Safe administration of a2a rector antagonist

Abstract

The present disclosure provides methods of treating lung cancer by administration of the A2a receptor antagonist. In particular, the methods include monotherapy and combination therapy with a checkpoint inhibitor and / or radiotherapy.

Description

[0001] Docket No: KAD6025WOPCT A2A RECEPTOR ANTAGONIST FOR USE IN TREATING LUNG CANCER TECHINICAL FIELD The application relates to methods of treating lung cancer comprising administering an A2a receptor antagonist. In particular, the methods include monotherapy with an A2a receptor antagonist and combination therapy with a checkpoint inhibitor and / or radiotherapy. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY This application contains a sequence listing, which is submitted electronically. The information contained in the electronic sequence listing (Sequence Listing_065768-164US3.xml; size: 15 KB; and date of creation: September 6, 2024) is incorporated herein by reference in its entirety. BACKGROUND Lung cancer is the leading cause of cancer related deaths world-wide, with patients suffering a very poor prognosis with a low 5-year survival rate. Additionally, cure rates for patients diagnosed with early-stage lung cancer are also worse than the other leading causes of cancer related death. Immune checkpoint inhibitors (ICIs) have altered the treatment landscape for advanced lung cancer. The era of lung cancer immunotherapy was launched after initial Phase 3 trials demonstrated superiority of anti-PD-1 antibody over 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 induces durable partial and complete responses. Today anti PD-(L)1 agents constitute the mainstay of front-line therapy in 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 a consolidation therapy in unresectable stage III NSCLC (Antonia, et al., N. Engl. J. Med. 2017, 377:1919-1929). In the metastatic setting, while responses to ICI therapy can be durable in many patients, clinical data indicate that majority of patients have only partial responses (Walsh, et al., Ther. Docket No: KAD6025WOPCT Adv. Med. Oncol.2020, 12:1-22). After failure of ICI and chemotherapy, approved therapies such as docetaxel with or without ramucirumab provide limited benefit (Fossella, Clin. Lung. Cancer. 2002 May, 3 Suppl 2:S23-8). As such, there is a need for therapies that can augment current ICI response rates and overcome or prevent resistance to immunotherapy in patients with metastatic NSCLC. Based on the success of ICI in cancer treatment, there has been high interest in evaluating combination treatment with additional immune modulators that have the potential to modify immunosuppressive features within the tumor microenvironment (TME) that induce resistance to immunotherapy. Adenosine signaling via the A2a receptor is immunosuppressive in the TME. High expression of A2a receptor is found on immune cells, in particular in T-cells, NK-cells, myeloid cells and neutrophils. In key anti-tumor effector cells such as T- and NK-cells adenosine signaling via A2a receptor is immunosuppressive, driving significant reduction of proliferation, activation, killing function, cytokine production and survival. The immunosuppressive role of adenosine signaling has been demonstrated by significant improvement in tumor growth control, metastasis and survival in multiple syngeneic tumor models. Therefore, it would be desirable to develop A2a receptor antagonist in combination with immunotherapies and / or radiotherapy for the treatment of lung cancer. BRIEF SUMMARY The application describes a first-in-human study of an A2a receptor antagonist, either as a monotherapy or as a combination with a checkpoint inhibitor and / or radiotherapy (RT). The primary objective of this study is to determine safe and tolerable dose(s) of Compund of Formula I for further investigation in combination with cetrelimab and RT. A secondary objective is determination of pK of Compound of Formula I when administered as monotherapy and in combination with cetrelimab and / or RT. In one general aspect, provided here is a method of treating lung cancer in a human subject by administering a compound of Formula (I): Docket No: KAD6025WOPCT a pharmaceutically acceptable salt thereof, In another general aspect, provided here is a method of treating lung cancer in a human subject by administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a human subject in need thereof, wherein a total dosage of the compound of Formula I administered is about 1 mg to about 200 mg per day, such as 1 mg to 150 mg per day, 1 mg to 120 mg per day or 1 mg to 90 mg per day which is some embodiments is administered orally. In another general aspect, provided here is a method of treating lung cancer in a human subject by orally administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a human subject in need thereof, wherein a total dosage of the compound of Formula I administered is about 5 mg to about 200 mg per day, such as 5 mg to 150 mg per day, 5 mg to 120 mg per day or 5 mg to 90 mg per day. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises: a. a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively; and / or b. a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; and / or c. 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. Docket No: KAD6025WOPCT In certain embodiments, an effective dose of the anti-PD-1 antibody or the antigen- binding fragment thereof is administered once every 2-6 weeks, such as once every 2, 3, 4, 5, or 6 weeks, particularly the effective dose of the anti-PD-1 antibody or the antigen-binding fragment thereof is administered once every three weeks. In some embodiments, the anti-PD-1 antibody or antigen binding fragment is administered subcutaneously. In certain embodiments, a loading dose of the anti-PD-1 antibody or the antigen-binding fragment thereof is administered prior to the administration of the effective dose. A loading dose, as used herein is a predetermined initial quantity of a pharmaceutical compound administered to a patient which is typically higher than subsequent doses. In particular, the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered with a loading dose of about 600 mg to 1200 mg, followed by an effective dose of about 300 mg to about 900 mg once every two to four weeks. In some embodiments, the method further comprises administering a radiotherapy (RT) to the subject. In certain embodiments, the radiotherapy is administered at a dose of about 3 Gy to 8 Gy fractions over 1 day to 2 weeks to 1.8 Gy to 3 Gy fractions over 3 to 7 weeks, or at a total dose of 5 to 100 Gy, such as a total dose of 8 to 30 Gy or 30-70 Gy, over 1 day to 8 weeks. In certain embodiments, the radiotherapy is started after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof, particularly, the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the first administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. In certain embodiments, the administration of the anti-PD-1 antibody or the antigen- binding fragment thereof is started after the radiotherapy is completed, particularly about 3-10 days, preferably about 5-7 days, after the radiotherapy is completed. In some embodiments, the human subject is in need of a cancer treatment. In one embodiment, provided here is a method of treating lung cancer in a human subject in need thereof, comprising: (1) administering to the subject a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a total dosage of the compound of Formula I or Docket No: KAD6025WOPCT the pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and (2) administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered with a loading dose of about 900 mg, followed by an effective dose of about 600 mg once every three weeks . In one embodiment, provided here is a method of treating lung cancer in a human subject in need thereof, comprising: (1) administering to the subject a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and (2) administering a radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8Gy for about 2 to 7 days, and the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. In one embodiment, provided here is a method of treating lung cancer in a human subject in need thereof, comprising: (1) administering to the subject a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein a total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; (2) administering a radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8Gy for about 2 to 7 days, and the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof; and (3) administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof is Docket No: KAD6025WOPCT subcutaneously administered with a loading dose of about 900 mg, followed by an effective dose of about 600 mg once every three weeks, and the administration of the anti-PD-1 antibody or the antigen-binding fragment thereof is started after the radiotherapy is completed, particularly about 3-10 days, preferably about 5-7 days, after the radiotherapy is completed. In some embodiments, the compound of Formula I or pharmaceutical salt thereof, is administered as a pharmaceutical composition comprising a compound of Formula I, or pharmaceutical salt thereof and a pharmaceutically acceptable carrier. In some embodiments, the compound of Formula I or pharmaceutical salt thereof, is administered orally once or twice per day. In some embodiments, the compound of Formula I or pharmaceutical salt thereof, is administered once or twice a day as a pharmaceutical composition comprising a compound of Formula I, or pharmaceutical salt thereof and pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is orally administered once per day or twice per day. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, or 60 mg. In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 1 mg, 2 mg, 5 mg, 15 mg, or 30 mg. Docket No: KAD6025WOPCT In some embodiments, the pharmaceutical composition comprises the compound of Formula I. In some embodiments, the radiotherapy is administered at a dose of about 6 Gy for about 3-7 days, preferably about 5 days. In some embodiments, the radiotherapy is administered at a dose of about 8 Gy for about 2-4 days, preferably about 3 days. In some embodiments, the radiotherapy is administered once per day or once every other day. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer. In some embodiments, the pharmaceutical composition is a tablet. In some embodiments, the human subject had received at least one prior therapy. In some embodiments, 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. In some embodiments, the non-small cell lung cancer has a genetic mutation, preferably mutation of EGFR, ALK, ROS1, BRAF. In some embodiments, the human subject has an ECOG performance status of 0 or 1. In some embodiments, the human subject has creatinine clearance rate > 50 mL / min using the Cockcroft-Gault method during the screening period and within 72 hours of the start of administration of the method. In some embodiments, the human subject has adequate liver function. In some embodiments, the method does not result in a serious adverse effect. In certain embodiments, the serious adverse effect is selected from the group consisting of death, life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability / incapacity, a congenital anomaly / birth defect, a suspected transmission of any infectious agent via a medicinal product, and a medically important event. In some embodiments, the method does not result in clinically significant changes from the predose baseline in a physical examination, an Eastern Cooperative Oncology Group Docket No: KAD6025WOPCT (ECOG) performance status scale, a vital sign, an echocardiograph (ECHO) scan, a multigated acquisition (MUGA) scan, an electrocardiogram (ECG), a laboratory assessment, or a pregnancy testing. In some embodiments, the method does not induce a Dose Limiting Toxicity (DLT) in the subject. In certain embodiments, the DLT rate does not exceed 30% in a cohort of at least 3 subjects. In certain embodiments, the DLT is hematologic toxicity or non-hematological toxicity, and the hematologic toxicity is preferably neutrophil count decreased, platelet count decreased, or any hematological toxicity of Grade 5, and the non-hematologic toxicity is preferably any non-hematological toxicity of Grade ≥3. In some embodiments, the human subject has no disease progression confirmed by iRECIST. In some embodiments, the method provides one or more events of efficacy selected from the group consisting of objective response rate (ORR), complete response rate (CRR), duration of response (DOR), disease control rate (DCR), where ORR is defined per RECIST v1.1 and iRECIST. In another general aspect, the invention presents a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the method of any of the foregoing embodiments. In one another general aspect, the invention presents a check point inhibitor, particularly, an anti-PD-1 antibody or an antigen fragment thereof for use in the method of any of the foregoing embodiments. In one another general aspect, the invention presents a radiotherapy for use in the method of any of the foregoing embodiments. The details of one or more embodiments of the invention are set forth in the description below. Other features and advantages will be apparent from the following detailed description, and the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS Docket No: KAD6025WOPCT The foregoing and other objects, aspects, features, and advantages of exemplary embodiments will become more apparent and may be better understood by referring to the following description taken in conjunction with the accompanying drawings. FIGs. 1A and 1B are the mean plasma concentration-time curves of the compound of Formula I. FIG. 1A: Cycle 1 Day 1; FIG. 1B: Cycle 1 Day 8. All participants received subcutaneous (SC) cetrelimab loading dose of 900 mg on Cycle 2 Day 1 followed by 600 mg every 3 weeks (Q3W) starting Cycle 3 Day 1. Error bars represent standard deviation. DETAILED DESCRIPTION The disclosed methods may be understood more readily by reference to the following detailed description, which form a part of this disclosure. It is to be understood that the disclosed methods are not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods. Various publications, articles and patents are cited or described in the background and throughout the specification; each of these references is herein incorporated by reference in its entirety. Discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is for the purpose of providing context for the invention. Such discussion is not an admission that any or all of these matters form part of the prior art with respect to any inventions disclosed or claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. Definitions It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For Docket No: KAD6025WOPCT example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.” To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term “about”. It is understood that whether the term “about” is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and / or measurement conditions for such given value. Further for conciseness, unless otherwise indicated, the term “at least” preceding a series of elements is to be understood to qualify every element in the series. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the invention. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integer or step. When used herein the term “comprising” can be substituted with the term “containing” or “including” or sometimes when used herein with the term “having”. When used herein “consisting of” excludes any element, step, or ingredient not specified in the claim element. When used herein, “consisting essentially of” does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. Any of the aforementioned terms of “comprising”, “containing”, “including”, and “having”, whenever used herein in the context of an aspect or embodiment of the invention can be replaced with the term “consisting of” or “consisting essentially of” to vary scopes of the disclosure. As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where two elements are conjoined by “and / or”, a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and therefore satisfy the requirement of Docket No: KAD6025WOPCT the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and therefore satisfy the requirement of the term “and / or.” As used herein, the phrases “adverse event (AE),” “treatment-emergent adverse event,” “adverse reaction,” and “adverse effect” mean any harm, unfavorable, unintended or undesired sign or outcome associated with or caused by administration of a pharmaceutical composition or therapeutic. However, abnormal values or observations are not reported as adverse events unless considered clinically significant by an investigator or a medical doctor. As used herein, the phrases “serious adverse event (SAE)” and “serious adverse effect” mean any adverse event that is serious, as defined by the Food and Drug Administration (FDA) Code of Federal Regulations (CFR), Chapter 21. A SAE can be any AE or suspected adverse reaction that in the view of an investigator or a medical doctor, results in any of the following outcomes: death, a life threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly / birth defect. Important medical events that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in the above definition. