this disclosure.

[0079] As used herein, the connecting term "and / or" between multiple listed elements is understood to include both individual options and combined options. For example, in the case where two elements are connected by "and / or", the first option means that the first element applies even without the second element. The second option means that the second element applies even without the first element. The third option means that both the first and second elements apply together. Any of these options is understood to fall within the meaning and therefore satisfies the requirement of the term "and / or" as used herein. The concurrent applicability of more than one option is also understood to fall within the meaning and therefore satisfies the requirement of the term "and / or".

[0080] As used herein, the phrases “adverse event (AE),” “treatment-period adverse event,” “adverse reaction,” and “adverse effect” mean any harm, adverse, unexpected, or undesirable sign or outcome related to or caused by the administration of the drug composition or therapeutic agent. However, abnormal values ​​or observations are not reported as adverse events unless the researcher or physician considers them clinically significant.

[0081] As used herein, the phrases “serious adverse event (SAE)” and “serious adverse effect” mean any serious adverse event as defined in Chapter 21 of the Code of Federal Regulations (CFR) of the U.S. Food and Drug Administration (FDA). An SAE can be any AE or suspected adverse reaction that, from the perspective of an investigator or physician, results in any of the following outcomes: death, a life-threatening adverse event, hospitalization or prolongation of existing hospitalization, persistent or severe loss of capacity or substantial impairment of normal life functioning, or congenital abnormality / birth defect. Certain significant medical events, even if they may not result in death, life-threatening events, or require hospitalization, may also be considered serious events if, based on appropriate medical judgment, they are deemed likely to endanger the life of a patient or subject and require medical or surgical intervention to prevent one of the outcomes listed above.

[0082] Complications occurring during hospitalization are classified as adverse events (AEs). If a complication prolongs hospitalization or meets any other criteria for an adverse event (SAE), the event is classified as an SAE.

[0083] As used herein, when referring to the safety assessment of a compound of Formula I or a pharmaceutically acceptable salt thereof, "clinically significant change" means a clinically evident change as determined by a physician or researcher using standards acceptable to a person of ordinary skill in the art. When the harm or undesirable outcome of an adverse event reaches this level of severity, a regulatory agency may deem the pharmaceutical composition or therapeutic agent unacceptable for the proposed use. These changes can be measured by physical examination, such as respiratory, cardiovascular, and gastrointestinal examinations; laboratory assessments, such as hematology, blood chemistry, urinalysis, viral serology, urine drug screening, breathalyzer tests, cotinine tests, follicle-stimulating hormone (FSH) tests, and pregnancy tests; vital signs, such as body temperature, respiratory rate, blood pressure, and heart rate; and electrocardiogram (ECG) monitoring, including a 12-lead safety ECG.

[0084] As used in this article, “treatment” means treating a patient (such as a mammal (especially a human)) for one or more of the following diseases, disorders, or medical conditions (such as non-small cell lung cancer):

[0085] (a) To prevent the recurrence of disease, disability or medical condition;

[0086] (b) Improvement of disease, disorder or medical condition, that is, elimination or remission of the patient’s disease, disorder or medical condition, including counteracting the effects of other therapeutic agents;

[0087] (c) To prevent the transfer of disease, disability or medical condition;

[0088] (d) Inhibit disease, disorder, or medical condition, that is, slow down or stop the progression of the patient's disease, disorder, or medical condition; or

[0089] (e) To alleviate the symptoms of a patient’s disease, disorder or medical condition.

[0090] As used herein, in the context of dosage, dosage regimen, treatment, or method, the terms "efficacy" and "effectiveness" refer to the effectiveness of a particular dosage, dosage regimen, or treatment regimen. Effectiveness can be measured based on changes in the course of the disease in response to the pharmaceutical agent of the invention. For example, a compound of Formula I is administered to a subject at an amount and for a duration sufficient to induce improvement in at least one indicator reflecting the severity of the treated disorder, preferably with sustained improvement. Whether the amount and duration of treatment are adequate can be determined by assessing various indicators reflecting the severity of the subject's disease, illness, or symptom. Such indicators include, for example, indicators of clinically recognized disease severity, symptoms, or manifestations of the disorder under consideration. The degree of improvement is typically determined by a physician, who may make this determination based on signs, symptoms, biopsy, or other test results, and may also use questionnaires administered to the subject, such as quality of life questionnaires developed for a given disease. For example, a compound of Formula I may be administered to achieve improvement in a subject's symptom, as provided by criteria such as those offered by Response Evaluation Criteria in Solid Tumors (such as RECIST v.1.1 and iRECIST), which include measurable tumor burden and lesion size. (Eisenhauer EA, Therasse P, Bogaerts J, et al., Eur J Cancer. 2009;45:228-247; Seymour, L, Bogaerts, J, Ford, R, et al., Lancet Oncol. 2017, 18: e8143-52).

[0091] The term "therapeutic effective dose" refers to the amount that is sufficient to achieve therapeutic effect when administered to a patient in need of treatment.

[0092] "Antigen" refers to any molecule (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, parts thereof, or combinations thereof) capable of binding by an antigen-binding domain or a T-cell receptor capable of mediating an immune response. Exemplary immune responses include antibody production and activation of immune cells such as T cells, B cells, or NK cells. Antigens can be genetically expressed, synthetic, or purified from biological samples such as tissue samples, tumor samples, cells or fluids containing other biological components, organisms, protein / antigen subunits, cytotoxic or inactivated whole cells, or lysates.

[0093] An "antigen-binding fragment" or "antigen-binding domain" refers to the portion of a protein that binds to an antigen. Antigen-binding domains can be synthetic, enzymatically produced, or genetically engineered polypeptides, and include portions of immunoglobulins that bind antigens, such as VH, VL, VH and VL, Fab, Fab', F(ab')2, Fd, and Fv fragments; domain antibodies (dAbs) consisting of a VH domain or a VL domain; shark variable IgNAR domains; humped VH domains; VHH domains; minimal recognition units consisting of amino acid residues of the CDRs of antibody mimics (such as FR3-CDR3-FR4 portions, HCDR1, HCDR2, and / or HCDR3, and LCDR1, LCDR2, and / or LCDR3); alternative scaffolds for binding antigens; and multispecific proteins containing antigen-binding fragments. Antigen-binding fragments (such as VH and VL) can be linked together via synthetic linkers to form various types of monoclonal antibody designs. In those cases where the VH and VL domains are expressed by separate single chains, the VH / VL domains can be paired intramolecularly or intermolecularly to form monovalent antigen-binding domains, such as single-chain Fv (scFv) or double-chain antibodies. Antigen-binding fragments can also be conjugated to other antibodies, proteins, antigen-binding fragments, or alternative scaffolds, which can be monospecific or multispecific to engineer bispecific and multispecific proteins.

[0094] "Antibody" broadly refers to and includes immunoglobulin molecules, specifically including monoclonal antibodies (including murine monoclonal antibodies, human monoclonal antibodies, humanized monoclonal antibodies, and chimeric monoclonal antibodies), antigen-binding fragments, multispecific antibodies (such as bispecific, trispecific, and tetraspecific antibodies), dimer, tetramer, or multimeric antibodies, single-chain antibodies, domain antibodies, and any other modified conformation of an immunoglobulin molecule containing an antigen-binding site with desired specificity. A "full-length antibody" comprises two heavy chains (HC) and two light chains (LC) linked by disulfide bonds, as well as their polymers (e.g., IgM). Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (composed of domains CH1, hinge, CH2, and CH3). Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL). The VH and VL regions can be further subdivided into hypervariable regions, called complementarity-determining regions (CDRs), interspersed with framework regions (FRs). Each VH and VL consists of three CDR and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. Immunoglobulins can be designated into five major classes based on the amino acid sequence of their heavy chain constant domain: IgA, IgD, IgE, IgG, and IgM. IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3, and IgG4. Based on the amino acid sequence of their constant domain, antibody light chains of any vertebrate species can be designated into one of two completely different types: κ and λ.

[0095] "Cancer" refers to a wide variety of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of a malignant tumor that can invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream. "Cancer" or "cancer tissue" can include tumors.

[0096] "Checkpoint inhibitors" refer to a type of immunotherapy used to treat cancers such as lung cancer. Checkpoint inhibitors block different checkpoint proteins, thereby preventing the immune system from attacking cancer cells. Examples of checkpoint inhibitors include, but are not limited to, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors.

[0097] The complementarity-determining region (CDR) is the antibody region that binds to the antigen. There are three CDRs (HCDR1, HCDR2, HCDR3) in VH and three CDRs (LCDR1, LCDR2, LCDR3) in VL. CDRs can be defined using various descriptions, such as Kabat (Wu et al., (1970) J Exp Med 132: 211-50; Kabat et al., "Sequences of Proteins of Immunological Interest", 5th ed., Public Health Service, National Institutes of Health, Bethesda, Md., 1991), Chothia (Chothia et al., (1987) J Mol Biol 196: 901-17), IMGT (Lefranc et al., (2003) Dev Comp Immunol 27: 55-77), and AbM (Martin and Thornton, J Bmol Biol 263: 800-15, 1996). The correspondence between various depictions and variable region numbers is described (see, for example, Lefranc et al., (2003) Dev Comp Immunol, 27: 55-77; Honegger and Pluckthun, J Mol Biol (2001) 309:657-70; International Immunogenetics (IMGT) database). Available programs (such as abYsis of UCL Business PLC) can be used to depict CDRs. Unless otherwise expressly stated in the specification, as used herein, the terms “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR”, “LCDR2”, and “LCDR3” include CDRs as defined by any of the above methods (Kabat, Chothia, IMGT, or AbM).

[0098] "Reduce," "decrease," "mitigate," "reduce," or "weaken" generally refers to the ability of a test molecule to mediate a reduced response (i.e., a downstream effect) when compared to a response mediated by a control or mediator. Exemplary responses include T cell expansion, T cell activation, or T cell-mediated tumor cell killing, or the binding of proteins to their antigens or receptors, enhanced binding to Fcγ, or enhanced Fc effector function, such as enhanced ADCC, CDC, and / or ADCP. A reduction can be a statistically significant difference in the measured response between the test molecule and a control (or mediator), or a reduction in the measured response, such as a reduction of approximately 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 times or more, or such as 500, 600, 700, 800, 900, or 1000 times or more (including all integers and decimals between these values ​​and greater than 1, such as 1.5, 1.6, 1.7, 1.8, etc.).

[0099] "Enhancement," "promotion," "increase," "amplification," or "improvement" generally refers to the ability of a test molecule to mediate a stronger response (i.e., downstream effect) when compared to a response mediated by a control or mediator. Exemplary responses are T cell amplification, T cell activation, or T cell-mediated tumor cell killing, or the binding of a protein to its antigen or receptor, enhanced binding to Fcγ, or enhanced Fc effector function, such as enhanced ADCC, CDC, and / or ADCP. Enhancement can be a statistically significant difference in the measured response between the test molecule and a control (or mediator), or an increase in the measured response, such as an increase of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or 30 times or more, such as 500, 600, 700, 800, 900, or 1000 times or more (including all integers and decimals between these values ​​and greater than 1, such as 1.5, 1.6, 1.7, 1.8, etc.).

[0100] An epitope is a portion of an antigen that specifically binds to an antibody. Epitopes typically consist of chemically active (e.g., polar, nonpolar, or hydrophobic) surface groups, such as amino acids or polysaccharide side chains, and may possess specific three-dimensional structural features and specific charge characteristics. Epitopes can be composed of continuous and / or discontinuous amino acids forming conformational spatial units. For discontinuous epitopes, amino acids from different portions of the linear sequence of the antigen are close together in three-dimensional space due to the folding of the protein molecule. Antibody epitopes depend on the method used to identify them.

[0101] "Expression" refers to the well-known transcription and translation that occurs in cells or in vitro. Therefore, the expression product (e.g., a protein) is expressed by cells or in vitro, and can be an intracellular protein, an extracellular protein, or a transmembrane protein.

[0102] “dAb” or “dAb fragment” refers to an antibody fragment composed of VH domains (Ward et al., Nature 341:544546 (1989)).

[0103] "Fab" or "Fab fragment" refers to an antibody fragment composed of the VH domain, CH1 domain, VL domain, and CL domain.

