WO2020202005A1

WO2020202005A1 - Combination of a fak kinase inhibitor and an agent targeting t-cell co-stimulatory receptors

Info

Publication number: WO2020202005A1
Application number: PCT/IB2020/053046
Authority: WO
Inventors: Alan SERRELS
Original assignee: Inxmed (Shanghai) Co., Ltd.
Priority date: 2019-04-02
Filing date: 2020-03-31
Publication date: 2020-10-08

Abstract

This invention discloses methods for treating cancer in a subject comprising administering the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and agent targeting T-cell co-stimulatory receptors selected from OX40 and 41BB such as anti-OX 40 or anti-41BB, and the CD80 based stratification method of cancer patients for treatment with FAK kinase inhibitor.

Description

COMBINATION OF A FAK KINASE INHIBITOR AND AN AGENT TARGETING T-CELL CO-STIMULATORY RECEPTORS

Field of the invention

The present invention belongs to the field of cancer treatment. In the particular, the present invention discloses a combination of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and41BB, and the CD80 based stratification method of cancer patients for treatment with FAK kinase inhibitor.

Background of the invention

A number of small molecular FAK kinase inhibitors have now either completed, or are currently in Phase-I clinical trials, with results thus far suggesting that they are generally well tolerated with promising signs of clinical activity in some patients. Therefore, several studies have attempted to identify biomarkers that predict sensitivity to FAK inhibition. Using panels of cancer cell lines, loss of expression of the tumor suppressor protein Merlin (also known as Neurofibromin 2) and / or E-cadherin has been shown to correlate with increased sensitivity to FAK kinase inhibitors [Kato, T., et al. E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin negative malignant mesothelioma cells. Oncogene 36, 5522-5531 (2017); Shah, N.R., et al. Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer. Gynecol Oncol 134, 104-111 (2014); Shapiro, I. M., et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. ; Sci Transl Med 6, 237ra268 (2014)]. However, a Phase II clinical trial in which patients with malignant pleural mesothelioma were tested for Merlin status was terminated early due to lack of improved efficacy against Merlin low tumors (ClinicalTrials.gov NCT01870609). Recently, the first in human phase I study of BI 853520 (ClinicalTrials.gov NCT01335269) was reported where the E-cadherin was studied as a potential biomarker [de Jonge, M J. A. Phase I Study of BI 853520, an Inhibitor of Focal Adhesion Kinase, in Patients with Advanced or Metastatic Nonhematologic Malignancies. Targeted Oncology 14, 43-55 (2019)]. But based on this study, the value of E-cadherin as a potential predictive biomarker could not be determined. Further studies are warranted to identify or confirm potential biomarkers to guide patient selection for FAK inhibitor treatment.

On the other hand, immunotherapy in oncology has shown tremendous potential for cancer therapy. Despite impressive results from anti-PD-l/anti-PD-Ll therapy, the overall response rate by single agent like anti-PD-l/anti-PD-Ll therapy is modest to moderate. Rationalized combination is a must for future cancer treatment. Focal Adhesion Kinase (FAK) is emerging as a potentially important regulator of the tumor microenvironment, especially immuno-suppressive tumor environment, and as a consequence, FAK kinase inhibitors (FAKi) are now undergoing clinical testing in combination with anti-PDl immune checkpoint blockade. However, which patients are most likely to benefit from FAK kinase inhibitor treatment, and what the optimal FAK / immunotherapy combinations are, is currently unknown.

Summary of the invention

The inventors identify that endogenous expression of the T-cell co-stimulatory ligand CD80 on the surface of cancer cells correlates with the response of tumors to the FAK kinase inhibitor BI 853520, and that exogenous expression of CD80 into cancer cells that do not normally express this ligand renders them sensitive to the anti-tumor activity of BI 853520. The inventors demonstrate that FAK kinase inhibitor BI 853520 has virtually no antitumor activity against tumor cells without CD80 expression, in contrast to the remarkable antitumor activities of BI 853520 against tumor cells with high expression of CD80.

This observation led to experiment using agonistic antibodies targeting T-cell co stimulatory receptors as rational combination with FAK kinase inhibitor BI 853520. Using SCC and pancreatic cancer models that do not express CD80 and exhibit little response to BI 853520, the combination of BI 853520 with a number of agonistic antibodies targeting T-cell costimulatory receptors, including glucocorticoid-induced TNFR-related protein (GITR, also known as Tumor necrosis factor receptor superfamily member 18 (TNFRSF18)), CD40 (also known as TNFRSF5), 4 IBB (also known as tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CD137), and 0X40 (also known as Tumor necrosis factor receptor superfamily member 4 (TNFRSF4) and CD134), were investigated. Only 0X40 and 41BB in combination with FAKi BI853520 result in enhanced anti-tumor immunity and even complete CD8 T-cell dependent tumor regression leading to lasting immunological memory. FAKi BI 853520 in combination with OX-40 or 4 IBB led to regression of tumors which were not sensitive to FAKi alone treatment. When treated animals were re-challenged with SCC6.2 cancer cell, no tumor growth was observed.

Mechanistically, BI853520 and anti-OX40 treatment both reduce the number of Regulatory T-cells (Tregs) in SCC tumors, while anti-OX40 drives elevated CD8 T-cell infiltration. BI853520 also significantly downregulates PDL2 expression on tumor associated macrophages, monocytic-myeloid derived suppressor cells (M-MDSCs) and cancer cells, establishing a novel role for FAK in the regulation of immune checkpoint signaling.

Accordingly, this invention relates to the treatment of cancer by using the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In one aspect, this invention relates to a combination comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In another aspect, this invention relates to a pharmaceutical composition comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In another aspect, this invention relates to a kit comprising a first composition including the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, and a second composition including an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In another aspect, this invention relates to a method for treating cancer comprising administrating the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In another aspect, this invention relates to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in the above methods. In another aspect, this invention relates to an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in the above methods.

In another aspect, this invention relates to a use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer.

In another aspect, this invention relates to a medicament comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in treating cancer in a subject, wherein the FAK kinase inhibitor is for use in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In another aspect, this invention relates to a use of medicament comprising an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in treating cancer in a subject, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is for use in combination with an agent directed to a FAK kinase inhibitor.

In other aspect, this invention relates to use of CD80 as a biomarker for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, wherein the subject is identified when CD80 expression (preferable high CD80 expression) is detected on the cancer cell.

In another aspect, this invention relates to use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in the preparation of medicament for treating cancer with CD80 expression (preferable with high CD80 expression) or the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for treating cancer with CD80 expression (preferable with high CD80 expression) in a subject.

In another aspect, this invention relates to a method for treating a cancer with CD80 expression (preferable with high CD80 expression) in a subject, comprising administering the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof to the subject.

In another aspect, this invention relates to a method for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, comprising detecting CD80 expression on the cancer cell, the subject is identified when CD80 expression (preferable with high CD80 expression) is detected.

Brief Description of the Drawings

These and other features of this disclosure will become more apparent in the following detailed description in which reference is made to the appended drawings, wherein:

Figure 1: Treatment of a range of tumor models with the FAK kinase inhibitor BI 853520 identifies a spectrum of responses. (A - G) Representative graphs of subcutaneous tumor growth in immune-competent mice treated once daily with either vehicle or 50 mg/kg BI 853520. * = comparison of vehicle to BI 853520, + = comparison of vehicle to BI 853520 partial response in graph (D). (H and I) Subcutaneous tumor growth of SCC7.1 and MetOl cells treated with either vehicle or BI 853520 and Isotype control antibody (IgG) or anti-CD8 T-cell depleting antibody. + = comparison of IgG vehicle to IgG BI 853520, * = comparison of anti-CD8 vehicle to anti-CD8 BI 853520. * or + = P < 0.05, ** or ++ = P < 0.01, *** or +++ = P < 0.001, **** _or ++++ = P < 0.0001, two-way ANOVA with Tukey’s multiple comparison test.

Figure 2: CD80 expression on cancer cells correlates with response of tumors to BI 853520. (A) Flow cytometry analysis of CD8+ T-cell infiltration in SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 tumors. (B) Flow cytometry quantification of the percentage of CD8+ T-cells expressing PD1 in SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 tumors. (C) Flow cytometry analysis of PDL1 expression on SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 cells following stimulation with 10 ng/ml IFNy for 24 hours under normal culture conditions. (D) Representative scatter plots from flow cytometry analysis of CD80 expression on SCC7.1, MetOl, SCC6.2, Panc43, Panc47, and Panel 17 cells under normal culture conditions. (E) Quantification of the percentage of live cells expressing CD80 under normal culture conditions. Data in A, B, and E represented as mean +/- s.e.m, n = 3.

Figure 3 - Expression of the immune costimulatory ligand CD80 in SCC6.2 cells renders tumors responsive to BI 853520. (A) Nanostring gene expression analysis of Major Histocompatibility Complex (MHC) genes in SCC7.1 and SCC6.2 cells. (B) Comparison of CD80 surface expression between SCC7.1 cells and SCC6.2 cells transfected with a pcDNA3-CD80 vector. Left - Flow cytometry analysis of the percentage of cells expressing CD80, Right - mean fluorescent intensity (MFI) of CD80 cell surface expression. (C) Left - Subcutaneous tumor growth of SCC6.2 cells transfected with either pcDNA3 empty vector or pcDNA3-CD80 vector and treated once daily with either vehicle or 50 mg/kg BI 853520. Right - Comparison of tumor volume on day 17 post-implantation of tumor cells. Graph represents mean +/- s.e.m. P < 0.01, one-way ANOVA with Dunnett’s multiple comparison.

Figure 4 - Genomics analysis identifies a subset of hematological malignancies that co-express high levels of CD80 and FAK. (A) Analysis of CD80 expression in genomics datasets derived from human cancer cell lines. The number of cell lines from each tumor type is listed below along with the percentage positive for expression. (B) Analysis of FAK expression in the same genomics datasets from human cancer cell lines. (C) Scatter plot of CD80 expression against FAK expression in all cell lines. (D) Analysis of CD80 expression in genomics datasets derived from human cancer cell lines from different types of hematological malignancies. (E) Analysis of FAK expression in genomics datasets derived from human cancer cell lines from different types of hematological malignancies Figure 5 - Treatment with BI 853520 enhances the response of SCC6.2 tumors to agonistic antibodies targeting the immune costimulatory molecules 41BB and 0X40 resulting in tumor regression. (A) Graphic of dosing schedule. (B - E) Left - Subcutaneous growth of SCC6.2 tumors treated with either vehicle or 50 mg/kg BI 853520 in combination with either lOOug GITR, CD40, 4 IBB, or 0X40 agonistic antibodies. Right - Comparison of tumor volume on day 24 post-implantation of tumor cells. Graph represents individual tumor measurements together with the mean +/- s.e.m. (F) Subcutaneous growth of SCC6.2 tumors treated with either vehicle or BI 853520 + 0X40 in combination with either isotype control or anti-CD8 T-cell depleting antibodies. (G) Subcutaneous growth of SCC6.2 tumors implanted into either naive FVB mice (Control) or FVB mice from E in which treatment with BI 853520 + 0X40 resulted in complete tumor regression and no tumor regrowth over a 2 months period off treatment (Rechallenge). (B - E) ns = not significant, * = P < 0.05, **** = P < 0.0001, unpaired t-test comparing immunotherapy to immunotherapy + BI853520.