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization, or meets any of the other SAE criteria, then the event is an SAE. As used herein, when referring to safety assessment of the administration of the compound of Formula I or the pharmaceutically acceptable salt thereof, “clinically significant changes” means clinically apparent changes as determined by a medical doctor or an investigator using standard acceptable to those of ordinary skill in the art. When the harm or undesired outcome of adverse events reaches such a level of severity, a regulatory agency can deem the pharmaceutical composition or therapeutic unacceptable for the proposed use. Such changes can be measured by physical examination, such as examination of respiratory, cardiovascular, and gastrointestinal systems; laboratory assessments, such as hematology, blood chemistry, urinalysis, virus serology, urine drug screen, alcohol breath test, cotinine test, follicle stimulating hormone (FSH) and urine pregnancy test; vital signs, such as body temperature, respiratory rate, Docket No: KAD6025WOPCT blood pressure and heart rate; and electrocardiogram (ECG) monitoring, including 12 lead safety ECGs. As used herein, “treatment” or “treat” refers to the treatment of a disease, disorder, or medical condition (such as a non-small cell lung cancer), in a patient, such as a mammal (particularly a human) which includes one or more of the following: (a) preventing reoccurrence of the disease, disorder, or medical condition; (b) ameliorating the disease, disorder, or medical condition, i.e., eliminating or causing regression of the disease, disorder, or medical condition in a patient, including counteracting the effects of other therapeutic agents; (c) preventing metastasis of the disease, disorder or medical condition; (d) suppressing the disease, disorder, or medical condition, i.e., slowing or arresting the development of the disease, disorder, or medical condition in a patient; or (e) alleviating the symptoms of the disease, disorder, or medical condition in a patient. The terms “efficacy” and “effective” as used herein in the context of a dose, dosage regimen, treatment or method refer to the effectiveness of a particular dose, dosage or treatment regimen. Efficacy can be measured based on change in the course of the disease in response to an agent of the present invention. For example, the compound of Formula I can be administered to a subject in an amount and for a time sufficient to induce an improvement, preferably a sustained improvement, in at least one indicator that reflects the severity of the disorder that is being treated. Various indicators that reflect the extent of the subject's illness, disease or condition can be assessed for determining whether the amount and time of the treatment is sufficient. Such indicators include, for example, clinically recognized indicators of disease severity, symptoms, or manifestations of the disorder in question. The degree of improvement generally is determined by a physician, who can make this determination based on signs, symptoms, biopsies, or other test results, and who can also employ questionnaires that are administered to the subject, such as quality-of-life questionnaires developed for a given disease. For example, the compound of Formula I can be administered to achieve an improvement in a subject’s condition as provided in accordance with criteria provided by Response Evaluation Criteria in Solid Tumors (such as RECIST v.1.1 and iRECIST) which include measurable tumor burden and lesion size. Docket No: KAD6025WOPCT (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). The term “therapeutically effective amount” means an amount sufficient to effect treatment when administered to a patient in need of treatment. “Antigen” refers to any molecule (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, portions thereof, or combinations thereof) capable of being bound 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 may be expressed by genes, synthetized, or purified from biological samples such as a tissue sample, a tumor sample, a cell or a fluid with other biological components, organisms, subunits of proteins / antigens, killed or inactivated whole cells or lysates. “Antigen binding fragment” or “antigen binding domain” refers to a portion of the protein that binds an antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as the VH, the VL, the VH and the VL, Fab, Fab′, F(ab′)2, Fd and Fv fragments, domain antibodies (dAb) consisting of one VH domain or one VL domain, shark variable IgNAR domains, camelized VH domains, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3- FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as VH and VL) may be linked together via a synthetic linker to form various types of single antibody designs where the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins. “Antibodies” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, Docket No: KAD6025WOPCT tetraspecific, dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. “Full length antibodies” are comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CH1, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains. “Cancer” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and may also metastasize to distant parts of the body through the lymphatic system or bloodstream. A “cancer” or “cancer tissue” can include a tumor. “Checkpoint inhibitor” refers to a type of immunotherapy, and it is a treatment for cancers such as lung cancer. Checkpoint inhibitors block different checkpoint proteins that stop immune system from attacking the cancer cells. Examples of checkpoint inhibitors include, but are not limited to, CTLA-4 inhibitors, PD-1 inhibitors and PD-L1 inhibitors. “Complementarity determining regions” (CDR) are antibody regions that bind an antigen. There are three CDRs in the VH (HCDR1, HCDR2, HCDR3) and three CDRs in the VL (LCDR1, LCDR2, LCDR3). CDRs may be defined using various delineations 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 Docket No: KAD6025WOPCT Immunol 27: 55-77) and AbM (Martin and Thornton J Bmol Biol 263: 800-15, 1996). The correspondence between the various delineations and variable region numbering is described (see e.g., 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 by UCL Business PLC may be used to delineate CDRs. The term “CDR”, “HCDR1”, “HCDR2”, “HCDR3”, “LCDR”, “LCDR2” and “LCDR3” as used herein includes CDRs defined by any of the methods described supra, Kabat, Chothia, IMGT or AbM, unless otherwise explicitly stated in the specification. “Decrease,” “lower,” “lessen,” “reduce,” or “abate” refers generally to the ability of a test molecule to mediate a reduced response (i.e., downstream effect) when compared to the response mediated by a control or a vehicle. Exemplary responses are T cell expansion. T cell activation or T-cell mediated tumor cell killing or binding of a protein to its antigen or receptor, enhanced binding to a Fcγ or enhanced Fc effector functions such as enhanced ADCC, CDC and / or ADCP. Decrease may be a statistically significant difference in the measured response between the test molecule and the control (or the vehicle), or a decrease in the measured response, such as a decrease of about 1.1, 1.2, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 or 30 fold or more, such as 500, 600, 700, 800, 900 or 1000 fold or more (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7, 1.8, etc.). “Enhance,” “promote,” “increase,” “expand” or “improve” refers generally to the ability of a test molecule to mediate a greater response (i.e., downstream effect) when compared to the response mediated by a control or a vehicle. Exemplary responses are T cell expansion, T cell activation or T-cell mediated tumor cell killing or binding of a protein to its antigen or receptor, enhanced binding to a Fcγ or enhanced Fc effector functions such as enhanced ADCC, CDC and / or ADCP. Enhance may be a statistically significant difference in the measured response between the test molecule and control (or vehicle), 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 fold or more, such as 500, 600, 700, 800, 900 or 1000 fold or more (including all integers and decimal points in between and above 1, e.g., 1.5, 1.6, 1.7, 1.8, etc.). “Epitope” refers to a portion of an antigen to which an antibody specifically binds. Epitopes typically consist of chemically active (such as polar, non-polar or hydrophobic) surface groupings of moieties such as amino acids or polysaccharide side chains and may have specific Docket No: KAD6025WOPCT three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be composed of contiguous and / or discontinuous amino acids that form a conformational spatial unit. For a discontinuous epitope, amino acids from differing portions of the linear sequence of the antigen come in close proximity in 3-dimensional space through the folding of the protein molecule. Antibody “epitope” depends on the methodology used to identify the epitope. “Express” and “expression” refers the to the well-known transcription and translation occurring in cells or in vitro. The expression product, e.g., the protein, is thus expressed by the cell or in vitro and may be an intracellular, extracellular or a transmembrane protein. “dAb” or “dAb fragment” refers to an antibody fragment composed of a VH domain (Ward et al., Nature 341:544546 (1989)). “Fab” or “Fab fragment” refers to an antibody fragment composed of VH, CH1, VL and CL domains. “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. “Fd” or “Fd fragment” refers to an antibody fragment composed of VH and CH1 domains. “Fv” or “Fv fragment” refers to an antibody fragment composed of the VH and the VL domains from a single arm of the antibody. Fv fragments lack the constant regions of Fab (CH1 and CL) regions. The VH and VL in Fv fragments are held together by non-covalent interactions. “Fc” polypeptide” of a dimeric Fc refers to one of the two polypeptide forming the dimeric Fc domain. For example, an Fc polypeptide of a dimeric IgG FC comprises an IgG CH2 and an IgG CH3 constant domain sequence). “Full length antibody” is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g. IgM). Each heavy chain is comprised of a heavy chain variable domain (VH) and a heavy chain constant domain, the heavy chain constant domain comprised of subdomains CH1, hinge, CH2 and CH3. Each light chain is comprised of a light chain variable domain (VL) and a light chain constant domain (CL). The VH and the VL may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each Docket No: KAD6025WOPCT VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy- terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. “Human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-96, and in Int. Patent Publ. No. WO2009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody”. “Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework is derived from human immunoglobulin sequences. Humanized antibody may include substitutions in the frameworks so that the frameworks may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences. Docket No: KAD6025WOPCT “In combination with” or “pharmaceutical combination” means that two or more therapeutic agents are be administered to a subject together in a mixture, concurrently as single agents or sequentially as single agents in any order. The use of the term “in combination” does not restrict the order in which therapies are administered to a subject. “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of 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 one antigenic epitope. A bispecific monoclonal antibody binds two distinct antigenic epitopes. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as bispecific, monovalent, bivalent or multivalent. 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 of the mature human PD-1 (without signal sequence) is shown in SEQ ID NO: 11. The extracellular domain spans residues 1-150, the transmembrane domain spans residues 151-171 and the cytoplasmic domain spans residues 172- 268 of SEQ ID NO: 11. “Anti-PD-1 antibody” refers to an antibody that specifically binds to PD-1. “PD-L1” refers to PD-1 ligand. PD-L1 is also known as CD279 or B7-H1. The amino acid sequence of the 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. “PD-L1” in the specification refers to human mature PD-L1, unless explicitly stated to the contrary. “Anti-PD-L1 antibody” refers to an antibody that binds specifically to PD-L1. “Pharmaceutical composition” refers to a composition that results from combining an active ingredient and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” or “excipient” refers to an ingredient in a pharmaceutical composition, other than the active ingredient, which is nontoxic to a subject. Exemplary pharmaceutically acceptable carriers are a buffer, stabilizer or preservative. “Protein” and “polypeptide” are used interchangeably herein and refer to a molecule that comprises one or more polypeptides each comprised of at least two amino acid residues linked Docket No: KAD6025WOPCT by a peptide bond. Protein may be a monomer, or may be protein complex of two or more subunits, the subunits being identical or distinct. Small polypeptides of less than 50 amino acids may be referred to as “peptides”. Protein may be a heterologous fusion protein, a glycoprotein, or a protein modified by post-translational modifications such as phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, citrullination, polyglutamylation, ADP-ribosylation, pegylation or biotinylation. Protein may be recombinantly expressed. “Recombinant” refers to polynucleotides, polypeptides, vectors, viruses and other macromolecules that are prepared, expressed, created or isolated by recombinant means. “Relapsed” refers to the return of a disease or the signs and symptoms of a disease after a period of improvement after prior treatment with a therapeutic. “Refractory” refers to a disease that does not respond to a treatment. A refractory disease can be resistant to a treatment before or at the beginning of the treatment, or a refractory disease can become resistant during a treatment. “Specifically binds,” “specific binding,” “specifically binding” or “binds” refer to a proteinaceous molecule binding to an antigen or an epitope within the antigen with greater affinity than for other antigens. Typically, the proteinaceous molecule binds to the antigen or the epitope within the antigen with an equilibrium dissociation constant (KD) of about 1×10−7M or less, for example about 5×10−8M or less, about 1×10−8M or less, about 1×10−9M or less, about 1×10−10M or less, about 1×10−11M or less, or about 1×10−12M or less, typically with the KD that is at least one hundred fold less than its KD for binding to a non-specific antigen (e.g., BSA, casein). In the context of the prostate neoantigens described here, “specific binding” refers to binding of the proteinacous molecule to the prostate neoantigen without detectable binding to a wild-type protein the neoantigen is a variant of. “Subject” refers to human subjects and can be used interchangeably with “patient” and “participant” herein. Unless indicated otherwise, the numbering of amino acid residues in the antibody constant region throughout the specification is according to the EU index as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), unless otherwise explicitly stated. Docket No: KAD6025WOPCT In some embodiments, antibodies described herein can comprise mutations (e.g., amino acid substitutions, additions, and / or deletions) outside of the CDRs (e.g., in framework regions (FRs) or constant regions). An amino acid substitution, addition, and / or deletion can be a substitution, addition, and / or deletion of one or more amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or more). An amino acid substitution, addition, and / or deletion can be a substitution, addition, and / or deletion 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, antibodies described herein may include amino acid substitutions, additions, and / or deletions in the constant regions (e.g., Fc region) of the antibody that, e.g., lead to decreased effector function, e.g., decreased complement-dependent cytolysis (CDC) antibody-dependent cell-mediated cytolysis (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and / or decreased 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 potentially pose a safety risk by causing off-mechanism toxicity. Modifying effector functions can be achieved by engineering the Fc regions to reduce their binding to FcgRs or the complement factors. The binding of IgG to the activating (FcgRI, FcgRIIa, FcgRIIIa and FcgRIIIb) and inhibitory (FcgRIIb) FcgRs or the first component of complement (C1q) depends on residues located in the hinge region and the CH2 domain. Mutations can be introduced in IgG1, IgG2 and IgG4 to reduce or silence Fc functionalities. Silencing mutations can 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 antigen-binding fragment thereof can contain the IgG1 AA (L234A, L235A) mutations. In some embodiments, the disclosed antibody or antigen-binding fragment thereof can contain IgG1 AAS (L234A, L235A, and D265S) mutations to eliminate effector function. The disclosed antibodies or antigen-binding fragments thereof can comprise an Fc region with one or more of the following properties: (a) reduced effector function when compared to the parent Fc; (b) reduced affinity to Fcg RI, Fcg RIIa, Fcg RIIb, Fcg RIIIb and / or Fcg RIIIa; (c) reduced affinity to FcgRI; (d) reduced affinity to FcgRIIa; I reduced affinity to FcgRIIb; (f) reduced affinity to Fcg RIIIb; or (g) reduced affinity to FcgRIIIa. Docket No: KAD6025WOPCT In some embodiment, one or more mutations can be introduced into the CH3 domain of two heavy chains to favor formation of the heterodimer during co-transfection. “Heterodimerization” as used herein refers to an interaction of two heavy chains having non- identical CH3 amino acid sequences. “Heterodimer” as used herein refers to an antibody having two heavy chains with non-identical CH3 amino acid sequences. The “knob-in-hole” strategy (see, e.g., PCT Publ. No. WO2006 / 028936) can be used to generate full length bispecific antibodies. Briefly, selected amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co- expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a “hole” with the heavy chain with a “knob.” Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S and T366W / T366S_L368A_Y407V. For example, one heavy chain can feature a knob mutation: T366W while another heavy chain can feature the hole mutations: T366S, L368A, Y407V, and the knobs-into-holes mutations promote heterodimerization of the two heavy chains. Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface can be used, as described in US Pat. Publ. No. US2010 / 0015133; US Pat. Publ. No. US2009 / 0182127; US Pat. Publ. No. US2010 / 028637; or US Pat. Publ. No. US2011 / 0123532. In other strategies, heterodimerization can be promoted by the following substitutions (expressed as modified position in the first CH3 domain of the first heavy chain / modified 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. Pat. Publ. No. US2012 / 0149876 or Docket No: KAD6025WOPCT U.S. Pat. Publ. No. US2013 / 0195849. For example, 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 of the L351Y, F405A and Y407V mutations in the first Ig constant region and T394W mutation in the second Ig constant region promotes heterodimerization of the two immunoglobulin constant regions. Methods of Treating Lung Cancer In one general aspect, the invention relates to a method of treating cancer in a human patient comprising administering a compound of Formula I: a pharmaceutically acceptable salt thereof, the invention, compound of Formula I is administered to a human subject orally. In still other aspects of the invention a pharmaceutical composition comprising compound of Formula I, and a pharmaceutically acceptable carrier, is administered to a human subject. In still further aspects of the invention is provided a method of treating cancer by orally administering to a human subject a pharmaceutical composition comprising compound of Formula I or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein a total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered is about 1 mg to about 200 mg per day, such as 1 mg to 150 mg per day, 1 mg to 120 mg per day or 1 mg to 90 mg per day. According to the embodiments of the invention, 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-methylbutan-2-yl]pyrazolo[1,5-a]pyrimidine-5- carboxamide, its synthesis, biologic activities, uses or other related information thereof are Docket No: KAD6025WOPCT described, for example, in International Patent Application Publication No. WO 2021 / 224636, the content of which is hereby incorporated by reference in its entirety. As used herein, the dosage of compound of Formula I or the pharmaceutically acceptable salt thereof refers to an amount based on the compound of Formula I, i.e., the free base form. For example, the dosage of 100 mg of a pharmaceutically acceptable salt means a dosage equivalent to 100 mg of the compound of Formula I. In some embodiments, the total dosage of compound of Formula I or the pharmaceutically acceptable salt thereof administered per day 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 dosage in between. In some embodiments, compound of Formula I is orally administered once per day or twice per day. In certain embodiments, compound of Formula I is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, compound of Formula I is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, or 60 mg. In some embodiments, compound of Formula I is orally administered twice per day. In certain embodiments, compound of Formula I is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, compound of Formula I is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 1 mg, 2 mg, 5 mg, 15 mg, or 30 mg. In some embodiments, the pharmaceutically acceptable salt of the compound of Formula I means a salt that is acceptable for administration to a human subject, e.g., salts having acceptable mammalian safety for a given dosage regime. Representative pharmaceutically Docket No: KAD6025WOPCT acceptable salts include salts of acetic, ascorbic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6- disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic and xinafoic acid, and the like. In some embodiments, the pharmaceutical composition comprises the compound of Formula I and a pharmaceutically acceptable carrier. Said pharmaceutical composition may be administered orally once per day or twice per day. In some embodiments, the method further comprises administering to the subject a checkpoint inhibitor, such as an anti-PD-L1 antibody, an anti-PD-1 antibody or an antigen- binding fragment thereof. Preferably, the method further comprises administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2 and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof 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. An anti-PD-1 antibody useful for the invention, such as those described herein, can be obtained or prepared using methods known in the art in view of the present disclosure. In certain embodiments, an anti-PD-1 antibody is an anti-PD-1 antibody described in U.S. Patent No. 10,894,830, the content of which is incorporated herein by reference in its entirety. In some embodiments, an effective dose of the anti-PD-1 antibody or the antigen-binding fragment thereof is administered once every 2-6 weeks, such as once every 2, 3, 4, 5, or 6 weeks. Particularly, the effective dose of the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered once every three weeks. Docket No: KAD6025WOPCT In some embodiments, a loading dose of the anti-PD-1 antibody or the antigen-binding fragment thereof is administered prior to the administration of the effective dose, particularly, the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered with a loading dose of about 600 mg to 1200 mg, followed by an effective dose of about 300 mg to about 900 mg once every two to four weeks. In certain embodiments, the loading dose is about 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, or 1200 mg, or any dosage in between. In certain embodiments, the loading dose is about 900 mg. In certain embodiments, the effective dose is about 400 mg, 500 mg, 600 mg, 700 mg, or 800 mg, or any dosage in between, the effective dose is subcutaneously administered once every three weeks. Particularly, the effective dose is about 600 mg. In some embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof is administered after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. For example, the anti-PD-1 antibody or the antigen- binding fragment thereof can be administered 1 day, 1 week, 2 weeks, 3 weeks, or 1 month, or any period in between, after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. In some embodiments, the anti-PD-1 antibody or the antigen binding fragment thereof is administered or provided for administration in a pharmaceutical composition comprising : (a) about 30 mg / ml of the anti-PD-1 antibody or the antigen binding fragment thereof, about 1.15 mg / ml of histidine, about 0.54 mg / ml 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 the antigen binding fragment thereof, 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; (c) a lyophilized formulation comprising about 600 mg of the anti-PD-1 antibody or the antigen binding fragment thereof and one or more pharmaceutically acceptable excipients; (d) a lyophilized formulation comprising about 900 mg of the anti-PD-1 antibody or the antigen binding fragment thereof and one or more pharmaceutically acceptable excipients; (e) about 600 mg of the anti-PD-1 antibody or the antigen binding fragment thereof and one or more Docket No: KAD6025WOPCT pharmaceutically acceptable excipients; or (f) about 900 mg of the anti-PD-1 antibody or the antigen binding fragment thereof and one or more pharmaceutically acceptable excipients. In some embodiments, the method further comprises administering a radiotherapy to the subject. According to embodiments of the invention, the radiotherapy is a medical device or medical technology that is administered in accordance with its intended use per institutional standard of care, and established oncology guidelines, and it can be any type of radiotherapy used in treating cancer. The dose and fractionation of the radiotherapy is individualized based on the physician’s assessment of goals of care, symptoms, sites of disease, performance status, and logistical considerations. In certain embodiments, the radiotherapy is administered at a dose of about 3 Gy to 8 Gy fractions over 1 day to 2 weeks to 1.8 Gy to 3 Gy fractions over 3 to 7 weeks, or at a total dose of 5 to 100 Gy, such as a total dose of 8 to 30 Gy or 30-70 Gy, over 1 day to 8 weeks. In certain embodiments, the total dose of the radiotherapy is about 8 to about 30 Gy. In other certain embodiments, the total dose of the radiotherapy is about 30 to about 70 Gy. In certain embodiments, the radiotherapy is administered at a dose of about 6 Gy for about 3-7 days, preferably about 5 days. In certain embodiments, the radiotherapy is administered at a dose of about 8 Gy for about 2-4 days, preferably about 3 days. In certain embodiments, the radiotherapy is administered once per day or once every other day. In certain embodiments, the radiotherapy is started after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof, particularly, the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the first administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. In certain embodiments, the administration of the anti-PD-1 antibody or the antigen- binding fragment thereof is started after the radiotherapy is completed, particularly about 3-10 days, preferably about 5-7 days, after the radiotherapy is completed. In certain embodiments, the human subject is in need of a cancer treatment. In some embodiments, the cancer is lung cancer. Docket No: KAD6025WOPCT In one embodiment, the invention provides a method of treating lung cancer in a human subject in need thereof, comprising: (1) orally administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I a pharmaceutically acceptable of Formula I or the pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and (2) subcutaneously administering to the subject an anti-PD-1 antibody or an antigen- binding fragment thereof, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered with a loading dose of about 900 mg, followed by an effective dose of about 600 mg once every three weeks. In certain embodiments, the pharmaceutical composition is orally administered once per day or twice per day. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, or 60 mg. In certain embodiments, the pharmaceutical composition is orally administered twice per day. Docket No: KAD6025WOPCT In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 1 mg, 2 mg, 5 mg, 15 mg, or 30 mg. In certain embodiments, the pharmaceutical composition comprises the compound of Formula I. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof 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. In certain embodiments, the radiotherapy is administered at a dose of about 3 Gy to 8 Gy fractions over 1 day to 2 weeks to 1.8 Gy to 3 Gy fractions over 3 to 7 weeks, or at a total dose of 5 to 100 Gy, such as a total dose of 8 to 30 Gy or 30-70 Gy, over 1 day to 8 weeks. In certain embodiments, the total dose of the radiotherapy is about 8 to about 30 Gy. In other certain embodiments, the total dose of the radiotherapy is about 30 to about 70 Gy. In certain embodiments, the radiotherapy is administered at a dose of about 6 Gy for about 3-7 days, preferably about 5 days. In certain embodiments, the radiotherapy is administered at a dose of about 8 Gy for about 2-4 days, preferably about 3 days. In certain embodiments, the radiotherapy is administered once per day or once every other day. Docket No: KAD6025WOPCT In certain embodiments, the radiotherapy is started after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof, particularly, the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the first administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. In certain embodiments, the administration of the anti-PD-1 antibody or the antigen- binding fragment thereof is started after the radiotherapy is completed, particularly about 3-10 days, preferably about 5-7 days, after the radiotherapy is completed. In one embodiment, the invention provides a method of treating lung cancer in a human subject in need thereof, comprising: (1) orally administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I a pharmaceutically acceptable of Formula I or the pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and (2) administering a radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8Gy for about 2 to 7 days, and the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition is orally administered once per day or twice per day. Docket No: KAD6025WOPCT In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, or 60 mg. In certain embodiments, the pharmaceutical composition is orally administered twice per day. In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 1 mg, 2 mg, 5 mg, 15 mg, or 30 mg. In certain embodiments, the pharmaceutical composition comprises the compound of Formula I. In certain embodiments, the total dose of the radiotherapy is about 8 to about 30 Gy. In other certain embodiments, the total dose of the radiotherapy is about 30 to about 70 Gy. In certain embodiments, the radiotherapy is administered at a dose of about 6 Gy for about 3-7 days, preferably about 5 days. In certain embodiments, the radiotherapy is administered at a dose of about 8 Gy for about 2-4 days, preferably about 3 days. In certain embodiments, the radiotherapy is administered once per day or once every other day. In certain embodiments, the method further comprises administering to the subject a checkpoint inhibitor, such as an anti-PD-L1 antibody, an anti-PD-1 antibody or an antigen- binding fragment thereof. Preferably, the method further comprises administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof. Docket No: KAD6025WOPCT In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof 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. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered with a loading dose of about 900 mg, followed by an effective dose of about 600 mg once every three weeks. In certain embodiments, the administration of the anti-PD-1 antibody or the antigen- binding fragment thereof is started after the radiotherapy is completed, particularly about 3-10 days, preferably about 5-7 days, after the radiotherapy is completed. In one embodiment, the invention provides a method of treating lung cancer in a human subject in need thereof, comprising: (1) orally administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I a pharmaceutically acceptable of Formula I or the Docket No: KAD6025WOPCT pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; (2) administering a radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8Gy for about 2 to 7 days, and the radiotherapy is started about 1-10 days, preferably about 3-10 days, more preferably about 3 days, after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof; and (3) subcutaneously administering to the subject an anti-PD-1 antibody or an antigen- binding fragment thereof, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof is subcutaneously administered with a loading dose of about 900 mg, followed by an effective dose of about 600 mg once every three weeks, and the administration of the anti-PD-1 antibody or the antigen-binding fragment thereof is started after the radiotherapy is completed, particularly about 3-10 days, preferably about 5-7 days, after the radiotherapy is completed. In certain embodiments, the pharmaceutical composition is orally administered once per day or twice per day. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. In certain embodiments, the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, or 60 mg. In certain embodiments, the pharmaceutical composition is orally administered twice per day. In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between. Docket No: KAD6025WOPCT In certain embodiments, the pharmaceutical composition is orally administered twice per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 1 mg, 2 mg, 5 mg, 15 mg, or 30 mg. In certain embodiments, the pharmaceutical composition comprises the compound of Formula I. In certain embodiments, the total dose of the radiotherapy is about 8 to about 30 Gy. In other certain embodiments, the total dose of the radiotherapy is about 30 to about 70 Gy. In certain embodiments, the radiotherapy is administered at a dose of about 6 Gy for about 3-7 days, preferably about 5 days. In certain embodiments, the radiotherapy is administered at a dose of about 8 Gy for about 2-4 days, preferably about 3 days. In certain embodiments, the radiotherapy is administered once per day or once every other day. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8. In certain embodiments, the anti-PD-1 antibody or the antigen-binding fragment thereof 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. According to the embodiments of the invention, the pharmaceutical composition of the compound of Formula I or the pharmaceutically acceptable salt thereof typically contains a therapeutically effective amount of the compound of Formula I or the pharmaceutically acceptable salt thereof. Those skilled in the art will recognize, however, that a pharmaceutical composition can contain more than a therapeutically effective amount, e.g., bulk compositions, Docket No: KAD6025WOPCT or less than a therapeutically effective amount, e. g., individual unit doses designed for multiple administration to achieve a therapeutically effective amount. The pharmaceutical compositions can further comprise a pharmaceutically acceptable carrier. As used herein, the term “carrier” refers to any excipient, diluent, buffer, stabilizer, or other material well known in the art for pharmaceutical formulations. Pharmaceutically acceptable carriers in particular are non-toxic and should not interfere with the efficacy of the active ingredient. The pharmaceutically acceptable carriers include excipients and / or additives suitable for use in the pharmaceutical compositions known in the art, e.g., as listed in “Remington: The Science & Practice of Pharmacy”, 19th ed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52nd ed., Medical Economics, Montvale, N.J. (1998), the disclosures of which are entirely incorporated herein by reference. Any conventional carrier or excipient may be used in the pharmaceutical compositions of the invention. The choice of a particular carrier or excipient, or combinations of carriers or excipients, will depend on the mode of administration being used to treat a particular patient or type of medical condition or disease state. In this regard, the preparation of a suitable pharmaceutical composition for a particular mode of administration is well within the scope of those skilled in the pharmaceutical arts. Additionally, the carriers or excipients used in the pharmaceutical compositions of this invention are commercially-available. By way of 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). Representative examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, such as microcrystalline cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; 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 glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free Docket No: KAD6025WOPCT water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical compositions. The pharmaceutical compositions of the disclosure are preferably packaged in a unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable for dosing a patient, i.e., each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect either alone or in combination with one or more additional units. For example, such unit dosage forms may be capsules, tablets, pills, and the like, or unit packages suitable for parenteral administration. According to the embodiments of the invention, suitable pharmaceutical compositions for oral administration can be in the form of capsules, tablets, pills, lozenges, cachets, dragees, powders, granules; or as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as an elixir or syrup; and the like; each containing a predetermined amount of a compound of the present disclosure as an active ingredient. In some embodiments, the pharmaceutical composition comprising the compound of Formula I or the pharmaceutically acceptable salt hereof is a tablet. The antibodies disclosed herein can be produced from a host cell. A host cell refers to a vehicle that includes the necessary cellular components, e.g., organelles, needed to express the polypeptides and constructs described herein from their corresponding nucleic acids. The nucleic acids may be included in nucleic acid vectors that can be introduced into the host cell by conventional techniques known in the art (e.g., transformation, transfection, electroporation, calcium phosphate precipitation, direct microinjection, infection, etc.). The choice of nucleic acid vectors depends in part on the host cells to be used. Generally, host cells are of either prokaryotic (e.g., bacterial) or eukaryotic (e.g., mammalian) origin. The antibodies disclosed herein can be administered in pharmaceutical compositions that include 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. Acceptable carriers and excipients in the pharmaceutical compositions are nontoxic to recipients at the dosages and concentrations employed. Acceptable carriers and excipients may include buffers, antioxidants, preservatives, polymers, amino acids, and carbohydrates. Pharmaceutical compositions can be administered parenterally in the form of an injectable formulation. Pharmaceutical compositions for injection can be formulated using a sterile solution Docket No: KAD6025WOPCT or any pharmaceutically acceptable liquid as a vehicle. Pharmaceutically acceptable vehicles include, but are not limited to, sterile water, physiological saline, and cell culture media (e.g., Dulbecco’s Modified Eagle Medium (DMEM), α-Modified Eagles Medium (α-MEM), F-12 medium). Formulation methods are known in the art, see e.g., Banga (ed.) Therapeutic Peptides and Proteins: Formulation, Processing and Delivery Systems (2nded.) Taylor & Francis Group, CRC Press (2006). In some embodiments, the antibodies useful for a method of the application can be packaged in one or more kits, which can optionally contain instructions for use. In some embodiments, the lung cancer is non-small cell lung cancer. In some embodiments, the lung cancer is locally advanced or metastatic non-small cell lung cancer. In some embodiments, the lung cancer is histologically or cytologically confirmed stage IIIB-IV NSCLC. In some embodiments, the human subject had received at least one prior therapy. In some embodiments, 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. In some embodiments, the non-small cell lung cancer has a genetic mutation, preferably mutation of EGFR, ALK, ROS1, BRAF. In some embodiments, the human subject has an ECOG performance status of 0 or 1. In some embodiments, the human subject has creatinine clearance rate > 50 mL / min using the Cockcroft-Gault method during the screening period and within 72 hours of the start of administration of the method. In some embodiments, the human subject has adequate liver function which includes human subjects who have: • AST <3 x ULN • ALT <3 x ULN • Total bilirubin <1.5 x ULN (isolated total bilirubin ≥1.5 x ULN with conjugated [direct] bilirubin <1.5 x ULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemias). or Docket No: KAD6025WOPCT • AST <5 x ULN • ALT <5 x ULN • Total bilirubin <3 x ULN (isolated total bilirubin ≥3 x ULN with conjugated [direct] bilirubin <1.5 x ULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemias). In some embodiments, the human subject has • ANC ≥1,000 / μL • Platelets ≥75,000 / μL • Hgb ≥9.0 g / dL or ≥5.6 mmol / L. In some embodiments, the subject does not meet any of the exclusion criteria listed in Example 1 of this application. In some embodiments, the method does not result in a serious adverse effect. In certain embodiments, the serious adverse effect is selected from the group consisting of death, life-threatening event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability / incapacity, a congenital anomaly / birth defect, a suspected transmission of any infectious agent via a medicinal product, and a medically important event. In some embodiments, the method does not result in clinically significant changes from the predose baseline in a physical examination, an Eastern Cooperative Oncology Group (ECOG) performance status scale, a vital sign, an echocardiograph (ECHO) scan, a multigated acquisition (MUGA) scan, an electrocardiogram (ECG), a laboratory assessment, or a pregnancy testing. In some embodiments, the method does not induce a Dose Limiting Toxicity (DLT) in the subject. In certain embodiments, the DLT rate does not exceed 30% in a cohort of at least 3 subjects. In certain embodiments, the DLT is hematologic toxicity or non-hematological toxicity, and the hematologic toxicity is preferably neutrophil count decreased, platelet count decreased, or any hematological toxicity of Grade 5, and the non-hematologic toxicity is preferably any non-hematological toxicity of Grade ≥3. Docket No: KAD6025WOPCT In some embodiments, the human subject has no disease progression confirmed by iRECIST. In some embodiments, the method provides one or more events of efficacy selected from the group consisting of objective response rate (ORR), complete response rate (CRR), duration of response (DOR), disease control rate (DCR), where ORR is defined per RECIST v1.1 and iRECIST. In another general aspect, the invention presents a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the method of any of the foregoing embodiments. In one another general aspect, the invention presents a check point inhibitor, particularly, an anti-PD-1 antibody or an antigen fragment thereof for use in the method of any of the foregoing embodiments. In one another general aspect, the invention presents a radiotherapy for use in the method of any of the foregoing embodiments. EXAMPLES Example 1: Efficacy Studies of the Compound of Formula (I) In vivo efficacy of the compound of Formula I was evaluated in 3 different immune competent syngeneic mouse cancer models: CT-26 colon carcinoma, EG7-OVA lymphoma, and B16F10 melanoma models. CT-26 colon carcinoma model The efficacy of the compound of Formula I was demonstrated in the CT-26 tumor model (BALB / c background) where animals were treated from tumor implantation. The compound of Formula I administered every 12 hours (BID) at 30 mg / kg, but not 10 mg / kg, caused significant inhibition of tumor growth both in monotherapy as well as in combination with immune- checkpoint blockade (anti-mPD-1). In pCREB assay, 30 mg / kg BID dose of the compound of Formula I was required to provide >90% target engagement at trough concentration, whereas a 10 mg / kg BID dose only resulted in 75% target engagement thus establishing a PK / PD correlation. Next, the compound of Formula I alone and / or in combination with anti-mPD-1 was evaluated for its ability to enhance response to radiation in a clinically relevant setting. A small animal radiation research platform (SARRP) was used to deliver stereotactic body radiation Docket No: KAD6025WOPCT therapy (SBRT) in mouse tumor models mimicking that applied in human patients. A sub- ablative radiation dose was used for the efficacy studies based on its capacity to trigger initial immunogenic cell death with effector NK and CD8+ T cell activation, but failed to induce a sustained antitumoral response. A dose of 30 mg / kg the compound of Formula I given orally BID was selected for the first combination study with biweekly anti-PD-1 (10 mg / kg intraperitoneal [IP] injection) and radiation. CT-26 colon carcinoma cells were implanted in female BALB / c mice and treatment started when mean tumor volume was approximately 100 mm3and continued for 18 days with the compound of Formula I and for 2 weeks with anti-mPD-1. The radiation dose selected was a single fraction of 5 Gy administered 1 day post-start of the compound of Formula I and anti-PD- 1 dosing. All treatments were well tolerated with minimal body weight loss. Analysis of delta tumor growth inhibition (dTGI) was performed on Day 24 when 2 / 3 or more animals remained in each group. Tumor volume (mm3) was assessed as (L*W2) / 2, where L and W are the respective orthogonal tumor length and width measurements (mm), and compared to the volume of tumor at the start of dosing. dTGI is calculated as % difference between baseline corrected mean tumor volume of the treatment and control groups: dTGI = ([(TVc-TVc0)-(TVt- TVt0)] / [TVc-TVc0])×100, where ‘TVc’ is the mean tumor volume of a control group, ‘TVc0’ is the mean tumor volume of a 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. If tumor regression (TR) occurs and volume decreases compared to the start of treatment, greater than 100% dTGI is achieved. Monotherapy treatment of the compound of Formula I failed to produce anti-cancer activity, with tumor growth similar to the control group. In contrast, anti-mPD-1 monotherapy showed a significant dTGI of approximately 33% and the combination of anti- mPD-1 + the compound of Formula I reached a dTGI of approximately 69%. Treatment of radiation + anti-mPD-1 was efficacious with 86.8% dTGI, radiation + the compound of Formula I with 101.1% dTGI and 31.9% TR, and radiation + anti-mPD-1+ the compound of Formula I with 107.73% TGI and 95.8% TR on Day 24. In the survival analysis at the end of the study (Day 119), treatment with radiation in combination with anti-mPD-1 or the compound of Formula I was efficacious with increased survival and incidence of complete tumor regression of 57.4% and 62.5%, respectively. Triple Docket No: KAD6025WOPCT combination of radiation + anti-mPD-1 + the compound of Formula I was highly efficacious, with 100% of mice classified as tumor free survivors (TFS) at the end of the study. All TFS mice were transferred to a rechallenge study in which tumor cells were injected into the animals 120 days after the initial engraftment. Importantly, none of the rechallenged animals with subcutaneous implantation of CT-26 cells developed tumors suggesting a durable systemic anti- tumor T cell memory response. EG7-OVA lymphoma model Similar results were obtained in the EG7-OVA lymphoma model. The compound of Formula I (30mg / kg) was dosed p.o. BID for 28 days. Anti-mPD-1 (5mg / kg) was dosed IP bi- weekly for 2 weeks. Treatment with the compound of Formula I and anti-PD-1 initiated when mean tumor volume per group was aproximately100 mm3(Day 7). 5 Gy single dose radiation was given 1-day post-staging. Analysis of dTGI was performed on Day 20, a time point when at least 2 / 3 of the animals were still alive in all the groups. Radiation monotherapy resulted in dTGI of 90.8%, and similar responses were observed in all the radiation combinations. The anti-tumor activity of radiation alone was not sustained, and tumors escaped the treatment effect after Day 20. In this context, radiation combinations promoted a more sustained anti-tumor response. When dTGI was analyzed on Day 30, only radiation-containing arms had more than 2 / 3 of the animals remaining on the study. At this time point and using radiation monotherapy as a comparator, a dTGI of 90.7% was observed with radiation + the compound of Formula I, 85.7% with radiation + anti- mPD-1 and 111.6% in the radiation + anti-mPD-1+ the compound of Formula I group. At the end of the study (Day 110), only 20% of the animals remained tumor-free in the radiation monotherapy group whereas 90% of animals were TFS in radiation + anti-mPD-1 or radiation + the compound of Formula I groups and 100% of animals were TFS in the radiation + anti-mPD-1 + the compound of Formula I group. None of the animals developed tumors when rechallenged with a second sub-cutaneous EG7-OVA tumor implantation further demonstrating, a durable systemic anti-tumor T cell memory response. B16F10 melanoma model The efficacy of the compound of Formula I alone or in combination with anti-mPD-1 and / or radiotherapy was evaluated in a third tumor model, B16F10 melanoma in a C57BL / 6 mouse background characterized by a very rapid and aggressive tumor growth with very low Docket No: KAD6025WOPCT basal T cell infiltration and being refractory to anti-mPD-1. The compound of Formula I (30mg / kg) was dosed p.o. BID for 21 days. Anti-mPD-1 (10mg / kg) was dosed IP bi-weekly for 2 weeks. Treatments with the compound of Formula I and anti-PD-1 initiated when mean tumor volume per group was100 mm3(Day 9). 10 Gy single dose of radiation was given 1 day later. All treatments were well tolerated, with no adverse clinical signs or significant changes in body weight. Analysis of TGI was performed on Day 17 where at least 2 / 3 of the animals were still present in all the groups. Monotherapy treatment with anti-mPD-1 or the compound of Formula I or with the combination of anti-mPD-1 + the compound of Formula I failed to produce any anti- cancer activity, with tumor growth kinetics similar to the control (vehicle) group. All the radiation-treated groups showed significant TGI compared to the vehicle, but no tumor regression was observed. Radiation monotherapy resulted in a moderate TGI of 40.5% whereas all the radiation combinations were more efficacious with TGI of 59.2%, 71.3% and 61.7% in radiation + the compound of Formula I, radiation + anti-mPD-1, and radiation + anti-mPD-1 + the compound of Formula I, respectively. Radiation monotherapy had a moderate effect on survival with only a 10% increase in lifespan with respect to the vehicle group. On the other hand, both radiation + anti-mPD-1 and radiation +the compound of Formula I combinations demonstrated a significantly longer survival (increase in lifespan of 55% and 45%, respectively). The triple combination of radiation + anti- mPD-1 + the compound of Formula I had the highest increase in lifespan with respect to the control group (75%). A multiple comparison of the different treatments was performed, which confirmed that the triple combination increased the survival significantly not only with respect to the vehicle group but also with respect to the radiation monotherapy. Example 2: A Phase 1 Study of a Compound of Formula (I), administered as monotherapy and in combination with cetrelimab and radiotherapy, for advanced non- small cell lung cancer This clinical study will be the first in human (FIH), open label, multicenter, and dose escalation study of a compound of Formula I in participants with advanced / metastatic non-small cell lung cancer (NSCLC). The purpose of this study is to evaluate the safety, PK, and PD of the Docket No: KAD6025WOPCT compound of Formula I administered as a monotherapy, in combination with cetrelimab, and in combination with cetrelimab and RT in the participants. This study will be conducted in two parts. In Part 1, the compound of Formula I will be administered in combination with cetrelimab, while in Part 2, the compound of Formula I will be administered in combination with cetrelimab and RT. The goal of the study is to identify a dose of the compound of Formula I which will provide an acceptable PK / PD profile and is safe and tolerable when combined with cetrelimab and RT. The study will also evaluate preliminary efficacy of the compound of Formula I in combination with cetrelimab and in combination with cetrelimab and RT to inform further development. Objectives and Endpoints Table 1 Objective Endpoints Primary To determine safe and tolerable dose(s) of the Incidence and severity of adverse events, compound of Formula I for further investigation including DLT in combination with cetrelimab and RT Secondary To characterize PK of the compound of Formula I Plasma concentration-time profiles and PK parameters **To assess efficacy of the compound of Formula ORR, CRR, DOR, DCR per RECIST v I in combination with cetrelimab and RT in 1.1 and iRECIST participants with NSCLC in Part 2 Exploratory • To characterize PD target engagement of the compound of Formula I by assessing pCREB inhibition in blood. • To explore the relationships between exposure, AEs, PD, and clinical activity of the compound of Formula I. • To assess the PK and immunogenicity of cetrelimab SC when administered with the compound of Formula I. • To explore the relationships between fed and fasting dosing conditions with PK, PD, and other endpoints. • To explore the metabolite profile of the compound of Formula I in plasma. • To explore plasma 4β-hydroxycholesterol as an endogenous marker of CYP3A activity. Docket No: KAD6025WOPCT • To evaluate biomarkers of pharmacology and response to the compound of Formula I, alone and in combination with RT and cetrelimab, in tumor and blood. • Part 1: To assess efficacy of the compound of Formula I in combination with cetrelimab in participants with NSCLC as measured by RECIST v1.1 and iRECIST. • Part 2: To evaluate PFS of participants receiving the compound of Formula I, cetrelimab and RT. Methods and Subjects Part 1 – Compound of Formula (I) + Cetrelimab Approximately 3~4 dose cohorts consisting of at least 3 participants each, will be enrolled sequentially. In each dose