[0104] "F(ab')2" or "F(ab')2 fragment" refers to an antibody fragment containing two Fab fragments connected by a disulfide bridge in the hinge region.

[0105] "Fd" or "Fd fragment" refers to an antibody fragment composed of a VH domain and a CH1 domain.

[0106] "Fv" or "Fv fragment" refers to an antibody fragment consisting of a VH domain and a VL domain from a single arm of the antibody. The Fv fragment lacks the constant regions of the Fab (CH1 and CL) regions. The VH and VL domains in the Fv fragment are held together by non-covalent interactions.

[0107] The "Fc polypeptide" of a dimer Fc refers to one of the two polypeptides that form the Fc domain of the dimer. For example, the FC polypeptide of the dimer IgG FC contains the constant domain sequences of IgG CH2 and IgG CH3.

[0108] A full-length antibody consists of two heavy chains (HC) and two light chains (LC) linked by disulfide bonds and their polymers (e.g., IgM). Each heavy chain comprises a variable domain (VH) and a constant domain, the constant domain consisting of subdomains CH1, hinge, CH2, and CH3. Each light chain comprises a variable domain (VL) and a constant domain (CL). VH and VL can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs) and interspersed with framework regions (FRs). Each VH and VL consists of three CDRs and four FR segments, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0109] "Human antibody" refers to an antibody optimized to produce a minimal immune response when administered to human subjects. The variable region of a human antibody is derived from a human immunoglobulin sequence. If a human antibody contains a constant region or a portion of a constant region, that constant region is also derived from a human immunoglobulin sequence. If the variable region of a human antibody is obtained using a system that uses human germline immunoglobulins or rearranged immunoglobulin genes, the human antibody contains both heavy-chain and light-chain variable regions "derived" from human-origin sequences. Exemplary systems of this kind are libraries of human immunoglobulin genes displayed on bacteriophages, and transgenic non-human animals, such as mice or rats carrying human immunoglobulin loci. Due to differences between the systems used to obtain human antibodies and human immunoglobulin loci, the introduction of somatic mutations, or the intentional substitution of elements introduced into the frame or CDR, or both, "human antibodies" typically contain amino acid differences compared to immunoglobulins expressed in humans. Typically, the amino acid sequence of a “human antibody” has at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence encoded by a human immunoglobulin gene or rearranged immunoglobulin gene. In some cases, a “human antibody” may comprise a common frame sequence derived from human frame sequence analysis (e.g., as described in Knappik et al., (2000) J Mol Biol 296:57-86), or a synthetic HCDR3 bound to a human immunoglobulin gene library displayed on a phage (e.g., as described in Shi et al., (2010) J Mol Biol 397:385-96 and International Patent Publication No. WO2009 / 085462). The definition of a “human antibody” does not include antibodies in which at least one CDR is derived from a non-human species.

[0110] "Humanized antibody" refers to an antibody in which at least one CDR is derived from a non-human species and at least one frame is derived from a human immunoglobulin sequence. Humanized antibodies may contain substitutions in the frame such that the frame may not be an exact copy of the expressed human immunoglobulin or the germline gene sequence of a human immunoglobulin.

[0111] "In combination with" or "drug combination" means administering two or more therapeutic agents, either as a mixture, as a single agent, simultaneously, or as single agents in any order, to a subject. The use of the term "combination" does not restrict the order in which the therapy is administered to the subject.

[0112] "Monoclonal antibody" refers to antibodies obtained from a substantially homogeneous population of antibody molecules; that is, the individual antibodies constituting the population are identical except for possibly well-known alterations (such as removal of a C-terminal lysine from the antibody heavy chain) or post-translational modifications (such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation). Monoclonal antibodies typically bind to one antigenic epitope. Bispecific monoclonal antibodies bind to two different antigenic epitopes. Monoclonal antibodies can have heterogeneous glycosylation within the antibody population. Monoclonal antibodies can be monospecific or multispecific, such as bispecific, monovalent, divalent, or multivalent.

[0113] “PD-1” refers to human programmed cell death protein 1, PD-1. PD-1 is also known as CD279 or PDCD1. The amino acid sequence (signal-free sequence) of mature human PD-1 is shown in SEQ ID NO: 11. The extracellular domain spans residues 1-150 of SEQ ID NO: 11, the transmembrane domain spans residues 151-171, and the cytoplasmic domain spans residues 172-268.

[0114] "Anti-PD-1 antibody" refers to an antibody that specifically binds to PD-1.

[0115] “PD-L1” refers to the PD-1 ligand. PD-L1 is also known as CD279 or B7-H1. The amino acid sequence of mature human PD-L1 is shown in SEQ ID NO: 5. The extracellular domain of human PD-L1 is shown in SEQ ID NO: 6. Unless explicitly stated to the contrary, “PD-L1” in this specification refers to mature human PD-L1. “Anti-PD-L1 antibody” refers to an antibody that specifically binds to PD-L1.

[0116] "Pharmaceutical composition" refers to a composition consisting of an active ingredient and a pharmaceutically acceptable carrier.

[0117] A "pharmaceuticalally acceptable carrier" or "excipient" refers to a component in a pharmaceutical composition other than the active ingredient that is non-toxic to the subject. Exemplary pharmaceutically acceptable carriers are buffers, stabilizers, or preservatives.

[0118] The terms "protein" and "peptide" are used interchangeably herein and refer to molecules comprising one or more polypeptides, each of which contains at least two amino acid residues linked by peptide bonds. Proteins can be monomers or protein complexes of two or more subunits, which may be identical or different. Small polypeptides of fewer than 50 amino acids may be referred to as "peptides." Proteins can be heterologous fusion proteins, glycoproteins, or proteins modified through post-translational modifications such as phosphorylation, acetylation, myristylation, palmitoylation, glycosylation, oxidation, formylation, amidation, citrullination, polyglutamylation, ADP-ribosylation, polyethylene glycolation, or biotinylation. Proteins may be recombinantly expressed.

[0119] "Recombination" refers to the preparation, expression, creation, or isolation of polynucleotides, polypeptides, vectors, viruses, and other macromolecules through recombination methods.

[0120] "Relapse" refers to the recurrence of the disease or signs and symptoms of the disease after a period of improvement following previous treatment with medication.

[0121] "Treatment refractory" refers to a disease that does not respond to treatment. A treatment refractory disease may be resistant to treatment before or at the start of treatment, or it may become resistant during treatment.

[0122] "Specific binding" or "binding" refers to the binding of protein molecules to an antigen or an epitope within an antigen with a greater affinity than to other antigens. Typically, protein molecules bind with an affinity of approximately 1 × 10⁻⁶. −7 M or smaller, for example, about 5×10 −8 M or smaller, approximately 1×10 −8 M or smaller, approximately 1×10 −9 M or smaller, approximately 1×10 −10 M or smaller, approximately 1×10 −11 M or smaller or approximately 1×10 − 12 An equilibrium dissociation constant (KD) of M or less binds to an antigen or an epitope within the antigen, typically with a KD at least one hundred times smaller than the KD at which it binds to nonspecific antigens (e.g., BSA, casein). In the context of prostate neoantigens as described herein, “specific binding” means the binding of a protein molecule to the prostate neoantigen without detectable binding to a wild-type protein of which the neoantigen is a variant.

[0123] "Subject" refers to human subjects and may be used interchangeably with "patient" and "participant" in this article.

[0124] Unless otherwise instructed or explicitly stated, throughout the specification, the amino acid residues in the antibody constant region shall be numbered according to the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, Public Health Service, National Institutes of Health, Bethesda, Md. (1991).

[0125] In some embodiments, the antibodies described herein may contain mutations (e.g., amino acid substitutions, additions, and / or deletions) outside the CDR (e.g., in the frame region (FR) or constant region). Amino acid substitutions, additions, and / or deletions may be substitutions, additions, and / or deletions of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more). Amino acid substitutions, additions, and / or deletions may be substitutions, additions, and / or deletions of eight or fewer, seven or fewer, six or fewer, five or fewer, four or fewer, three or fewer, or two or fewer single amino acids. In some embodiments, the antibodies described herein may include amino acid substitutions, additions, and / or deletions in the constant region (e.g., the Fc region) of the antibody, which, for example, result in reduced effector functions, such as reduced complement-dependent cell lysis (CDC), antibody-dependent cell-mediated cell lysis (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and / or reduced B cell killing. For many applications of therapeutic antibodies, Fc-mediated effector functions are not part of the mechanism of action. These Fc-mediated effector functions can be detrimental and may pose safety risks by inducing extramechanistic toxicity. Modification of effector functions can be achieved by altering the Fc region to weaken its binding to FcgR or complement factors. The binding of IgG to the first component of activating FcgR (FcgRI, FcgRIIa, FcgRIIIa, and FcgRIIIb) and repressive FcgR (FcgRIIb) or complement (C1q) depends on residues located in the hinge region and CH2 domain. Mutations can be introduced into IgG1, IgG2, and IgG4 to reduce or silence Fc function. Silent mutations may include, but are not limited to, IgG1 AA (F234A, L235A), IgG4 PAA (S228P, F234A, L235A), IgG2 AA (V234A, G237A), IgG1 FEA (L234F, L235E, or D265A), IgG1 AAS (L234A, L235A, and D265S), or IgG1 FES (L234F / L235E / P331S). In some embodiments, the disclosed antibody or its antigen-binding fragment may contain an IgG1 AA (L234A, L235A) mutation. In some embodiments, the disclosed antibody or its antigen-binding fragment may contain an IgG1 AAS (L234A, L235A, and D265S) mutation to eliminate effector function.The disclosed antibody or its antigen-binding fragment may contain an Fc region having one or more of the following characteristics: (a) reduced effector function compared to the parental Fc; (b) reduced affinity for Fcg RI, Fcg RIIa, Fcg RIIb, Fcg RIIIb and / or Fcg RIIIa; (c) reduced affinity for Fcg RI; (d) reduced affinity for Fcg RIIa; (f) reduced affinity for Fcg RIIb; or (g) reduced affinity for Fcg RIIIa.

[0126] In some implementations, one or more mutations can be introduced into the CH3 domains of two heavy chains to facilitate the formation of heterodimers during co-transfection. As used herein, “heterodimerization” refers to the interaction of two heavy chains with different CH3 amino acid sequences. As used herein, “heterodimer” refers to an antibody having two heavy chains containing different CH3 amino acid sequences. The “mortar and pestle” strategy (see, for example, PCT Publication WO2006 / 028936) can be used to generate full-length bispecific antibodies. Briefly, selected amino acids that form the junctions of the CH3 domains in human IgG can be mutated at positions that affect CH3 domain interactions, thereby promoting heterodimer formation. An amino acid with a small side chain (mortar) is introduced into the heavy chain of an antibody that specifically binds to the first antigen, and an amino acid with a large side chain (mortar) is introduced into the heavy chain of an antibody that specifically binds to the second antigen. After co-expression of the two antibodies, a heterodimer is formed due to the preferential interaction between the heavy chain with the “mortar” and the heavy chain with the “mortar”. Exemplary CH3 substitution pairs forming the pestle and mortar (denoted as modification positions in the first CH3 domain of the first heavy chain / modification positions in the second CH3 domain of the second heavy chain) are: T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S, and T366W / T366S_L368A_Y407V. For example, one heavy chain may be characterized by the pestle mutation: T366W, while the other heavy chain may be characterized by the mortar mutation: T366S, L368A, Y407V, and the pestle-mortar mutation promotes heterodimerization of the two heavy chains.

[0127] Other strategies may also be used, such as promoting heavy chain heterodimerization by electrostatic interaction through the substitution of positively charged residues on one CH3 surface and negatively charged residues on a second CH3 surface, as described in U.S. Patent Publication No. US2010 / 0015133, U.S. Patent Publication No. US2009 / 0182127, U.S. Patent Publication No. US2010 / 028637, or U.S. Patent Publication No. US2011 / 0123532. In other strategies, heterodimerization can be promoted by the following substitutions (represented as the modification position in the first CH3 domain of the first heavy chain / the modification position in the second CH3 domain of the second heavy chain): L351Y_F405AY407V / T394W, T3661_K392M_T394W / F405A_Y407V, T366L_K392M_T394W / F405A_Y407V, L351Y_Y407A / T366A_K409F, L351Y_Y407A / T366V K409F Y407A / T366A_K409F, or T350V_L351Y_F405A Y407V / T350V_T366L_K392L_T394W, as described in U.S. Patent Publication No. US2012 / 0149876 or U.S. Patent Publication No. US2013 / 0195849. For example, the L351Y, F405A, and Y407V mutations can be introduced into one immunoglobulin constant region, and T394W can be introduced into another immunoglobulin constant region, and the interaction between the L351Y, F405A, and Y407V mutations in the first Ig constant region and the T394W mutation in the second Ig constant region promotes heterodimerization of the two immunoglobulin constant regions.

