NZ722296B2 - Combination of a pd-1 antagonist and a vegfr inhibitor for treating cancer - Google Patents

Abstract

The present disclosure describes combination therapies comprising an antagonist of Programmed Death 1 receptor (PD-1) and a VEGFR inhibitor, and the use of the combination therapies for the treatment of cancer, and in particular for treating cancers that express PD-Ll.

Description

_ l , lNA'l‘lON 0F A PD—l ANl‘AGQNlST AND A VEGFR lNHlBl’l‘OR FOR 'l‘REA’l‘lNG CANCER RELATEB Ali‘PLECATEQNS .g {Milli} This ation claims the benefit ofUS provisional application til/935,8tl9, filed on February 4., 2% l4, which is incorporated by reference in its entirety.

CE LESTING {?llilZl The instant ation contains a Sequence Listing which has been submitted electronically in ASCll format and is hereby incorporated, by reference in its entirety. Said ll) AStiIll copy, d on January ’29, Zill 5, is named PCPC-QSé—WD]_Sl,.t'xt and is 32,535 bytes in, size.

HELD {Hi THE ENVENE‘EQN llltllliil The present invention relates to combination ies useful tor the treatment of cancer. ln particular. the invention relates to a ation tl'ierapy which comprises an antagonist of a Programmed, Death l protein (PD—l) and, an ii'ihibitor of the vascular endothelial growth factor receptor (VEGFR) pathway.

BACKGRQUND {BF THEE: lNVEMT} ()N {Milli} PDnl is recognized, as an important player in immune regulation and the maintenance of eral tolerance. PDnl is moderately expressed on naive Ti, B and, NKT cells and ulated by T/B cell receptor signaling on lymphocytes, monocytes and myeloid cells lilllll?l Two known ligands for PD—l? P?le (B7~Hl) and PDILZ {BWDCL are expressed in human cancers arising in various tissues. ln large sample sets of eg ovarian, renal, colorectal, pancreatic, liver cancers and melanoma, it was shown that l’D—Ll sion correlated with poor prognosis and reduced overall survival irrespective of subsequent treatment {243).

Similarly, l’D-l expression on tumor ating lymphocytes was found to mark dysfunctional T cells in breast cancer and melanoma (Hal 5) and to correlate with poor prognosis in renal cancer (_ l ti). Thus, it has been proposed, that Pill—Ll sing tumor cells interact with PD—l expressing T cells to attenuate T cell activation and evasion of immune surveillance, thereby contributing to an impaired immune response against the tumor.

Several monoclonal antibodies that inhibit the interaction between PD-1 and one or both of its ligands PD-L1 and PD-L2 are in clinical development for treating cancer.

It has been proposed that the efficacy of such antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune ing agents.

Protein ne kinases have been identified as crucial targets in the therapeutic treatment of . Growth factor ligands and their respective receptor tyrosine kinases are ed for tumor angiogenesis and growth. Vascular endothelial growth factor (VEGF) is a critical component in the s leading to the branching, ion, and survival of endothelial cells forming new blood s during angiogenesis.

Unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, sis, rheumatoid arthritis, lated macular degeneration (AMD), and cancer (including solid tumors) Folkman, Nature Med., 1, 27-31 (1995).

Vascular endothelial growth factor receptor (VEGFR) inhibitors have been approved for the treatment of various types of cancer, including advanced and metastatic renal-cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma, and continue to be investigated in the clinical setting. It has been ed that the efficacy of such inhibitors might be enhanced if administered in combination with other approved or experimental cancer ies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune ing agents.

SUMMARY OF THE INVENTION [0008a] According to a first aspect, the present invention provides a use of pembrolizumab and axitinib for the manufacture of a medicament for combination therapy treatment of renal cell carcinoma in an individual. [0008b] According to a second aspect, the present invention provides a use of pembrolizumab for the manufacture of a medicament for the treatment of renal cell carcinoma in an dual wherein the pembrolizumab is to be administered in combination with axitinib.

Page 2a followed by page 3 [0008c] According to a third aspect, the present ion provides a use of axitinib for the manufacture of a medicament for the treatment of renal cell carcinoma in an individual wherein the axitinib is to be administered in combination with lizumab. [0008d] According to a fourth aspect, the present invention provides a ment comprising a combination of pembrolizumab and axitinib for use in treating renal cell carcinoma in an individual. [0008e] According to a fifth aspect, the present invention provides a use according to any one of aspects 1 to 3 ntially as herein described with reference to any one or more of the examples but excluding comparative examples.

] According to a sixth aspect, the t invention provides a ment according to aspect 4 substantially as herein described with reference to any one or more of the examples but excluding comparative examples.

In one embodiment, the invention provides a method for treating a cancer in an individual sing administering to the individual a combination therapy which comprises a PD-1 antagonist and a VEGFR inhibitor.

In another embodiment, the invention provides a medicament comprising a PD-1 antagonist for use in combination with a VEGFR inhibitor for treating a cancer.

In yet another embodiment, the invention provides a medicament sing a VEGFR inhibitor for use in combination with a PD-1 antagonist for treating a cancer. _ 3 , lillillZE Other embodiments provide use of a P?m'l antagonist in the manufacture of medicament for treating a cancer in an individual when administered in combination with a VEGFR inhibitor and use of a Vliiilli‘li inhibitor in the manufacture of a medicament for treating a cancer in an individual when administered in combination with a PD~l nist.

U1 lillil‘liil in a still r ment, the ion provides use of a PD—l antagonist and a Vlitiili‘R inhibitor in the manufacture icaments for treating a cancer in an individual, in some embodiments, the medicaments comprise a hit, and the kit also comprises a package insert comprising instructions for using the PD—l antagonist in combination with a VEGFR. inhibitor to treat a cancer in an individual. it} llllllz-l-l in all of the above treatment method, medicaments and uses, the PD—l antagonist inhibits the binding of PIE—Ll to Fill, and preferably also inhibits the binding ot‘ P942 to PD— l, in some embodiments of the above treatment method, medicaments and uses, the Pill antagonist is a monoclonal antibody, or an antigen binding fragment thereof, which speci?cally binds to PD—l or to PD—Ll and blocks the binding of PDnLl to PDnl. in one embodiment, the l’D—l nist is an anti—PD—l antibody which comprises a heavy chain and a light chain, and wherein the heavy and light chains se the amino acid sequences shown in Figure 6 (SEQ ll) N021 and SEQ ll) NQ?Z . lillillSl in all of the above embodiments of the treatment method, medicaments and uses herein, the VEGFR inhibitor is N—methle-{El—((E)—2—pyridin-2—yl—vinyl)—leindazol— daylsulfanyl]~henzamide or a ceutically acceptable salt thereof.

{Milo} in some embodiments of the above treatment method, medicaments and uses of the invention, the individual is a human and the cancer is a solid tumor and in some ments, the solid tumor is bladder cancer, breast cancer, clear cell kidney , head/neck squamous cell carcinoma, lung squamous cell carcinoma, malignant melanoma, non- small—cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate , renal cell cancer, small~cell lung cancer (SCI...C) or triple negative breast cancer, in some embodiments, the cancer is renal cell carcinoma (RCC). in some embodiments, the cancer is clear cell kidney llllll‘Yl in other embodiments ot‘ the above treatment method, medicaments and uses ot‘ the invention, the dual is a human and the cancer is a Heme malignancy and in some embodiments, the Heme malignancy is acute lymphoblastic leukemia (ALL), acute myeloid _ 4 , leulremia (Ah/IL), chronic lymphocytic leukemia (CELL), chronic rnyeloid leukemia (Ch/IL}, e large lit—cell ma (DLBCL), EBV-positive DLBCL, primary niediastinal large B— cell lymphoma, 'I'wcell/histiocyte-rich large Ilscell lymphoma, follicular lymphoma, Hodgkin’s lymphoma (ISL), mantle cell lymphoma {MCL}, multiple myeloma (MM), id cell U1 leulcemia—l protein (hIclsl), myelodysplastic syndrome (PADS), lodgkin’s lymphoma (NHL), or small lymphocytic lymphoma {S It l1).

{WISE Also, in some emhodinients of any of the above treatment , medicaments and uses, the cancer tests positive for the expression of one or both ot‘I’II—Ll and IIIEsLZ In still other embodiments, the cancer has elevated PD—l, l expression. lil {tllllh} In one embodiment of the ahove treatment method, tnedicarnents and uses, the individual is a human and the cancer is RCC that tests positive for human I’D-Isl. l In another embodiment of the above ent , medicaments and uses, the cancer is advanced RCC with clear cell suhtype and is present in a human who has not been previously treated for RCC.

BRIEF BESCRIP’I‘IQN (I I? THE BRA‘WINGS {IIIIZI'E FIGURE l shows amino acid sequences of the light chain and heavy chain CBRs for an exemplary anti—I334 monoclonal antibody useful in the present invention (SEQ ID NOs: l— {Iltlzzl FIGURE 2 shows amino acid sequences of the light chain and heavy chain CDRs for another exemplary anti—PD—l monoclonal antibody useful in the present invention (SEQ ID 'N0s17wl2). {llil23l FIGURE 3 shows amino acid sequences of the heavy chain variable region and full length heavy chain for an exemplary anti~PD~l onal antibody useful in the present invention (SEQ ID NO:I3 and SEQ ID N0: ill). {tlllzcl} l9‘IGUIIlEi 4 shows amino acid, sequences of alternative light chain le regions for an exemplary anti~PD~l n'ionoclonal antibody useful in the present invention (8 EQ ID NOs:l5~l7)t {IIIIZS} FIGURES 5Am?B show amino acid sequences of alternative light chains for an ary antiwl’D-l monoclonal antibody useful in the present invention, with IIIG. SA g atH) the amino acid sequences for the K091’X"Ex‘l l and KIIEIA—L—lo light chains (SEQ II) NGs: l 8‘ and _ 5 , l9, respectively) and Fifi. SB showing the amino aeitl sequence for the KQ9A-Lymi7 light chain {SEQ 1D N020). {tress} FEGURE 6 shows ai'nino acid sequences oftlie heavy and light chains for MK— 3475 {SEQ ED NOs. 21 and 2% respectively).