cohort, participants will receive treatment with a designated dose of the compound of Formula I and a fixed dose of cetrelimab. In each dose cohort, participants will first receive monotherapy with the compound of Formula I for 21 days and individual participants will be evaluated for dose limiting toxicities (DLTs) (monotherapy DLT). If no DLTs are reported for individual participants and in agreement with the sponsor, the participant will begin cetrelimab treatment (cetrelimab to start on Day 22) in combination with the compound of Formula I following which a combination DLT period of 21 days will be observed. Once a dose level is determined by the study evaluation team (SET) to be safe as monotherapy (i.e., SET review after a minimum of 3 participants complete the monotherapy DLT observation period), participants may be enrolled in the subsequent dose cohorts to receive monotherapy regimen with the compound of Formula I as guided by the Bayesian optimization interval (BOIN) design with a target DLT rate of 30%. The first administered dose of the compound of Formula I will be 5 mg QD, anticipated to achieve approximately 81% target inhibition at trough concentrations based on nonclinical evaluation, toxicology assessments, and human PK / PD modeling. If the BOIN model recommends de-escalation from this dose level, the Sponsor may evaluate a dose of 2 mg and / or BID dosing. The dose escalation will be 15 mg, 30 mg, and 60 mg. Cetrelimab will be administered subcutaneously every 3 weeks, with a loading dose of 900 mg followed by subsequent doses of 600 mg. BID dosing may be explored as an intermediate de-escalation based on the totality of data observed including DLTs at the same dose level, inadequate trough PK concentrations, and insufficient PD. In this case, subsequent dose escalation will continue as BID. Docket No: KAD6025WOPCT Participants in all dose cohorts will receive treatment with the compound of Formula I and cetrelimab for up to 2 years from the first study treatment administration or until confirmed disease progression by iRECIST, unequivocal clinical progression, unacceptable toxicity, investigator’s decision to discontinue, consent withdrawal, start of a subsequent anticancer therapy, pregnancy, loss to follow-up, or study termination by the sponsor. The goal of Part 1 is to determine a dose of the compound of Formula I which provides an acceptable PK / PD profile and is safe and tolerable when combined with cetrelimab for further evaluation in Part 2. If no dose level exceeds the target DLT rate of 30%, then the highest dose tested will be the maximum administered dose (MAD). The SET will review the available data and determine the dose to be evaluated in Part 2. At least 6 participants should have been observed through both the monotherapy and combination DLT evaluation periods at the provisional recommended dose level prior to Part 2 start. Determination of Food Effect Throughout the trial, the compound of Formula I will be dosed under semi-fasting condition in which food should not be consumed 2 hours before and 1 hour after the compound of Formula I administration (unless otherwise instructed by the SET based on emerging data). A limited number of participants (approximately 10 in a Part 1 cohort at the dose level selected for Part 2) will take part in the preliminary assessment of food effect on the PK of the compound of Formula I. On the 2 days selected for the food effect assessment (planned as Cycle 1 Day 8 and Day 9), participants will fast overnight for at least 8 hours before the compound of Formula I intake. On the fasted assessment day (planned as Cycle 1 Day 8), participants will remain fasting for 4 hours after the compound of Formula I administration. On the day of the high-fat meal assessment (planned as Cycle 1 Day 9), participants will be dosed 30 minutes after the start of a high-fat breakfast. Part 2 – Compound of Formula (I) + Cetrelimab + RT Once a safe dose combination of the compound of Formula I and cetrelimab is identified and acceptable for further investigation, and based upon the SET decision, the combination of the compound of Formula I, cetrelimab, and RT will be investigated in Part 2 of this study. Up to 60 participants will be enrolled. Cohort A of Part 2 will consist of participants with advanced metastatic NSCLC, with tumors characterized as being PD-L1 <1% at initial diagnosis, and who have progressed after Docket No: KAD6025WOPCT treatment with anti-PD-1 and chemotherapy. Cohort B will consist of participants with treatment-naïve metastatic NSCLC with PD-L1 ≥50%, and who are eligible for standard of care anti-PD1 monotherapy. Cohort A in part 2 will be initiated with a safety run-in of 6 participants treated with the combination of the compound of Formula I, cetrelimab, and RT. Additional participants in cohorts A and B will be enrolled only after the first 6 participants in Cohort A have been treated with the combination of the compound of Formula I, RT and cetrelimab, completed all study evaluations up to the end of Cycle 2, and approval is granted by sponsor, upon review by the SET of all reported safety data. If the safety profile is not acceptable, then additional cohorts may be added to investigate a lower dose of the compound of Formula I (which may include a BID dose) in combination with cetrelimab and RT or additional dose regimens, as needed. An initial 15 participants will be enrolled into each cohort, with potential expansion to approximately 30 participants in each cohort, by SET decision, based on observed safety, preliminary efficacy and biomarker data. Participants may be added to Cohorts A and B based on emerging data. Additional expansion cohorts may also be added via a protocol amendment. Starting on Day 1 Cycle 1, participants will receive a daily dose of the compound of Formula I identified in Part 1. On Day 3 (+7) of Cycle 1, participants will begin RT, and cetrelimab will be administered Q3W starting 5 –7 days after completion of RT. One of the following 2 RT regimens will be selected by the investigator, based on location of lesion(s) and clinical judgment: • 6 Gy x 5 days (may be delivered daily or every other day) • 8 Gy x 3 days (may be delivered daily or every other day) RT is to be administered per standard radiation oncology guidelines and further instructions are provided in the RT guidance document. A consultation with the sponsor may be conducted if desired to finalize RT dose selection and radiation field(s) or if there is a concern with lesions in close proximity to vital structures. If RT administration takes longer than 1 week, a radiation oncologist should perform weekly directed physical exams and assess the participant’s weight. Lymph nodes should not be target lesions for radiation and must be excluded from the direct field of irradiation if possible and clinically acceptable. If lymph nodes cannot be excluded from the direct field of radiation, this must be documented with reasons. RT regimen will be administered as a single course during study treatment. Additional RT is permitted at later times Docket No: KAD6025WOPCT during study treatment if clinically indicated. If used, the clinical indication for palliative RT, the timing, site, number of lesions irradiated and doses of RT used must be clearly documented. For participants with multiple lesions (e.g., lung, liver), as many lesions as clinically indicated and technically feasible should be irradiated, with a maximum of 3 lesions per day, and keeping in mind that there should be one target lesion that is not irradiated and will be used for RECIST v1.1 assessment. The protocol aims to irradiate lesions in multiple locations, including thoracic, extrathoracic, and bone. Additional details on how radiation will be delivered will be detailed in a separate radiation manual. Similar to Part 1, participants in Part 2 may receive treatment with the compound of Formula I and Cetrelimab for up to 2 years from the first study treatment administration or until confirmed disease progression by iRECIST, unequivocal clinical progression, unacceptable toxicity, investigator’s decision to discontinue, consent withdrawal, start of a subsequent anticancer therapy, pregnancy, loss to follow-up, or study termination by the sponsor. Determination of Relative Bioavailability The oral tablet formulation used in Part 2 consists of fine jet-milled compound of Formula I. To facilitate optimization of the tablet formulation for future studies and commercialization, the relative bioavailability of a prototype formulation with coarse milled drug product may be evaluated in Part 2. A limited number of participants (approximately 10 participants in Part 2) will take part in the relative bioavailability assessment. This PK run-in phase evaluation will be conducted between 7 to 10 days before the start of Cycle 1 of the treatment phase. A single dose of the compound of Formula I with the prototype formulation will be administered on Day 1 of the PK run-in phase and samples will be collected on run-in Days 1 – 5. Participants will then begin administration of formulation fine jet-milled drug product starting Cycle 1 Day 1. On the 2 days selected for the relative bioavailability assessment (planned as Day 1 of PK run-in phase and Day 1 of Cycle 1), participants will fast overnight for at least 8 hours before the intake of the compound of Formula I. There will be at least 7 days between the run-in phase Day 1 and Cycle 1 Day 1. Based on ongoing review of evolving data, the number of participants enrolled can be increased (e.g. testing additional prototypes) or decreased (e.g. if less than 10 participants are deemed sufficient). Should the PK profiles of the milled and coarse tablets not be comparable, additional milled tablets to may be tested. Inclusion Criteria Docket No: KAD6025WOPCT Each potential participant must satisfy all of the following criteria to be enrolled in the study. Inclusion Criteria for Part 1 and Part 2: 1. Be ≥18 years of age at the time of signing the informed consent or be of legal age of consent in the jurisdiction in which the study is taking place. 2. Individuals with histologically or cytologically confirmed stage IIIB-IV NSCLC. 3. For Part 1 and Cohort A of Part 2: Participants lacking actionable genetic mutations must have been previously treated with: (a) anti-PD-1 / PD-L1 therapy; and (b) platinum-based chemotherapy, either as combination or sequentially for metastatic disease or developed metastatic disease within a year and have progressed on or after therapy. Individuals who cannot tolerate or have previously refused platinum-based chemotherapy or who or are unable to receive it are eligible to enroll based on progression after anti-PD-1 / PD-L1 therapy alone. Individuals who have previously refused platinum-based chemotherapy in consultation with their health care professional may participate as long as documentation of the medical endorsement for their decision is provided. For Cohort B of Part 2: • have not received previous systemic therapy for metastatic disease. Participants who have received 1 dose of anti-PD-(L)1 treatment (first dose of standard of care) may be eligible as long as they (a) have not had any disease assessment scans after anti-PD-(L)1 administration AND (b) are able to complete all screening assessments and begin study treatment at the time of the next scheduled anti-PD-(L)1 administration (+ / - 4 days). • have never received anti-PD-(L)1 or anti-CTLA4 therapy except as described in the bullet point above. 4. For Part 1: NSCLC with a known actionable genetic mutation (e.g., EGFR, ALK, ROS1, BRAF) must have received all approved targeted therapies and have progressed. Participants with unknown mutation status due to a failed testing status or lack of access to testing are allowed in the study. For Part 2: see exclusion criteria. Cohort-specific criteria are outlined below: Docket No: KAD6025WOPCT • Cohort A: have a PD-L1 <1% tumor expression based on the results of local testing performed in a CLIA-certified laboratory at the time of initial diagnosis • Cohort B: have a PD-L1 >50% tumor expression local testing performed in a CLIA-certified laboratory at the time of initial diagnosis Can have a prior or concurrent second malignancy (other than the disease under study), which due to natural history or treatment is unlikely to interfere with any study endpoints of safety or the efficacy of the study treatment(s). Consultation with the sponsor is required in such cases prior to enrollment. Have an ECOG performance status of 0 or 1 (see Section 10.8). Have creatinine clearance rate > 50 mL / min using the Cockcroft-Gault method during the screening period and within 72 hours of the start of administration of study treatment. Adequate liver function: a. Participants with no underlying hepatic metastases are eligible if they have: • AST <3 x ULN • ALT <3 x ULN • Total bilirubin <1.5 x ULN (isolated total bilirubin ≥1.5 x ULN with conjugated [direct] bilirubin <1.5 x ULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemias). b. Participants with known hepatic metastases are eligible if they have: • AST <5 x ULN • ALT <5 x ULN • Total bilirubin <3 x ULN (isolated total bilirubin ≥3 x ULN with conjugated [direct] bilirubin <1.5 x ULN is allowed for those participants with known congenital nonhemolytic hyperbilirubinemias) Hematology laboratory parameters within the following range, independent of transfusion or growth factors within 1 week prior to first dose of study treatment: Docket No: KAD6025WOPCT • ANC ≥1,000 / μL • Platelets ≥75,000 / μL • Hgb ≥9.0 g / dL or ≥5.6 mmol / L Left ventricular ejection fraction within the institutional limits. A participant of childbearing potential must have a negative highly sensitive serum (β-hCG) pregnancy test at screening and within 72 hours prior to the first dose of study treatment. They must agree to further serum or urine pregnancy tests during study treatment. A participant of childbearing potential must practice at least 2 highly effective methods of contraception from the first dose through at least 6 months after the last dose of the compound of Formula I and through at least 5 months after the last dose of cetrelimab. Male participants must agree to follow instructions for acceptable contraception use from the first dose through at least 95 days after the last dose of the compound of Formula I and through at least 5 months after the last dose of cetrelimab. A female participant must agree to not get pregnant, breastfeed, or plan to become pregnant while enrolled in this study or within 6 months after the last dose of the compound of Formula I or 5 months after the last dose of cetrelimab, whichever is longer. A participant must agree not to donate gametes (i.e., eggs or sperm) or freeze for future use for the purposes of assisted reproduction during the study and for a period of at least 5 months after the last dose of cetrelimab and at least 6 months (female eggs) or 95 days (male sperm) after the last dose of the compound of Formula I. Participants should consider preservation of gametes prior to study treatment as anti- cancer treatments may impair fertility. A male participant must agree to not plan to father a child while enrolled in this study and through at least 95 days after the last dose of the compound of Formula I and through at least 5 months after the last dose of cetrelimab. Must sign an ICF indicating that the participant understands the purpose of, and procedures required for, the study and is willing to participate in the study. Be willing and able to adhere to the lifestyle restrictions specified in this protocol. Docket No: KAD6025WOPCT Additional Inclusion Criteria for Part 2 Only: 18. Participants must have at least 3 lesions: • At least one lesion suitable for irradiation • At least one measurable lesion per RECIST 1.1 that has not received prior RT and is not planned for RT in the study a. At least one lesion suitable for biopsy 19. Agree to submit tumor samples prior to study treatment which can be an archival tumor tissue sample obtained within 3 months prior to start of treatment and without any therapy for NSCLC being administered within these 3 months, or newly obtained core or incisional biopsy of a tumor lesion during screening. 20. Response to prior anti-PD-1 antibody treatment was CR, PR, or SD for at least 3 months. Exclusion Criteria Any potential participant who meets any of the following criteria will be excluded from participating in the study. Exclusion Criteria for Part 1 and Part 2: 1. The participant is a candidate for a curative therapy for their disease. 2. Active disease involvement (e.g., primary central nervous system tumors, metastases, leptomeningeal disease) of the central nervous system with the exception of definitively, locally treated brain metastases that are clinically stable and asymptomatic for >2 weeks and who are off or receiving low dose corticosteroid treatment (≤10 mg prednisone or equivalent) for at least 2 weeks prior to start of study treatment. 3. Active autoimmune disease that requires systemic immunosuppressive medications (e.g., chronic corticosteroid, methotrexate, or tacrolimus) within the 12 months prior to signing consent. 