[0128] Treatment methods for lung cancer

[0129] In one general aspect, the present invention relates to a method for treating cancer in a human patient, the method comprising administering a compound of formula I to a human subject in need:

[0130] Or, or a pharmaceutically acceptable salt thereof. In some aspects of the invention, a compound of formula I is administered orally to a human subject. In other aspects of the invention, a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier is administered to a human subject. In still other aspects of the invention, a method of treating cancer is provided by orally administering to a human subject a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 200 mg per day, such as from 1 mg to 150 mg per day, from 1 mg to 120 mg per day, or from 1 mg to 90 mg per day.

[0131] According to embodiments of the present invention, the compound of Formula I has activity as an A2a receptor agonist. The compound of Formula I, 2-(3-cyanophenyl)-3-(2,6-dimethylpyridin-4-yl)-N-[(2S)-3-hydroxy-3-methylbut-2-yl]pyrazolo[1,5-a]pyrimidine-5-carboxamide, its synthesis, biological activity, uses, or other relevant information are described, for example, in International Patent Application Publication No. WO 2021 / 224636, the contents of which are incorporated herein by reference in their entirety.

[0132] As used herein, a dose of a compound of Formula I or a pharmaceutically acceptable salt thereof refers to an amount based on the compound of Formula I (i.e., in its free base form). For example, a dose of 100 mg of a pharmaceutically acceptable salt refers to a dose equivalent to 100 mg of a compound of Formula I.

[0133] In some embodiments, the total daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg, or any dose in between.

[0134] In some implementations, the compound of formula I is administered orally once or twice daily.

[0135] In some embodiments, the compound of formula I is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg, or any dose in between.

[0136] In some embodiments, the compound of formula I is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg or 60 mg.

[0137] In some implementations, the compound of formula I is administered orally twice daily.

[0138] In some embodiments, the compound of formula I is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 60 mg, or any dose in between.

[0139] In some embodiments, the compound of formula I is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 15 mg or 30 mg.

[0140] In some embodiments, a pharmaceutically acceptable salt of a compound of formula I refers to a salt that is acceptable for administration to human subjects, such as a salt that has acceptable mammalian safety for a given dosage regimen. Representative pharmaceutically acceptable salts include salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, ethanedisulfonic acid, fumaric acid, gentian acid, gluconic acid, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, mesylate, mucoic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and hydroxynaphthoic acid, etc.

[0141] In some embodiments, the pharmaceutical composition comprises a compound of formula I and a pharmaceutically acceptable carrier. The pharmaceutical composition may be administered orally once daily or twice daily.

[0142] In some embodiments, the method further includes administering a checkpoint inhibitor, such as an anti-PD-L1 antibody, an anti-PD-1 antibody, or an antigen-binding fragment thereof, to the subject. Preferably, the method further includes administering an anti-PD-1 antibody or an antigen-binding fragment thereof to the subject.

[0143] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises heavy chain complementarity-determining regions (HCDR) 1, HCDR 2 and HCDR 3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain complementarity-determining regions (LCDR) 1, LCDR 2 and LCDR 3 of SEQ ID NO: 4, 5 and 6, respectively.

[0144] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8.

[0145] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 10.

[0146] In view of this disclosure, anti-PD-1 antibodies that can be used in this invention can be obtained or prepared using methods known in the art, such as those described herein. In some embodiments, the anti-PD-1 antibody is the anti-PD-1 antibody described in U.S. Patent No. 10,894,830, the entire contents of which are incorporated herein by reference.

[0147] In some implementations, an effective dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every 2 to 6 weeks, such as every 2, 3, 4, 5, or 6 weeks. In particular, an effective dose of the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously every three weeks.

[0148] In some implementations, a loading dose of anti-PD-1 antibody or its antigen-binding fragment is administered before the effective dose. Specifically, the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously at a loading dose of about 600 mg to 1200 mg, followed by an effective dose of about 300 mg to about 900 mg every two to four weeks.

[0149] In some embodiments, the loading dose is about 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg or 1200 mg, or any dose in between.

[0150] In some implementations, the loading dose is approximately 900 mg.

[0151] In some implementations, the effective dose is about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, or any dose in between, administered subcutaneously every three weeks. Specifically, the effective dose is about 600 mg.

[0152] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof. For example, the anti-PD-1 antibody or its antigen-binding fragment may be administered 1 day, 1 week, 2 weeks, 3 weeks, or 1 month or any time in between, after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment is administered or provided for administration in the form of a pharmaceutical composition comprising: (a) about 30 mg / ml of the anti-PD-1 antibody or its antigen-binding fragment, about 1.15 mg / ml of histidine, about 0.54 mg / ml of histidine monohydrochloride monohydrate, about 80 mg / ml of sucrose, about 0.4 mg / ml of polysorbate 20, and about 20 µg / ml of EDTA; (b) about 150 mg / ml of the anti-PD-1 antibody or its antigen-binding fragment, about 1.15 mg / ml of histidine, about 0.54 mg / ml of histidine monohydrochloride monohydrate, about 48.45 mg / ml of arginine hydrochloride, about 0.5 mg / ml of polysorbate 80, and about 20 µg / ml of EDTA. EDTA; (c) a lyophilized formulation comprising about 600 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients; (d) a lyophilized formulation comprising about 900 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients; (e) about 600 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients; or (f) about 900 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof and one or more pharmaceutically acceptable excipients.

[0154] In some implementations, the method also includes administering radiation therapy to the subject.

[0155] According to embodiments of the invention, radiotherapy is a medical device or medical technique administered according to institutional standards of care and established oncology guidelines, based on its intended use, and can be any type of radiotherapy used to treat cancer. The dosage and fractionation of radiotherapy are individualized based on the physician's assessment of care goals, symptoms, disease location, performance status, and logistical considerations.

[0156] In some implementations, radiotherapy is administered in doses of approximately 3 to 8 Gy over 1 day to 2 weeks, or in doses of 1.8 to 3 Gy over 3 to 7 weeks, or in a total dose of 5 to 100 Gy over 1 day to 8 weeks, such as 8 to 30 Gy or 30 to 70 Gy.

[0157] In some embodiments, the total dose of radiotherapy is from about 8 Gy to about 30 Gy. In other embodiments, the total dose of radiotherapy is from about 30 Gy to about 70 Gy.

[0158] In some implementations, radiotherapy is administered at a dose of about 6 Gy for about 3 to 7 days, preferably about 5 days.

[0159] In some implementations, radiotherapy is administered at a dose of about 8 Gy for about 2 to 4 days, preferably about 3 days.

[0160] In some implementations, radiation therapy is administered once daily or every other day.

[0161] In some embodiments, radiotherapy is initiated after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, specifically, radiotherapy is initiated about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0162] In some implementations, the administration of anti-PD-1 antibody or its antigen-binding fragment is initiated after radiotherapy is completed, particularly about 3 to 10 days after radiotherapy is completed, preferably about 5 to 7 days.

[0163] In some implementations, human subjects need to be treated for cancer.

[0164] In some implementations, the cancer is lung cancer.

[0165] In one embodiment, the present invention provides a method for treating lung cancer in a human subject in need, the method comprising:

[0166] (1) Oral administration to the subject of a compound comprising a pharmaceutically acceptable carrier and formula I. A pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 120 mg per day; and

[0167] (2) The subject was given an anti-PD-1 antibody or its antigen-binding fragment subcutaneously, wherein the anti-PD-1 antibody or its antigen-binding fragment was given subcutaneously at a loading dose of about 900 mg, followed by an effective dose of about 600 mg every three weeks.

[0168] In some embodiments, the pharmaceutical composition is administered orally once daily or twice daily.

[0169] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg, or any dose in between.

[0170] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg or 60 mg.

[0171] In some implementations, the pharmaceutical composition is administered orally twice daily.

[0172] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 60 mg, or any dose in between.

[0173] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 15 mg or 30 mg.

[0174] In some embodiments, the pharmaceutical composition comprises a compound of formula I.

[0175] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises heavy chain complementarity-determining regions (HCDR) 1, HCDR 2 and HCDR 3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain complementarity-determining regions (LCDR) 1, LCDR 2 and LCDR 3 of SEQ ID NO: 4, 5 and 6, respectively.

[0176] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8.

[0177] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 10.

[0178] In some implementations, radiotherapy is administered in doses of approximately 3 to 8 Gy over 1 day to 2 weeks, or in doses of 1.8 to 3 Gy over 3 to 7 weeks, or in a total dose of 5 to 100 Gy over 1 day to 8 weeks, such as 8 to 30 Gy or 30 to 70 Gy.

[0179] In some embodiments, the total dose of radiotherapy is from about 8 Gy to about 30 Gy. In other embodiments, the total dose of radiotherapy is from about 30 Gy to about 70 Gy.

[0180] In some implementations, radiotherapy is administered at a dose of about 6 Gy for about 3 to 7 days, preferably about 5 days.

[0181] In some implementations, radiotherapy is administered at a dose of about 8 Gy for about 2 to 4 days, preferably about 3 days.

[0182] In some implementations, radiation therapy is administered once daily or every other day.

[0183] In some embodiments, radiotherapy is initiated after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof, specifically, radiotherapy is initiated about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0184] In some implementations, the administration of anti-PD-1 antibody or its antigen-binding fragment is initiated after radiotherapy, particularly about 3 to 10 days after radiotherapy, preferably about 5 to 7 days.

[0185] In one embodiment, the present invention provides a method for treating lung cancer in a human subject in need, the method comprising:

[0186] (1) Oral administration to the subject of a compound comprising a pharmaceutically acceptable carrier and formula I. A pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 120 mg per day; and

[0187] (2) The subject is given radiotherapy, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8 Gy for about 2 to 7 days, and the radiotherapy is initiated about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the pharmaceutical composition is administered orally once daily or twice daily.

[0189] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg, or any dose in between.

[0190] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg or 60 mg.

[0191] In some implementations, the pharmaceutical composition is administered orally twice daily.

[0192] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 60 mg, or any dose in between.

[0193] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 15 mg or 30 mg.

[0194] In some embodiments, the pharmaceutical composition comprises a compound of formula I.

[0195] In some embodiments, the total dose of radiotherapy is from about 8 Gy to about 30 Gy. In other embodiments, the total dose of radiotherapy is from about 30 Gy to about 70 Gy.

[0196] In some implementations, radiotherapy is administered at a dose of about 6 Gy for about 3 to 7 days, preferably about 5 days.

[0197] In some implementations, radiotherapy is administered at a dose of about 8 Gy for about 2 to 4 days, preferably about 3 days.

[0198] In some implementations, radiation therapy is administered once daily or every other day.

[0199] In some embodiments, the method further includes administering a checkpoint inhibitor, such as an anti-PD-L1 antibody, an anti-PD-1 antibody, or an antigen-binding fragment thereof, to the subject. Preferably, the method further includes administering an anti-PD-1 antibody or an antigen-binding fragment thereof to the subject.

[0200] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises heavy chain complementarity-determining regions (HCDR) 1, HCDR 2 and HCDR 3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain complementarity-determining regions (LCDR) 1, LCDR 2 and LCDR 3 of SEQ ID NO: 4, 5 and 6, respectively.

[0201] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8.

[0202] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 10.

[0203] In some implementations, the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously at a loading dose of about 900 mg, followed by subcutaneous administration every three weeks at an effective dose of about 600 mg.

[0204] In some implementations, the administration of anti-PD-1 antibody or its antigen-binding fragment is initiated after radiotherapy, particularly about 3 to 10 days after radiotherapy, preferably about 5 to 7 days.