Figure 6 - 0X40 and BI 853520 display overlapping and distinct immune modulatory activity. (A-C) Flow cytometry quantification of tumor infiltrating Tregs, CD4 (non-Treg) T-cells, and CD8eff T-cells. (D) Flow cytometry quantification of the percentage of CD8eff T-cells positive for expression of PD1 / LAG3 (left) and PD1 / Tim3 (right). (E) Flow cytometry quantification of tumor infiltrating macrophages. (F) Flow cytometry quantification of the percentage of macrophages expressing PDL1 (left), and the mean fluorescent intensity of PDL1 expression (right). (G) Flow cytometry quantification of the percentage of macrophages expressing PDL2 (left), and the mean fluorescent intensity of PDL2 expression (right). (H) Representative histogram of PDL2 fluorescent intensity in a control sample stained with all antibodies except for PDL2 (FMO), cancer cells, G-MDSCs, M-MDSCs, Macrophages, and CDl lb+ Dendritic cells. (I) Flow cytometry quantification of the percentage of M- MDSCs, G-MDSCs, cancer cells, and dendritic cells positive for expression of PDL2. Statistical analysis performed using an ordinary one-way ANOVA with Tukey’s multiple comparison. * = P < 0.05, ** = P < 0.01, *** = P < 0.001, **** = P < 0.0001. N = 4 - 8 tumors per condition. Data represents mean +/- s.e.m., N= 4 - 6 tumors.

Figure 7 - Treatment with BI 853520 renders Panc47 tumors responsive to treatment with agonistic antibodies targeting the immune co-stimulatory molecules 41BB and 0X40. (A - D) Left - Subcutaneous growth of Panc47 tumors treated with either vehicle or 50 mg/kg BI 853520 in combination with either lOOug GITR, CD40, 4 IBB, or 0X40 agonistic antibodies. Right - Comparison of tumor volume on day 25 / 28 post-implantation of tumor cells. Graph represents individual tumor measurements together with the mean +/- s.e.m. Dosing schedule identical to Fig. 4A. (E) Left - Subcutaneous growth of Panc47 tumors treated with either vehicle, vehicle + 100 mg/kg gemcitabine (GEM), 50 mg/kg BI 853520 + GEM, 0X40 + GEM, or BI 853520 + 0X40 + GEM. Right - Comparison of tumor volume on day 28 post implantation of tumor cells. Graph represents individual tumor measurements together with the mean +/- s.e.m. Dosing schedule identical to Fig. 4A. GEM dosed twice weekly I.P. for the duration of the experiment starting 3 days post-implantation of cancer cells. * = P < 0.05, ** = P < 0.01, *** = P < 0.001, **** = P < 0.0001, unpaired t-test.

Figure 8 - Frequency of immune cell populations in SCC6.2 tumors treated with either vehicle, 0X40, BI 853520 or 0X40 + BI 853520. (A - D) Flow cytometry quantification of tumor infiltrating M-MDSCs, G-MDSCs, Cancer cells, and CDl lb+ Dendritic Cells. Data represents mean +/- s.e.m. Statistical analysis performed using an ordinary one-way ANOVA with Tukey’s multiple comparison. ** = P < 0.01, *** = P < 0.001, N = 4 tumors per condition.

Definitions

As used herein, the following definitions apply, unless stated otherwise:

As used herein, the articles "a" and "an" refer to one or to more than one (e.g., at least one) of the grammatical object of the article.

As used herein, "About" and "approximately" shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20 percent (%), typically, within 10%, and more typically, within 5% of a given value or range of values.

As used herein, the term "pharmaceutically acceptable," refers to a compound or carrier (e.g., excipient) that may be administered to a subject, together with a compound described herein, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

As used herein, the term "administration" and "treatment," as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell. "Administration" and "treatment" also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.

As used herein, the term "agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB" means any chemical compound or biological molecule capable of binding to 0X40 or 41BB. In some embodiments, the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is an 0X40 binding protein or a 41BB binding protein.

As used herein, the term "0X40 binding protein" as used herein refers to antibodies and other protein constructs, such as domains, which are capable of binding to 0X40. In some instances, the 0X40 is human 0X40.

As used herein, the term "0X40 binding protein" can be used interchangeably with "0X40 antigen binding protein." Thus, as is understood in the art, anti-OX40 antibodies and/or 0X40 antigen binding proteins would be considered 0X40 binding proteins. The terms "anti-OX40 antibody", "anti-OX40", and "0X40 antibody" are interchangeable. The term "0X40 antibody" as used herein means an antibody, as defined herein, capable of binding to human 0X40 receptor. As used herein, "antigen binding protein" is any protein, including but not limited to antibodies, domains and other constructs described herein, that binds to an antigen, such as 0X40. As used herein "antigen binding portion" of an 0X40 binding protein would include any portion of the 0X40 binding protein capable of binding to 0X40, including but not limited to, an antigen binding antibody fragment.

As used herein, the term "41BB binding protein" as used herein refers to antibodies and other protein constructs, such as domains, which are capable of binding to 41BB. In some instances, the 41BB is human 41BB.

As used herein, the term "4 IBB binding protein" can be used interchangeably with "4 IBB antigen binding protein." Thus, as is understood in the art, anti-4 IBB antibodies and/or 4 IBB antigen binding proteins would be considered 4 IBB binding proteins. The terms "anti-41BB antibody", "anti-41BB", and "41BB antibody" are interchangeable. The term "4 IBB antibody" as used herein means an antibody, as defined herein, capable of binding to human 41BB receptor. As used herein, "antigen binding protein" is any protein, including but not limited to antibodies, domains and other constructs described herein, that binds to an antigen, such as 41BB. As used herein "antigen binding portion" of a 4 IBB binding protein would include any portion of the 4 IBB binding protein capable of binding to 4 IBB, including but not limited to, an antigen binding antibody fragment.

As used herein, the term "antagonist" refers to an antigen binding protein including but not limited to an antibody, which upon contact with a co-signaling receptor causes one or more of the following (1) attenuates, blocks or inactivates the receptor and/or blocks activation of a receptor by its natural ligand, (2) reduces, decreases or shortens the activity, function or presence of the receptor and/or (3) reduces, decrease, abrogates the expression of the receptor. Antagonist activity can be measured in vitro by various assays know in the art such as, but not limited to, measurement of an increase or decrease in cell signaling, cell proliferation, immune cell activation markers, cytokine production. Antagonist activity can also be measured in vivo by various assays that measure surrogate end points such as, but not limited to the measurement of T cell proliferation or cytokine production. As used herein the term "cross competes for binding" refers to any agent such as an antibody that will compete for binding to a target with any of the agents of the present invention. Competition for binding between two antibodies can be tested by various methods known in the art including Flow Cytometry, Meso Scale Discovery and ELISA. Binding can be measured directly, meaning two or more binding proteins can be put in contact with a co-signaling receptor and bind may be measured for one or each. Alternatively, binding of molecules or interest can be tested against the binding or natural ligand and quantitatively compared with each other.

As used herein, the term "binding protein" as used herein refers to antibodies and other protein constructs, such as domains, which are capable of binding to an antigen.

As used herein, the term "antibody" is used herein in the broadest sense to refer to molecules with an immunoglobulin-like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies, a single variable domain (e.g., VH, VHH, VL, domain antibody (dAb™)), antigen binding antibody fragments, Fab, F(ab')2, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, TANDABS™, etc. and modified versions of any of the foregoing.

Alternative antibody formats include alternative scaffolds in which the one or more CDRs of the antigen binding protein can be arranged onto a suitable non- immunoglobulin protein scaffold or skeleton, such as an affibody, a SpA scaffold, an LDL receptor class A domain, an avimer or an EGF domain. The term "domain" refers to a folded protein structure which retains its tertiary structure independent of the rest of the protein. Generally, domains are responsible for discrete functional properties of proteins and in many cases may be added, removed or transferred to other proteins without loss of function of the remainder of the protein and/or of the domain.

As used herein, the term "single variable domain" refers to a folded polypeptide domain comprising sequences characteristic of antibody variable domains. It therefore includes complete antibody variable domains such as VH, VHH and VL and modified antibody variable domains, for example, in which one or more loops have been replaced by sequences which are not characteristic of antibody variable domains, or antibody variable domains which have been truncated or comprise N- or C-terminal extensions, as well as folded fragments of variable domains which retain at least the binding activity and specificity of the full-length domain. A single variable domain is capable of binding an antigen or epitope independently of a different variable region or domain. A "domain antibody" or "dAb (1M)" may be considered the same as a "single variable domain". A single variable domain may be a human single variable domain, but also includes single variable domains from other species such as rodent nurse shark and Camelid VHH dAbs™ Camelid VHH are immunoglobulin single variable domain polypeptides that are derived from species including camel, llama, alpaca, dromedary, and guanaco, which produce heavy chain antibodies naturally devoid of light chains. Such VHH domains may be humanized according to standard techniques available in the art, and such domains are considered to be "single variable domains". As used herein VH includes camelid VHH domains.

An antigen binding fragment may be provided by means of arrangement of one or more CDRs on non-antibody protein scaffolds. "Protein Scaffold" as used herein includes but is not limited to an immunoglobulin (Ig) scaffold, for example an IgG scaffold, which may be a four chain or two chain antibody, or which may comprise only the Fc region of an antibody, or which may comprise one or more constant regions from an antibody, which constant regions may be of human or primate origin, or which may be an artificial chimera of human and primate constant regions.

The protein scaffold may be an Ig scaffold, for example an IgG, or IgA scaffold. The IgG scaffold may comprise some or all the domains of an antibody (i.e. CHI, CH2, CH3, VH, VL). The antigen binding protein may comprise an IgG scaffold selected from IgGl, IgG2, IgG3, IgG4 or IgG4PE. For example, the scaffold may be IgGl. The scaffold may consist of, or comprise, the Fc region of an antibody, or is a part thereof.