4. Toxicity related to prior anticancer therapy that has not returned to Grade ≤1 or baseline levels (except for alopecia, vitiligo, Grade ≤2 peripheral neuropathy, and endocrinopathies that are stable on hormone replacement, which may be Grade 2). Docket No: KAD6025WOPCT History of irAEs from prior anticancer therapy leading to permanent treatment discontinuation. Known positive test result for HIV or other immunodeficiency syndrome. Active infection or condition that requires treatment with systemic anti-infective agents (e.g., antibiotics, antifungal or antivirals) within 7 days prior to the first dose of study treatment or chronic use of anti-infective agents. Note: Intermittent use of topical anti-infective agents is not exclusionary. History of solid organ or hematologic stem cell transplantation. Symptomatic herpes zoster within 3 months prior to screening. Prolonged corrected QT interval by Fredericia (QTcF) >470 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (e.g., placement of implantable cardioverter defibrillator or atrial fibrillation with uncontrolled rate or abnormalities in conduction or morphology of ECG [e.g., complete left bundle branch block, third- or second-degree heart block, PR interval >250 msec]). Any factors that increase the risk of corrected QT interval (QTc) prolongation or risk of arrhythmic events such as congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medications known to prolong QT interval or induce Torsades de Pointes. Note: Participants with cardiac pacemakers who are clinically stable are eligible. Note: Serum potassium, sodium, calcium and magnesium should be kept within normal limits while on study. Clinically significant cardiovascular disease, including any of the following within 6 months prior to signature of informed consent: a. Myocardial infarction, severe or unstable angina, or coronary artery bypass surgery b. Clinically significant arrhythmias (e.g., ventricular arrhythmias or atrial fibrillation with uncontrolled heart rate) c. Congestive heart failure (NYHA class III / IV) Docket No: KAD6025WOPCT d. Cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event e. Myocarditis Known allergies, hypersensitivity, or intolerance to excipients of the compound of Formula I Known allergies, hypersensitivity, or intolerance to cetrelimab excipients Active bleeding diathesis or requirement for therapeutic anticoagulation that cannot be interrupted or altered for procedures. Had a major surgery, (e.g., requiring general anesthesia) within 4 weeks before the first dose of study treatment, or will not have fully recovered from surgery prior to the first dose. Received immunosuppressive doses of systemic medications, such as corticosteroids (doses >10 mg / day prednisone or equivalent) within 7 days prior to the first dose of study treatment. A single course of corticosteroids is permitted, e.g., as allergy prophylaxis for imaging contrast. Received or plans to receive any live vaccine within 28 days before the first dose of study treatment, while on treatment or within 5 months after the last dose of study treatment. Non-live or non-replicating vaccines approved (e.g., influenza) or authorized for emergency use (e.g., COVID-19) by local health authorities are allowed. Participation in any other clinical trial within 30 days of first dose, which contained investigational product. Prior anti-PD-L1 or anti-CTLA4 therapy within 4 weeks or other anticancer therapy within 14 days before the first dose of study treatment. Prior treatment with adenosine pathway inhibitors (e.g., istradefylline (Nourianz), oleclumab, taminadenant, ciforadenant, etrumadenant, inupadenant, BMS-986179). Participant received treatment with proton pump inhibitors (PPIs) within 48 h prior to the first dose of the compound of Formula I or is unable to discontinue treatment with PPIs for the duration of the compound of Formula I administration. Active or chronic HBV or HCV infection: Docket No: KAD6025WOPCT • See Section 10.10 for instructions regarding HBV serologic testing requirements of HBV-specific antigens and antibodies in the full protocol. • HCV infection defined by a positive anti-HCV antibody. Participants who test positive for antibodies to HCV are eligible if HCV viral RNA load is undetectable (spontaneous recovery or after completing treatment for HCV infection). 23. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments. Additional Exclusion Criteria for Part 2 Only 24. NSCLC with an actionable genetic mutation for which an approved therapy is available: EGFR, ALK, ROS1, or BRAF. Confirmation of the absence of actionable mutations is required. 25. Participants with interstitial lung disease who have an oxygen saturation of ≤92% at rest or ≤88% with activity without supplemental oxygen or who have already been diagnosed with idiopathic pulmonary fibrosis. 26. In the opinion of the investigator, the participants received prior RT that precludes further radiation administration. Meals and Dietary Restrictions Food should not be consumed 2 hours before and 1 hour after the administration of the compound of Formula I unless otherwise instructed by the SET based on emerging data. Participants taking part in the relative bioavailability or food effect assessment will enter the PK run-in phase one week before the start of Cycle 1 of the treatment phase. Participants of the relative bioavailability assessment will be administered a single dose after an overnight for at least 8 hours on the two days of assessments (planned as Day 1 of PK run-in phase and Cycle 1 Day 1 before the intake of the compound of Formula I. Participants of the food effect assessment will undergo PK evaluations following dosing on 2 days, planned as Day 1 of PK run-in phase for the high-fat meal assessment and Day 1 of Cycle 1 for the fasted assessment. On the day of the high-fat meal assessment (planned as PK run-in phase Day 1), participants will consume a high calorie high fat breakfast after an Docket No: KAD6025WOPCT overnight fast for at least 8 hours; a single dose of the compound of Formula I will then be administered dosed 30 minutes after the start of a high-fat breakfast. On the fasted assessment day (planned as Cycle 1 Day 1), participants will be dosed after an overnight fast for at least 8 hours and will remain fasting for 4 hours after the administration of compound of Formula I. On the day of the relative bioavailability and food effect assessments (run in phase day 1 and Cycle 1 Day 1), water can be allowed as desired except for one hour before and after the drug administration. Study Treatments For this study, “study treatment” refers to the compound of Formula I, cetrelimab, and RT. the compound of Formula I and cetrelimab will be manufactured and provided under the responsibility of the sponsor. • the compound of Formula I: 1 mg, 5 mg, 15 mg, and 50 mg tablets (see Table 2 below), oral administration; • Cetrelimab: 300 mg pre-filled syringes, subcutaneous (SC) injection (see Table 3 below); and • RT: a medical device that will be administered in accordance with its intended use per institutional standard of care, and established oncology guidelines. Table 2: Qualitative Composition of the 1, 5, 15, and 50 mg Oral Tablets Component Function A compound of Formula I Active ingredient Silicified Microcrystalline Cellulose Filler Magnesium Stearate Lubricant Croscarmellose Sodium Disintegrant Silica, Colloidal Anhydrous Glidant Cetrelimab is supplied in a 300mg / syringe drug product. The 300 mg / syringe drug product is supplied as a sterile solution in a single-use pre-filled syringe (PFS) and does not contain a preservative. The PFS is composed of a BD Neopak™ 2.25-ml syringe with HyFlow™ 27G half-inch stainless steel needle, stoppered with Flurotec® plunger stopper. The DP is filled aseptically with 2.07 ml to deliver a nominal 300 mg in 2.0ml per syringe. The targeted composition is provided below in Table 3: Docket No: KAD6025WOPCT Table 3 Ingredient Function Nominal Amount Targeted Amount per syringe (300 per ml (mg / ml) mg / syringe)aCetrelimab Active 300 150 L-Histidine Buffer 2.30 1.15 L-Histidine Buffer 1.08 0.54 monohydrochloride monohydrate L-arginine Stabilizer 96.9 48.45 hydrochloride Polysorbate 80bSurfactant 1.00 0.5 EDTA Chelator 0.04 0.02 Water for injection Solvent q.s. q.s. a Amounts are calculated based on the measurements of drug substance batches and a nominal PFS fill volume of 2.0 mL b Super refined EDTA = ethylenediaminetetraacetic acid disodium salt dihydrate Alternatively, cetrelimab can be supplied in a sterile, lyophilized formulation reconstituted for subcutaneous injection and does not contain a preservative. The formulation is filled aseptically in a glass vial, lyophilized, sealed and stored at 5±3oC, protected from light. Each vial contains 90 mg per vial that after reconstitution is a 30 mg / mL solution of cetrelimab in 10 mM histidine, 8.0% (w / v) sucrose, 0.04% Polysorbate 20 (w / v), 20 µg / ml. EDTA, pH 6.5.The targeted composition is provided below in Table 4. Table 4 Ingredient Function Targeted Fill Targeted Amount Amount per vialaper ml (mg / ml)b(mg) Cetrelimab Active 99 30 L-Histidine Buffer 3.8 1.15 L-Histidine Buffer 1.78 0.54 monohydrochloride monohydrate Sucrose Stabilizer / Tonicifier 264 80 Polysorbate 20bSurfactant 1.32 0.4dEDTA, disodium Chelator 0.07 0.02 salt, dihydrate crystal Docket No: KAD6025WOPCT Water for injection Solvent Reconstitute with q.s. 3.0ml a The target fill volume is 3.3 mL. This includes 10% overfill to allow withdrawal of at least 90 mg / vial (3.0 mL volume) b Target amount per mL post reconstitution c Vegetable based; low peroxide d Estimated value is based on process addition. The actual concentration will be measured at a later stage in development. EDTA = ethylenediaminetetraacetic acid disodium salt dihydrate Study Assessments Efficacy Assessments Response will be assessed by radiographic image assessment including CT scans and MRI, per the RECIST v1.1 and iRECIST criteria. Safety and Tolerability Assessments Safety and tolerability will be assessed at pre-specified timepoints throughout the studies by physical examination, eastern cooperative oncology group (ECOG) performance status, vital signs measurements, echocardiography or MUGA scan, electrocardiograms (ECG) examinations, clinical safety laboratory tests, and pregnancy testing. Adverse Events Reporting All adverse events (AEs) and special reporting situations, whether serious or non-serious, will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally acceptable representative) for the duration of the study. Any AEs occurring outside the reporting period above but considered to be related to study treatment must be reported to the sponsor. Pharmacokinetic Assessments Plasma samples will be used to evaluate the PK of the compound of Formula I, and serum samples will be used to evaluate the PK of cetrelimab. Samples collected for PK may additionally be used to evaluate safety or efficacy aspects that address concerns arising during or after the study period or for the evaluation of relevant biomarkers. Genetic analyses will not be performed on these samples. Participant confidentiality will be maintained. Statistical Methods A target of approximately 12 to 36 participants will be treated across the dose escalation cohorts in Part 1. This number may increase if further evaluations of the doses are required. At least 6 participants will be treated at the identified safe dose to be used in Part 2 prior to initiation Docket No: KAD6025WOPCT of Part 2. However, the number of participants enrolled will depend on the rate of DLTs observed in each cohort and the corresponding decisions of the SET. Up to 40 participants will be treated in Part 2. This number is based on feasibility and may increase if additional cohorts are added via an amendment. Part 1 – Compound of Formula (I) + Cetrelimab The BOIN design will be implemented to guide the dose escalation. In this study, the target DLT rate is 30%; the optimal boundaries for dose escalation and de‑escalation are 0.236 and 0.359 in the BOIN design. .Part 2 – Compound of Formula (I) + Cetrelimab + RT Part 2 is an open-label, single arm cohort to evaluate the safety and preliminary efficacy of the combination of the compound of Formula I, RT, and cetrelimab. Up to 30 participants may be treated in each Cohort A and B. Results Participants 17 participants were dosed as of the data cut-off of 21 July 2024 as follows: • 14 participants were treated with the compound of Formula I and cetrelimab; • 2 participants were treated with the compound of Formula I; and • 1 participant for which exposure data were not entered into the EDC at the time of the data cut-off date. Pharmacokinetics and Product Metabolism Preliminary PK of the compound of Formula I were evaluated from this ongoing FIH Phase 1 Study based on available data (cutoff date of 25 September 2024). Preliminary PK analysis was conducted on available data from the first 4 cohorts where participants received daily oral doses of 5, 15, 30 or 60 mg of the compound of Formula I. After daily dosing of Compound of Formula I, plasma concentrations increased post dose reaching peak concentrations (time to maximum concentration [Tmax] 1–2 hours [median] within each dose level; Table 5) on Cycle 1 Day 1 and Cycle 1 Day 8. The concentration time profiles displayed a gradual decrease in concentrations (Figures 1a and 1b) post Cmaxand is supportive of daily dosing of Compound of Formula I. An approximate dose proportional increase in exposures were Docket No: KAD6025WOPCT observed in peak (Cmax) and total (AUC) exposures on Cycle 1 Day’s 1 and 8 within the dose range of 5-60 mg. Metabolism data for the compound of Formula I in humans are not available at this time. Table 5: Summary of Pharmacokinetic Parameters of the Compound of Formula (I) Pharmacokinetics of Cohort 1 Cohort 2 Cohort 3 Cohort 4 Compound of 5 mg QD 15 mg QD 30 mg QD 60 mg QD Formula I#Cycle 1 Day 1 n 4 7 5 6aCmax, ng / mL (mean [SD]) 55.3 (18.6) 181 (62.5) 358 (130) 862 (406) tmax, h (median [range]) 1.50 (1.00 – 2.00 (0.50 – 4.00) 1.00 (0.50 – 2.00) 1.50 (0.50 - 6.00) 4.00) AUC24h, ng.h / mL (mean[SD])773 (91.6) 1936 (782) 4436 (1727) 10526 (4411)Cycle 1 Day 2 n 4 7 5 5 Ctrough, ng / mL (mean 21.1 (2.02) 50.6 (17.0) 107 (49.9) 288 (132) [SD]) Cycle 1 Day 8 n 3b6 5 6cCtrough, ng / mL (mean 65.3 (13.3) 86.3 (31.4) 346 (322) 661 (248) [SD]) Cmax, ng / mL (mean 126 (24.7) 279 (109) 770 (461) 1487 (776) [SD]) tmax, h (median [range]) 1.00 (1.00 – 1.00 (1.00 – 2.00) 1.00 (0.50 – 2.00) 1.50 (0.50 - 1.00) 24.00) AUCr, ng.h / mL (mean1923 (173)[SD])3460 (1494) 11700 (8645) 19754 (4899)Cycle 1 Day 9 n 4 6 5 6 Ctrough, ng / mL (mean 74.7 (8.12) 96.7 (39.8) 406 (429) 678 (244) [SD]) Cycle 2 Day 1dn 3 5 4 1 Ctrough, ng / mL (mean 51.2 (7.39) 126 (139) 425 (337) 609 [SD]) #PK Data presented assume sample collection at protocol specified nominal times: 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 QD. Cohort 4: Multiple oral doses of 60 QD. a n=5 for AUC24h Docket No: KAD6025WOPCTdParticipants received SC cetrelimab loading dose of 900 mg on C2D1 followed by 600 mg Q3W starting C3D1 AUC= area under the curve; C2D1 = Cycle 2 Day 1; C3D1 = Cycle 3 Day 1; Cmax= maximum concentration; Ctrough = Concentration of drug before next dose; PK = pharmacokinetic; Q3W = every 3 weeks; QD = every day; SC = subcutaneous; SD = standard deviation; tmax = time to maximum concentration Safety and Tolerability As of the data cut-off of 21 July 2024, preliminary demographic and safety and tolerability data are available for 16 participants in this ongoing FIH study. Most participants were white (50.0%), and the median age at the time of study entry was 64 years (range: 40 to 88 years); 11 were male and 5 were female (Table 6). Table 6: Summary of Demographics and Baseline Characteristics; All Treated Analysis Set 5mg QD + CET 15mg QD + CET 30mg QD + CET Total Analysis set: All Treated 4 7 5 16 Age (years)N 4 7 5 16 Mean (SD) 60.8 (9.54) 65.3 (14.96) 62.6 (10.16) 63.3 (11.79) Median 62.0 64.0 65.0 64.0 Range (48; 71) (40; 88) (45; 70) (40; 88) SexN 4 7 5 16 Female 2 (50.0%) 2 (28.6%) 1 (20.0%) 5 (31.3%) Male 2 (50.0%) 5 (71.4%) 4 (80.0%) 11 (68.8%) RaceN 4 7 5 16 American Indian or Alaska Native 0 0 0 0 Asian 0 1 (14.3%) 2 (40.0%) 3 (18.8%) Black or African American 1 (25.0%) 1 (14.3%) 0 2 (12.5%) Native Hawaiian or Other Pacific 0 0 0 0 Islander White 2 (50.0%) 4 (57.1%) 2 (40.0%) 8 (50.0%) Not Reported 1 (25.0%) 0 0 1 (6.3%) Unknown 0 1 (14.3%) 1 (20.0%) 2 (12.5%) Ethnicity N 4 7 5 16 Hispanic or Latino 1 (25.0%) 0 0 1 (6.3%) Not Hispanic or Latino 3 (75.0%) 6 (85.7%) 5 (100.0%) 14 (87.5%) Unknown 0 1 (14.3%) 0 1 (6.3%) Not Reported 0 0 0 0 Weight (kg) N 4 7 5 16 Mean (SD) 63.83 (19.339) 73.94 (18.970) 60.46 (4.508) 67.20 (16.235) Median 65.35 75.40 61.30 62.05 Range (39.4; 85.2) (52.2; 109.9) (53.3; 65.6) (39.4; 109.9) Docket No: KAD6025WOPCT Height (cm) N 4 7 5 16 Mean (SD) 165.60 (12.977) 172.49 (13.671) 165.04 (6.752) 168.44 (11.586) Median 162.75 169.00 167.00 167.70 Range (154.0; 182.9) (152.4; 188.5) (154.0; 171.4) (152.4; 188.5) Body mass index (kg / m2) N 4 7 5 16 Mean (SD) 22.83 (4.185) 24.52 (3.346) 22.19 (0.820) 23.37 (3.054) Median 24.61 23.40 22.47 23.00 Range (16.6; 25.5) (21.0; 30.9) (21.1; 23.0) (16.6; 30.9) IQ range (20.34; 25.31) (22.48; 26.91) (21.51; 22.82) (21.99; 24.61) Note: N’s for each parameter reflect non-missing values. All treatment-emergent adverse events (TEAEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 27.0 and were summarized by system organ class (SOC) and preferred term (PT). TEAEs experienced by at least 10% of participants are presented in Tables 7a and 7b and Tables 8a and 8b below by SOC, PT and cohort. All 16 participants experienced at least 1 TEAE. The most frequently reported TEAEs by PT were nausea (5 participants, 31.3%), dizziness, headache, and fatigue (4 participants each [25.0%]). Treatment-emergent serious adverse events (SAEs) were reported for 3 (18.8%) participants and were pneumonia, tumor pain, and embolism (1 participant each) (Tables 9a and 9b and Tables 10a and 10b below). None of the SAEs were deemed by investigators to be related to treatment drugs. Compound of Formula (I) Any potential safety risks associated with administration of the compound of Formula I are unknown at this early stage of development. Potential safety risks are based on the known mechanism of action of the compound of Formula I, nonclinical data, and available clinical data from clinical studies with other adenosine pathway inhibitors. Combination with Cetrelimab Cetrelimab is a fully human IgG4 kappa monoclonal antibody that binds to PD-1 with high affinity and specificity, blocks binding to both PD-1 ligands (PD-L1 and PD-L2), enhances proinflammatory cytokine production from ex vivo stimulated T cells, and is predicted to antagonize PD-1 function and enhance T cell activity and antitumor immunity. Clinical experience with cetrelimab is based on data from 2 monotherapy studies (63723283LUC1001 and 63723283LUC1002 Phase 1a) and 7 combination studies (63723283LUC1002 Phase 1b, Docket No: KAD6025WOPCT 54767414MMY2036, 64091742PCR2002, 42756493BLC2002, 17000139BLC2001 [SunRISe‑1], 17000139BLC3001 [SunRISe‑2], and 56021927PCR2032). Cetrelimab has demonstrated a safety and efficacy profile in pretreated melanoma and NSCLC patients comparable with approved anti-PD-1 antibodies.