[0205] In one embodiment, the present invention provides a method for treating lung cancer in a human subject in need, the method comprising:

[0206] (1) Oral administration to the subject of a compound comprising a pharmaceutically acceptable carrier and formula I. A pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day;

[0207] (2) Administering radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8 Gy for about 2 to 7 days, and the radiotherapy begins about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days after the initial administration of the compound of Formula I or a pharmaceutically acceptable salt thereof; and

[0208] (3) The subject is given an anti-PD-1 antibody or its antigen-binding fragment subcutaneously, wherein the anti-PD-1 antibody or its antigen-binding fragment is given subcutaneously at a loading dose of about 900 mg, followed by an effective dose of about 600 mg every three weeks, and the administration of the anti-PD-1 antibody or its antigen-binding fragment begins after radiotherapy is completed, particularly about 3 to 10 days after radiotherapy is completed, preferably about 5 to 7 days.

[0209] In some embodiments, the pharmaceutical composition is administered orally once daily or twice daily.

[0210] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg, or any dose in between.

[0211] In some embodiments, the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg or 60 mg.

[0212] In some implementations, the pharmaceutical composition is administered orally twice daily.

[0213] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 60 mg, or any dose in between.

[0214] In some embodiments, the pharmaceutical composition is administered orally twice daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 15 mg or 30 mg.

[0215] In some embodiments, the pharmaceutical composition comprises a compound of formula I.

[0216] In some embodiments, the total dose of radiotherapy is from about 8 Gy to about 30 Gy. In other embodiments, the total dose of radiotherapy is from about 30 Gy to about 70 Gy.

[0217] In some implementations, radiotherapy is administered at a dose of about 6 Gy for about 3 to 7 days, preferably about 5 days.

[0218] In some implementations, radiotherapy is administered at a dose of about 8 Gy for about 2 to 4 days, preferably about 3 days.

[0219] In some implementations, radiation therapy is administered once daily or every other day.

[0220] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises heavy chain complementarity-determining regions (HCDR) 1, HCDR 2 and HCDR 3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain complementarity-determining regions (LCDR) 1, LCDR 2 and LCDR 3 of SEQ ID NO: 4, 5 and 6, respectively.

[0221] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8.

[0222] In some embodiments, the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 10.

[0223] According to embodiments of the invention, pharmaceutical compositions of compounds of Formula I or pharmaceutically acceptable salts thereof typically contain a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. However, those skilled in the art will recognize that pharmaceutical compositions may contain more than a therapeutically effective amount, for example, in bulk compositions, or less than a therapeutically effective amount, for example, in single unit doses designed for multiple administrations to achieve a therapeutically effective amount.

[0224] Pharmaceutical compositions may also contain pharmaceutically acceptable carriers. As used herein, the term "carrier" means any excipient, diluent, buffer, stabilizer, or other material well known in the art for use in pharmaceutical formulations. Pharmaceutically acceptable carriers are non-toxic and should not interfere with the efficacy of the active ingredient. Pharmaceutically acceptable carriers include excipients and / or additives suitable for use in pharmaceutical compositions known in the art, for example, as listed in the following literature: "Remington: The Science & Practice of Pharmacy," 19th edition, Williams & Williams, (1995) and "Physician's Desk Reference," 52nd edition, Medical Economics, Montvale, NJ (1998), the entire contents of which are incorporated herein by reference. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the present invention.

[0225] The choice of a specific carrier or excipient, or a combination of carriers or excipients, will depend on the administration modality or the type of medical condition or disease state intended to treat a particular patient. In this regard, the preparation of a suitable pharmaceutical composition for a specific administration modality is entirely within the capabilities of a person skilled in the pharmaceutical art. Furthermore, the carriers or excipients used in the pharmaceutical compositions of this invention are commercially available. As further illustration, conventional formulation techniques are described in Remington: The Science and Practice of Pharmacy, 20th edition, Lippincott Williams & White, Baltimore, Maryland (2000); and H.C. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition, Lippincott Williams & White, Baltimore, Maryland (1999).

[0226] Representative examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, the following substances: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose; and derivatives thereof, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragali gum; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solution; and other non-toxic compatible substances for use in pharmaceutical compositions.

[0227] The pharmaceutical compositions disclosed herein are preferably packaged in unit dosage forms. The term "unit dosage form" refers to a physically discrete unit suitable for administration to a patient, i.e., each unit contains a predetermined amount of active agent that is calculated to produce the desired therapeutic effect whether used alone or in combination with one or more other units. For example, such unit dosage forms may be capsules, tablets, pills, etc., or unit packages suitable for parenteral administration.

[0228] According to embodiments of the present invention, suitable pharmaceutical compositions for oral administration may be in the following forms: capsules, tablets, pills, lozenges, flat capsules, sugar-coated pills, powders, granules; or as solutions or suspensions in aqueous or non-aqueous liquids; or as oil-in-water or water-in-oil liquid emulsions; or as elixirs or syrups; etc.; each of these forms contains a predetermined amount of the compound of the present disclosure as an active ingredient.

[0229] In some embodiments, the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof is a tablet.

[0230] The antibodies disclosed herein can be produced from host cells. A host cell is defined as a carrier comprising the necessary cellular components (e.g., organelles) required for the expression of the polypeptides and constructs described herein from their corresponding nucleic acids. Nucleic acids may be contained in a nucleic acid carrier, which can be introduced into the host cell using conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.). The choice of nucleic acid carrier depends in part on the host cell to be used. Typically, the host cell is of prokaryotic (e.g., bacterial) or eukaryotic (e.g., mammalian) origin.

[0231] The antibodies disclosed herein can be administered in the form of a pharmaceutical composition comprising an effective amount of the antibody and one or more pharmaceutically acceptable carriers or excipients, which can be formulated by methods known to those skilled in the art.

[0232] The acceptable carriers and excipients in the pharmaceutical composition are non-toxic to the recipient at the dose and concentration used. Acceptable carriers and excipients may include buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates. The pharmaceutical composition may be administered parenterally in the form of an injectable formulation. Sterile solutions or any pharmaceutically acceptable liquids may be used as media to formulate the pharmaceutical composition for injection. Pharmaceutically acceptable media include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco modified Eagle medium (DMEM), α-modified Eagle medium (α-MEM), F-12 medium). Formulation methods are known in the art; see, for example, Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (2nd edition), Taylor & Francis Group, CRC Press (2006).

[0233] In some embodiments, antibodies that can be used in the methods of this application may be packaged in one or more kits, which may optionally contain instructions for use.

[0234] In some implementation schemes, lung cancer is non-small cell lung cancer.

[0235] In some implementation schemes, lung cancer is locally advanced or metastatic non-small cell lung cancer.

[0236] In some implementation schemes, lung cancer is stage IIIB-IV NSCLC that is confirmed by histology or cytology.

[0237] In some implementations, the human subject has received at least one prior therapy.

[0238] In some implementations, the prior therapy is selected from the group consisting of immune checkpoint inhibitor therapy and chemotherapy, preferably anti-PD-1 / PD-L1 therapy, docetaxel therapy and platinum-based chemotherapy.

[0239] In some implementation schemes, non-small cell lung cancer has gene mutations, preferably EGFR, ALK, ROS1, and BRAF mutations.

[0240] In some implementations, human subjects have an ECOG fitness level of 0 or 1.

[0241] In some implementations, human subjects had a creatinine clearance rate of >50 mL / min calculated using the Cockcroft-Gault method during the screening period and within 72 hours of starting administration of the method.

[0242] In some implementation schemes, human subjects with good liver function include those who meet the following criteria:

[0243] •AST<3×ULN

[0244] •ALT<3×ULN

[0245] • Total bilirubin <1.5×ULN (For participants with known congenital non-hemolytic hyperbilirubinemia, isolated total bilirubin ≥1.5×ULN and conjugated [direct] bilirubin <1.5×ULN are permitted).

[0246] or

[0247] •AST<5×ULN

[0248] •ALT<5×ULN

[0249] • Total bilirubin <3×ULN (for participants with known congenital non-hemolytic hyperbilirubinemia, isolated total bilirubin ≥3×ULN and conjugated [direct] bilirubin <1.5×ULN are permitted).

[0250] In some implementation schemes, human subjects meet the following criteria:

[0251] •ANC≥1,000 / μL

[0252] • Platelet count ≥75,000 / μL

[0253] • Hgb ≥ 9.0 g / dL or ≥ 5.6 mmol / L.

[0254] In some implementations, the subject does not meet any of the exclusion criteria listed in Example 1 of this application.

[0255] In some implementations, this method does not lead to serious adverse effects.

[0256] In some implementations, serious adverse effects are selected from the group consisting of: death, life-threatening events, hospitalization or prolongation of existing hospitalization, persistent or severe disability / loss of ability, congenital abnormalities / birth defects, suspected transmission of any infectious agent through the pharmaceutical product, and medically significant events.

[0257] In some implementations, the method does not result in clinically significant changes from pre-drug baseline in physical examination, Eastern Cooperative Oncology Group (ECOG) performance status score, vital signs, echocardiography (ECHO) scan, multi-gated acquisition (MUGA) scan, electrocardiogram (ECG), laboratory assessment, or pregnancy testing.

[0258] In some implementations, the method does not induce dose-limiting toxicity (DLT) in subjects.

[0259] In some implementations, the DLT rate does not exceed 30% in a cohort of at least 3 subjects.

[0260] In some embodiments, DLT is a hematologic toxicity or a non-hematologic toxicity, and hematologic toxicity is preferably a decrease in neutrophil count, a decrease in platelet count, or any grade 5 hematologic toxicity, and non-hematologic toxicity is preferably any grade 3 or higher non-hematologic toxicity.

[0261] In some implementations, iRECIST confirmed that human subjects did not experience disease progression.

[0262] In some implementations, the method provides one or more efficacy events selected from a group consisting of objective response rate (ORR), complete response rate (CRR), duration of response (DOR), and disease control rate (DCR), wherein ORR is defined according to RECIST v1.1 and iRECIST.

[0263] In another general aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in the method of any one of the foregoing embodiments.

[0264] In another general aspect, the present invention provides checkpoint inhibitors for use in the methods of any of the foregoing embodiments, particularly anti-PD-1 antibodies or antigenic fragments thereof.

[0265] In another general aspect, the present invention provides radiotherapy for use in any of the foregoing embodiments.

[0266] Example

[0267] Example 1: Efficacy study of the compound of formula (I)

[0268] The in vivo efficacy of the compound of formula I was evaluated in three different immunocompetent syngeneic mouse cancer models: CT-26 colon cancer, EG7-OVA lymphoma, and B16F10 melanoma.

[0269] CT-26 colon cancer model

[0270] The efficacy of the compound of formula I was demonstrated in a CT-26 tumor model (BALB / c background) in which animals underwent tumor implantation. The compound of formula I, administered at a dose of 30 mg / kg every 12 hours (BID), caused significant inhibition of tumor growth in both monotherapy and combination therapy with immune checkpoint blockade (anti-mPD-1), but not at 10 mg / kg. In the pCREB assay, a dose of 30 mg / kg BID of the compound of formula I was required to provide >90% target binding at trough concentrations, while a dose of 10 mg / kg BID resulted in only 75% target binding, thus establishing the PK / PD correlation.

[0271] Next, the ability of compounds of Formula I alone and / or in combination with anti-mPD-1 to enhance the response to radiation was evaluated in a clinically relevant setting. Stereotactic body radiotherapy (SBRT) was delivered in a mouse tumor model using a small animal radiation research platform (SARRP) to mimic treatment applied to human patients. Subablation doses were used in efficacy studies because they were able to trigger initial immunogenic cell death by activating effector NK cells and CD8+ T cells, but failed to induce a sustained antitumor response.

[0272] A compound of formula I was selected at a dose of 30 mg / kg (bid oral administration) for a first combined study with anti-PD-1 (10 mg / kg intraperitoneal [IP] injection) administered every two weeks and radiation. CT-26 colon cancer cells were implanted into female BALB / c mice when the average tumor volume was approximately 100 mm. 3 Treatment was initiated at [time] and continued for 18 days with the compound of Formula I, followed by 2 weeks of continued treatment with anti-mPD-1. The selected radiation dose was a single 5 Gy administered one day after the start of administration of the compound of Formula I and anti-PD-1. All treatments were well tolerated with minimal weight loss.