Affinity is the strength of binding of one molecule, e.g. an antigen binding protein of the invention, to another, e.g. its target antigen, at a single binding site. The binding affinity of an antigen binding protein to its target may be determined by equilibrium methods (e.g. enzyme-linked immunoabsorbent assay (ELISA) or radioimmunoassay (RIA)), or kinetics (e.g. BIACORE™ analysis). Avidity is the sum total of the strength of binding of two molecules to one another at multiple sites, e.g. taking into account the valency of the interaction.

As used herein, the term "Patient" or "subject" refers to any single subject for which therapy is desired or that is participating in a clinical trial, epidemiological study or used as a control, including humans and mammalian veterinary patients such as cattle, horses, dogs, and cats.

The terms "cancer", "cancerous", or "malignant" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include but are not limited to, carcinoma, lymphoma, leukemia, blastoma, and sarcoma. More particular examples of such cancers include squamous cell carcinoma, myeloma, small-cell lung cancer, non-small cell lung cancer, glioma, hodgkin's lymphoma, non-hodgkin's lymphoma, acute myeloid leukemia (AML), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphoblastic leukemia, lymphocytic leukemia, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, thyroid cancer, melanoma, chondrosarcoma, neuroblastoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, brain cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon carcinoma, and head and neck cancer. Another particular example of cancer includes renal cell carcinoma.

Detailed description

In one aspect, this invention relates to a combination comprising aFAK kinase inhibitor and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

The FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is an 0X40 binding protein or a 41BB binding protein. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof. In some embodiments, the anti- 0X40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015, the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

In some embodiments, the combination further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons. In some embodiments, the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

In another aspect, this invention relates to a pharmaceutical composition comprising the FAR kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

In some embodiments, the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof. In some embodiments, the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015, the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).

In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons. In some embodiments, wherein the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

In another aspect, this invention relates to a kit comprising a first composition including a FAK kinase inhibitor, and a second composition including an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB.

This invention relates to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, preferably BI853520 tartaric acid salt. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist. In some embodiments, the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-41BB antibody or antigen binding portion thereof. In some embodiments, the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015, the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

In some embodiments, the kit further comprises a third composition including an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons. In some embodiments, the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

In some embodiments, the kit further comprising a package insert, the package insert comprises instructions for treating cancer in a subject by using them.

In some embodiments, the method further comprises administration of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons. In some embodiments, the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer. In some embodiments, the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non-melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma(EHE) Desmoplastic small round cell tumor, or Liposarcoma.

In some embodiments, the cancer is hematological malignancies or lymphomas. In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL). In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, and Diffuse Large B-cell (DLBCL) Lymphoma.

In some embodiments, the FAK kinase inhibitor is administered orally. In some embodiments, the FAK kinase inhibitor is administered at least once a day. In some embodiments, the FAK kinase inhibitor is administered once a day. In some embodiments, the FAK kinase inhibitor is administered twice a day. In some embodiments, the FAK kinase inhibitor is administered at about 100 mg to about 2000 mg. In some embodiments, the FAK kinase inhibitor is administered before the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is administered. In some embodiments, the FAK kinase inhibitor is administered after the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is administered. In some embodiments, the FAK kinase inhibitor is administered concurrently with the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is administered.

In another aspect, this invention relates to a use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof and an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer. In some embodiments, the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein. In some embodiments, the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof. In some embodiments, the anti-OX40 antibody is PF- 04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015, the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).

In some embodiments, the medicament is further used in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti- angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons. In some embodiments, the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer. In some embodiments, the cancer is hematological malignancies and lymphomas. In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, or T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), or small lymphocytic lymphoma (SLL). In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, and Diffuse Large B-cell (DLBCL) Lymphoma.

In another aspect, this invention relates to the use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in the preparation of medicament for treating cancer, wherein the medicament is used in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB. In another aspect, this invention relates to a use of an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer, wherein the medicament is used in combination with a FAR kinase inhibitor.

In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is renal cell carcinoma (RCC), bladder cancer, breast cancer, kidney cancer, head/neck squamous cell carcinoma (SCCHN), lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, small-cell lung cancer (SCLC) or breast cancer. In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

In some embodiments, the cancer is hematological malignancies or lymphomas. In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL). In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, and Diffuse Large B-cell (DLBCL) Lymphoma. In another aspect, this invention relates to a medicament comprising the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for use in treating cancer in a subject, wherein the FAK kinase inhibitor is for use in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB. In another aspect, this invention relates to a use of medicament comprising an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in treating cancer in a subject, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is for use in combination with an agent directed to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof.

In some embodiments, the cancer is hematological malignancies or lymphomas. In some embodiments, the cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), EBV-positive DLBCL, primary mediastinal large B-cell lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myeloid cell leukemia- 1 protein (Mcl-1), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), and small lymphocytic lymphoma (SLL). In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

In other aspect, this invention relates to use of the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in the preparation of medicament for treating cancer with CD80 expression, preferably with high CD80 expression.

In some embodiments, the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma (endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non-melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma (EHE) Desmoplastic small round cell tumor, or Liposarcoma.

In some embodiments, the cancer is hematological malignancies or lymphomas. In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

In another aspect, this invention relates to the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof for treating cancer with CD80 expression, preferable with high CD80 expression, in a subject.

In another aspect, this invention relates to a method for treating a cancer with CD80 expression, preferable with high CD80 expression, in a subject, comprising administering the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof to the subject.

In some embodiments, the subject is human. In some embodiments, the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non-melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma (EHE) Desmoplastic small round cell tumor, or Liposarcoma. In some embodiments, the cancer is hematological malignancies or lymphomas. In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

In another aspect, this invention relates to a method for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, comprising detecting CD80 expression on the cancer cell, the subject is identified when CD80 expression, preferable high CD80 expression, is detected.

In some embodiments, the subject is human. In some embodiments, the pharmaceutical acceptable salts are preferably BI853520 tartaric acid salt. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma (endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor (GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non-melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma (EHE) Desmoplastic small round cell tumor, or Liposarcoma.

In some embodiments, the cancer is hematological malignancies or lymphomas. In some embodiments, the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma. In another aspect, this invention relates to use of CD80 as a biomarker for identifying a subject with cancer that could benefit from treatment with the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof, wherein the subject is identified when CD80 expression, preferable high CD80 expression, is detected on the cancer cell.

Aeent tareetine T-cell co-stimulatory receptor 0X40

The agent targeting T-cell co-stimulatory receptor 0X40 that can be used in the present invention is any chemical compound or biological molecule capable of binding to 0X40.

In one embodiment, the agent targeting T-cell co-stimulatory receptor 0X40 can be an 0X40 agonist. In one embodiment, the agent targeting T-cell co-stimulatory receptor 0X40 can be an 0X40 binding protein. In one embodiment, the agent targeting T-cell co-stimulatory receptor 0X40 can be an anti-OX40 antibody or antigen binding portion thereof.

Examples of mAbs that bind to human 0X40, and useful in the treatment method, medicaments and uses of the present invention, are described in, for example, U.S. Patent No. 7,960,515, PCT Patent Application Publication Nos. WO2013028231 and W02013/119202, and U.S. Patent Application Publication No. 20150190506. Examples of an anti-OX40 antibody used in the present invention are PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015. Asent tarsetins T-cell co-stimulatory receptor 4 IBB

The agent targeting T-cell co-stimulatory receptor 4 IBB that can be used in the present invention is any chemical compound or biological molecule capable of binding to 41BB.

In one embodiment, the agent targeting T-cell co-stimulatory receptor 4 IBB can be a 4 IBB agonist. In one embodiment, the agent targeting T-cell co-stimulatory receptor 4 IBB can be a 4 IBB binding protein. In one embodiment, the agent targeting T-cell co stimulatory receptor 4 IBB can be an anti-4 IBB antibody or antigen binding portion thereof.

Examples of mAbs that bind to human 4 IBB, and useful in the treatment method, medicaments and uses of the present invention, are described in, for example, US Patent Nos. 7,288,638 and 8,962,804. Examples of an anti-41BB antibody used in the present invention are utomilumab (PF-05082566) or urelumab (BMS-663513).

FAK kinase inhibitors

Potent inhibitors of the FAK protein tyrosine kinases may be adapted to therapeutic use as antiproliferative agents (e.g., anticancer), antitumor (e.g., effective against solid tumors), antiangiogenesis (e.g., stop or prevent proliferation of blood vessels) in mammals, particularly in humans. The compound described herein, BI853520 or the pharmaceutical acceptable salts thereof, may be useful in the prevention and treatment of a disease or disorder described herein (e.g., abnormal cell growth, e.g., cancer (e.g., a cancer described herein)).

In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, are present in a composition in the amount of 5, 10, 11, 12, 12.5, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60% w/w or greater. In some embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, is present in a composition in the amount from about 5% to 60%, 5% to 50%, 10% to 50%, 10% to 40% w/w.

Exemplary FAK kinase inhibitors that can be used in the present invention include the compounds disclosed in W02010058032A. In some embodiments, the FAK kinase inhibitor is BI 853520, which has the following structure:

Additional Therapeutic Asents/Combination Therapy

The methods of the present invention may be administered in combination with an additional agent (e.g., therapeutic agent). The additional agent can include but are not limited to, an anti-tumor or anti-cancer agent, e.g., an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti hormones, and anti-androgens.

In some embodiments, the methods and compositions described herein (e.g., a FAK kinase inhibitor in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB) is administered together with an additional therapy (e.g., cancer treatment). In one embodiment, a mixture of one or more compounds or pharmaceutical compositions may be administered with the combination described herein, e.g., a FAK kinase inhibitor in combination with an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB, to a subject in need thereof. In yet another embodiment, one or more compounds or compositions (e.g., pharmaceutical compositions) may be administered with the combination described herein, e.g., a FAK kinase inhibitor in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, for the treatment or avoidance of disease relates to abnormal cell growth.

In various embodiments, combination therapies comprising a compound or pharmaceutical composition described herein may refer to (1) pharmaceutical compositions that comprise one or more compounds in combination with the combination described herein, e.g., the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, and (2) co-administration of one or more compounds or pharmaceutical compositions described herein with the combination described herein, e.g., the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, wherein the compound or pharmaceutical composition described herein have not been formulated in the same compositions.