[0002] Docket No: KAD6025WOPCT Table 7a: Number of Subjects With Treatment-emergent Adverse Events With Frequency of at Least 10% by System Organ Class and Preferred Term; 5 mg QD + CET Compound of Formula I: 5mg QD + CET Total Cycle 1 Cycle 2+ Analysis set: All Treated 4 4 3 Subjects with 1 or more TEAEs 4 (100.0%) 3 (75.0%) 3 (100.0%) Gastrointestinal disorders 2 (50.0%) 2 (50.0%) 2 (66.7%) Nausea 2 (50.0%) 2 (50.0%) 0 2 1 1

[0003] Docket No: KAD6025WOPCT Table 7b: Number of Subjects With Treatment-emergent Adverse Events With Frequency of at Least 10% by System Organ Class and Preferred Term; 15 mg + CET Compound of Formula I: 15mg QD + CET Total Cycle 1 Cycle 2+ Analysis set: All Treated 7 7 6 Subjects with 1 or more TEAEs 7 (100.0%) 5 (71.4%) 6 (100.0%) Gastrointestinal disorders 3 (42.9%) 1 (14.3%) 2 (33.3%) Nausea 1 (14.3%) 0 1 (16.7%) 0 0 0

[0004] Docket No: KAD6025WOPCT Table 8a: Number of Subjects With Treatment-emergent Adverse Events With Frequency of at Least 10% by System Organ Class and Preferred Term; 30 mg + CET Compound of Formula I: 30 mg QD + CET Total Cycle 1 Cycle 2+ Analysis set: All Treated 5 5 5 Subjects with 1 or more TEAEs 5 (100.0%) 4 (80.0%) 4 (80.0%) Gastrointestinal disorders 4 (80.0%) 2 (40.0%) 2 (40.0%) Nausea 2 (40.0%) 1 (20.0%) 1 (20.0%) Vomiting 1 (20.0%) 0 1 (20.0%) Abdominal discomfort 1 (20.0%) 1 (20.0%) 0 Abdominal pain 0 0 0 Constipation 0 0 0 Gastrooesophageal reflux disease 0 0 0 Musculoskeletal and connective tissue disorders 2 (40.0%) 2 (40.0%) 0 Musculoskeletal chest pain 0 0 0 Neck pain 1 (20.0%) 1 (20.0%) 0 Pain in extremity 0 0 0 Nervous system disorders 1 (20.0%) 1 (20.0%) 0 Dizziness 0 0 0 Headache 1 (20.0%) 1 (20.0%) 0 Dysgeusia 0 0 0 General disorders and administration site conditions1 (20.0%) 0 1 (20.0%)Fatigue 0 0 0 Oedema peripheral 1 (20.0%) 0 1 (20.0%) Metabolism and nutrition disorders 0 0 0 Decreased appetite 0 0 0 Respiratory, thoracic and mediastinal disorders 1 (20.0%) 1 (20.0%) 0 Cough 0 0 0 Injury, poisoning and procedural complications 1 (20.0%) 0 1 (20.0%) Fall 0 0 0 Psychiatric disorders 1 (20.0%) 1 (20.0%) 0 Insomnia 1 (20.0%) 1 (20.0%) 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 0 0 0 Tumour pain 0 0 0