{Ml27} li‘lGUREEQ 7 shows amino aeicl sequences of’tlte heavy and light chains for nivoinmab (SEQ ED ‘NQs. '23 and 24, tively} BETAELEB BESCREPTEGN Abbreviations. Throughout the detailed description and examples of the ion the following abbreviations will he used: {@028} El l) One dose twice daily {MR9} CDR Complementarity determining region {Mlilll} CHO Chinese hamster ovary {M331} DES e free survival {M82} DTR Dose limiting toxicity {M83} FFPE fGI'?lalill—?va’il? paraftiiineinbedded {@634} FR Framework region {M85} igG lrrnnuitogiobulii't G {M86} lHC liistoehemistry or immuhohistoehernieal {@637} MTD Maximum tolerated dose {Ml38} NtiiBl National Center for Biotechnology information {9939} NCl National Cancer institute {@640} OR Overall response } OS {Ilverali survival U1 {Ml-42} PD Progressive disease {M343} PPS Progression free survival {llllclci} PR Partial response {Ml-45} QZW One dose every two weeks {M346} Q3W One dose every three weeks {W47} QED One dose per day {@048} RQlitiIlS'l’ Response Evaluation ia in Solid ors {M349} SD Stable disease {MlSll} VH immunoglohulih heavy chain variable region _ {y ,. {@651} VK lrnmunoglobulin kappa light chain variable region Tl. BEFENETEQNS {M52} So that the ion may be more readily understood, certain technical and scienti?c terms are speci?cally defined below. Unless specifically defined elsewhere in this document, all other technical and scienti?c terms used herein have the meaning commonly understood by one of ordinary shill in the art to which this invention belongs. {llllSB} "About" when used to modify a numerically defined parameter (eg, the dose of a i’D—l antagonist or "V'EGFR inhibitor, or the length of treatment time with a combination therapy described herein} means that the parameter may vary by as much as ltl‘l/o below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/l:g may vary between 45 mg/kg and 5.5 lug/leg.I {llllSzl} As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the," include their corresponding plural references unless the context clearly dictates otherwise.

{MESS} "Administration" and "treatment," as it applies to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refers to t of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid. ’l'reatrnent 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 t with the cell. "Administration" and "treatment" also means in wire and ex viva treatments, eg, ot‘ a cell, by a reagent, diagnostic, binding compound, or by r cell, The term "subj ect" includes any sm, ably an animal, more preerably a mammal (sag, rat, mouse, dog, cat, rabbit) and most preferably a human. b.) U1 {@055} As used , the term ody" refers to any form of antibody that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and cally covers, but is not limited to, onal antibodies (including lull length monoclonal antibodies), polyclonal dies, multispeeilic antibodies (eg, bispecitic antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies.

"Parental antibodies" are dies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic. _ 7 , i:®657'l in general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 RDa) and one "heavy" chain (about 5t)~'7(l kl)ai). 'l'he terminal portion of each chain includes a variable region of about lllll to lll) or more amino acids primarily responsible for n U1 recognition, The carbonyl—terminal portion of the heavy chain may de?ne a constant region primarily responsible for effector function. Typically, human light chains are classified as leappa and lambda light . Furthermore, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and de?ne the antibody‘s e as lgM, lgD, lgG, lgA, and lgE, respectively. Within light and heavy , the variable and constant regions are joined by a "l" ll} region of about l2 or more amino acids, with the heavy chain also including a "D" region of about l0 more amino acids, See lly, Fundamental linrnunology Ch, 7 (Paul, W,, ed, 2nd ed. Raven Press, NY, U989). illlngl The variable regions of each light/heavy chain pair form the antibody binding site.

Thus, in general, an intact antibody has two binding sites. Except in bifunctional or liispeciiic antibodies, the two binding sites are, in general, the same. {@553} Typically, the variable domains ot‘both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located Within vely conserved framework regions (FR). The CDRs are usually d by the framework regions, enabling binding to a specific epitope. in general, from N-terrninal to C— terminal, both light and heavy chains variable domains comprise FRl, CDRl , FREE, CDR2, FR3, {DR} and FEM, The assignment of amino acids to each domain is, generally, in ance with the de?nitions of Egeggent " 52‘...0{ml1lllllll?éllgglg'sllulllléil"i?ill Kiribati, er ait; National institutes ofllealth, Bethesda, Md. 3 5th ed; Nlll Publ. No. 91—3242 l); Kabat (1978) Adv, Prot. Chem. 322ln75; Kabat, er ad, (l9???) J. Biol. Chem. 252:6609nool6; Chothia, et (15., @987) 3 Mol. Biol. l9€iz99l—9l7 or Chothia, er of. (l989) Nature 341878883. {llllolll As used herein, the term "hypervariable " refers to the amino acid residues of an antibody that are responsible for anti gen~binding The hypervariable region comprises airline acid residues from a "complementarity 'iining region" or "CDR." (lie. CDRLl , CDRLZ and CDRL3 in the light chain variable domain and CDRHl, CDRHZ and CDRH3 in the heavy chain variable domain). See Rabat er of. (l99l) Sequences of Proteins of logical interest, 5th Ed. Public Health Service, National institutes of Health, Bethesda, Md. (_defining the CDR regions of an antibody by sequence); see also Chothia and Leslr 3987} J. Moi. Biol. l 96: gill—Ell? (defining the CDR regions or" an dy by structure). As used herein, the term _ g , "framework" or "FR" residues refers to those variable domain residues other than the hypeiyariable region residues defined herein as CDR residues. llllltill As used herein, unless otherwise indicate ody fragment" or , "antigen binding fragment" refers to antigen binding fragments of antibodies, i.e antibody fragments that (J‘i retain the y to bind speci?cally to the antigen bound by the fullnlength dy, eg. fragments that retain one or more CDR regions. es of antibody binding fragments include, but are not d to, Fab, Fab’, ?abby, and Fv' nts; diabodies; linear antibodies; singleschain dy molecules, e.g., ; nanobodies and multispecific antibodies formed from antibody fragments. ll} llllléZl An antibody that "specifically binds to" a specified target protein is an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding icity. An antibody is considered "specific’ 7 for its intended target it its binding is determinative of the presence of the target protein in a sample, eg. without producing undesired results such as false positives. Antibodies, or binding fragments thereof, useful in the present invention will bind to the target protein with an affinity that is at least two fold greater, preferably at least ten times greater, more prelbrably at least 29—tirnes greater, and most ably at least mes greater than the affinity with non—target proteins.

As used herein, an antibody is said to bind speci?cally to a polypeptide comprising a given amino acid ce, eg the amino acid sequence of a mature human PD—l or human PD—Ll molecule, if it binds to polypeptides comprising that sequence but does not bind to ns ng that sequence. {sass} "Chimeric antibody" refers to an antibody in which a n of the heat y and/or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species te.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chains?s) is identical with or homologous to corresponding sequences in an antibody derived from another species (eg, mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

} "Human antibody" refers to an antibody that comprises human immunoglobulin protein sequences only. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridorna derived from a mouse cell. Similarly, "mouse antibody" or "rat antibody" refer to an antibody that comprises only mouse or rat innnurioglobuliri sequences, respectively. _ 9 , guess: "Humanized dy" refers to forms of antibodies that contain sequences from non—human (cg, rnurine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from nonshurnan inununoglolnrlin, in general, the humanized antibody will comprise ntially all of at least one, and typically two, le domains, in U1 which all or substantially all ot‘ the hyperyariable loops correspond, to those. ot‘ a non—human imrnunoglohulin and all or substantially all of the FR regions are those of a. human imniunoglohulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglohulin constant region (Fe), typically that of a human innnunoglobulin. 'l‘he prefix "hum", "hu" or "h" is added to antihody clone designations when necessary to ll} distinguish humanized antibodies from parental rodent dies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent dies, although certain amino acid tutions may be included to se affinity, increase stability of the humanized dy, or for other s. {tilled} The terms "cancer", rous", or "malignant" refer to or descrihe the physiological condition in mannnals that is typically characteiized, by unregulated cell growth.

Examples of cancer include but are not limited to, carcinoma, lymphoma, leukemia, blastorna, and sarcoma. More particular examples of such cancers include squamous cell carcinoma, niyeloma, small—cell lung cancer, non—small cell lung cancer, glioma, hodgkin's lymphoma, non" hodgkin's lymphoma, acute myeloid leukemia (AlVlL), multiple myeloma, gastrointestinal (tract) cancer, renal cancer, ovarian cancer, liver cancer, lymphohlastic leukemia, lymphocydic leukemia, colorectal cancer, etrial , kidney cancer, prostate cancer, thyroid cancer, melanoma, osarcorna, lastoma, pancreatic cancer, gliohlastorna rnultiforrne, cervical cancer, brain cancer, stomach cancer, bladder , hepatonia, breast cancer, colon oma, and head and neck cancer. Another particular example of cancer includes renal cell carcinoma, A further particular example of cancer includes clear cell kidney cancer. Cancers that may he treated in accordance with the present invention include those terized by elevated expression of one or both of P?le and PD—LZ in tested tissue samples.