In some embodiments, the combinations described herein (e.g., the FAK kinase inhibitor BI853520 or the pharmaceutical acceptable salts thereof in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 or 4 IBB) are administered with an additional treatment (e.g., an additional cancer treatment). In some embodiments, the additional treatment (e.g., an additional cancer treatment) can be administered simultaneously (e.g., at the same time), in the same or in separate compositions, or sequentially. Sequential administration refers to administration of one treatment before (e.g., immediately before, less than 5, 10, 15, 30, 45, 60 minutes, 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 48, 72, 96 or more hours, 4, 5, 6, 7, 8, 9 or more days, 1, 2, 3, 4, 5, 6, 7, 8 or more weeks before) administration of an additional treatment (e.g., a compound or therapy). The order of administration of the first and secondary compound or therapy can also be reversed.

The methods of the invention may be used or administered in combination with one or more additional therapies (e.g., cancer treatment, e.g., surgery, additional drug(s) or therapeutic agents) for the treatment of the disorder/diseases mentioned. The additional therapies (e.g., cancer treatment, e.g., drug(s) or therapeutic agents described herein) can be administered in the same formulation or in separate formulations. If administered in separate formulations, the compounds of the invention may be administered sequentially or simultaneously with the other drug(s).

In addition to being able to be administered in combination with one or more additional therapies (e.g., cancer treatment, e.g., surgery, additional drug(s) or therapeutic agents), methods of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result.

Exemplary cancer treatments include, for example: chemotherapy, targeted therapies such as antibody therapies, immunotherapy, and hormonal therapy. Examples of each of these treatments are provided below. Chemotherapy

In some embodiments, the methods of the invention are administered with a chemotherapy. "Chemotherapy" usually refers to cytotoxic drugs which affect rapidly dividing cells in general, in contrast with targeted therapy. Chemotherapy drugs interfere with cell division in various possible ways, e.g., with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target all rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage, while normal cells generally can.

The methods of the invention may be used with antitumor agents, alkylating agents, antimetabolites, antibiotics, plant-derived antitumor agents, camptothecin derivatives, tyrosine kinase inhibitors, antibodies, interferons, and/or biological response modifiers. In this regard, the following is a non-limiting list of examples of additional agents, e.g., additional therapeutic agents that may be used with the methods of the invention.

• Alkylating agents include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, mafosfamide, and mitolactol, platinum- coordinated alkylating compounds include but are not limited to, cisplatin, carboplatin, eptaplatin, lobaplatin, nedaplatin, oxaliplatin or satrplatin,

• Antimetabolites include but are not limited to, methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-l, gemcitabine, fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethynylcytidine, cytosine arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, nolatrexed, ocfosfate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine, or for example, one of the preferred anti-metabolites disclosed in European Patent Application No. 239362 such as N-(5-[N-(3,4- dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L- glutamic acid.

• Antibiotics include but are not limited to: aclarubicin, actinomycin D, amrubicin, annamycin, bleomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, galarubicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin or zinostatin,

• Hormonal therapy agents, e.g., exemestane (Aromasin), Lupron, anastrozole (Arimidex), doxercalciferol, fadrozole, formestane, anti-estrogens such as tamoxifen citrate (Nolvadex) and fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene, letrozole (Femara), or anti-androgens such as bicalutamide, flutamide, mifepristone, nilutamide, Casodex® (4'-cyano-3-(4- fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide) and combinations thereof.

Plant derived anti-tumor substances include for example those selected from mitotic inhibitors, for example vinblastine, docetaxel (Taxotere) and paclitaxel, Cytotoxic topoisomerase inhibiting agents include one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10- hydroxycamptothecin, 9- aminocamptothecin, diflomotecan, irinotecan HC1 (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone, pirarubicin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, and topotecan, and combinations thereof.

Immunological s include but are not limited to, interferons and numerous other immune enhancing agents. Interferons include but are not limited to, interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma- la or interferon gamma- nl. Other agents include but are not limited to, filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAX-CL, sargramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab, and Provenge.

Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include but are not limited to, krestin, lentinan, sizofiran, picibanil, or ubenimex. Other anticancer agents include but are not limited to, alitretinoin, ampligen, atrasentan, bexarotene, bortezomib, Bosentan, calcitriol, exisulind, finasteride, fotemustine, ibandronic acid, miltefosine, mitoxantrone, 1 -asparaginase, procarbazine, dacarbazine, hydroxycarbamide, pegaspargase, pentostatin, tazarotne, TLK-286, Velcade, Tarceva, or tretinoin.

Other anti-angiogenic compounds include but are not limited to, acitretin, fenretinide, thalidomide, zoledronic acid, angiostatin, aplidine, cilengtide, combretastatin A-4, endostatin, halofuginone, rebimastat, removab, Revlimid, squalamine, ukrain and Vitaxin.

Platinum-coordinated compounds include but are not limited to, cisplatin, carboplatin, nedaplatin, or oxaliplatin.

• Camptothecin derivatives include but are not limited to camptothecin, 10- hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, and topotecan.

Because some drugs work better in combination than alone, two or more drugs are often given at the same time or sequentially. Often, two or more chemotherapy agents are used as combination chemotherapy. In some embodiments, the chemotherapy agents (including combination chemotherapy) can be used in combination with the methods described herein.

Targeted therapy

In some embodiments, the methods of the invention are administered with a targeted therapy. Targeted therapy constitutes the use of agents specific for the deregulated proteins of cancer cells. Small molecule targeted therapy drugs are generally inhibitors of enzymatic domains on mutated, overexpressed, or otherwise critical proteins within the cancer cell. Prominent examples are the tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib, desatinib, erolotinib, imatinib, gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, Iressa, SU5416 and Vandetanib, and also cyclin-depdendent kinase inhibitors such as Alvocidib and Seliciclib. Monoclonal antibody therapy is another strategy in which the therapeutic agent is an antibody which specifically binds to a protein on the surface of the cancer cells. Examples include but are not limited to, the anti-HER2/neu antibody trastuzumab (HERCEPTIN®) typically used in breast cancer, and the anti-CD20 antibody rituximab and Tositumomab typically used in a variety of B-cell malignancies. Other exemplary antibodies include but are not limited to, Ctuximab, Panitumumab, Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusion proteins include but are not limited to, Aflibercept and Denileukin diftitox. Targeted therapy can also involve small peptides as "homing devices" which can bind to cell surface receptors or affected extracellular matrix surrounding the tumor. Radionuclides which are attached to these peptides (e.g., RGDs) eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes BEXXAR®. In some embodiments, the targeted therapy can be used in combination with the methods of the invention.

Radiation therapy

The methods of the invention are can be used in combination with directed energy or particle, or radioisotope treatments, e.g., radiation therapies, e.g., radiation oncology, for the treatment of proliferative disease, e.g., cancer, e.g., cancer associated with cancer stem cells. The methods of the invention may be administered to a subject simultaneously or sequentially along with the directed energy or particle, or radioisotope treatments. For example, the methods of the invention may be administered before, during, or after the directed energy or particle, or radioisotope treatment, or a combination thereof. The directed energy or particle therapy may comprise total body irradiation, local body irradiation, or point irradiation. The directed energy or particle may originate from an accelerator, synchrotron, nuclear reaction, vacuum tube, laser, or from a radioisotope. The therapy may comprise external beam radiation therapy, teletherapy, brachytherapy, sealed source radiation therapy, systemic radioisotope therapy, or unsealed source radiotherapy. The therapy may comprise ingestion of, or placement in proximity to, a radioisotope, e.g., radioactive iodine, cobalt, cesium, potassium, bromine, fluorine, carbon. External beam radiation may comprise exposure to directed alpha particles, electrons (e.g., beta particles), protons, neutrons, positrons, or photons (e.g., radiowave, millimeter wave, microwave, infrared, visible, ultraviolet, X-ray, or gamma-ray photons). The radiation may be directed at any portion of the subject in need of treatment.

Surgery

The methods of the invention can be used in combination with surgery, e.g., surgical exploration, intervention, biopsy, for the treatment of proliferative disease, e.g., cancer, e.g., cancer associated with cancer stem cells. The methods of the invention may be administered to a subject simultaneously or sequentially along with the surgery. For example, the methods of the invention may be administered before (pre -operative), during, or after (post-operative) the surgery, or a combination thereof. The surgery may be a biopsy during which one or more cells are collected for further analysis. The biopsy may be accomplished, for example, with a scalpel, a needle, a catheter, an endoscope, a spatula, or scissors. The biopsy may be an excisional biopsy, an incisional biopsy, a core biopsy, or a needle biopsy, e.g., a needle aspiration biopsy. The surgery may involve the removal of localized tissues suspected to be or identified as being cancerous. For example, the procedure may involve the removal of a cancerous lesion, lump, polyp, or mole. The procedure may involve the removal of larger amounts of tissue, such as breast, bone, skin, fat, or muscle. The procedure may involve removal of part of, or the entirety of, an organ or node, for example, lung, throat, tongue, bladder, cervix, ovary, testicle, lymph node, liver, pancreas, brain, eye, kidney, gallbladder, stomach, colon, rectum, or intestine. In one embodiment, the cancer is breast cancer, e.g., triple negative breast cancer, and the surgery is a mastectomy or lumpectomy. Examples

Materials and Methods

Materials. BI 853520 was provided by Boehringer Ingelheim GmbH or synthesized according to W02010058032A. pcDNA3 construct encoding the ORF for murine CD80 was synthetized by GeneArt (Invitrogen). All flow cytometry antibodies used are listed in Tables 1 and 2.

Table 1 : T-cell flow cytometry panel

Table 2: Non- T-cell flow cytometry panel

Table 3 : Markers used to identify tumor infiltrating cell populations

Cell lines. A selection of murine tumor derived cell lines were used in this study, namely, Squamous Cell Carcinoma cell lines (SCC7.1 and SCC6.2), an MMTV-PyMT mammary tumor cell line (MetOl), and LSL-Kras^G12D/+, LSL-Trp53^R172H/+, Pdx-l-Cre derived pancreatic cancer cell lines (Panc43, Panc47, Panel 17). Cells were pathogen tested in September 2016 using the Impactlll test (Idex Bioresearch) and were negative for all pathogens. Cell lines were routinely tested for mycoplasma every 2-3 months in- house and were never found to be mycoplasma positive. Cell lines were cultured for no more than 3 months following freeze thawing. SCC cell lines were generated and cultured as previously described [Serrels, A., et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160-173 (2015); Serrels, A., et al. The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells. Int J Cancer 131, 287-297 (2012)]. SCC6.2 cells stably expressing pcDNA3-CD80 were generated by transfection using Lipofectamine 2000 (Invitrogen) and selection with 0.6mg/ml geneticin. MetOl and Pane cell lines were cultured in DMEM supplemented with 4500 mg/L glucose, L- glutamine, sodium pyruvate, sodium bicarbonate, and 10% FBS.