[0273] δ-tumor growth inhibition (dTGI) analysis was performed on day 24, when two-thirds or more of the animals in each group still remained. Tumor volume (mm3) was assessed as (L*W) 2 ) / 2, where L and W are their respective orthogonal measurements of tumor length and width (mm), compared with the tumor volume at the start of drug administration. dTGI was calculated as the percentage difference between the baseline-corrected mean tumor volume of the treatment and control groups:

[0274] dTGI = ([(TVc-TVc0)-(TVt- TVt0)] / [TVc-TVc0])×100,

[0275] Where "TVc" is the mean tumor volume of the control group, "TVc0" is the mean tumor volume of the control group at the start of treatment, "TVt" is the mean tumor volume of the treatment group, and "TVt0" is the mean tumor volume of the treatment group at the start of treatment. A dTGI greater than 100% is achieved if tumor regression (TR) occurs and the volume decreases compared to the start of treatment. Monotherapy with compounds of Formula I failed to produce anticancer activity, and tumor growth was similar to that of the control group. In contrast, anti-mPD-1 monotherapy showed a significant dTGI of approximately 33%, and combination therapy of anti-mPD-1 + compounds of Formula I achieved a dTGI of approximately 69%.

[0276] On day 24, radiation plus anti-mPD-1 therapy was effective with a dTGI of 86.8%; radiation plus compound of formula I therapy was effective with a dTGI of 101.1% and a TR of 31.9%; and radiation plus anti-mPD-1 plus compound of formula I therapy was effective with a TGI of 107.73% and a TR of 95.8%.

[0277] In the survival analysis at the end of the study (day 119), treatment with radiation in combination with anti-mPD-1 or a compound of formula I was effective, increasing survival and achieving complete tumor regression rates of 57.4% and 62.5%, respectively. The triple combination therapy of radiation, anti-mPD-1, and a compound of formula I was highly effective, with 100% of mice classified as tumor-free survivors (TFS) at the end of the study. All TFS mice were transferred to a re-challenge study, in which tumor cells were injected into the animals 120 days after the initial implantation. Importantly, no tumors grew in the animals after re-challenge with subcutaneously implanted CT-26 cells, indicating a durable systemic anti-tumor T-cell memory response.

[0278] EG7-OVA lymphoma model

[0279] Similar results were obtained in the EG7-OVA lymphoma model. Compound I (30 mg / kg) was administered orally, twice daily (BID), for 28 days. Anti-mPD-1 (5 mg / kg) was administered intraperitoneally every two weeks for 2 weeks. When the mean tumor volume in each group approached 100 mm... 3 Treatment began on day 7 with the compound of formula I and anti-PD-1. A single dose of 5 Gy of radiation was administered one day after the stage.

[0280] dTGI analysis was performed on day 20, the time point when at least two-thirds of the animals in all groups were still alive. Radiation monotherapy resulted in a dTGI of 90.8%, and similar responses were observed in all radiation combination therapies. The antitumor activity of radiation alone was not sustained, and the tumors were freed from treatment effects after day 20. In this case, radiation combination therapies promoted a more durable antitumor response. When dTGI was analyzed on day 30, only the radiation-received groups had more than two-thirds of the animals still participating in the study. At this time point, using radiation monotherapy as a comparison, 90.7% dTGI was observed in the radiation + compound I group, 85.7% in the radiation + anti-mPD-1 group, and 111.6% in the radiation + anti-mPD-1 + compound I group. At the end of the study (day 110), only 20% of animals in the radiotherapy monotherapy group remained tumor-free, while 90% of animals in the radiotherapy + anti-mPD-1 group or the radiotherapy + compound I group were TFS, and 100% of animals in the radiotherapy + anti-mPD-1 + compound I group were TFS. Animals did not develop tumors after a second subcutaneous implantation of EG7-OVA tumor, further demonstrating a durable systemic anti-tumor T-cell memory response.

[0281] B16F10 melanoma model

[0282] The efficacy of compounds of Formula I, alone or in combination with anti-mPD-1 and / or radiotherapy, was evaluated in a third tumor model: B16F10 melanoma in C57BL / 6 mice, characterized by very rapid and aggressive tumor growth, very low basal T cell infiltration, and resistance to anti-mPD-1. Compounds of Formula I (30 mg / kg) were administered orally, twice daily (BID), for 21 days. Anti-mPD-1 (10 mg / kg) was administered intraperitoneally every two weeks for 2 weeks. The efficacy was evaluated when the mean tumor volume in each group was 100 mm. 3 Treatment began on day 9 with the compound of formula I and anti-PD-1. A single dose of radiation, 10 Gy, was administered one day later.

[0283] All treatments were well tolerated, with no adverse clinical signs or significant changes in weight.

[0284] TGI analysis was performed on day 17, at which point at least two-thirds of the animals in all groups were still alive. Monotherapy with anti-mPD-1 or a compound of formula I, or combination therapy with anti-mPD-1 plus a compound of formula I, failed to produce any anticancer activity; tumor growth kinetics in these groups were similar to the control (carrier) group. All radiation treatment groups showed significant TGI compared to the carrier group, but no tumor regression was observed. Radiation monotherapy produced an intermediate TGI of 40.5%, while all radiation combination therapies were more effective, with TGIs of 59.2% for radiation plus a compound of formula I, 71.3% for radiation plus anti-mPD-1, and 61.7% for radiation plus anti-mPD-1 plus a compound of formula I.

[0285] Radiation monotherapy had a moderate effect on survival, increasing lifespan by only 10% compared to the mediator group. On the other hand, both radiation plus anti-mPD-1 combination therapy and radiation plus a compound of formula I showed significant survival extensions (55% and 45% increases, respectively). The triple combination therapy of radiation plus anti-mPD-1 plus a compound of formula I showed the largest increase in lifespan (75%) compared to the control group. Multiple comparisons of different treatments confirmed that the triple combination therapy significantly increased survival not only compared to the mediator group but also compared to radiation monotherapy.

[0286] Example 2: Formula (I) administered as a monotherapy and in combination with cialis and radiotherapy Phase 1 study of the compound for advanced non-small cell lung cancer

[0287] This clinical study will be the first-in-human (FIH), open-label, multicenter, dose-escalation study of the compound of Formula I in participants with advanced / metastatic non-small cell lung cancer (NSCLC). The aim of this study is to evaluate the safety, pharmacokinetic (PK), and disease progression (PD) of the compound of Formula I in participants as monotherapy, in combination with cilimab, and in combination with cilimab and RT.

[0288] This study will be conducted in two parts. In Part 1, the compound of Formula I will be administered in combination with cialis, while in Part 2, the compound of Formula I will be administered in combination with cialis and RT. The aim of this study is to determine the dosage of the compound of Formula I that, when combined with cialis and RT, will provide an acceptable PK / PD profile and be safe and tolerable. This study will also evaluate the preliminary efficacy of the compound of Formula I in combination with cialis and in combination with cialis and RT to guide further development.

[0289] Goals and End Points

[0290] Table 1

[0291]

[0292] Methods and Subjects

[0293] Part 1 – Compound of Formula (I) + Silimab

[0294] Approximately 3 to 4 dosing cohorts will be recruited sequentially, each consisting of at least 3 participants. In each dosing cohort, participants will receive a specified dose of the compound of Formula I and a fixed dose of cialis. In each dosing cohort, participants will initially receive a 21-day monotherapy regimen of the compound of Formula I, and individual participants will be evaluated for dose-limiting toxicities (DLTs) (monotherapy DLT). If no DLT is reported in an individual participant and with the sponsor's consent, the participant will begin cialis treatment in combination with the compound of Formula I (cialis initiated on day 22), followed by a 21-day combined DLT period. Once the Study Evaluation Panel (SET) determines that the dose level is safe as monotherapy (i.e., reviewed by the SET after at least 3 participants have completed the monotherapy DLT observation period), participants may be recruited into subsequent dosing cohorts to receive a monotherapy regimen of the compound of Formula I guided by a Bayesian optimization interval (BOIN) design, with a target DLT rate of 30%.

[0295] The initial dose of the compound of Formula I will be 5 mg QD, based on non-clinical evaluation, toxicological assessment, and human PK / PD modeling, with an expected target inhibition of approximately 81% at trough concentration. If the BOIN model recommends tapering from this dose level, the sponsor may evaluate a 2 mg dose and / or BID dosing. Dose escalations will be 15 mg, 30 mg, and 60 mg.

[0296] Cilimab will be administered subcutaneously every 3 weeks, with a loading dose of 900 mg followed by a subsequent dose of 600 mg.

[0297] Based on all observed data, including insufficient DLT, glutar PK concentration, and inadequate PD at the same dose level, a BID dosing approach can be explored as an intermediate tapering regimen. In this case, subsequent dose escalations will continue with BID.

[0298] Participants in all dosing cohorts will receive treatment with a compound of Formula I and cilimab for up to 2 years from the first administration of study treatment, or until iRECIST-confirmed disease progression, clear clinical progression, unacceptable toxicity, investigator's decision to discontinue treatment, withdrawal of informed consent, initiation of subsequent anticancer therapy, pregnancy, follow-up failure, or termination of the study by the sponsor.

[0299] The objective of Part 1 is to determine the dosage of Formula I compounds that provide an acceptable PK / PD curve and are safe and tolerable when combined with cialimab for further evaluation in Part 2. The highest dose tested will be the maximum administered dose (MAD) if all dose levels do not exceed 30% of the target DLT rate. SET will examine available data and determine the doses to be evaluated in Part 2. Prior to the start of Part 2, at least six participants should be observed completing the DLT evaluation period for both monotherapy and combination therapy at the provisional recommended dose levels.

[0300] Determining the effects of food

[0301] Throughout the trial, the compound of Formula I will be administered under semi-fasting conditions, meaning no food should be consumed 2 hours before and 1 hour after administration of the compound of Formula I (unless otherwise instructed by SET based on emerging data). A limited number of participants (approximately 10 participants from the Part 1 cohort selected as the Part 2 dose group) will participate in the initial assessment of the pharmacokinetic (PK) effects of food on the compound of Formula I. On the two selected days for food effect assessment (planned for days 8 and 9 of Cycle 1), participants will fast overnight for at least 8 hours before ingesting the compound of Formula I. On the day of the fasting assessment (planned for day 8 of Cycle 1), participants will remain fasted for 4 hours after administration of the compound of Formula I. On the day of the high-fat diet assessment (planned for day 9 of Cycle 1), participants will receive the compound 30 minutes after starting a high-fat breakfast.

[0302] Part 2 – Compound of Formula (I) + Silimab + RT

[0303] Once a safe dose of the compound of Formula I and cilimab is determined and deemed suitable for further investigation, the combination of the compound of Formula I, cilimab, and RT will be investigated in Part 2 of this study based on SET decisions. Up to 60 participants will be recruited.

[0304] Part 2, Cohort A, will consist of participants with advanced metastatic NSCLC whose tumors were characterized by PD-L1 <1% at initial diagnosis and have progressed after treatment with anti-PD-1 and chemotherapy. Cohort B will consist of treatment-naïve participants with metastatic NSCLC who have PD-L1 ≥50% and meet the criteria for receiving anti-PD-1 monotherapy.

[0305] Cohort A in Part 2 will begin with a safety introductory period, with 6 participants receiving combination therapy of the compound of Formula I, cialimab, and RT. Other participants in Cohorts A and B will only be recruited after the first 6 participants in Cohort A have received combination therapy of the compound of Formula I, RT, and cialimab, completed all study evaluations up to the end of Cycle 2, and received sponsor approval after SET has reviewed all reported safety data. If the safety profile is unacceptable, additional cohorts may be added to investigate combinations of lower doses of the compound of Formula I (which may include BID doses) with cialimab and RT or other dosing regimens (as needed).

[0306] Each cohort will initially recruit 15 participants, and may be expanded to approximately 30 participants per cohort based on observed safety, preliminary efficacy, and biomarker data, at the discretion of SET. Participants may be added to cohorts A and B based on emerging data. Additional expansion cohorts may also be added through protocol amendments.