Who’ll "Biotherapeutic agent" means a biological molecule, such as an antibody or fusion protein, that blocks ligand receptor signaling in any biological pathway that supports tumor maintenance and/or growth or suppresses the anti—tumor immune response. - it) _ iiiltltigl "CDR" or "CDRs" as used herein means complementarity determining regionts) in a iinmunoglobulin variable region, de?ned using the Kabat numbering system, unless ise indicated. {tilitilll therapeutic agent" is a al compound useful in the treatment of £11 cancer. Classes of chemotherapeutic agents include, but are not limited to: allrylating agents, antimetabolites, kinase inhibitors, spindle poison plant allraloids, cytoXic/antitunior antibiotics, topisonierase inhibitors, photosensitizers, anti—estrogens and selective estrogen receptor modulators (SERl‘x/ls), antiaprogesterones, estrogen receptor downaregulators (ERDS), estrogen receptor antagonists, leutinizing h,orrnone~releasing hormone agonists, anti—androgen s, aroniatase ll} inhibitors, EGFR inhibitors, VEGF inhibitors, and anti—sense oligonucleotides that inhibit sion of genes implicated in abnormal cell proliferation or tumor growth.

Chemotherapeutic agents useful in the treatment methods of the present invention include cytostatic and/or cytotoxic agents. {lili‘llll "Chothia" as used herein means an antibody numbering system described in Al~ Lazihani er cal, {El/1’8 273:927—948 G997). lillinl "Conservatively ed variants" or "conservative substitution" refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (eg, charge, hain size, hydrophobieity/hydrophilieity, backbone conformation and rigidity, etc), such that the s can frequently be made Without ng the biological activity or other desired property of the protein, such as n affinity and/or speci?city. Those of skill in this art recognize that, in general, single amino acid substitutions in sential regions of a polypeptide do not substantially alter biological activity (see, eg, Watson at ai’. (l9???) rifoferrttiar Biology of the Gene, The Benjamin/Cummings Pub. Co, p, 224 (4th Ed». in addition, substitutions of structurally or onally siniilar amino acids are less likely to disrupt biological activity, laiy ative substitutions are set forth in Table l below. {saver 'i‘ABLE l. Exemplary Conservative Amino Acid Substitutions {)ri inal e Conservative substitution (3 lv; Set luvs; l—lis /119930 PCTYUSZOISKHAZIZ Ori final residue Censervative substitution lis l—ll le (ll 'eu L is (K) iiet M he (F) 1 vr; Met; Leu 'ro (P _er S at (W fat (V) lie; Leu l9973i "Consists essentially of," and variations such as "consist essentially oi" i er "consisting essentially of," as used hout the specification and claims, indicate the inclusion of any recited elements or group of elements, and the optional inclusion at other elements, of similar or ent nature than the recited elements, that do not materially change the basic or (J‘i novel properties of the specified dosage regimen, method, or composition. As a non~limiting example, a PD—l antagonist that consists essentially of a recited amino acid sequence may also include one er more amino acids, including substitutions of one or more amino acid residues, which do not materially affect the properties of the hinding compound {M74} "Diagnostic antinPDnL monoclonal antibody" means a nLAh whieh ically l0 1binds to the mature form of the designated PD—L {FDJA or PDLZ) that is expressed on the e cf certain mammalian cells. A mature l’D—L lacks the presecretory leader sequence, also referred to as leader peptide The terms "PD—L" and "mature PD—L" are used interchangeably herein, and shall he understond to mean the same niniecule unless ctherwise indicated or readily apparent front the context.

NEWS} As used , a diagnostic uman PDnLl mAh or an antinhPDnLl mAh refers to a monoclonal antibody that speci?cally binds to mature human PD—Ll. A mature human l’D—Ll molecule consists of amino acids l 93% of the following sequence: M'IFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVWKQW?hAAPTVYWVMp?KNTT QFVHGEEDLKVCHCSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMESYGGADYKRITVKV 2i) NAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGXTTTTNSKREEKLFNVTS TLttNtTlNhinYCTnKRLUeEnNHIAELViEELPLAHPPNERTHLVILGnILLCLGVALTFIFR L KGRMMDVKKCGIQDTNSKKQSDTHLEET (SEQIDTN3QS) W0 19930 PCT/U82015/014212 - 12 _ iilllanl Specific examples of stic anti—human PD—Ll mAbs useful as diagnostic mAhs for irnrnunohistochernistry (ll-ll?) ion of l’D—Ll expression in tonnaliiufised, paraf?n—embedded (PEPE) tumor tissue sections are antibody 23433 and antibody 22(13, which are described in the copending international patent application PCT/USl 3/075932, filed l8 December U1 20l3 and published as Vy’OCZOl/il/lOOO'ZI'Q on 26 lune 2014i Another anti—human PD—Ll mAb that has been ed to he useful for HR? detection of PD~Ll expression in PEPE tissue sections (Chen, Bl. et al, Cit}? Cancer Res l9: 34626473 (208)) is a rabbit antinhunian PDnLl mAb publicly available from Sino Biological, lnc. ng, PR. China; Catalog number lllllSZl—RtllS). {llll77l "Framework region" or "FR" as used herein means the innnunoglobulin variable ll} regions excluding the CDR regions. iilltl’ml "ll-lomology" refers to ce similarity between two ptide sequences when they are optimally aligned. When a position in both of the two compared ces is occupied, by the same amino acid monomer subunit, e.g., if a position in a light chain CDR of two different Abs is occupied lay alanine, then the two Abs are homologous at that position. The percent of homology is the number of homologous positions shared by the two sequences d by the total number of positions compared Xllltl. For example, if 8 of ll) of the positions in two sequences are matched or homologous when the sequences are optimally aligned then the two sequences are 80% homologous. Generally, the ison is made when two sequences are aligned to give maximum percent homology. For example, the comparison can be performed hy a BLAS'l' algorithm wherein the parameters of the algorithm are selected to give the largest match between the tive sequences over the entire length of the respective nce ’lCQSi iilllwlll The ing references relate to BLAST algorithms often used. for sequence analysis: BLAS’l‘ ALGORl'l'Hh/lS: Altschul, SE, at (IL, (lggtl) ,l. l‘vlol. Biol. 2l51403—4l0; Gish, NU1 W., a: st, (1993} Nature Genet, 3266—272; Madden, TL, at at, 0996) Meth. linsyrnol. assist—i4}; Altschul, SE, at at, (3997) c Acids Res 25:3389—3402; Zhang, l, at all, (l9???) Genome Res, 7:649~656; Wootton, J.C., et ai, 0993) Cemput Chern. l7:l49—l63; llancoclt, lil‘vli at at, @994) Comput. Appli Biosci. l0:67~7{l; ALlGNMENT SCORQENG SYSTEMS: Dayhoff, NEG, et al., "A model of evolutionary change in proteins." in Atlas of Protein Sequence and Structure, G978) vol. 5, suppl. 3. MQ. Dayhoff (ed), pp. 345—352, Natl.

Biomed. Res Found, "y'Vashington, DC; Schwartz, next, at 625., "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, 0978) vol. 5, suppl. 3;" i it). Dayhoff {eds}, pp. 3534558, Natl. Biomed Res. Found, Washington, DC; Altschul, Salli, (19%) J. Mol. - 13 _ Biol. 565; States, DJ, at at, tl99l) Methods 3:66~70; Henikoff, 8., at at, (1992) Proc.

Natl. Acad. Sci. USA l5—l09l9; Altschul, SE, a! 621., U993} J. Mol. Evol. 361290—300; [%1_4,1(3:N1\/3ENT S'l'A'l‘lS’l‘lCS: Karlin, S, e; (15., U990) Proc. Natl. Acad. Sci USA 87:2264~ 2268; Karlin, S, at cl, 0993) Proc. Natl. Acad. Sci. USA 93:58:735877; Semho, A, e? (15., U1 0994) Ann. Prob. 22:2022~2039; and Altschul, SF. "liivaluating the statistical significance of multiple distinct local alignmm’its." in tical and Computational Methods in Genome Research (S. Suhai, ed), (l 997) pp. l~l4, Plenum, New Yorlr. ll "lsolated antibody" and "isolated antibody fragment" refers to the purification status and in such context means the named molecule is substantially free of other biological ll} molecules such as nucleic acids, proteins, lipids, carbohydrates, or other al such as cellular debris and growth media. lly, the term "isolated" is not intended to refer to a complete absence of such material or to an absence of water, buffers. or salts, unless they are present in s that substantially interfere with experimental or therapeutic use of the binding compound as described .

{Mill} " as used herein means an in'ununoglobulin alignment and nun'ibering system, pioneered, by Elvin A. Kabat ((l99l) Sequences of Proteins of immunological interest, 5th Ed. Fublic Health Service, National institutes of Health, Bethesda, Md).

SZl "Monoclonal antibody" or "’mAb" or "Mab", as used herein, refers to a population of substantially neous antibodies, 1263., the antibody molecules comprising the population are identical in arnino acid sequence except for possible naturally occurring mutations that may be present in minor ts. in contrast, corwentional (polyclonal) antibody preparations typically include a multitude of different antibodies haying (litterent amino acid sequences in The modifier "monoclonal" tes the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular . l:or example, the monoclonal antibodies to be used in accordance with the present invention may he made by the hybridoma method first described by Kohler at of. U975) Mantra 25.6: 495. or may be made by recombinant DNA, methods (see, eg US Pat. No. 4.8l 6.567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson er of. (mill) Nature 352: 624—628 and Marks at all. (199?; 7. M’oi. Biol. 222: 58lw597, for example. See also Fresta {2005) J. Allergy Clin. /{11051. ilti:73l. - 14 _ iitltl83'l "Patient" er "subject" refers to any single subject for which therapy is d or that is participating in a clinical trial, epidemiological study er used as a control, including humans and mammalian veterinary ts such as cattle, horses, dogs, and cats. zll "PD—l antagonist" means any chemical compound or biological molecule that £11 blocks binding cf PD—Ll expressed on a cancer cell te PD—l expressed on an immune cell (T cell, B cell or NK’l‘ cell) and ably also blocks binding of llD—LZ expressed on a cancer cell to the immune-cell expressed Pill. Alternative names or synonyms for PD—l and its ligands include: l’DCDl, l’Dl, CD279 and SLEB’IZ fer PD—l; PDCDl Ll, l-"DLl, B7l-ll, 87-4, CD274 and B7~ll fer PD~lilg and PDCDlLZ, PDLZ, B7—DC, Btdc and CD273 for PD~LZ in any of the treatment method, medicaments and uses cf the present invention in which a human individual is being treated, the PD—l antagonist blocks binding of human PD—Ll to human F34, and preferably blocks binding of both human PDnLl and FD~L2 to human P?ml. Human PDnl amino acid sequences can he found in NCBl Locus No; Nl’_005()tl9. Human P‘D—Ll and l’D-LZ amino acid sequences can be found in NCBI Locus No: NP_tl54862 and Nl?‘_0795l5, respectively.