Subcutaneous tumor growth. All animal work was carried out in compliance with UK Home Office guidelines. 1 x 10⁶ (SCC FAK-wt, SCC FAK-/-, and MetOl) or 5 x 10⁵ (SCC7.1, SCC6.2, Panc43, Panc47, and Panel 17) cells were injected subcutaneously into each flank of either FVB/N (SCC and MetOl cell lines) or C57BL/6 mice (Pane cell lines), and tumor growth measured twice weekly using calipers. Animals were euthanized when tumors reached maximum allowed size, or more commonly when signs of ulceration, bleeding, or exudation were evident. For studies involving treatment with BI 853520, drug was prepared in 0.5% carboxymethyl cellulose (Vehicle) (Sigma-Aldrich), and mice were treated at 50 mg/kg QD by oral gavage. Isotype control, anti-GITR (clone DTA-1), anti-CD40 (clone FGK4.5), anti- 41BB (clone LOB12.3), anti-OX40 (clone OX-86), and anti-CD28 (clone 37.51) antibodies were dosed twice weekly by intraperitoneal injection at a concentration of 100 pg/mouse diluted in PBS (BioXcell). Animals were visually monitored for signs of toxicity and weighed prior to each dose of BI 853520 or antibody. No signs of toxicity or weight loss were observed. Group sizes ranged from 3-5 mice, each bearing two tumors, and tumor volume was calculated in Excel (Microsoft) using the formula V = ½ (length x width²). Statistics and graphs were calculated using Prism (GraphPad).

Tumor Growth following Re-Challenge . SCC6.2 cells were injected into both flanks of FVB/N mice and treatment administered as above. Following tumor regression, mice were maintained without treatment for 5 weeks prior to re-challenge with 5 x 10⁵ SCC6.2 cells per flank. Tumor growth was measured twice-weekly as described above. At the time of re-challenge, an age-matched control cohort of mice that had not previously been challenged with tumor cells were injected on both flanks using the same cell preparation and tumor growth monitored as above. Tumor volume was calculated as described above.

CD8+ T Cell Depletion. Anti-mouse CD8 depleting antibody (clone 53-6.7) and isotype control were purchased from BioXcell. As described previously [Serrels, A., et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160-173 (2015)] mice were treated with 150 pg of antibody administered by intraperitoneal injection for 3 consecutive days, followed by a rest period of 3 days. Following this, SCC or MetOl cells were injected subcutaneously into both flanks and T-cell depletion maintained by further administration of 150 pg depleting antibody at 3 -day intervals for the remainder of the experiment. Tumor growth was measured twice-weekly as described above.

FACS Analysis. Tumors established following subcutaneous injection of cells into mice were removed at day 12 into DMEM (Sigma-Aldrich). Tumor tissue was mashed using a scalpel and re-suspended in DMEM (Sigma-Aldrich) supplemented with 2 mg/ml collagenase D (Roche) and 40 units/ml DNasel (Roche). Samples were incubated for 30 minutes at 37°C, 5% C02 on an orbital shaker set at 120 rpm, and then pelleted by centrifugation at 1300 rpm for 5 min at 4°C. Samples were re-suspended in 5 ml of red blood cell lysis buffer (Pharm Lysis Buffer, Becton Dickinson) for 10 min at 37°C, pelleted by centrifugation at 1300 rpm for 5 min at 4°C, re-suspended in PBS and mashed through a 70-pm cell strainer using the plunger from a 5ml syringe. The cell strainer was further washed with PBS. The resulting single cell suspension was pelleted by centrifugation at 1300 rpm for 5 min at 4°C and re-suspended in PBS. This step was repeated twice. The resulting cell pellet was re-suspended in PBS containing Zombie NIR viability dye [1 : 1000 dilution (BioLegend)] and incubated at 4°C for 30 minutes then pelleted by centrifugation at 1300 rpm for 5 min at 4°C. Cells were resuspended in FACS buffer and pelleted by centrifugation at 1300 rpm for 5 min at 4°C. This step was repeated twice. Cell pellets were resuspended in 100 pi of Fc block [1 :200 dilution ofFc antibody (eBioscience) in FACS buffer] and incubated for 15 min. lOOul of antibody mixture [diluted in FACS buffer (antibody details listed in supplementary tables 1 and 2)] was added to each well and the samples incubated for 30 min in the dark. The cells were then pelleted by centrifugation at 1300 rpm for 5 min at 4°C and washed twice with FACS buffer as above. Finally, cells were re-suspended in FACS buffer and analyzed using a BD Fortessa. Data analysis was performed using FlowJo software. Statistics and graphs were calculated using Prism (GraphPad). For flow cytometry analysis of cell lines, growth media was removed and cells washed twice in PBS. Adhered cells were dissociated from tissue culture flasks by incubating them in enzyme free cell dissociation solution (Millipore) for 10 minutes at 37°C, 5% C02, and then scraping with a cell scraper. Cells were pelleted by centrifugation at 1300 rpm for 5 min at 4°C and washed with PBS. This step was repeated twice. Cells were then resuspended in viability dye and stained as above.

Nanostring analyses. RNA extracts were obtained using a RNeasy kit (Qiagen), following manufacturer’s instructions. 100 ng of RNA was analyzed using a mouse nanostring PanCancer Immune Profiling panel as per the manufacturer’s instructions. Hybridization was performed for 18 hours at 65°C and samples processed using the nanostring prep station set on high sensitivity. Images were analyzed at maximum (555 fields of view). Data was normalized using nSolver 4.0 software.

Analysis of CD80 expression in human cancer cell line data. The expression of CD80 and FAR were assessed across the panels of cell lines from the Cancer Cell Line Encyclopedia (https://www.ncbi.nlm.nih.gov/pubmed/22460905) using data downloaded from The Broad Institute portal (https://portals.broadinstitute.org/ccle).

Example 1: Endogenous expression of the T-cell co-stimulatory ligand CD80 on the surface of cancer cells correlates with the response of tumors to the FAK, and may potentially serve as a biomarker for patient stratification

A. Treatment of a panel of syngeneic mouse tumor models with BI 853520 reveals a spectrum of vastly different responses.

We have previously shown using a murine model of skin SCC that depletion of FAK expression or treatment with a small molecule FAK kinase inhibitor can result in immune-mediated tumor regression in syngeneic mice [Serrels, A., et al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160-173 (2015)]. Using this same model system we first determined the anti-tumor efficacy of the FAK kinase inhibitor BI 853520 by monitoring tumor growth following injection of 1 x 10⁶ FAK-deficient cells (FAK-/-) or FAK-deficient cells that re expressed wild-type FAK (FAK-WT) at comparable levels to endogenous. Daily treatment of SCC FAK-wt tumors with 50 mg/kg BI 853520 resulted in complete tumor regression with similar kinetics to that of SCC FAK-/- tumors (Fig. 1A).

Therapeutic efficacy of FAK inhibition was investigated using a panel of six syngeneic cancer cell lines originating from tumors arising on three commonly used mouse cancer models: (1) skin squamous cell carcinomas induced using the DMBA/ TPA two-stage chemical carcinogenesis protocol (SCC cell lines) [Serrels, A., et al. The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells. Int J Cancer 131, 287-297 (2012)], (2) a primary breast tumor arising on the MMTV-PyMT genetically engineered mouse (GEM) model of breast cancer (MetOl cell line) [Qian, B.Z., et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222-225 (2011)]; (3) Pancreatic Ductal Adenocarcinoma (PD AC) arising on the LSL-Kras^GI2D/+ ; LSL-Trp53^R172H/+ ; Pdx-l-Cre (KPC) GEM model of pancreatic cancer (Pane cell lines) [Hingorani, S. R. et al., Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469-483 (2005)].

FVB/N mice were injected subcutaneously with 0.5 x 10⁶ SCC7.1 or SCC6.2 cells and treated daily with either Vehicle (drug vehicle) or 50 mg/kg BI 853520. We observed complete regression of SCC7.1 tumors by day 27 (Fig. IB), while in contrast SCC6.2 tumors exhibited only a modest growth delay (Fig. 1C). SCC7.1 cells are the parental population from which the SCC FAK-wt and FAK-/- cell model was developed, hence the similarity of response to FAK kinase inhibition. Subcutaneous injection of 1 x 10⁶ MetOl cells into FVB/N mice followed by daily treatment with either Vehicle or BI 853520 identified a heterogeneous response, with 3 out of 10 tumors showing a partial response / growth delay and 7 out of 10 tumors displaying stable disease for the duration of the study (Fig. ID). Lastly, subcutaneous injection of 0.5 x 10⁶ Panc43, Panc47, or Panel 17 cells into C57BL/6 mice followed by daily treatment with either Vehicle or BI 853520 identified that Panc43 tumors exhibit a modest growth delay in response to FAK inhibition (Fig. IE), while Panc47 and Panel 17 tumors exhibit little to no response (Figs. IF and 1G). Collectively, these results identify a spectrum of response to treatment with BI 853520.

B. CD8 T-cells are required for tumor regression / stable disease in response to BI 853520 treatment.

We have previously shown that targeting FAK can result in an anti-tumor CD8 T-cell response that is sufficient to drive tumor regression [Serrels, A., el al. Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity. Cell 163, 160-173 (2015)). Therefore, we used antibody-mediated CD8 T-cell depletion to determine whether SCC7.1 tumor regression and MetOl stable disease was also CD8 T-cell dependent. In mice treated with a CD8 T-cell depleting antibody, SCC7.1 and MetOl tumors exhibited only a modest growth delay in response to treatment with BI 853520 when compared to vehicle treated controls, while in mice treated with an isotype control antibody all SCC7.1 tumors underwent complete regression and all MetOl tumors exhibited stable disease following treatment with BI 853520 (Figs. 1H and II). Thus, FAK kinase inhibition elicits CD8 T-cell mediated anti-tumor immunity that is required for SCC7.1 tumor regression and MetOl stable disease.