[0307] Starting on day 1 of cycle 1, participants will receive a daily dose of the compound of formula I as defined in Part 1. On day 3 (+7) of cycle 1, participants will begin RT, and cilimab will be administered 5 to 7 days after the completion of RT on a Q3-week basis. Researchers will choose one of the following two RT regimens based on lesion location and clinical judgment:

[0308] • 6Gy x 5 days (delivery can be made daily or every other day)

[0309] • 8Gy x 3 days (delivery can be made daily or every other day)

[0310] RT will be administered according to standard radiation oncology guidelines, and further instructions are provided in the RT guidance document. Consultation with the sponsor is possible if finalization of RT dose selection and irradiation field is required, or if there are concerns about lesions near vital organs. If RT administration takes more than one week, the radiation oncologist should conduct targeted physical examinations and assess participants' weight weekly. Lymph nodes should not be considered target lesions for radiation and must be excluded from the direct irradiation field if clinically permissible and feasible. If exclusion of lymph nodes from the direct irradiation field is not possible, this must be documented and the reasons explained. The RT regimen will be administered as a single course during the study treatment period. Additional RT may be administered later if clinically indicated during the study treatment period. If used, the clinical indications, timing, location, number of lesions irradiated, and RT dose used for palliative RT must be clearly documented. For participants with multiple lesions (e.g., lungs, liver), as many lesions as clinically indicated and technically feasible should be irradiated, but no more than three lesions per day. It is crucial to remember that one unirradiated target lesion should be reserved for RECIST v1.1 evaluation. This protocol aims to irradiate lesions in multiple locations, including the pleural cavity, extrapleural cavity, and bones. Additional details regarding radiation delivery will be described in detail in a separate radiology manual.

[0311] Similar to Part 1, participants in Part 2 may receive treatment with a compound of Formula I and cilimab for up to 2 years from the first administration of the study treatment, or until the occurrence of iRECIST-confirmed disease progression, clear clinical progression, unacceptable toxicity, investigator's decision to discontinue treatment, withdrawal of informed consent, initiation of subsequent anticancer therapy, pregnancy, follow-up failure, or termination of the study by the sponsor.

[0312] Determination of relative bioavailability

[0313] The oral tablet formulation used in Part 2 consists of a finely air-milled compound of Formula I. To facilitate optimization of the tablet formulation for future research and commercialization, the relative bioavailability of the prototype formulation containing the coarsely milled drug product will be evaluated in Part 2. A limited number of participants (approximately 10 participants in Part 2) will participate in the relative bioavailability assessment. This PK induction assessment will be conducted 7 to 10 days prior to the start of Cycle 1 of the treatment period. A single dose of the prototype formulation of the compound of Formula I will be administered on Day 1 of the PK induction period, and samples will be collected from Day 1 to Day 5 of the induction period. Participants will then begin administering the finely air-milled drug product formulation from Day 1 of Cycle 1. On the two selected days for the relative bioavailability assessment (planned for Day 1 of the PK induction period and Day 1 of Cycle 1), participants will fast overnight for at least 8 hours before ingesting the compound of Formula I. There will be at least a 7-day interval between Day 1 of the induction period and Day 1 of Cycle 1. Based on ongoing review of the evolving data, the number of participants recruited may be increased (e.g., if additional prototypes need to be tested) or decreased (e.g., if fewer than 10 participants are deemed sufficient). Additional crushed tablets may be tested if the PK curves for pulverized and coarse tablets are not comparable.

[0314] Selection criteria

[0315] Each potential participant must meet all of the following research recruitment criteria.

[0316] Selection criteria for Part 1 and Part 2:

[0317] 1. Be 18 years of age or older when signing the informed consent form, or have reached the legal age of majority in the jurisdiction where the research is conducted.

[0318] 2. Individuals with stage IIIB-IV NSCLC confirmed by histology or cytology.

[0319] 3. For Cohort A of Parts 1 and 2: Participants lacking an operable genetic mutation must have previously received: (a) anti-PD-1 / PD-L1 therapy; and (b) platinum-based chemotherapy, whether in combination or sequential therapy (for metastatic disease), or developed metastatic disease within one year and experienced disease progression during or after treatment. Patients who cannot tolerate or have previously refused or are unable to receive platinum-based chemotherapy are eligible for enrollment if they have experienced disease progression after receiving anti-PD-1 / PD-L1 therapy alone. Individuals who have previously refused platinum-based chemotherapy after consultation with a healthcare professional are eligible to participate, provided they provide documentation demonstrating that their decision was medically justified.

[0320] For queue B in part 2:

[0321] • No prior systemic therapy for metastatic disease. Participants who have received one dose of antiPD-(L)1 therapy (first dose of standard care) are eligible if they meet the following criteria: (a) no disease assessment scan was performed after antiPD-(L)1 administration, and (b) they are able to complete all screening assessments and begin study treatment by the time of their next scheduled antiPD-(L)1 administration (+ / - 4 days).

[0322] • Except as described in the points above, they have never received anti-PD-(L)1 or anti-CTLA4 therapy.

[0323] 4. For Part 1: NSCLC patients with known operable gene mutations (e.g., EGFR, ALK, ROS1, BRAF) must have received all approved targeted therapies and have experienced disease progression. Participants whose mutation status is unknown due to test failure or inability to undergo testing are permitted to participate in this study.

[0324] For Part 2: See Exclusion Criteria. The cohort-specific criteria are summarized below:

[0325] • Cohort A: Based on local testing results performed in a CLIA-certified laboratory at initial diagnosis, PD-L1 tumor expression <1%.

[0326] • Cohort B: Local testing performed in a CLIA-certified laboratory at initial diagnosis, with PD-L1 tumor expression >50%.

[0327] 5. May have a second malignant tumor that is pre-existing or co-existing (other than the disease studied).

[0328] The premise is that the tumor, due to its natural course or treatment, is unlikely to interfere with any

[0329] Safety study endpoints or efficacy studies of the treatment. In such cases, consultation with the sponsor is necessary before recruitment.

[0330] 6. Has an ECOG fitness level of 0 or 1 (see section 10.8).

[0331] 7. During the screening period and within 72 hours of the start of study treatment, a creatinine clearance rate of >50 mL / min calculated using the Cockcroft-Gault method was observed.

[0332] 8. Good liver function:

[0333] a. Participants without potential liver metastases are eligible if they meet the following criteria:

[0334] •AST<3×ULN

[0335] •ALT<3×ULN

[0336] • Total bilirubin <1.5×ULN (For participants with known congenital non-hemolytic hyperbilirubinemia, isolated total bilirubin ≥1.5×ULN and conjugated [direct] bilirubin <1.5×ULN are permitted).

[0337] b. Participants with known liver metastases are eligible if they meet the following criteria:

[0338] •AST<5×ULN

[0339] •ALT<5×ULN

[0340] • Total bilirubin <3×ULN (for participants with known congenital non-hemolytic hyperbilirubinemia, isolated total bilirubin ≥3×ULN and conjugated [direct] bilirubin <1.5×ULN are permitted).

[0341] 9. Within one week prior to the first administration of the study treatment, without dependence on blood transfusions or growth factors, hematological laboratory parameters were within the following ranges:

[0342] •ANC≥1,000 / μL

[0343] • Platelet count ≥75,000 / μL

[0344] • Hgb ≥ 9.0 g / dL or ≥ 5.6 mmol / L

[0345] 10. Left ventricular ejection fraction is within the limits specified by the institution.

[0346] 11. Participants of fertility potential must undergo a high-sensitivity serum (β-hCG) test at screening and within 72 hours prior to the first dose of study treatment, and the result must be negative. They must agree to continue serum or urine pregnancy testing during study treatment.

[0347] 12. Participants of reproductive potential must use at least two highly effective methods of contraception from the first dose until at least 6 months after the last dose of a Formula I compound and for at least 5 months after the last dose of cilimab. Male participants must agree to follow acceptable contraceptive guidelines from the first dose until at least 95 days after the last dose of a Formula I compound and for at least 5 months after the last dose of cilimab.

[0348] 13. Female participants must agree not to become pregnant, breastfeed, or plan to become pregnant at the time of participation in this study or within 6 months after the last dose of a compound of Formula I or within 5 months after the last dose of cilimumab (whichever is longer).

[0349] 14. Participants must agree not to donate gametes (i.e., eggs or sperm) or freeze them for future assisted reproductive purposes during the study period and for at least 5 months after the last dose of cilimumab and at least 6 months (female oocytes) or 95 days (male sperm) after the last dose of a compound of Formula I. Participants should consider preserving their gametes before receiving study treatment, as anticancer treatment may impair fertility.

[0350] 15. Male participants must agree not to have children at the time of participation in this study and for at least 95 days after the last dose of compound I and for at least 5 months after the last dose of cilimab.

[0351] 16. Participants must sign an ICF (Initial Clinical Filing Form) indicating that they understand the purpose of the study and the required procedures and are willing to participate in the study.

[0352] 17. Willing and able to comply with the lifestyle restrictions set forth in this plan.

[0353] Additional selection criteria for Part 2 only:

[0354] 18. Participants must have at least 3 lesions:

[0355] • At least one lesion suitable for irradiation

[0356] • At least one measurable lesion according to RECIST 1.1 criteria, which has not previously received RT and is not planned to receive RT in this study.

[0357] a. At least one lesion suitable for biopsy

[0358] 19. Agree to submit a tumor sample prior to the start of the study treatment. The sample may be an archived tumor tissue sample obtained within 3 months prior to the start of treatment (without any NSCLC therapy administered during these 3 months), or a puncture or incision biopsy sample of a newly acquired tumor lesion during the screening period.

[0359] 20. The response to previous anti-PD-1 antibody therapy was CR, PR, or SD, lasting for at least 3 months.

[0360] Exclusion criteria

[0361] Any potential participant who meets any of the following criteria will be excluded.

[0362] Outside of this study.

[0363] Exclusion criteria for Part 1 and Part 2:

[0364] 1. Participants are candidates whose diseases qualify for curative treatments.

[0365] 2. Patients with active central nervous system involvement (e.g., primary central nervous system tumors, metastases, leptomeningeal diseases), but excluding those with clinically stable and asymptomatic brain metastases that have undergone definitive local treatment for >2 weeks and who have discontinued corticosteroid therapy or received only low-dose corticosteroid therapy (≤10 mg prednisone or equivalent) for at least 2 weeks prior to starting study treatment.

[0366] 3. Within 12 months prior to signing the consent form, you have an active autoimmune disease that requires systemic immunosuppressive drugs (e.g., long-term use of corticosteroids, methotrexate, or tacrolimus).

[0367] 4. Toxicity associated with previous anticancer therapy has not recovered to grade 1 or baseline levels (except for alopecia, vitiligo, grade 2 peripheral neuropathy, and endocrine disorders stabilized by hormone replacement therapy, which can be grade 2).

[0368] 5. Previous anticancer therapies caused irreversible adverse events (irAEs) and led to permanent discontinuation of treatment.

[0369] 6. A known positive result for HIV or other immunodeficiency syndromes.

[0370] 7. Having an active infection or condition that requires treatment with a systemic anti-infective agent (e.g., antibiotic, antifungal, or antiviral agent) within 7 days prior to the first dose of the study treatment, or being on long-term anti-infective agents.

[0371] Note: Intermittent use of topical anti-infective agents does not constitute a criterion for exclusion.

[0372] 8. History of solid organ or hematopoietic stem cell transplantation.

[0373] 9. Those who have had symptomatic shingles within the 3 months prior to screening.

[0374] 10. Prolonged corrected QT interval or clinically significant arrhythmia or electrophysiological disorder caused by Fredericia (QTcF) >470 ms (e.g., implantation of an implantable cardioverter defibrillator, or atrial fibrillation with poor heart rate control, or abnormal conduction or morphology of ECG [e.g., complete left bundle branch block, third- or second-degree heart block, PR interval >250 ms]).

[0375] Any factor that increases the risk of corrected QT interval (QTc) prolongation or the risk of arrhythmic events (such as congenital long QT syndrome, a family history of long QT syndrome or unexplained sudden death in a first-degree relative under 40 years of age), or any concomitant medications known to prolong the QT interval or induce torsades de pointes ventricular tachycardia.

[0376] Note: Clinically stable participants with implanted pacemakers are eligible.

[0377] Note: Serum potassium, calcium, and magnesium levels should be kept within normal limits during the study.

[0378] 11. Clinically significant cardiovascular disease, including any of the following within 6 months prior to signing the informed consent form:

[0379] a. Myocardial infarction, severe or unstable angina, or coronary artery bypass grafting

[0380] b. Clinically significant arrhythmias (e.g., ventricular arrhythmias or atrial fibrillation with poor heart rate control).