{MESS} PD—l antagonists useful in the any of the treatment method, medicaments and uses of the present invention include a monoclonal antibody (rm—lib), or antigen g fragment thereof, which speci?cally binds to PD—l or l’D-Ll, and preferably ically binds to human l’D—l or human l’D-Ll. The mAb maybe a human dy, a zed antibedy or a chimeric antibody, and may include a human nt region. in some embodiments the human constant region is selected from the group consisting of lgGl l gG3 and lgG4 constant regions, and , lgG’Z, in, preterred embrulin'ients, the human constant reginn is an lgGl or lgt’jll constant region. in some embodiments, the antigen binding fragment is selected from the group consisting of Fab, H, Ftab’h, scFv and Fy fragments h.) U1 390%} Examples cf mAbs that bind to human l’D—l, and useful in the treatment method, medicaments and uses of the present invention, are described in USMSS‘SOZ, US752l05l, US$908449, U88354599, U88l587’57, Vv’QZGQll-x’lltl477l, V’V’QZGQ4/072286, WONM/GShWi and USZQl 358. Specific anti—human Pill mAbs useful as the PD~l antagcnist in the ent method, medicaments and uses of the present invention include: Mid—3475, a humanized lgG4 mAh with the structure described in WHO Drug Elijah/tartan, Vol. 27, No. 2, pages ldl—l62 (2M3) and which comprises the heavy and light chain amino acid sequences shown in Figure 6, niah {EMS—936558), a human lgG4 mAb with the structure described in WHO Drag [afbrmazimn Vcl. 27, No. l, pages sacs (2313} and which comprises the heavy and light chain amino acid sequences shown in Figure 7; the humanized antibodies h4tl9All, h4tl9Al6 and. 7, which are bed in WOZQGS/lSWlE, and AMP—514, which is heing developed by Medlnunune. {@877} es of niAhs that bind to hurnan PDnLl, and useful in the treatment methotlf, (J‘i rnedicarnents and uses of the present invention are described in W02013/0l9906., W020i 01/077634 Al and US8383796. Specific anti—hurnan PD—Ll rnAhs useful as the PD—l antagonist in the treatment rnethod, niedicanients and uses of the present invention include MPDEEZSOA, BMS4B6559, l4736, MSBGQlWlSC antl an antihocly which comprises the heavy chain and light chain variahle regions of SEQ ii) N024 ancl SEQ ll) l, respectively, ll} of WOZOl 3/0 19906.

{WSS'E cher PD—l antagonists useful in the any of the treatment method, arnents and uses of the present invention include an irnnrunoadhesin that specifically hinds to PD~l or PDll, and preferably speci?cally hintis to human i’D—l or human i’D-lul, e.g., a fusion protein containing the extracellular or PD—l hintiing portion of PD—Ll or FELL? fused to a constant region such as an Fc region of an irnrnunogiohulin molecule Examples of imrnunoatlhesion n'iolecules that specifically bind to Pit—l are described in \VQZtllG/OZ7827 and WG201l/066342.

Specific fusion proteins useful as the PDml nist in the treatment methoth medicaments and uses of the present invention include 4 (also known as g), which is a EC fusion protein and hinds to hurnan PD—l. {9989} in some preferred embodiments of the treatrnent method", ntetlicaments and uses of the present ii'ivention, the PD~l antagonist is a monoclonal antibody, or n binding fragment f; which comprises: (a) light chain CDRs SEQ 1D NQs: l, 2 and 3 and heavy chain CDRs SEQ ll) NQs: 4, 5 and 6; or (h) light chain CDRs SEQ 1D NQs: 7f, 8 and 9 and heavy chain CDRs SEQ ll) NQs: ll), ll and l2. {9999} in other preferred, embodiments of the treatnunit methodn medicanumts and uses of the present ntion, the PD~l antagonist is a monoclonal antibody, or antigen binding fragment thereof; which specifically binds to human PDnl and comprises (a) a heavy chain variable region comprising SEQ ID NQ:13 or a variant thereof, and (b) a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ 1D N015 or a variant thereof; SEQ if) N016 or a variant thereof; and SEQ 11) N0: l? or a variant thereof. A variant of a heavy chain variable region sequence is identical to the reference sequence except having up to 17 conservative amino acid substitutions in the framework region tie, outside of the (:TIERS'), antl preferably has less than ten, nine, eighta seven, six or live conservative amino acid - 16 _ substitutions in the framework region. A variant of a light chain variable region sequence is identical to the re "erence sequence except having up to five conservative amino acid substitutions in the framework region tie, outside of the CDRsL and preferably has less than four, three or two conservative amino acid substitution in the framework region.

(J? {??hll In another preferred embodiment of the treatment method, medicaments and uses of the t invention, the PD—l antagonist is a onal antibody which speci?cally bincls to human PD—l and comprises (a) a heavy chain comprising SEQ lD NO: l4 and (b) a light chain comprising SEQ 1D N018, SEQ l1) N039 or SEQ ll) N020 {M92} in yet another prefeired embodiment of the treatment method, medicaments and l0 uses of the present invention, the F34 antagonist is a monoclonal dy which speci?cally binds to human PD~l and comprises (_a) a heavy chain sing SEQ ID N0: 14 and {h} a light chain comprising SEQ ii) NO:18. {9993} Table 2 below provides a list of the amino acid ces of exemplary anti—PB—l mAbs for use in the treatment method? medicaments and uses of the present ioin and the sequences are shown in s l6.

Table 2. EXEMPIARY ANTImHUMAN sent nonocnonm ANTIBODIES A. Comprises light and heavy chain CDRS of h?D~i.08A in W 2098/156712 CPR. J IJ] CDRHl D. Comprises the mature 469 heavy chain and one of the mature KOQA light chains in W02008/156712 ID NOui9 or {sites} "Pillsl" or "PD—L72" expression as used herein means any detectable level of expression of the designated PD—L protein on the cell surface or of the designated PILL mRNA within a cell or tissue. FELL protein expression may be de ected with a diagnostic PD—L antibody in an lHC assay of a tumor tissue section or by flow cytometry. Alternatively, PD—L protein expression by tumor cells may be detected by PET imaging, using a binding agent (Meg dy fragment, aflihody and the like) that specifically binds to the desired PD—L target, cg, soar or l’D—LZ. Techniques for detecting and measuring l’D-L rnRNA expression include R'lL PCR and realtime quantitative R,T~PCR..

{W95} Several approaches have been described for fying PD—Ll protein expression ll} in HR? assays of tumor tissue sections. See, eg, Thompson, R. ll, et al., PMS till (:49); l7l74~ l7l79 (2904); Thompson, Rt ll. et al.., Cancer Res: 66:338l «3385 (2906); t, 3., et al., Cancer ll7z2l92—22Gl {ZGl l); Taube, .l. M» et al, Sci Trans] Mfed 4, l27ra37 (2M2); and ’l‘oplian, S. L. et al., New Eng. JMed. 366 (:26): 24433454 (2012). {sass} One approach employs a simple binary endpoint of positive or negative for Film Ll expression? with a positive result defined in terms of the percentage of tumor cells that exhibit histologic evidence of cellmsurface membrane ng. A tumor tissue section is d as positive for PD—Ll sion is at least 19/ and preferably 5% of total tumor cells. {@997} in another approach, Pit—M expression in the turner tissue section is quanti?ed in the tumor cells as well as in infiltrating immune cells? which predominantly comprise lymphocytes. The percentage oftumor cells and infiltrating immune cells that exhibit membrane staining are separately quantified as <. 5%, 5 to 9%, and then in lllll/LE; ents up to . For tumor cells, l’D—Ll expression is counted as negative if the score is < 5% score and positive if the score is >_ 5%. PD—Ll expression in the immune infiltrate is reported as a semi—quantitative ement called the adjusted inflammation score (ASS), which is ined by lying the percent ot‘rnenihrane staining cells by the intensity of the rate, which i s graded as none (ll), mild (_score of i, rare lymphocytes), moderate (score of 2, focal infiltration of tumor by lymphohistiocytic aggregates). or severe (score of 3, diffuse infiltration). A tumor tissue section is counted as positive for PD~Ll expression by immune infiltrates if the AIS is \l>‘q .1. - 13 _ lllllllgl The level of PD~L mRNA expression may he compared to the mRNA expression levels or" one or more reference genes that are frequently used in quantitative Rfflll’CR, such as tin C. {@959} in some embodiments, a. level of PD—Ll sion (protein and/or mRNA) by if! malignant cells and/or by infiltrating immune cells within a tumor is determined to he "overexpressed" or "elevated" based on comparison with the level of PD—Ll expression in and/ or mltNA} by an appropriate l. For example, a control l’D—Ll protein or mR‘NA expression level may he the level {plantilied in nonmalignant cells of the same type or in a section from a matched normal ti ssue, ln sortie preferred, embodiments, PIE—Ll expression in a l0 tumor sample. is determined to be elevated it‘PD—Ll protein (and/or PD~lil mRNA) in the sample is at least lilo/El, 29%, or 30% greater than in the control. {llllllllll "RECIST l.l Response Criteria" as used herein means the de?nitions set forth in auer et al., EA. et al., Eur. J Cancer 45:228—247 (2009) for target lesions or nontarget lesions, as riate based on the context in which response is being measured. l5 lillllltlll "Sustained response" means a sustained therapeutic effect after cessation of treatment with a therapeutic agent, or a ation therapy described, herein. ln some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least l ,5, 2,9, 2.5 or 3 times longer than the treatn'ient duration {?lllllZ} "Tissue Section" refers to a single part or piece of a tissue , e.g., a thin slice of tissue cut from a sample of a normal tissue or of a tumor. {@183} "Treat" or "treating" a cancer as used, herein means to ster a combination therapy of a PD—l antagonist and a VEGFR inhibitor to a subject having a cancer, or diagnosed with a , to achieve at least one positive therapeutic effect, such as for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral NU1 organs, or reduced rate of tumor metastasis or turner growth. Positive therapeutic effects in cancer can be ed in a number or" ways (See, W. A. Weber, J, Navel, Med. 5338408 (2009)). For example, with t to tumor growth inhibition, according to NCl standards, a T/C E4296 is the minimum level of antistumor activity. A "ll/C < l{l% is considered a high anti-tumor activity level, with T/C (9/0) Median tumor volume of tlie treated/Median tumor volume of the control X lllll. in some embodiments, the treatment achieved by a combination of the invention is any of PR, CR, OR, PFS, DFS and, OS. PPS, also referred to as "Time to Tumor Progression" tes the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time - 19 _ patients have enced SD. DES refers to the length of time during and after treatment that the patient remains free of disease. 0S refers to a prolongation in life ancy as compared to naive or untreated individuals or patients. in some preferred, embodiments, response to a combination of the invention is any of PR, CR, PPS, DES, OR or GS that is assessed, using U1 REClS'l‘ l.l response criteria. The treatment regimen for a combination of the invention that is effective to teat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the y to elicit an anti—cancer response in the subject.