[0005] Docket No: KAD6025WOPCT Table 8b: Number of Subjects With Treatment-emergent Adverse Events With Frequency of at Least 10% by System Organ Class and Preferred Term; Total Total Total Cycle 1 Cycle 2+ Analysis set: All Treated 16 16 14 Subjects with 1 or more TEAEs 16 (100.0%) 12 (75.0%) 13 (92.9%) Gastrointestinal disorders 9 (56.3%) 5 (31.3%) 6 (42.9%) Nausea 5 (31.3%) 3 (18.8%) 2 (14.3%) Vomiting 3 (18.8%) 1 (6.3%) 2 (14.3%) Abdominal discomfort 2 (12.5%) 1 (6.3%) 1 (7.1%) Abdominal pain 2 (12.5%) 0 2 (14.3%) Constipation 2 (12.5%) 1 (6.3%) 2 (14.3%) Gastrooesophageal reflux disease 2 (12.5%) 0 2 (14.3%) Musculoskeletal and connective tissue disorders 8 (50.0%) 5 (31.3%) 5 (35.7%) Musculoskeletal chest pain 2 (12.5%) 0 2 (14.3%) Neck pain 2 (12.5%) 1 (6.3%) 1 (7.1%) Pain in extremity 2 (12.5%) 1 (6.3%) 1 (7.1%) Nervous system disorders 7 (43.8%) 2 (12.5%) 6 (42.9%) Dizziness 4 (25.0%) 1 (6.3%) 3 (21.4%) Headache 4 (25.0%) 1 (6.3%) 3 (21.4%) Dysgeusia 2 (12.5%) 0 2 (14.3%) General disorders and administration site conditions6 (37.5%) 1 (6.3%) 5 (35.7%) Fatigue 4 (25.0%) 1 (6.3%) 3 (21.4%) Oedema peripheral 3 (18.8%) 0 3 (21.4%) Metabolism and nutrition disorders 5 (31.3%) 1 (6.3%) 4 (28.6%) Decreased appetite 3 (18.8%) 0 3 (21.4%) Respiratory, thoracic and mediastinal disorders 5 (31.3%) 3 (18.8%) 2 (14.3%) Cough 2 (12.5%) 2 (12.5%) 0 Injury, poisoning and procedural complications 3 (18.8%) 0 3 (21.4%) Fall 2 (12.5%) 0 2 (14.3%) Psychiatric disorders 3 (18.8%) 2 (12.5%) 1 (7.1%) Insomnia 2 (12.5%) 1 (6.3%) 1 (7.1%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 2 (12.5%) 2 (12.5%) 1 (7.1%) Tumour pain 2 (12.5%) 1 (6.3%) 1 (7.1%) Note: TEAE = Treatment-emergent Adverse Event. Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.

[0006] Docket No: KAD6025WOPCT Table 9a: Number of Subjects With Serious Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Cycle; 5 mg + CET Compound of Formula I: 5 mg QD+ CET Total Cycle 1 Cycle 2+ Analysis set: All Treated 4 4 3 Subjects with 1 or more Serious 2 (50.0%) 1 (25.0%) 1 (33.3%) TEAEs System organ class Preferred term Infections and infestations 0 0 0 Pneumonia 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps)1 (25.0%) 0 1 (33.3%)Tumour pain 1 (25.0%) 0 1 (33.3%) Vascular disorders 1 (25.0%) 1 (25.0%) 0 Embolism 1 (25.0%) 1 (25.0%) 0

[0007] Docket No: KAD6025WOPCT Table 9b: Number of Subjects With Serious Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Cycle; 15 mg + CET Compound of Formula I: 15 mg QD+ CET Total Cycle 1 Cycle 2+ Analysis set: All Treated 7 7 6 Subjects with 1 or more Serious 1 (14.3%) 1 (14.3%) 0 TEAEs System organ class Preferred term Infections and infestations 1 (14.3%) 1 (14.3%) 0 Pneumonia 1 (14.3%) 1 (14.3%) 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps)0 0 0Tumour pain 0 0 0 Vascular disorders 0 0 0 Embolism 0 0 0

[0008] Docket No: KAD6025WOPCT Table 10a: Number of Subjects With Serious Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Cycle; 30 mg + CET Compound of Formula I: 30 mg QD+ CET Total Cycle 1 Cycle 2+ Analysis set: All Treated 5 5 5 Subjects with 1 or more Serious 0 0 0 TEAEs System organ class Preferred term Infections and infestations 0 0 0 Pneumonia 0 0 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps)0 0 0Tumour pain 0 0 0 Vascular disorders 0 0 0 Embolism 0 0 0

[0009] Docket No: KAD6025WOPCT Table 10b: Number of Subjects With Serious Treatment-emergent Adverse Events by System Organ Class, Preferred Term and Cycle; Total Total Total Cycle 1 Cycle 2+ Analysis set: All Treated 16 16 14 Subjects with 1 or more Serious 3 (18.8%) 2 (12.5%) 1 (7.1%) TEAEs System organ class Preferred term Infections and infestations 1 (6.3%) 1 (6.3%) 0 Pneumonia 1 (6.3%) 1 (6.3%) 0 Neoplasms benign, malignant and unspecified (incl cysts and polyps)1 (7.1%)Tumour pain 1 (7.1%) Vascular disorders 1 (6.3%) 1 (6.3%) 0 Embolism 1 (6.3%) 1 (6.3%) 0 Note: TEAE = Treatment-emergent Adverse Event. Subjects are counted only once for any given event, regardless of the number of times they actually experienced the event.

[0010] Docket No: KAD6025WOPCT It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present inventions as defined by the specific description. Sequence Listing: SEQ ID NO: 1 SYAIS SEQ ID NO: 2 GIIPIFDTANYAQKFQG SEQ ID NO: 3 PGLAAAYDTGSLDY SEQ ID NO: 4 RASQSVRSYLA SEQ ID NO: 5 DASNRAT SEQ ID NO: 6 QQRNYWPLT SEQ ID NO: 7 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFDTAN YAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGT LVTVSS SEQ ID NO: 8 Docket No: KAD6025WOPCT EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNYWPLTFGQGTKVEIK SEQ ID NO: 9 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFDTAN YAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARPGLAAAYDTGSLDYWGQGT LVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPRE EQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLP PSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 10 EIVLTQSPATLSLSPGERATLSCRASQSVRSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRNYWPLTFGQGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 11 PGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKL AAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESL RAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAAR GTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGM GTSSPARRGSADGPRSAQPLRPEDGHCSWPL

Claims

Docket No: KAD6025WOPCT CLAIMS 1. A method of treating lung cancer in a human subject by administering a compound of Formula (I):human subject in need thereof.

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

3. The method of claim 3, wherein the compound of Formula I is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration 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 dosage in between.

4. The method of claim 4, wherein the compound of Formula I is orally administered once per day, and the total dosage of the compound of Formula I or the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, 60 mg, 100 mg, 110 mg or 120 mg.

5. The method of any of claims 1-4, wherein the method further comprises orally administering to the subject a pharmaceutical composition comprising the compound of Formula I or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.Docket No: KAD6025WOPCT 6. The method of any of claims 1-5, wherein the method further comprises administering to the subject a checkpoint inhibitor, such as an anti-PD-L1 antibody, an anti-PD-1 antibody or an antigen-binding fragment thereof.

7. The method of claim 6, wherein the method further comprises administering to the subject the anti-PD-1 antibody or the antigen-binding fragment thereof comprising a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively.

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

8.

9. The method of any one of claims 1-8, wherein the anti-PD-1 antibody or the antigen- binding fragment thereof 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 of any one of claims 1-9, wherein the method further comprises administering a radiotherapy to the subject.

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

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

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

14. The method of claim 13, wherein the loading dose is about 900 mg.Docket No: KAD6025WOPCT 15. The method of any one of claims 6-14, wherein the radiotherapy is administered at a dose of about 3 Gy to 8 Gy fractions over 1 day to 2 weeks to 1.8 Gy to 3 Gy fractions over 3 to 7 weeks, or at a total dose of 5 to 100 Gy, such as a total dose of 8 to 30 Gy or 30-70 Gy, over 1 day to 8 weeks.

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

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

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

19. The method of any one of claims 6-18, wherein the radiotherapy is started after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof, particularly, the radiotherapy is started about 1-10 days, preferably about 3- 10 days, more preferably about 3 days, after the first administration of the compound of Formula I or the pharmaceutically acceptable salt thereof.

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

21. A method of treating lung cancer in a human subject in need thereof, comprising: (1) orally administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula IDocket No: KAD6025WOPCT I ormg about 120 mg per day; and (2) subcutaneously administering to the subject an anti-PD-1 antibody or an antigen- binding fragment thereof, comprising a. a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively; b. a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; and c. 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. wherein the anti-PD-1 antibody or the antigen-binding fragment thereof, with a loading dose of about 900 mg, followed by an effective dose of about 600 mg once every three weeks.

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

23. The method of any one of claims 21-22, wherein the pharmaceutical composition is orally administered once per day, and the total dosage of the compound of Formula I orDocket No: KAD6025WOPCT the pharmaceutically acceptable salt thereof administered per administration is about 2 mg, 5 mg, 15 mg, 30 mg, 60 mg., 100 mg., 110 mg, or 120 mg.

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

25. The method of any one of claims 22-24, wherein the radiotherapy is started after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof, particularly, the radiotherapy is started about 1-10 days after the first administration of the compound of Formula I or the pharmaceutically acceptable salt thereof.

26. A method of treating lung cancer in a human subject in need thereof, comprising: (1) orally administering to the subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula II or the pharmaceutically acceptable salt thereof administered is about 1 mg to about 120 mg per day; and (2) administering a radiotherapy to the subject, wherein the radiotherapy is administered at a dose of about 6 Gy to about 8Gy for about 2 to 7 days, and the radiotherapy is started about 1-10 days after the initial administration of the compound of Formula I or the pharmaceutically acceptable salt thereof.Docket No: KAD6025WOPCT 27. The method of claim 26, wherein the method further comprises administering to the subject an anti-PD-1 antibody or an antigen-binding fragment thereof.

28. The method of claim 27, wherein the anti-PD-1 antibody or the antigen-binding fragment thereof comprises: a. a heavy chain complementarity determining region (HCDR) 1, a HCDR2 and a HCDR3 of SEQ ID NOs: 1, 2, and 3, respectively, and a light chain complementarity determining region (LCDR)-1, a LCDR2 and a LCDR3 of SEQ ID NOs: 4, 5, and 6, respectively; b. a heavy chain variable region (VH) of SEQ ID NO: 7 and a light chain variable region (VL) of SEQ ID NO: 8; and c. 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.

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

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

31. The method of 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 had 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 of claim 1, wherein the non-small cell lung cancer has a genetic mutation, preferably mutation of EGFR, ALK, ROS1, BRAF.Docket No: KAD6025WOPCT 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 creatinine clearance rate > 50 mL / min using the Cockcroft-Gault method during the screening period and within 72 hours of the start of administration of the method.

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

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