[0381] c. Congestive heart failure (NYHA Class III / IV)

[0382] d. Cerebrovascular accident, transient ischemic attack or other arterial thromboembolic events

[0383] e. Myocarditis

[0384] 12. Known allergy, hypersensitivity, or intolerance to excipients of compounds of formula I.

[0385] 13. Known hypersensitivity, hypersensitivity, or intolerance to cilimab excipients.

[0386] 14. Has an active bleeding tendency, or requires therapeutic anticoagulation that cannot be interrupted or adjusted due to surgery.

[0387] 15. Underwent major surgery (e.g., requiring general anesthesia) within 4 weeks prior to the first dose of the study treatment, or did not fully recover from surgery before the first dose.

[0388] 16. Received an immunosuppressive dose of a systemic medication, such as a corticosteroid (prednisone or equivalent, dose >10 mg / day), within 7 days prior to the first dose of study treatment. A single course of corticosteroids is permitted, for example, as allergy prophylaxis for imaging contrast agents.

[0389] 17. Received or planned to receive any live vaccine within 28 days prior to the first dose of study treatment, during treatment, or within 5 months after the last dose of study treatment. Inactive or non-replicating vaccines approved (e.g., influenza) or authorized for emergency use by local health authorities (e.g., COVID-19) are permitted.

[0390] 18. Participate in any other clinical trial containing the investigational product within 30 days of the first dose.

[0391] 19. Received anti-PD-L1 or anti-CTLA4 therapy within 4 weeks prior to the first dose of study treatment, or received other anticancer therapy within 14 days prior to the first dose of study treatment.

[0392] 20. Patients who have received treatment with an adenosine pathway inhibitor (e.g., itratheline (Nourianz), olerutumab, tamminadenan, cifortinam, itradinam, inupadinam, BMS-986179).

[0393] 21. Participants received proton pump inhibitor (PPI) treatment within 48 hours prior to the first administration of the compound of Formula I, or were unable to interrupt PPI treatment during administration of the compound of Formula I.

[0394] 22. Active or chronic HBV or HCV infection:

[0395] • See section 10.10 for instructions on HBV serological testing requirements for HBV-specific antigens and antibodies in the complete protocol.

[0396] • Defined as HCV infection with positive anti-HCV antibodies. Participants who test positive for HCV antibodies are eligible if HCV viral RNA load is undetectable (either after spontaneous recovery or completion of treatment for HCV infection).

[0397] 23. Any medical condition that the researchers believe is not in the best interests of the participants (e.g., may impair their health) or may prevent, limit, or obscure the assessments specified in the protocol.

[0398] Additional exclusion criteria for Part 2 only

[0399] 24. NSCLC patients with the following operable gene mutations and for whom an approved therapy is available: EGFR, ALK, ROS1, or BRAF. Confirmation is required to confirm the absence of operable mutations.

[0400] 25. Participants with interstitial lung disease who have ≤92% oxygen saturation at rest, or ≤88% oxygen saturation during activity without supplemental oxygen, or who have been diagnosed with idiopathic pulmonary fibrosis.

[0401] 26. The researchers believed that the participants had previously received RT, and therefore could not be given radiation again.

[0402] Diet and dietary restrictions

[0403] Unless SET provides further instructions based on newly emerging data, no food should be consumed 2 hours before and 1 hour after administration of compounds of Formula I. Participants participating in the relative bioavailability or food effect assessment will enter the PK induction phase one week prior to the start of cycle 1 of treatment.

[0404] During the two-day evaluation, a single dose will be administered to participants participating in the relative bioavailability assessment at least 8 hours after overnight administration (planned for day 1 of the PK induction period and day 1 of cycle 1 prior to ingestion of compound I).

[0405] Participants in the food impact assessment will undergo a pharmacokinetic (PK) evaluation 2 days after administration. The high-fat diet assessment is planned for Day 1 of the PK introductory period, and the fasting assessment for Day 1 of Cycle 1. On the day of the high-fat diet assessment (planned for Day 1 of the PK introductory period), participants will consume a high-calorie, high-fat breakfast after fasting for at least 8 hours overnight; a single dose of compound I will then be administered 30 minutes after the start of the high-fat breakfast. On the day of the fasting assessment (planned for Day 1 of Cycle 1), participants will administer the medication after fasting for at least 8 hours overnight and will remain fasted for 4 hours after administration of compound I.

[0406] On the day of relative bioavailability and food impact assessment (done on day 1 of the introductory period and day 1 of the first cycle), drinking water may be consumed as needed, except one hour before and after drug administration.

[0407] Research on treatment

[0408] For this study, "investigation treatment" refers to the compound of formula I, cilimab, and RT. The compound of formula I and cilimab will be manufactured and supplied by the sponsor.

[0409] • Compounds of Formula I: 1 mg, 5 mg, 15 mg and 50 mg tablets (see Table 2 below), for oral administration;

[0410] • Cilimab: 300 mg pre-filled syringe, subcutaneous (SC) injection (see Table 3 below); and

[0411] •RT: The medical device will be administered according to its intended use, in accordance with institutional care standards and established oncology guidelines.

[0412] Table 2: Qualitative Composition of 1mg, 5mg, 15mg and 50mg Oral Tablets

[0413]

[0414] Cilimab is supplied as a 300 mg / syringe drug product. The 300 mg / syringe drug product is provided as a sterile solution in a single-use pre-filled syringe (PFS) and is preservative-free. The PFS is manufactured by BD Neopak. ™ 2.25ml syringe and HyFlow ™ Composed of 27G half-inch stainless steel needles and made with Flurotec ® Piston seal. DP syringes are aseptically filled to 2.07 ml, with each 2.0 ml syringe delivering a nominal dose of 300 mg. The target composition is provided in Table 3 below:

[0415] Table 3

[0416]

[0417] a. Amount calculated based on the measured value of the active pharmaceutical ingredient batch and the nominal PFS filling volume of 2.0 mL.

[0418] Ultrasound Refinement

[0419] EDTA = disodium ethylenediaminetetraacetate dihydrate

[0420] Alternatively, cilimumab can be provided in a sterile, lyophilized formulation, reconfigurable for subcutaneous injection and preservative-free. The formulation is aseptically filled into glass vials, lyophilized, sealed, and stored at 5±3°C, protected from light. Each vial contains 90 mg of cilimumab reconfigured to 30 mg / mL in solution of 10 mM histidine, 8.0% (w / v) sucrose, 0.04% polysorbate 20 (w / v), and 20 μg / mL EDTA, pH 6.5. Target compositions are provided in Table 4 below.

[0421] Table 4

[0422]

[0423] The target fill volume is 3.3 mL. This includes 10% excess fill to allow for the removal of at least 90 mg / vial (3.0 mL volume).

[0424] b Target volume after reconstruction / mL

[0425] c. Plant-based; Low peroxide

[0426] The estimated value for d is based on the amount added during the process. The actual concentration will be measured in the later stages of research and development.

[0427] EDTA = disodium ethylenediaminetetraacetate dihydrate

[0428] Research Evaluation

[0429] Efficacy evaluation

[0430] The response will be assessed using radiographic imaging (including CT scans and MRI) in accordance with RECIST v1.1 and iRECIST standards.

[0431] Safety and tolerability assessment

[0432] Safety and tolerability will be assessed at pre-specified time points throughout the study via physical examination, Eastern Cooperative Oncology Group (ECOG) performance status, vital sign measurements, echocardiography or MUGA scans, electrocardiogram (ECG) examinations, clinical safety laboratory tests, and pregnancy testing.

[0433] Adverse event reporting

[0434] During the study, all adverse events (AEs) and special reporting circumstances, whether serious or not, will be reported by the participant (or, where appropriate, by a caregiver, substitute, or legally acceptable representative of the participant). Any AEs occurring outside the aforementioned reporting period but deemed relevant to the study treatment must be reported to the sponsor.

[0435] Pharmacokinetic assessment

[0436] Plasma samples will be used to evaluate the pharmacokinetic (PK) of the compound of Formula I, and serum samples will be used to evaluate the PK of cilimab. Samples collected for PK may also be used to evaluate the safety or efficacy in addressing problems that arise during or after the study period, or to evaluate relevant biomarkers. No genetic analysis will be performed on these samples. Participant confidentiality will be maintained.

[0437] Statistical methods

[0438] In the dose escalation cohort of Part 1, approximately 12 to 36 participants are planned to be recruited for treatment. This number may increase if further dose evaluation is required. At least six participants will be treated with the established safe dose used in Part 2 before starting Part 2. However, the number of participants recruited will depend on the observed DLT rate and the corresponding SET decision in each cohort.

[0439] In Part 2, up to 40 participants will receive treatment. This number is based on feasibility and may increase if additional cohorts are added through amendments.

[0440] Part 1 – Compound of Formula (I) + Silimab

[0441] A BOIN design will be implemented to guide dose escalation. In this study, the target DLT rate is 30%; in the BOIN design, the optimal boundaries for dose escalation and deceleration are 0.236 and 0.359, respectively.

[0442] Part 2 – Compound of Formula (I) + Silimab + RT

[0443] Part 2 is an open-label, single-arm cohort study designed to evaluate the safety and preliminary efficacy of the combination of the compound of Formula I, RT, and cilimab. Up to 30 participants may receive treatment in each cohort, A and B.

[0444] result

[0445] Participants

[0446] As of the data cutoff date of July 21, 2024, 17 participants received the following medication:

[0447] • Fourteen participants received compound of formula I and cilimab treatment;

[0448] • Two participants received treatment with a compound of formula I; and

[0449] • Exposure data for one participant was not entered into the EDC at the data cutoff date.

[0450] Pharmacokinetics and Product Metabolism

[0451] Based on available data (cutoff date: September 25, 2024), preliminary pharmacokinetic (PK) analysis of the compound of formula I was performed according to this ongoing Phase 1 FIH study. Preliminary PK analysis was conducted on available data from the first four cohorts, where participants received oral doses of the compound of formula I daily at doses of 5 mg, 15 mg, 30 mg, or 60 mg. Following daily administration of the compound of formula I, plasma concentrations increased post-dose, reaching peak concentrations on day 1 and day 8 of cycle 1 (time to maximum concentration [T] within each dose group). max [The median value is 1 to 2 hours; Table 5]. The concentration-time curve shows that the concentration at C... max The concentration was then gradually reduced (Figures 1a and 1b), supporting daily dosing of the compound of formula I. Peak values ​​were observed on days 1 and 8 of cycle 1 within a dose range of 5 mg to 60 mg (C). max The total (AUC) exposure increases approximately proportionally to the dose.

[0452] There is currently no data on the metabolism of compounds of Formula I in the human body.

[0453] Table 5: Summary of pharmacokinetic parameters of compounds of formula (I)

[0454]

[0455] # The PK data presented assume that samples were collected at the nominal time specified in the protocol: Cohort 1: Multiple oral doses of 5 mg QD. Cohort 2: Multiple oral doses of 15 mg QD. Cohort 3: Multiple oral doses of 30 mg QD. Cohort 4: Multiple oral doses of 60 mg QD.

[0456] a For AUC 24h n=5

[0457]

[0458] Safety and tolerability

[0459] As of the data cutoff date of July 21, 2024, preliminary demographic, safety, and tolerability data for 16 participants in this ongoing FIH study were available. The majority of participants were white (50.0%), with a median age of 64 years at study participation (range: 40 to 88 years); 11 were male and 5 were female (Table 6).

[0460] Table 6: Summary of demographic and baseline characteristics; analysis set of all patients receiving treatment.

[0461]

[0462] All treatment-adverse events (TEAEs) were coded using the MedDRA version 27.0 and summarized by system organ classification (SOC) and preferred terminology (PT). TEAEs experienced by at least 10% of participants are shown in Tables 7a and 7b, and Tables 8a and 8b below, by SOC, PT, and cohort. All 16 participants experienced at least one TEAE. The most frequently reported TEAEs by PT were nausea (5 participants, 31.3%), dizziness, headache, and fatigue (4 participants each [25.0%]).

[0463] Three participants (18.8%) reported serious adverse events (SAEs) during treatment: pneumonia, tumor pain, and embolism (one participant each) (Tables 9a and 9b, and 10a and 10b below). The researchers considered all SAEs to be unrelated to the treatment.