While an embodiment of any of the aspects of the invention may not be effective in achieving a ve eutic effect in every subject, it should do so in a statistically significant number of l0 subjects as determined by any statistical test known in the art such as the Student’s t—test, the chizmtest, the U-test according to Mann and Whitney, the Krttsltal—‘ilv’allis test (ll—test), Joncleheereil'erpstrastest and the on—test. llltlltldl The terms "treatment regimen", "dosing protocol" and "dosing regimen" are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a l5 ation of the invention.

{MEWS} "Tumor" as it applies to a t diagnosed with, or ted of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an al growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas, Leulremias (cancers of the blood) generally do not form solid tumors (National Cancer institute, Dictionary of Cancer Terms). {llllllllil "Tumor hurden" also referred to as "tumor load", refers to the total amount of tumor material distributed throughout the body. "l‘umor hurden refers to the total number of cancer cells or the total size of tumorts), throughout the body, including lymph nodes and bone narrow. 'l‘umor burden can be determined by a variety of methods known in the art, such as, eg. by measuring the dimensions oftumor(s) upon removal from the t, eg, using calipers, or While in the body using imaging ques, cg, ultrasound, bone scan, computed tomography (CT) or magnetic resonance imaging {MRl} scans, iilltllflill The term "tumor size" refers to the total size of the tumor which can he measured as the length and Width of a tumor. Tumor size may he determined by a variety of methods known in the art, such as, e, g. by measuring the dimensions of turnor(s) upon removal from the subject, eg, using calipers, or while in the body using imaging techniques, eg, bone scan, ultrasound, CT or MRI scans. {tltllllhl "Variable regions" or "V region" as used herein means the segment of lgG chains which is le in sequence between rent antibodies. it extends to Kabat residue l09 in (Jr the light chain and ll3 in the heavy chain. lilltlllléli "VEESGFR inhibitor" means a small molecule inhibitor of vascular endothelial growth tactor (VEGF) receptor or a monoclonal antibody against ar elial growth factor (VEGF). in an embodiment, a "VEGFR inhibitor" means a small molecule inhibitor of vascular elial growth factor (VEGF) receptor. Speci?c VEGFR inhibitors useful as the ll} VEGFR inhibitor in the ent method, medicaments and uses of the present invention, include ib, sunitinib, sorafenib, tivozanib, and bevacizumab. in an embodiment, specific VEGFR inhibitors useful as the VEGFR inhibitor in the treatment method, medicaments and uses of the present invention, include axitinib, sunitinib, sorafenib, and tivozanib. liltilllll in an embodiment of the treatment method, inedicainents and uses of the present invention, the VEGFR inhibitor is the compound, Ailmethyan—[S{(3%"pyridin—Z—yl—vinyl}lHn indazoluo—ylsulfanyll—benzamide or o—[2~(methylcarbamoyljmhenylsulfanyl]~3—E—[IE—(pyridin—Zu yl)ethenyllindazole, of the following structure: which is known as ib or AGwGl3736.

{Milli Axitinib is a potent and selective. inhibitor of vascular endothelial growth factor {VEGF} receptors l, 2 and 3, These receptors are implicated in 'pa'tliologic angiogenesis, tumor growth, and metastatic progression of cancer, Axitinib has been shown to potently inhibit VEGmeediated, endothelial cell proliferation and survival W'Q 3.3., at cal, Clin Cancer Res l4: 7272—7283 (2008); ej, 3., at at, Biochemistry 48: 70l9—3l (2009)). Clinical trials are currently on—going or have been ted to study the use of axitinib for the treatment of various cancers, ing liver cancer, melanoma, mesothelioma, non—small cell lung , prostate cancer, renal cell carcinoma, soft tissue sarcomas and solid tumors. lnlytal'w (axitinib) has been approved in the United States, Europe, Japan and other jurisdictions for the treatment of renal cell carcinoma.

{MHZ} Axitinib, as well as ceutically acceptable salts thereof, is described in US.

Patent No. -‘lv,§24l. Methods ing axitinih. are described in US. Patent Nos. 6,884,899 and 7,232,9l0, in US. ation Nos. aces—march? and 2007—0203196 and in lhternational Publication No.

No. 2004~0224988 Polymorphic forms and pharmaceutical compositions of asitinih are also described in US Patent No. 8,79l,l40 and US. Publication Nos. 2005—0094763, 2{l€38~0274l92, and 20l4—0248347. Uses ofaxitinih, including use as a single agent or in combination treatment, ll} are described in US. Patent No. 7,l4l,58l and in US Publication No. 2Gl4~0288l25 The s and patent applications listed above are incorporated herein by reference. {llllll?} Axitinih is understood to include reference to salts thereof, unless ise indicated. Axitinih is basic in nature and capable of forming a wide variety of salts with various inorganic and organic acids. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids. Pharmaceutically acceptable salts of axitinih. may he formed, for example, by reacting axitini‘o with an arnount of acid, such as an equivalent amount, in a medium such as one in which the salt itates or in an aqueous medium followed lay lyophilization. {hill 14} Exemplary acid addition salts of axitihih include acetates, ates, henzoates, henzenesultonates, bisulfates, horates, hutyrates, citrates, camphorates, carnphorsult'onates, fumarates, hydrochlorides, hydrobronildes, hydroiodides, lactates, inaleates, metliahesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, proplohates, salicylates, succihates, sulfates, ates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.

Additionally, acids which are generally considered suitable for the thrmation cl" pharmaceutically useful salts from 1basic ceutical compounds are discussed, for exarnple, by S. Berge 61' (ii, Journal of Pharrmzeeun’ea! Sciences U977) gem l—l9; l), Gould, International J. of Pharmaceutics @986) $3: 20ln9l7; Andersen et al, The ce inrlrfedicz‘nai Chemistry G996), ic Press, New York; and in The Orange 800k (Food 8.: Drug Administration, Washington, DC. on their e). These disclosures are incorporated herein by reference thereto. iilllll 15E All such acid salts are intended to he pharmaceutically acceptahle salts within the scope of axitinih, as used in the t invention and all acid salts are considered etutivalent to the free forms of the corresponding compound for purposes of the invention.