C. Cancer cell expression of the T-cell costimulatory ligand CD80 correlates with response to BI 853520

A number of FAK kinase inhibitors, including BI 853520, are now in early-phase (I/II) clinical trials as experimental cancer therapies [Shapiro, I. M. et. al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Trans Med , 6, (237):237ra68 (2014); Hirt, U. A. et. al. Efficacy of the highly selective focal adhesion kinase inhibitor BI 853520 in adenocarcinoma xenograft models is linked to a mesenchymal tumor phenotype. Oncogenesis , 7, 21, (2018)]. However, we do not know which patients are most likely to benefit from these inhibitors, and to-date there are no validated biomarkers that would enable patient stratification. Based on our findings in Figure 1, we hypothesized that either CD8 T-cell infiltration or expression of immune regulatory molecules that can modulate CD8 T-cell function might underlie sensitivity to FAK inhibition. To test this, we established subcutaneous tumors from each of the cell line models, and 12 days after implantation used flow cytometry to profile the CD8 T-cell infiltrate. This analysis identified that SCC7.1 and MetOl tumors have a higher frequency of CD8 T-cell infiltration than SCC6.2, Panc43 and Panc47 tumors (Fig. 2A). However, Panel 17 tumors also had a higher frequency of CD8 T-cell infiltration when compared to SCC6.2, Panc43, and Panc47 tumors. Therefore, CD8 T-cell infiltration alone does not accurately predict response to BI 853520.

CD8 T-cell function can be regulated in a number of ways, including through coinhibitory and costimulatory receptors expressed on the surface of CD8 T-cells (REF). We therefore sought to determine whether differential expression of these pathways correlated with response to BI 853520. Initially, we used flow cytometry to identify whether the immune checkpoint receptor Programmed Death Receptor 1 (PD1) was differentially expressed on tumor infiltrating CD8 T-cells. However, PD1 was expressed on activated (CD44⁺) CD8 T-cells in all tumor types (Fig. 2B). We next used flow cytometry to determine the expression of Programmed Death Ligands 1 and 2 (PDL1 and 2), the two ligands for PD1, on each of the cell lines. None of the cell lines expressed PDL1 or PDL2 under basal culture conditions (Data not shown). However, when the cell lines were stimulated with 10 ng/ml interferon-gamma (IFNy) for 24 hours all cell lines upregulated PDL1 to a similar extent (Fig. 2C) implying that all were capable of engaging the PD1-PDL1 axis. None of the cell lines upregulated the expression of PDL2 in response to IFNy treatment (Data not shown). Therefore, we did not identify any relationship between the PD1-PDL1/2 axis and response to BI 853520. PDL1 and 2 belong to the family of B7 ligands that can engage coinhibitory and costimulatory receptors to regulate CD8 T-cell activity. We therefore used flow cytometry to further profile the expression of the B7 family of proteins across the tumor cell lines. While many of these ligands were not expressed by any of the cell lines, CD80 (also known as B7.1) was expressed exclusively by the SCC7.1 and MetOl cell lines that respond best to FAK inhibition (Figs. 2D and 2E). Therefore, expression of the costimulatory ligand CD80 on the surface of cancer cells correlated with response to BI 853520. D. In vivo studies support CD80 expression level can potentially to identify tumors with increased sensitivity to FAK kinase inhibition

CD80 was expressed into a cell line that showed a poor response to BI 853520 when grown as a tumor in a syngeneic host (Fig. 1). SCC6.2 cell line was selected as these are most similar to the SCC7.1 cells that when grown as tumors undergo complete CD8 T-cell mediated regression in response to treatment with BI 853520 (Fig. IB). Using nanostring gene expression analysis we first confirmed that SCC6.2 cells have a similar expression profile of Major Histocompatibility Complex (MHC) molecules to that of SCC7.1 cells (Fig. 3A), ensuring that SCC6.2 cells express MHC-I molecules required for CD8 T-cell recognition and effective anti-tumor immunity. We next transfected SCC6.2 cells with either the mammalian expression vector pcDNA3, or pcDNA3- CD80, and used flow cytometry to determine the percentage of SCC6.2 pcDNA3-CD80 cells expressing CD80 on their cell surface (Fig. 3B, left graph ) and the mean fluorescent intensity of CD80 surface expression in comparison to that of SCC7.1 cells (Fig. 3B, right graph). These results identified that the level of CD80 expression in SCC6.2 pcDNA3-CD80 cells was comparable to SCC7.1 cells, but that only approximately 60% of the SCC6.2 cells transfected with pcDNA3-CD80 were actually expressing CD80.

Next 0.5 x 10⁶ SCC6.2 pcDNA3 or SCC6.2 pcDNA-CD80 cells were injected subcutaneously into FVB/N mice and tumor growth monitored in response to either treatment with vehicle or BI 853520 (Fig. 3C). Expression of CD80 had no impact on SCC6.2 tumor growth. However, SCC6.2 pcDNA3-CD80 tumors showed a significantly improved response to BI 853520 in comparison to either vehicle treated controls or SCC6.2 pcDNA3 tumors treated with BI 853520. Thus, CD80 expression sensitizes SCC6.2 tumors to BI 853520. These findings suggest that cancer cell expression of CD80, most likely in combination with MHC-I, has the potential to identify tumors with increased sensitivity to FAK kinase inhibition.

E. High expression of both CD80 and FAK is restricted to human cancer cell lines originating from a subset of hematological malignancies

The prevalence of human tumors positive for cancer cell CD80 expression is currently unknown, and attempts to define this using genomics data derived from tumor samples, such as is publicly available through the Cancer Genome Atlas (TCGA), are confounded by the fact that CD80 is also expressed by antigen presenting cells that infiltrate the tumor microenvironment. Therefore, to more broadly assess cancer cell cd80 expression in human cancer we turned to publicly available genomics data spanning a large number of human cancer cell lines (Fig. 4A). This analyses identified that CD80 transcript is present in a substantial proportion of cell lines, but that only a subset of these express high levels of cd80. In particular, cell lines derived from hematological malignancies including lymphomas generally expressed higher levels of CD80 in comparison to all others. Analysis of FAK expression in the same genomics datasets identified that FAK transcript is highly expressed in most cell lines originating from solid epithelial cancers, but that only a subset of cell lines from hematological malignancies express comparably high levels of FAK (Fig. 4B). Plotting CD80 expression against FAK expression further confirmed these findings (Fig. 4C). Given that hematological malignancies represents a broad group of cancers we next sought to determine whether co-expression of high CD80 and high FAK was restricted to particular hematological malignancies by subdividing this category based on origin (Figs. 4D and E). These analyses suggested that co-expression of high levels of cd80 and FAK transcript occurs preferentially in cancer cell lines originating from patients with Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chromic Myeloid Leukemia, and Diffuse Large B-cell (DLBCL) Lymphoma. To our knowledge FAK inhibitors have not been tested in patients diagnosed with these cancer types.

Example 2: Combination of FAK inhibition with agonistic antibodies targeting T- cell co-stimulatory receptors in cancer models that do not express CD80 results in enhanced antitumor activities

A. FAK inhibition enhances the response of SCC6.2 tumors to agonistic antibodies targeting T-cell costimulatory receptors.

Anti-tumor efficacy studies of FAK inhibition in combination with a number of agonistic antibodies targeting T-cell costimulatory receptors, including glucocorticoid- induced TNFR-related protein (GITR, also known as Tumor necrosis factor receptor superfamily member 18 (TNFRSF18)), CD40 (also known as TNFRSF5), 4 IBB (also known as tumor necrosis factor receptor superfamily member 9 (TNFRSF9) and CD137), and 0X40 (also known as Tumor necrosis factor receptor superfamily member 4 (TNFRSF4) and CD 134), were investigated.

0.5 x 106 SCC6.2 cells were injected subcutaneously into FVB/N mice and mice treated with either Vehicle, Vehicle + 100 pg/mouse anti-GITR, Vehicle + 100 pg/mouse CD40, Vehicle + 100 pg/mouse 4- IBB, Vehicle + 100 pg/mouse 0X40, BI 853520 + 100 pg/mouse anti-GITR, BI 853520 + 100 pg/mouse CD40, BI 853520 + 100 pg/mouse 4-1BB or BI 853520 + 100 pg/mouse 0X40 (treatment schedule shown in Fig. 5A). Treatment of SCC6.2 tumors with Vehicle + anti-GITR agonistic antibody resulted in a small growth delay when compared to control treated tumors, which was not improved when the anti-GITR antibody was combined with BI 853520 (Fig. 5B). Similar results were observed using an anti-CD40 agonistic antibody alone or in combination with BI 853520 (Fig. 5C). However, treatment of SCC6.2 tumors with Vehicle + anti-4- IBB agonistic antibody resulted in 2 out of 8 tumors undergoing complete regression and the remaining 6 tumors exhibiting a delay in growth when compared to control treated tumors. Combining anti-4- IBB with BI 853520 further improved this response, resulting in 4 out of 8 tumors undergoing complete regression, and the remaining 4 tumors exhibiting an improved growth delay when compared with Vehicle + anti-4- IBB (Fig. 5D). Finally, treatment of SCC6.2 tumors with Vehicle + anti-OX40 agonistic antibody resulted in 2 out of 8 tumors undergoing complete regression, and the remaining 6 exhibiting a growth delay when compared to control treated tumors. Combining anti-OX40 with BI 853520 resulted in complete regression of all tumors (Fig. 5E). Thus, FAR kinase inhibition in combination with activation of either 0X40 or 4- IBB represents a potentially promising therapeutic strategy for further investigation. To determine whether the potent anti-tumor efficacy of BI 853520 + anti- 0X40 was dependent on CD8 T-cells, we depleted CD8 T-cells using an anti-CD8 antibody, and measured SCC6.2 tumor growth in FVB/N mice receiving either Vehicle or BI 853520 + anti-OX40 (Fig. 5F). In mice receiving anti-CD8 antibody the combination of BI 853520 + anti-OX40 resulted in a growth delay when compared to mice treated with anti-CD8 antibody and Vehicle. However, only in mice receiving an isotype control antibody did the combination of BI 853520 + anti-OX40 result in complete regression of all tumors, implying that tumor regression in response to this combination is dependent on CD8 T-cells. An anti-tumor CD8 T-cell response should also result in lasting immunological memory. To test this, we aged mice for two months following regression of SCC6.2 tumors in response to treatment with BI 853520 + anti- 0X40, and re-challenged these mice with a fresh preparation of SCC6.2 cells. All mice remained tumor free during the two months following initial regression of SCC6.2 tumors, and following re-challenge no tumor growth was observed (Fig. 5G). In contrast, subcutaneous injection of the same SCC6.2 cell preparation into FVB/N mice that had never previously been challenged resulted in robust growth of all tumors. Therefore, SCC6.2 tumor regression in response to BI 853520 + anti-OX40 results in lasting immunological memory that renders mice resistant to further tumor growth. B. Mechanistic studies show that FAK inhibition and anti-OX40 have overlapping and distinct immune-modulatory activity.