[0464] Compound of formula (I)

[0465] In the early stages of development, any potential safety risks associated with the administration of compounds of Formula I are unknown. Potential safety risks are derived based on the known mechanisms of action of compounds of Formula I, non-clinical data, and available clinical data from clinical studies using other adenosine pathway inhibitors.

[0466] Combination with cialis

[0467] Cilimab is a fully human IgG4κ monoclonal antibody that binds to PD-1 with high affinity and specificity, blocking the binding of PD-1 to two ligands (PD-L1 and PD-L2), thereby enhancing the production of pro-inflammatory cytokines by in vitro stimulated T cells, and is expected to antagonize PD-1 function and enhance T cell activity and anti-tumor immunity. Clinical experience with cialis is based on data from two monotherapy studies (63723283LUC1001 and 63723283LUC1002 Phase 1a) and seven combination studies (63723283LUC1002 Phase 1b, 54767414MMY2036, 64091742PCR2002, 42756493BLC2002, 17000139BLC2001 [SunRISe 1], 17000139BLC3001 [SunRISe 2] and 56021927PCR2032).

[0468] Cilimab has demonstrated a safety and efficacy profile comparable to approved anti-PD-1 antibodies in treated melanoma and NSCLC patients.

[0469] Table 7a: Subjects with a frequency of at least 10% of treatment-period adverse events, based on system organ classification and preferred terminology. Number of people; 5mg QD + CET

[0470]

[0471] Table 7b: Subjects with a frequency of at least 10% of treatment-period adverse events, based on system organ classification and preferred terminology. Number of people; 15mg + CET

[0472]

[0473] Table 8a: Subjects with a frequency of at least 10% of treatment-period adverse events, based on system organ classification and preferred terminology. Number of people; 30mg + CET

[0474]

[0475] Table 8b: Subjects with a frequency of at least 10% of treatment-period adverse events, based on system organ classification and preferred terminology. The number of people; total

[0476]

[0477] Note: TEAE = Treatment-term adverse events. For any given event, subjects are counted only once, regardless of how many times they actually experienced the event.

[0478] Table 9a: Subjects experiencing serious adverse events during treatment, based on system organ classification, preferred terminology, and treatment period. Number of people; 5mg + CET

[0479]

[0480] Table 9b: Subjects experiencing serious adverse events during treatment, based on system organ classification, preferred terminology, and treatment period. Number of people; 15mg + CET

[0481]

[0482] Table 10a: Subjects experiencing serious adverse events during treatment, based on system organ classification, preferred terminology, and treatment period. Number of people; 30mg + CET

[0483]

[0484] Table 10b: Subjects experiencing serious adverse events during treatment, based on system organ classification, preferred terminology, and treatment period. The number of people; total

[0485]

[0486] Note: TEAE = Treatment-term adverse events. For any given event, subjects are counted only once, regardless of how many times they actually experienced the event.

[0487] Those skilled in the art will understand that modifications can be made to the above embodiments without departing from the broad inventive concept of the present invention. Therefore, it should be understood that the present invention is not limited to the specific embodiments disclosed, but is intended to cover modifications within the spirit and scope of the invention, as defined in the specific description.

[0488] sequence list :

[0489] SEQ ID NO: 1

[0490] SYAIS

[0491] SEQ ID NO: 2

[0492] GIIPIFDTANYAQKFQG

[0493] SEQ ID NO: 3

[0494] PGLAAAYDTGSLDY

[0495] SEQ ID NO: 4

[0496] RASQSVRSYLA

[0497] SEQ ID NO: 5

[0498] DASNRAT

[0499] SEQ ID NO: 6

[0500] QQRNYWPLT

[0501] SEQ ID NO: 7

[0502] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLVTVSS

[0503] SEQ ID NO: 8

[0504] EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNYWPLTFGQGTKVEIK

[0505] SEQ ID NO: 9

[0506] QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFDTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0507] SEQ ID NO: 10

[0508] EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNYWPLTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0509] SEQ ID NO: 11

[0510] PGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL

Claims

1. A compound of formula (I) administered to a human subject in need: Or a method of treating lung cancer in human subjects with a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof is about 1 mg to about 200 mg per day.

3. The method according to claim 3, wherein the compound of formula I is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg or 120 mg or any dose between thereof.

4. The method according to claim 4, wherein the compound of formula I is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg, 60 mg, 100 mg, 110 mg or 120 mg.

5. The method according to any one of claims 1 to 4, wherein the method further comprises orally administering to the subject a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. The method according to any one of claims 1 to 5, wherein the method further comprises administering a checkpoint inhibitor, such as an anti-PD-L1 antibody, an anti-PD-1 antibody, or an antigen-binding fragment thereof, to the subject.

7. The method of claim 6, wherein the method further comprises administering the anti-PD-1 antibody or its antigen-binding fragment to the subject, the anti-PD-1 antibody or its antigen-binding fragment comprising heavy chain complementarity-determining regions (HCDR) 1, HCDR2 and HCDR3 of SEQ ID NO: 1, 2 and 3, respectively, and light chain complementarity-determining regions (LCDR) 1, LCDR2 and LCDR3 of SEQ ID NO: 4, 5 and 6, respectively.

8. The method according to claim 7, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises the heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO:

8.

9. The method according to any one of claims 1 to 8, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and a light chain (LC) containing the amino acid sequence of SEQ ID NO:

10.

10. The method according to any one of claims 1 to 9, wherein the method further comprises administering radiotherapy to the subject.

11. The method according to any one of claims 1 to 10, wherein an effective dose of the anti-PD-1 antibody or its antigen-binding fragment is administered every 2 to 6 weeks.

12. The method according to any one of claims 1 to 11, wherein an effective dose of the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously every three weeks.

13. The method according to any one of claims 1 to 12, wherein a loading dose of the anti-PD-1 antibody or its antigen-binding fragment of about 600 mg to 1200 mg is administered, followed by an effective dose of about 300 mg to about 900 mg every three weeks.

14. The method of claim 13, wherein the loading dose is about 900 mg.

15. The method according to any one of claims 6 to 14, wherein the radiotherapy is administered in doses of about 3 Gy to 8 Gy in fractions over 1 day to 2 weeks, or in fractions of 1.8 Gy to 3 Gy in fractions over 3 to 7 weeks, or in a total dose of 5 Gy to 100 Gy in fractions over 1 day to 8 weeks, such as 8 Gy to 30 Gy or 30 Gy to 70 Gy.

16. The method according to any one of claims 6 to 15, wherein the radiotherapy is administered at a dose of about 6 Gy for about 3 to 7 days, preferably about 5 days.

17. The method according to any one of claims 6 to 16, wherein the radiotherapy is administered at a dose of about 8 Gy for about 2 to 4 days, preferably about 3 days.

18. The method according to any one of claims 6 to 17, wherein the radiotherapy is administered once daily or every other day.

19. The method according to any one of claims 6 to 18, wherein the radiotherapy is initiated after the initial administration of the compound of formula I or a pharmaceutically acceptable salt thereof, specifically, the radiotherapy is initiated about 1 to 10 days, preferably about 3 to 10 days, more preferably about 3 days, after the initial administration of the compound of formula I or a pharmaceutically acceptable salt thereof.

20. The method according to any one of claims 6 to 19, wherein the administration of the anti-PD-1 antibody or its antigen-binding fragment is initiated after the completion of the radiotherapy, particularly about 3 to 10 days after the completion of the radiotherapy, preferably about 5 to 7 days.

21. A method for treating lung cancer in a human subject in need, the method comprising: (1) The subject was orally administered a compound comprising a pharmaceutically acceptable carrier and formula I. A pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 120 mg per day; and (2) Subcutaneously administering an anti-PD-1 antibody or its antigen-binding fragment to the subject, wherein the anti-PD-1 antibody or its antigen-binding fragment contains... a. Heavy chain complementarity determination regions (HCDR) 1, HCDR 2 and HCDR 3 of SEQ ID NO: 1, 2 and 3 respectively, and light chain complementarity determination regions (LCDR) 1, LCDR 2 and LCDR 3 of SEQ ID NO: 4, 5 and 6 respectively; b. The heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8; and c. Heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and light chain (LC) containing the amino acid sequence of SEQ ID NO:

10. The anti-PD-1 antibody or its antigen-binding fragment is administered as a loading dose of about 900 mg, followed by an effective dose of about 600 mg every three weeks.

22. The method of claim 21, wherein the method further comprises administering radiotherapy to the subject.

23. The method according to any one of claims 21 to 22, wherein the pharmaceutical composition is administered orally once daily, and the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered each time is about 2 mg, 5 mg, 15 mg, 30 mg, 60 mg, 100 mg, 110 mg or 120 mg.

24. The method according to any one of claims 22 to 23, wherein the radiotherapy is administered in doses of about 3 Gy to 8 Gy in fractions over 1 day to 2 weeks, or in fractions of 1.8 Gy to 3 Gy in fractions over 3 to 7 weeks, or in a total dose of 5 Gy to 100 Gy in fractions over 1 day to 8 weeks, such as 8 Gy to 30 Gy or 30 Gy to 70 Gy.

25. The method according to any one of claims 22 to 24, wherein the radiotherapy is initiated after the initial administration of the compound of formula I or a pharmaceutically acceptable salt thereof, specifically, the radiotherapy is initiated about 1 to 10 days after the initial administration of the compound of formula I or a pharmaceutically acceptable salt thereof.

26. A method for treating lung cancer in a human subject of need, the method comprising: (1) The subject was orally administered a compound comprising a pharmaceutically acceptable carrier and formula I. A pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the total dose of the compound of formula I or a pharmaceutically acceptable salt thereof administered is from about 1 mg to about 120 mg per day; and (2) The subject is given radiotherapy, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8 Gy for about 2 to 7 days, and the radiotherapy is initiated about 1 to 10 days after the initial administration of the compound of Formula I or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, wherein the method further comprises administering an anti-PD-1 antibody or an antigen-binding fragment thereof to the subject.

28. The method of claim 27, wherein the anti-PD-1 antibody or its antigen-binding fragment comprises: a. Heavy chain complementarity determination regions (HCDR) 1, HCDR 2 and HCDR 3 of SEQ ID NO: 1, 2 and 3 respectively, and light chain complementarity determination regions (LCDR) 1, LCDR 2 and LCDR 3 of SEQ ID NO: 4, 5 and 6 respectively; b. The heavy chain variable region (VH) of SEQ ID NO: 7 and the light chain variable region (VL) of SEQ ID NO: 8; and c. Heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 9 and light chain (LC) containing the amino acid sequence of SEQ ID NO:

10.

29. The method according to any one of claims 27 to 28, wherein the anti-PD-1 antibody or its antigen-binding fragment is administered subcutaneously at a loading dose of about 900 mg, followed by subcutaneous administration every three weeks at an effective dose of about 600 mg.

30. The method according to any one of claims 27 to 29, wherein the administration of the anti-PD-1 antibody or its antigen-binding fragment is initiated after the completion of the radiotherapy, particularly about 3 to 10 days after the completion of the radiotherapy, preferably about 5 to 7 days.

31. The method according to claim 1, wherein the lung cancer is non-small cell lung cancer.

32. The method of claim 1, wherein the lung cancer is locally advanced or metastatic non-small cell lung cancer.

33. The method of claim 1, wherein the human subject has received at least one prior therapy.

34. The method of claim 1, wherein the prior therapy is selected from the group consisting of immune checkpoint inhibitor therapy and chemotherapy, preferably anti-PD-1 / PD-L1 therapy, docetaxel therapy and platinum-based chemotherapy.

35. The method according to claim 1, wherein the non-small cell lung cancer has a gene mutation, preferably a mutation of EGFR, ALK, ROS1, or BRAF.

36. The method of claim 1, wherein the human subject has an ECOG performance status of 0 or 1.

37. The method of claim 1, wherein the human subject has a creatinine clearance rate of >50 mL / min calculated using the Cockcroft-Gault method during the screening period and within 72 hours of starting administration of the method.

38. The method of claim 1, wherein the method provides one or more efficacy events selected from the group consisting of objective response rate (ORR), complete response rate (CRR), duration of response (DOR), and disease control rate (DCR), wherein the ORR is defined according to RECIST v1.1 and iRECIST.

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