Willie} Prodrugs of axitinih are also plated for use in the methods, medicaments £11 and uses of the present invention. The term "prodrug", as employed , denotes a nd that is a drug sor which, upon administration to a subject, undergoes chemical conversion by metaholic or chemical processes to yield axitinih or a salt thereof, A discussion of prodrugs is provided in 'l". liiguchi and V. Stella, Pro-drugs as Novel Deluxe/'37 Systems @987) if; of" the ACS. Symposium, Series, and in Bioreversz‘hie rs in Drug Design (l98'7) Edward B. ll} Roche, ed, American Pharmaceutical ation and Pergamon Press, 1ooth of which are incorporated herein by reference thereto. ll. METHOBS, USES ANB MEDICAMENTS {@117} in one aspect of the invention, the invention provides a method for treating a cancer in an individual comprising administering to the individual a combination therapy which .1 comprises a l’D—l antagonist and a VEGR inhibitor. ?lling} The combination therapy may also comprise one or more additional therapeutic agents, The additional therapeutic agent may he, cg, a chemotherapeutic other than a. VEGR inhibitor, a rapeutic agent (including hut not limited to antihodies to VEGF, EGFR, Heri/heu, other growth factor receptors, CD21), CDKlG, {TD—40L, C'l'LA—ll, OX—4?, 4—lBB, and RIOS), an immunogenic agent (for example, ated cancerous cells, turner antigens, antigen presenting cells such as dendritic cells pulsed with tumor derived antigen or nucleic acids, ii'nmune stimulating cytoliines (for example, ill—2, lFNo2, GM—CSF), and cells translected with genes encoding immune stimulating cytolrines such as hut not d to GM—CSF), {hill 19E Examples of chemotherapeutic agents include all and cyclosphcsphamide; allcyl sulfonates such as husult‘an, improsulfan and piposulfan; aziridines such as hertzodopa, carhoquone, meturedopa, and uredcpa; ethyleniinines and n'iethylamelamines including amine, triethyleneinelamine, trietylenephosphoramide, ylenethiophosphoramide and trimetliyloloinelamine; enins (especially hullatacin and acinone); a camptothecin ding the synthetic analogue topotecan); hryostatin; callystatin, ClelltiS (including its adozelesin, esin and hizelesin synthetic analogues); cryptophycins (particularly cryptophycin l and ciyptophycin 8); dolastatin; duocarinycin {including the synthetic analogues, KWthg and CBl—l‘h/ll); eleutherohin; pancratistatin; a sarcodictyin; spongisiatin; niti'cgen niustai‘ds such as chlorai’nbucii, chiurnaphazinc, choiuphasphamidc, csu‘amustine, ifosfamide? mcchiorethamine, mechim‘cthaminc cxidc hydrochiuride, rnciphalan, novcmhichin, phenesterinc, predniinus‘unc, imibsfamidc, uracil mustard; niirusui‘eas such as carinusiinc, chiurczctucina ictcinusiine, Eoni'usiine, ine, U1 ranimustinc; antibictics such as the cnediyne antibiutics (cg. cahcheamicin, especiaiiy amicin ganunali and calichcamiciu phiii, see, ?g, Agnew, Chem. int}. Ed. Fungi, 33:183—186 (1994); dynernicinn including dyucn'iiciu A; hisphusplmnatcs, such as clodmnatc; an cspcraniicin; as wall as zinosiatin ophuic and related chminopmtcin cancdiync antibiutic chromomuphorcs? aclacinomysins actinumycin? authramycin, azascrinc, cins cactincinycin, carahicin, caminomycin, cai'zinnphiiin, chromcinycins, dactinomycin, u’bicin, detcrubicin, {i—diazo-S~0X0—L—noricucine, domrubicin {including moi‘phchna— dcémi'uhicin, cyanomm‘phuiinu—dcxuruhicin, 2—pyrmiinwduxonihicin and decxydnxumhicin), epicubicin, csui'uhicin, idai’ubicin, mai‘ceiinniycin, inituniycins such as mimmycin C, mycuphcnclic acid, nogaiamyciu, ulivui’i'ijminsn pcpicmycim pat?mmyc?n, pumrnycim quaiamycim mdui'ubicih, straptuuigring s'trcpiuzucing tuhcrcidin, uhcuin'iex, zii'msta‘iin, mmhicin; anti—metabolites such as nicthuti‘cxatc and §~?uumuracii ; fulic acid analogucs such as dcncptcrin, nicthotrexatc, ptcmptcrin, ti‘imcircxate; purine analogs such as ?udarabinc? 6— mercapmpui'inc, thiamiprine? thioguanine; pyrimidine s such as ancitahinc, azacitidine, (3— azaui'idine? carmufui‘, c?arahinc, didecan'idine, ridinc, enocitabine, ?axui'idinc; andi‘ugcns such as emne, dmnmsiannionc pmpinnatc, cpiticstanni, nstane, icsiuiactunc; anti—adrenais such as iutethimide, niitctanca irilnstane; iciic acid i‘epienisher such as 'iic acid; accglatcnc; aldcliihusphamidc giyccsidc; avuhnic acid; enihnacii; amsacrine; bcsirabucii; bisantreue; cdah‘axatc; cfu?rniuc; dcmccnicinc; diaziqnuuc; clfcmuthinc; ciliptiniuni acetate; an cpcthilonc; cid; gallium e; hydroxyuica; icntinan; lonidaminc; inaytansinoids such as mayiansinc and ansamiiucins; mitoguazun?‘; niitoxantmnc; niupidainoi; nitracrinc; pentostatin; phcnamci; piraiubicin; luscxantrcnc; paduphyilinic acid; 2~ethylhydrazidc; procarbazinc; raznxanc; rhizoxin; siznfuran; spimgermaniuin; tcnuazonic acid; triaziquanc; 2," 222"—irichiumtricihyiamine; trichnthccencs {especiahy "532 tcxin, vcrracui'in A, mi‘idin A and anguidine); ui'ethan; ine; dacarhazine; 3 (3 mannumustinc; mimhmnimi; rnitoiactui; pipubi‘onian; gacytosinc; arahinuside ("Ara-C"); cyc}ophusphamide; ihiutcpa; taxaids, cg paclitaxcl and xci; chimainhucii; gemcitahine; 6—ihi0guaninc; marcap‘mpnrine; rcxate; piatinum analcgs such as cispiatin and carhuplatiu; Vinbiastinc; platinum; idc {VP~16); ifosfanude; mitcxantmnc; V’i?c?s?‘?"; vinurcibinc; ncvantrcnc; teniposidc; cdatrcxatc; daunumycin; amincptcrin; xclodag ibandmnate; CPT—l i; topoisomerase inhibitor RFS 20th:); difluoron'iethylomithine (DMFQ); retinoids such as retinoic acid; capecitahine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included are antishoi‘monal agents that act to regulate or inhibit e action on tumors such as antisestrogens and selective estrogen receptor modulators (SiliRMs), including, U1 for example, tamoxifen, raloxifene, droloxifene, Alwhydroxytanioxifen, trioxifene, keoxifene, 70l 8n, oi'iapristone, and toreniifene (Farestoh); aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glandsr such as, for exampleg 4(5)— iinidazolesf, aminoglutethimide? megestrol acetate, exemestane, forrnestanq fadrozolei vorozole? ole, and anastrozole; and anti—androgens such as llutaniidd nilutamidef, hicalutainide, l0 leuprolide, and goserelin; and pharmaceutically acceptable salts," acids or tives of any of the above.

{Mind} Each therapeutic agent in a combination therapy of the invention may be administered either alone or in a medicament (also referred to herein as a pharmaceutical composition) which comprises the therapeutic agent and one or more pharmaceutically l5 acceptable carriers, excipients and diluents, according to standard pharmaceutical practice. {lllllZl} Each therapeutic agent in a ihation y of the invention may be administered simultaneously lie, in the same medicament}, concurrently (ice in te medicaments administered one right after the other in any order) or sequentially in any order.

Sequential administration is particularly useful when the therapeutic agents in the combination therapy are in different dosage forms (one agent is a tablet or capsule and another agent is a sterile liquid} and/or are administered on different dosing schedules, eg, a chemotherapeutic that is administered at least daily and a hiotherapeutic that is administered less ntly, such as once weekly, once every two weeks, or once every three weeks. {@122} in some embodiments, the "V'EGFR tor is administered before administration of the PD—l antagonist, while in other embodiments, the VEGFR tor is administered after stration of the Pill antagonist {@123} in some ments, at least one of the therapeutic agents in the combination therapy is administered using the same dosage regimen (dose, frequency and, duration of treatment) that is lly employed when the agent is used as erapy for treating the same cancer. in other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, egi, smaller doses, less frequent doses, and/or shorter ent duration. lZdE Each small molecule therapeutic agent in a combination therapy of the invention can he administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, topical, and transdermal routes of administration. {@125} A combination therapy of the invention may he used prior to or following surgery £11 to remove a tumor and may he used prior to," during or after radiation therapy. {series} in some embodiments, a combination therapy of the invention is administered to a patient who has not been previously treated with a hiotherapeutic or chemotherapeutic agent, i.e.? is treatmentwna'ive in other embodiments, the combination y is administered to a patient who failed to e a sustained se after prior therapy with a hiotherapeutic or ll) chemotherapeutic agent, i.e., is treatmentuexperienced. {993.27% A combination therapy of the invention is typically used to treat a tumor that is large enough to he found by palpation or by imaging techniques well known in the art, such as MR1, ultrasound, or CAT scan. in some preferred embodiments, a combination therapy of the in *ention is used to treat an advanced stage tumor having dimensions of at least about 20d mmg' Lilli) mm5 400 mms, 500 1311113, 750 mm‘z‘, or up to l?GO mmg.

{MEZSE A con'ihination therapy of the ion is preferably administered to a human patient who has a cancer that tests positive for FD~Ll expression. in some preferred embodiments, PD—Ll expression is detected using a diagnostic antinhuman PDnLl antibody or antigen binding nt thereof, in an lHC assay on an FFPE or frozen tissue n of a tumor sample removed from the patient. 'l'ypically, the patient’s physician would order a diagnostic test to determine PD—Ll sion in a tumor tissue sample removed from the t prior to initiation of treatment with the l’D-l antagonist and VEGFR inhibitor, but it is envisioned that the physician could order the ?rst or subsequent diagnostic tests at any time after initiation of veatn'ient, such as for example after completion of a treatment cycle. {@129} Selecting a dosage regimen (also referred to herein as an administration regimen) for a combination therapy of the invention depends on several factors, including the serum or tissue turnover rate of the entity, the level of symptoms, the irnmunogenicity of the entity, and the accessibility of the target cells, tissue or organ in the individual being treated. Preferably, a dosage regimen zes the amount of each therapeutic agent delivered to the patient consistent with an acceptable level of side s. Accordingly, the dose amount and dosing frequency of each hiotherapeutic and chemotherapeutic agent in the combination depends in part on the ular therapeutic agent, the severity of the cancer heing d, and patient characteristics. Gniciance in selecting appropriate doses of antibodies, cytolrines, and. small molecules are available. See. cg, Wawrzynczak (i996) Antibody therapy, Bios Scientific i’ub.