Flow cytometry was used to profile the tumor immune cell infiltrate and its regulation in response to treatment with either Vehicle, anti-OX40 (clone OX-86), BI 853520, or BI 853520 + anti-OX40 (clone OX-86).

0.5 x 10⁶ SCC6.2 cells were injected subcutaneously into FVB/N mice and treatment administered as detailed in Figure 5A. Mice were culled 9-days post tumor cell implantation and tumors processed for analysis using flow cytometry. Both anti-OX40 and BI 853520 treatment resulted in a reduction in the frequency of Tregs, as did the combination of BI 853520 + anti-OX40 (Fig. 6A). In tumors treated with anti-OX40 or anti-OX + BI 853520 this was accompanied by an increase in the frequency of non- Treg CD4⁺ T-cells (Fig 6B). Treatment with anti-OX40 or BI 853520 + anti-OX40 also resulted in an increase in effector CD8 T-cells (CD8^eff) when compared to control treated and BI 853520 treated tumors (Fig. 6C), implying that anti-OX40 is required to drive increased CD8^eff T-cell representation in SCC6.2 tumors. However, this did not explain why BI 853520 enhanced the anti-tumor immune response when used in combination with anti-OX40. We therefore analyzed the expression of CD8 T-cell surface markers associated with T-cell exhaustion. No statistically significant difference was observed in the frequency of CD8 T-cells co-expressing either PD-1 and LAG-3 or PD-1 and Tim-3 (Fig. 6D), although there was a trend towards increased PD-l⁺Tim-3⁺ CD8 T-cells in both 0X40 and OX-40 + BI 853520 treated tumors. We next investigated other cell types within the tumor microenvironment. No statistically significant difference was observed in the frequency of macrophages, granulocytic myeloid derived suppressor cells (G-MDSC), monocytic myeloid derived suppressor cells (M- MDSC), or cancer cells (Fig. 6E and Figs. 8A, B, and C). However, we did observe a significant increase in CDl ltf dendritic cells (DCs) in response to 0X40, which was restored to control levels when 0X40 was combined with BI 853520 (Fig. 8D). Further flow cytometry analysis, with particular emphasis on macrophage expression of the immune checkpoint ligands PD-L1 and PD-L2, identified that neither treatment alone nor in combination has any effect on PD-L1 expression (Fig. 6F). However, BI 853520 either alone or in combination with 0X40 resulted in a small decrease in the number of macrophages positive for any expression of PD-L2 (Fig. 6G, left graph), but this was due to a marked reduction in total PD-L2 expression on macrophages (Fig. 6G, right graph). Comparison of PD-L2 expression on cancer cells, G-MDSCs, M-MDSCs, macrophages, and CDl lb+ DCs revealed that macrophages and DCs express the highest levels of PD-L2 from this range of cell types (Fig. 6H). BI 853520 treatment either alone or in combination with anti-OX40 was also found to result in a reduction in PD-L2⁺ cancer cells and M-MDSCs (Fig. 61). Therefore, BI 853520 treatment broadly depletes the availability of PD-L2 within the tumor microenvironment, likely impacting on PD-L2 - PD-1 signaling and ultimately CD8 T-cell exhaustion.

C. FAK inhibition in combination with immune costimulatory antibodies renders poorly immunogenic Panc47 tumors responsive to treatment.

SCC6.2 cancer cells were generated using the DMBA / TPA chemical carcinogenesis protocol that results in a large number of somatic mutations, and therefore likely increased immunogenicity. Hence, one would predict that these will respond better to immunotherapy than poorly immunogenic tumor models such as those derived from the KPC GEM model of pancreatic cancer. We therefore tested the same combinations of BI 853520 +/- immune costimulatory antibodies to determine whether FAK inhibition in combination with T-cell co-stimulation was also active in a more poorly immunogenic tumor model. 0.5 x 10⁶ Panc47 cells were injected subcutaneously into C57BL/6 mice and mice treated with either Vehicle, 100 ug/mouse anti-GITR, CD40, 4- IBB or 0X40, or BI 853520 + anti-GITR, CD40, 4- IBB or 0X40 (treatment schedule shown in Fig. 5A). Anti-GITR alone had no effect on the growth of Panc47 tumors, while in combination with BI 853520 we observed a small growth delay (Fig. 7A). In contrast, treatment with an anti-CD40 agonistic antibody resulted in a significant delay in the growth of Panc47 tumors, and this was not improved when used in combination with BI 853520 (Fig. 7B). Treatment of Panc47 tumors with an anti-4- 1BB agonistic antibody had no effect on tumor growth, but a significant growth delay was observed when used in combination with BI 853520 (Fig. 7C). Lastly, treatment with an anti-OX40 agonistic antibody had no effect on Panc47 tumor growth, but again when used in combination with BI 853520 was observed to result in a significant growth delay (Fig. 7D). Therefore, FAK kinase inhibition renders Panc47 tumors sensitive to anti-4- IBB and anti-OX40 immunotherapies, further supporting the development of these combinations as potential cancer therapies.

In contrast to the response of SCC6.2 tumors to the combination of BI 853520 + anti-OX40 or BI 853520 + anti-4- IBB, we did not observe regression of Panc47 tumors when using either of these combinations. FAK inhibition has previously been shown to sensitize pancreatic tumors to immune checkpoint therapy, specifically anti-PD-1 and anti-CTLA-4, when used in combination with the chemotherapy Gemcitabine. We therefore tested Gemcitabine alone and in combination with either BI 853520, anti- 0X40, or BI 853520 + anti-OX40. 0.5 x 10⁶ Panc47 cells were injected subcutaneously into C57BL/6 mice and tumor growth monitored in response to therapy (Fig. 7E). Gemcitabine treatment of Panc47 tumors resulted in a significant growth delay that was not further improved by combination with either BI 853520 or anti-OX40. However, the triple combination of Gemcitabine + BI 853520 + anti-OX40 did show a significant improvement in response when compared to Gemcitabine alone, Gemcitabine + BI 853520, or Gemcitabine + 0X40, and tumors were also smaller than corresponding measurements for BI 853520 + anti-OX40 (Fig. 7D). Therefore, Gemcitabine exhibits anti-tumor efficacy that can further add to that of BI 853520 + anti-OX40.

The above is a further detailed description of the present disclosure in connection with the specific preferred embodiments, and the specific embodiments of the present disclosure are not limited to the description. It will be apparent to those skilled in the art that the present disclosure may be practiced by making various simple deduction and replacement, without departing from the spirit and scope of the invention.

Claims

1. Combination, comprising a FAK kinase inhibitor and an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

2. The combination according to claim 1, wherein the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

3. The combination according to any one of claims 1-2, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

4. The combination according to any one of claims 1-3, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

5. The combination according to claim 4, wherein the anti-OX40 antibody is PF- 04518600, MEDIO 562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI or ATOR-1015, and the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

6. The combination according to any one of claims 1-5, which further comprising an additional therapeutic agent.

7. The combination according to claim 6, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

8. The combination according to claim 7, wherein the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

9. Pharmaceutical composition, comprising a FAK kinase inhibitor and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

10. The pharmaceutical composition according to claim 9, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

11. The pharmaceutical composition according to any one of claims 9-10, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

12. The pharmaceutical composition according to any one of claims 9-11, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

13. The pharmaceutical composition according to claim 12, wherein the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998,

MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015, the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

14. The pharmaceutical composition according to any one of claims 9-13, which further comprising an additional therapeutic agent.

15. The pharmaceutical composition according to claim 14, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

16. The pharmaceutical composition according to claim 15, wherein the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

17. A kit, comprising a first composition including a FAK kinase inhibitor, and a second composition including an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

18. The kit according to claim 17, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

19. The kit according to any one of claims 17-18, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

20. The kit according to any one of claims 17-19, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

21. The kit according to claim 20, wherein the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV- 368, IBIIOI or ATOR-1015, the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

22. The kit according to any one of claims 17-21, which further comprising a third composition including an additional therapeutic agent.

23. The kit according to claim 22, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

24. The kit according to claim 23, wherein the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

25. The kit according to any one of claims 17-24, wherein further comprising a package insert, the package insert comprises instructions for treating cancer in a subject by using them.

26. Use of a FAK kinase inhibitor in the preparation of medicament for treating cancer, wherein the medicament is used in combination with an agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB, and the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

27. The use according to claim 26, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and41BB is an 0X40 agonist or a 4 IBB agonist.

28. The use according to any one of claims 26-27, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

29. The use according to any one of claims 26-28, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

30. The use according to claim 29, where the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV- 368, IBIIOI orATOR-1015, the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

31. The use according to any one of claims 26-30, wherein the medicament is further used in combination with an additional therapeutic agent.

32. The use according to claim 31, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

33. The use according to claim 32, wherein the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

34. Use of an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer, wherein the medicament is used in combination with a FAK kinase inhibitor, and the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

35. The use according to claim 34, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

36. The use according to any one of claims 34-35, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

37. The use according to any one of claims 34-36, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

38. The use according to claim 37, wherein the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV- 368, IBIIOI and ATOR-1015, the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).

39. The use according to any one of claims 34-38, wherein the medicament is further used in combination with an additional therapeutic agent.

40. The use according to claim 39, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

41. The use according to claim 40, wherein the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

42. Use of a FAK kinase inhibitor and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB in the preparation of medicament for treating cancer, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

43. The use according to claim 42, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

44. The use according to any one of claims 42-43, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

45. The use according to any one of claims 42-44, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

46. The use according to claim 45, wherein the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV- 368, IBIIOI and ATOR-1015, the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).

47. The use according to any one of claims 42-46, wherein the medicament is further used in combination with an additional therapeutic agent.

48. The use according to claim 47, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

49. The use according to claim 48, wherein the therapeutic agent is Anti-metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

50. A method for treating cancer in a subject, comprising administering a FAK kinase inhibitor and an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

51. The method according to claim 50, wherein the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

52. The method according to any one of claims 50-51, wherein the agent targeting T- cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

53. The method according to any one of claims 50-52, wherein the agent targeting T- cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-4 IBB antibody or antigen binding portion thereof.

54. The method according to claim 53, wherein the anti-OX40 antibody is PF- 04518600, MEDIO 562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBIIOI and ATOR-1015, the anti-41BB antibody is utomilumab (PF- 05082566) or urelumab (BMS-663513).

55. The method according to any one of claims 50-54, wherein the method further comprising administration of an additional therapeutic agent.