Ltd, ()X?irdshire, UK; Kresina (ed) 0991) Monoclonal xiii!ii)t)tt’ies. (ljiitokines and lotteries, Marcel Deklrer, New York, NY; Bach (ecl) £3993) .Iit’t)i’l0(i'!'()i’liill Antibodies and Peptide iii/tempt? U1 in Az?oz‘mmzme Diseases, Marcel Deklter, New York, NY; Baert er a1. (2003) New Engl. J. Med. 348:601m608; Miigroin e! ai. U999) New EngI. J. Med. 34119664973; Slamon er of. (200i) New EngI. J. Med. 344:783792; ninovitz et ai. (2000) New Engi. J. fired. 342613—619; Ghosh et at. (2003) New Engi. J. Med. 34824—32; Lipsky et aI. {2000) New Engi. J. ’. 44602; Physicians’ Desk nce 2003 {thsicians' Desk Reference, 57th Ed); Medical Economics Company; iSBN: i563634457; 57th edition (November 2002:}. ination of the appropriate dosage regimen may be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment or predicted to affect treatment, and wilt , for example, the patient’s ciinicai history (cg, previous y), the type and stage of the cancer to be treated and biornarhers of response to one or more of the therapeutic agen ts in th e cornhin ation th erapy. {00130} Biotberapentic agents in a ation therapy of the invention may be administered by continuous infusion, or by closes at intervals of, e.g, daily, every other day, three times per week, or one time each week, two weeks, three weeks, monthly, bimonthiy, etc. A total weekly dose is generally at least 0.05 rig/kg. 0.2 gig/kg. 0.5 gig/kg. i rig/kg, l0 [rig/kg, 100 rig/kg, .2 mg/kg, l0 rng/itg, 2.0 mg/kg, 10 trig/kg, 25 trig/kg, 50 g body weight or more.

S,ee e.g., Yang et at. {2003) New Engl. J. ?red. 3491427434; Herold et at. (2002) New Engl. J. ?led. 346216924698; Lin, et aI. (1999) J. Neural. I 7eur0surg. Psych. 67145141356; Portielji et at. {20003) Caneeri’mmunol. Immunoz‘her. 52: 33m'i44. {0013M in some embodiments that employ an uman Pill mAb as the Pit—i antagonist in the ination therapy, the dosing regimen wili con'iprise administering the anti ~ human Ple night) at a. dose of l, 2, 3, 5 or wing/kg at intervals of about 1-4 days (i 2 days) or about El days (:: 2 days) or about 30 days (:: 2 days) throughout the course of treatment. {00132} in other embodiments that employ an uman PD—i inAh as the P111 antagonist in the combination therapy, the dosing regimen will comprise administering the anti— human Pill mAb at a dose of from about 0.005 mg/kg to about 10 rng/itg, with intra~patient dose escalation. in other escaiating dose embodiments, the interval n doses will be progressively shortened, cg, about 30 days (i 2 days) between the first and second dose, about 14 days (i 2 days} hetween the second and third doses. in certain ments, the dosing interval will he ahout 14 days (3: 2 days), for doses suhsequent to the second dose. {993.3% in certain embodiments, a subject will be administered an intravenous (W) infusion of a medicament sing any of the Ple antagonists described herein.

U} {titllfld} in one preferred, embodiment of the invention, the Pill antagonist in the combination therapy is nivolumah, which is stered intravenously at a dose selected from the group consisting of: l pig/kg Q2W, ’2 mg/lg'g QZW, 3 mg/lg'g QZW, S mg/lg'g QZW, it} mg QZW, l dig/kg (33W, 2 trig/kg QSW, 3 mg/lcg Q3W, 5 mg/kg QBW, and it? mg QSW. {$01353 in another preferred embodiment of the invention, the FEM antagonist in the combination therapy is MKAM’FS, which is stered in a liquid medicament at a dose selected trom the group consisting of l mg/lrg QZW, 2 mg/lrg QZW, El trig/leg QZW, 5 trig/kg QZW, ll} mg Q’ZW, l mg/lrg Q3W, 2 trig/kg QBW, 3 trig/kg QBW, 5 ag Q3W, it? mg QSW and fiat—dose equivalents of any of these doses, i.e., such as Ztltl mg QEW. in some particularly preferred enihndiments, MKn3475 is administered as a liquid medicament which comprises 25 mg/ml MK—3475, 7% (w/V) e, 0.02% (w/V) polysorbate 30 in lit niM ine buffer pH .5, and the selected dose of the medicament is stered hy 1V infusion over a time period of about 30 minutes. {@136} The optimal dose for MKn3475 in combination with axitinih may be identified by dose escalation of one or bath of these agents. in one embodiment, axitinih is administered at 5 mg Bil) and MK~3475 is administered at a starting dose of 2 mg/kg QZW, and if this dose eomhination is tolerated hy the patient, the Mid—3475 dose is increased up to a dose of it) mg/hg Q2W, While if the starting dose ation is not tolerated by the patient, then the dose of MK— 3475 is d, to l ing/lrg QZZVV'. {@137} in another embodiment, ih is administered at 5: mg Bil) and Mid—3475 is administered at a starting dose of 2 mg/hg QSW, and if this starting dose combination is not tolerated by the patient, then the dose of Mid—3475 is reduced te l mg/hg QBW.

{MESS} in another embodiment, ib is administered at 5. mg Bit} and Elli—3:475 is administered at a ng dose of 2 mg/kg QBW, and it" this dose combination is not tolerated by the patient, then the dose ofaxitinih is reduced to 3 mg BID. 3 0 {titll39} in an embodiment, :3 mg of axitinih is administered with our Without food BED, with each dose admistered about 12 hours apart. On the day (wildlife—3475 administration, axitinih may he given prior to or alter the MK.~3475 administration. llltll in some embodiments, the patient is treated with a 7—day lead-in period of single-agent ib directly preceding the administration of the PAR—3475 and, axitinih combination. {@141} in some embodiments, a treatment cycle begins with the ?rst day of combination £11 ent and last for 2 weeks. in such embodiments, the combination therapy is preferably administered for at least l 2 weeks {6 cycles of treatment), more preferably at least 24 weeks, and even more preferably at least 2 weeks after the patient achieves a CR. {hold-2} in some preferred embodiments, the dose of axitinib is increased after 6 cycles if the patient tolerates axitinih with no r‘elated grade >2 e events for 2 consecutive . ’l‘he axitinib dose may be increased by 2 mg BED each cycle up to a m dose of ll) mg Bil). whiz-$3} in some ments, the patient is selected for treatment with the con'thination therapy of the invention is the patient has been diagnosed with advanced RCC with predominantly clear cell subtype, and the primary tumor has been ed. Preferably, the patient has not received prior systemic therapy for advanced RCC. {993.4% The present ion also provides a medicament which comprises a Pit—l antagonist as described above and a pharmaceutically acceptable excipient. When the FD~l antagonist is a biotherapentic agent, eg, a in?ll), the antagonist may be produced in CHO cells using conventional cell culture and recovery/purification technologies. whiz-$5} in some embodiments, a medicament comprising an anti~PD~l antibody as the PD—l antagonist may be provided as a li dui d tormnlation or prepared, by reconstituting a lyophilized powder with sterile water for iniection prior to use. WC 20l2/l35408 describes the preparation of liquid and lized medicaments comprising MKw3475 that are suitable for use in the present invention. in some preferred embodiments, a medicament comprising lViK—Sél75 is provided in a glass vial which contains about 50 mg of 75. é? The present invention also provides a medicament which comprises axitinib and a pharmaceutically acceptable excipient. {tlillél’i} The anti—PD—l and, VlEGlR inhibitor medicaments described herein may be provided as a kit which comprises a first container and a second containiner and a paclrage insert.

The tirst container contains at least one dose of a medicament comprising an anti~PD~l antagonist, the second, container contains at least one dose of a niedican’tent comprising a VEGFR inhibitor, and the package , or label, which comprises ctions for treating a patient for cancer using the medicaments. The first and second containers may be comprised of the same or ent shape (eg, viais, syringes and botties) and/or materiai (eg, plastic or giass). The kit may further comprise other materiais that may be nsefui in administering the medicaments, such as dihtents, fiiters, 1V bags and tines, needles and syringes. in some preferred U1 embodiments of the kit, the anti—PDJ antagonist is an anti~PD~1 antibody and the instructions state that the inedicarnents are intended for use in treating a patient having a cancer that tests positive for FEE—Li expression by an THC assay. {$01483 These and other aspects of the invention, inciuding the exempiary specific embodiments iisted heiow, Wiii be apparent from the ngs contained herein. ary Speci?c Embodiments of the invention 1. A method for treating a cancer in an individuai comprising administering to the individual a combination therapy which ses a PDJ antagonist and a VEGFR inhibitor. 2. The method of embodiment 1, wherein the P34 antagonist is a onal antibody. or an antigen binding fragment thereof.

.J 3. The method of embodiment i or 2, wherein the VEGFR inhibitor the compound N— rnethyi—2— [3 '2—nyridin—Z~yi~viny i)~ 1H—indazoi «Es—y is i]—benzarnide or a rib arn'iaceuticahy acceptable salt thereof. 4. A medicament comprising a PD—i antagonist for use in ation with a VEGFR inhibitor for ng a cancer in an individual, wherein the PD—T antagonist is a monocionai antibody, or an antigen binding fragment thereof.

. A n'iedicanient comprising a VEGFR inhibitor for use in combination with a Pit—i nist for treating a cancer in an individual. 6. The ment of embodiment 4 or 5., which further comprises a pharmaceuticaiiy acceptahie excipient. 7. Use of a Pill antagonist in the cture of medicament for treating a cancer in an individual when administered in combination with a VEG FR inhibitor. 6. Use. of a VEGFR tor compound in the manufacture of a medicament for treating a cancer in an individnai when administered in combination with a PB-i antagonist.