56. The method according to claim 55, wherein the additional therapeutic agent is selected from: Alkylating agents, Anti-metabolites, Antibiotics, Hormonal therapy agents, Plant derived anti-tumor substances, Cytotoxic topoisomerase inhibiting agents, Immunological s, Biological response modifiers, Other anticancer agents, Other anti-angiogenic compounds, Platinum-coordinated compounds, Tyrosine kinase inhibitors, Antibodies, and Interferons.

57. The method according to claim 56, wherein the therapeutic agent is Anti metabolites or Plant derived anti-tumor substances, preferable gemcitabine or paclitaxel.

58. The method according to any one of claims 50-57, wherein the cancer is a solid tumor.

59. The method according to claim 58, wherein the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor(GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma(EHE) Desmoplastic small round cell tumor, or Liposarcoma.

60. The method according to any one of claims 50-57, wherein the cancer is hematological malignancies or lymphomas.

61. The method according to claim 60, wherein the cancer is selected from Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS- related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, Chronic Myeloid Leukemia, and Diffuse Large B-cell (DLBCL) Lymphoma.

62. The method according to any one of claims 50-61, wherein the FAK kinase inhibitor is administered orally.

63. The method according to claim 62, wherein the FAK kinase inhibitor is administered at least once a day.

64. The method according to claim 62, wherein the FAK kinase inhibitor is administered once a day.

65. The method according to claim 62, wherein the FAK kinase inhibitor is administered twice a day.

66. The method according to claim 62, wherein the FAK kinase inhibitor is administered at about 100 mg to about 2000 mg.

67. The method according to any one of claims 50-66, wherein the FAK kinase inhibitor is administered before the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is administered.

68. The method according to any one of claims 50-66, wherein the FAK kinase inhibitor is administered after the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB is administered.

69. The method according to any one of claims 50-66, wherein the FAK kinase inhibitor is administered concurrently with the agent targeting T-cell co stimulatory receptors selected from 0X40 and 4 IBB is administered.

70. A FAK kinase inhibitor for use in the methods according to any one of claims 50- 69.

71. An agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB for use in the methods according to any one of claims 50-69.

72. The agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB according to claim 71, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 agonist or a 4 IBB agonist.

73. The agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB according to claim 71, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an 0X40 binding protein or a 4 IBB binding protein.

74. The agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB according to claim 71 wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is an anti-OX40 antibody or antigen binding portion thereof, or an anti-41BB antibody or antigen binding portion thereof.

75. The agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB according to claim 74, where the anti-OX40 antibody is PF-04518600, MEDI0562, INCAGN1949, GSK3174998, MOXR0916, BMS-986178, ABBV-368, IBI101 or ATOR-1015, the anti-41BB antibody is utomilumab (PF-05082566) or urelumab (BMS-663513).

76. A medicament comprising a FAK kinase inhibitor for use in treating cancer in a subject, wherein the FAK kinase inhibitor is for use in combination with an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB, and the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

77. A medicament comprising an agent targeting T-cell co-stimulatory receptors selected from 0X40 and 41BB for use in treating cancer in a subject, wherein the agent targeting T-cell co-stimulatory receptors selected from 0X40 and 4 IBB is for use in combination with an agent directed to a FAK kinase inhibitor, and the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

78. Use of a FAK kinase inhibitor in the preparation of medicament for treating cancer with CD80 expression, preferable with high CD80 expression, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

79. The use according to claim 78, wherein the cancer is a solid tumor.

80. The use according to claim 79, wherein the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor(GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma(EHE) Desmoplastic small round cell tumor, or Liposarcoma.

81. The use according to claim 78, wherein the cancer is hematological malignancies or lymphomas.

82. The use according to claim 81 , wherein the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T- cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

83. FAK kinase inhibitor for treating cancer with CD80 expression, preferable with high CD80 expression, in a subject, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

84. The FAK kinase inhibitor for treating cancer with CD80 expression according to claim 83, wherein the subject is human.

85. The FAK kinase inhibitor for treating cancer with CD80 expression according to any one of claims 83-84, wherein the cancer is a solid tumor.

86. The FAK kinase inhibitor for treating cancer with CD80 expression according to claim 85, wherein the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor(GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma(EHE) Desmoplastic small round cell tumor, or Liposarcoma.

87. The FAK kinase inhibitor for treating cancer with CD80 expression according to any one of claims 83-84, wherein the cancer is hematological malignancies or lymphomas.

88. The FAK kinase inhibitor for treating cancer with high CD80 expression according to claim 87, wherein the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T- cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

89. A method for treating a cancer with CD80 expression, preferable with high CD80 expression, in a subject, comprising administering a FAK kinase inhibitor to the subject, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

90. The method according to claim 89, the subject is human.

91. The method according to any one of claims 89-90, wherein the cancer is a solid tumor.

92. The method according to claim 91, wherein the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor(GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor, Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma (EHE) Desmoplastic small round cell tumor, or Liposarcoma.

93. The method according to any one of claims 89-90, wherein the cancer is hematological malignancies or lymphomas.

94. The method according to claim 93, wherein the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

95. A method for identifying a subject with cancer that could benefit from a FAK kinase inhibitor treatment, comprising detecting CD80 expression on the cancer cell, the subject is identified when CD80 expression, preferable high CD80 expression, is detected, wherein the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

96. The method according to claim 95, wherein the subject is human.

97. The method according to any one of claims 95-96, wherein the cancer is a solid tumor.

98. The method according to claim 97, wherein the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor(GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor , Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer,, Salivary gland cancer, Hypopharyngeal cancer, Basal-cell carcinoma, Melanoma, Skin cancer (non melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma (EHE) Desmoplastic small round cell tumor, or Liposarcoma.

99. The method according to any one of claims 95-96, wherein the cancer is hematological malignancies or lymphomas.

100. The method according to claim 99, wherein the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.

101. Use of CD80 as a biomarker for identifying a subj ect with cancer that could benefit from a FAK kinase inhibitor treatment, wherein the subject is identified when CD80 expression, preferable high CD80 expression, is detected on the cancer cell, and the FAK kinase inhibitor is BI853520 or the pharmaceutical acceptable salts thereof, preferable BI853520 tartaric acid salt.

102. The use according to claim 101, wherein the subject is human.

103. The use according to any one of claims 101-102, wherein the cancer is a solid tumor.

104. The use according to claim 103, wherein the cancer is Chondrosarcoma, Ewing's sarcoma, Malignant fibrous histiocytoma of bone/osteosarcoma, Osteosarcoma, Rhabdomyosarcoma, Heart cancer, Astrocytoma, Brainstem glioma, Pilocytic astrocytoma, ependymoma, Primitive neuroectodermal tumor, Cerebellar astrocytoma, Cerebral astrocytoma, Glioma, Medulloblastoma, Neuroblastoma, Oligodendroglioma, Pineal astrocytoma, Pituitary adenoma, Visual pathway and hypothalamic glioma, Breast cancer, Invasive lobular carcinoma, Tubular carcinoma, Invasive cribriform carcinoma, Medullary carcinoma, Male breast cancer, Phyllodes tumor, Inflammatory Breast Cancer, Adrenocortical carcinoma, Islet cell carcinoma(endocrine pancreas), Multiple endocrine neoplasia syndrome, Parathyroid cancer, Pheochromocytoma, Thyroid cancer, Merkel cell carcinoma, Uveal melanoma, Retinoblastoma, Anal cancer, Appendix cancer, Cholangiocarcinoma, Carcinoid tumor, gastrointestinal, Colon cancer, Extrahepatic bile duct cancer, Gallbladder cancer, Gastric (stomach) cancer, Gastrointestinal carcinoid tumor, Gastrointestinal stromal tumor(GIST), Hepatocellular cancer, Pancreatic cancer, islet cell, Rectal cancer, Bladder cancer, Cervical cancer, Endometrial cancer, Extragonadal germ cell tumor, Ovarian cancer, Ovarian epithelial cancer (surface epithelial-stromal tumor), Ovarian germ cell tumor , Penile cancer, Renal cell carcinoma, Renal pelvis and ureter, Prostate cancer, Testicular cancer, Gestational trophoblastic tumor, Ureter and renal pelvis, transitional cell cancer, Urethral cancer, Uterine sarcoma, Vaginal cancer, Vulvar cancer, Wilms tumor, Esophageal cancer, Head and neck cancer, Nasopharyngeal carcinoma, Oral cancer, Oropharyngeal cancer, Paranasal sinus and nasal cavity cancer, Pharyngeal cancer, Salivary gland cancer, Hypopharyngeal cancer, Basal cell carcinoma, Melanoma, Skin cancer (non-melanoma), Bronchial adenomas/carcinoids, Small cell lung cancer, Mesothelioma, Non-small cell lung cancer, Pleuropulmonary blastoma, Laryngeal cancer Thymoma and thymic carcinoma, AIDS-related cancers, Kaposi sarcoma, Epithelioid hemangioendothelioma(EHE) Desmoplastic small round cell tumor, or Liposarcoma.

105. The use according to any one of claims 101-102, wherein the cancer is hematological malignancies or lymphomas.

106. The use according to claim 105, wherein the cancer is Acute biphenotypic leukemia, Acute eosinophilic leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, Acute myeloid dendritic cell leukemia, AIDS-related lymphoma, Anaplastic large cell lymphoma, Angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt's lymphoma, Chronic lymphocytic leukemia, Chronic myelogenous leukemia, Cutaneous T-cell lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Hairy cell leukemia, Hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, Hairy cell leukemia, Intravascular large B-cell lymphoma, Large granular lymphocytic leukemia, Lymphoplasmacytic lymphoma, Lymphomatoid granulomatosis, Mantle cell lymphoma, Marginal zone B-cell lymphoma, Mast cell leukemia, Mediastinal large B cell lymphoma, Multiple myeloma/plasma cell neoplasm, Myelodysplastic syndromes, Mucosa-associated lymphoid tissue lymphoma, Mycosis fungoides, Nodal marginal zone B cell lymphoma, Non-Hodgkin lymphoma, Precursor B lymphoblastic leukemia, Primary central nervous system lymphoma, Primary cutaneous follicular lymphoma, Primary cutaneous immunocytoma, Primary effusion lymphoma, Plasmablastic lymphoma, Sezary syndrome, Splenic marginal zone lymphoma, T-cell prolymphocytic leukemia, preferable Burkitt’s Lymphoma, Hodgkin’s Lymphoma, Chronic Myeloid Leukemia, or Diffuse Large B-cell (DLBCL) Lymphoma.