I. Use of a PD—i antagonist and, a VEGFR inhibitor in the manui‘actare ot‘rnedicarnents for teating a cancer in an individuai. - 30 .. 8. A kit which comprises a first container, a second container and a e insert, wherein the first container comprises at least one dose of a medicament comprising an anti—PD—l antagonist, the second container comprises at least one dose of a medicament comprising a VEGFR inhibitor, and the package insert comprises instructions tor treating an individual for U1 cancer using the medicaments. 9. The hit of ment 8, wherein the instructions state that the medicaments are intended for use in treating an individual having a cancer that tests positive for PDnLl expression by an immunohistochemical (lHC) assay. ll}. The method, medicament, use or hit of any of ments l to 9, wherein the individual i (3 is a human and the Pill antagonist is a monoclonal antibody, or an antigen binding fragment thereof, which speci?cally binds to human Pit—M and blocks the binding of human PDALl to human PD—l. ll. The method, ment, use or hit of emhodiment 9, wherein the l’B—l antagonist is h'lPDl3280/5i, BMS~936559, Mliii?lél?o, MSBGOMWlSC or a monoclonal antihody which comprises the heavy chain and light chain variable regions of SEQ ll} N{):24 and SEQ ED N012}, respectively, of WOZQl 3/0} 9996. l2. The method, medicament, use or hit of any of embodiments l to 9, wherein the individual is a human, and the PD—l antagonist is a monoclonal dy, or an antigen g nt f, which speci?cally hinds to human PD—l and blocks the binding of human l’D-Li to human PD-l. l3. The method, medicament, use or hit of embodiment l2, wherein the PD—l antagonist also hioclcs binding of human PD~LZ to human PD—l ., 14. The method, medicament, use or l antibody, or antigen binding fragment thereof, comprises: (a) light chain CDRS of SEQ 1D NOs: h.) U1 l, ’2 and 3 and heavy chain CDRS of SEQ ED ‘NQs: 4, 5 and, a, or {h} light chain CDRS of SEQ ED NOS: '7, 8 and 9 and heavy chain CDRS of SEQ ii) NGs: ll}, ll and, l2, l5. The method, medicament, use or hit of embodiment l3, wherein the monoclonal dy, or antigen binding fragment thereof, comprises light chain C‘DRS of SEQ TD NOS: 7, 8 and 9 and heavy chain CDRs ofSEQ 1D NOS: it), i i and l2. 16. The method, medicament, use or hit of embodiment ii 3, wherein the PD—i nist is an anti—PD—i monoclonal antihody which comprises a heavy chain and a light chain, and wherein the heavy chain comprises SEQ ED NO:2T and the light chain ses SEQ 3D NUQZ. 17. The n'iethod, medicament, use or hit of embodiment i3, wherein the PEP—i antagonist is an U1 anti—PD—l monocionai antibody which comprises a heavy chain and, a tight chain, and wherein the heavy chain comprises SEQ ED N023 and the light chain comprises SEQ TD N024. 18. The , medicament, use or hit of any of embodiments 1047, wherein the cancer is a soiid tumor. 19. The method, medicament, use or hit of any of ments IQ—l 7, wherein the cancer is l0 bladder cancer, breast cancer, clear cell kidney cancer, head/neck squamous eeii oma, iung squamous cell carcinoma, malignant melanoma, nonnsmailwceii iung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, smaii—ceil hing cancer (SCLC) or tripie negative hreast cancer. 2t}. The method, medicament, use or hit of any of embodiments IQ—l 7, wherein the cancer is advanced renai ceii carcinoma. 2i. The method, medicament, use or hit of any of emhodiments ii 0-17, wherein the individual has not been previousiy treated for ed renai cell carcinoma. 2'2. The method, n'iedican'ient, use or itit of any of embodiments 1347, wherein the cancer is clear ceii kidney cancer. 23. The , medicament, use or hit of any of embodiments 1047, wherein the cancer is acute iymphohlastic leukemia (ALL), acute myeioid leukemia (AML), c lymphocytic leukemia (CLE), chronic myeioid leukemia (Ch/EL), e iarge B—celi lymphoma (DLBCL), uiar lymphoma, i—iodghin’s lymphoma (Hie), mantle ceii lymphoma {MCL}, muitipie myeioma (MM), myeioid ceil ieukemia-l protein ), myeiodysplastic syndrome (MUS), dgkin’s iyrnphoma (NHL), or smaii iymphocytic iyrnphoma (SELL). 24. The method, medicament, use or hit of any of embodiments i023, the cancer tests positive for human ED~L ii.

. The method, medicament, use or hit of embodiment ’24, n the human FEE-Ll expression is elevated, 26. The method, medicament, use or hit of embodiment 13, wherein the FBI} antagonist is Mid—3475 or nivolumah. - 32 .. 27. The method, medicament, use or kit of einhodiinent 26" wherein the Mid—3475 is formulated as a liquid medicament which comprises 25 mg/mi MK~3475, 7% (w/V) sucrose, €l.{}2% ("f/IV) polysorhate St} in 10 mM ine lmi‘fer pH 5.53 48.A The ’iOdK, medicament", use or kit of any of embodiments l to 2.7n wherein the VEGR.

U1 inhibitor is sunitinih soral‘enih or tivozanib. 29. The method, medicament, use or kit of any of embodiments l to 27," n the VEGR inhibitor is i’V-methyl—Z—[S~{{E)-2—pyridin—2—yi—Vinyi)—lH—indazol~6—yisulfanyli—henzamide or a pharmaceuticaliy acceptable salt thereof 3%. The method, medicament, use or kit of any of embodiments I to '27, wherein the VEFR. it} inhibitor is axitinib and is torinulated as a 1 mg tablet or a 5 mg tablet. 31. A method for treating a human individual diagnosed with a cancer, comprising administering to the individual a combination y which ses MKéEd? and ih, wherein (a) axitinih is administered at a dose of 5 mg RED and, MK—3475 is administered at a dose selected, {item the group consisting of l ing/kg QBW, '2 mg/kg QBW and 200 mg QEW or (b) axitinih is administered at a dose of 3 mg RED and Mtg—3475 is administered at a dose ed from the group ting of} mg/kg QBW, 2 mg/kg QSW and 200 mg QSW. 32. A medicament comprising Mid—3475 for use in combination with axitinih for treating a cancer in a human individuai by a method comprising administering to the individual (a) axitinih at a dose of 5 mg BED and MKASMS at a dose selected from the group consisting of l mg/lcg (2399‘!n 2 mg/kg QBW and 296) rng/kg Q3W or (b) axitinih at a dose of 3 mg BED and, h’iii—3475 at a dose selected from the group consisting oft rng/kg QBW, 2 nig/hg Q3W and 296) mg QSW. 33. A medicament comprising axitinih for use in combination with MKw3475 for treating a cancer in a human individual by a method comprising administering to the dual (_a) aXitinib at a dose of 5 mg BID and Misc—3475 at a dose selected from the group consisting of l mg/hg NU1 QBW, 2 mg/itg QEW and 200 mg QSW or (b) axitinih at a dose of 3 mg BID and PAR—3475 at a dose selected, from the group consisting of 1 mg/kg Q3W, 2 mg/kg {33W and 230 mg QBW. 34. The method or ment of any of embodiments 31 to 33., wherein axitinih is administered at a dose of? mg BID and MK~3475 is administered at 1 mg/kg Q3W.

. The method or medicament of any of embodiments 31 to 33, wherein axitinih is 3 (3 administered at a dose of 5 mg BID and, M K6475 is administered at 2 nig/kg Q3W~ - 33 .. 36. The method or medieament of any of embodiments 31 to 33, wherein axitinib is administered at a dose of 3 mg BID and MEL—3.475 is administered at l mgx’kg Q3W. 37. The method or medicament of any of embodiments 31 to 33, wherein axitinih is administered at a dose of 3 ing Bl D and MK~3475 is administered at 2 trig/leg QEW. 38. The method or medicament of any of embodiments 31 to 33, wherein axitinih is administered at a dose ot‘3 mg Bl D and MK—3475 is administered at 230 mg QBW. 39. The method or medicament of any of embodiments 31 to 38, wherein the eaneer is renal cell cancer 4b. The method or medicament of ment 39, wherein the individual has not been previously treated for renal cell , 41. The method or medicament of any of embodiments 31 to 38, n the eaneer is clear cell kidney eancer. 42. The method or medicament of any of embodiments 31 to 41, wherein a tissue section of the eaneer removed from the individual prior to administration of the combination therapy tested positive for PIE—Ll expression, 43. The method or medieament of embodiment 4-2, wherein at least 50% of the tumor cells in the tissue section tested positive for 1313le expression by an immunohistochemieal {111C} assay. 44. The method or medicament of embodiment 43, n the EEC assay employed the antibody 22C3 to deteet 1311141 expression. 45. The method or medieament of any of embodiments 3l to 4-4, wherein MK—3l-‘l75 is administered by TV on.

GENERAL METHQDS {@149} Standard methods in molecular biology are deseribed Sambrook, Fritseh and NU1 Maniatis "1982 32; 1989 2'"d Edition, 2t}01 3"d Edition lar Cloning, A Lahommrr Wheat/ti, _ J/ Cold, Spring Harbor laboratory Press, Cold Spring Harbor, NY; Samhrook and Russell (2001) ,zlt’ofecalar Gaming, 3"", ed Cold Spring Harbor Laboratory Press, Cold Spring , NY; Wu {1993) Recombinant DNA, Vol, 217, Academic Press, San Diego, CA), Standard methods also appear in Ausbel, er al. (2901) Current Protocois in ilioieeaiar Bioiogy, 15053.14, John Wiley and Sons, lne. New York, NY, whieli describes g in bacterial cells and DNA mutagenesis - 24 _ (V01. 1), clening in mammaiian cells and yeast (V01. 2), glycoccnjugates and pretein expression (Vol. 3), and fermatics (V01. 4:}. {001.501 Methods for protein puri?cation, ineiuding 1111111rineprecipitatinn, aregraphy, e1ectrnphcresis, centrifugation, and crystallization are described (Celigan, er a1. (2000) Current iii P10108011 in Pmrein Science, 1’01. 1, 101111 Wiley and Sens, 1110., New ank). Chemical aiiaiysis, c11e1111ca1 medi?ealien, pesl~trans1ati011a1 modificatien, preducti0n of fusion proteins, g1ycnsy1atien 01° preteins are described (see, 6.53., C01igan, er a]. (2000) Current ols in sz‘ez'n Science, 1’01". 3, 101111 Wiley and Sens, 11113., New anlr; Austibei, e! 0.1. (2001) Carreni PFCPEOC'OlS in 1110107211111" 310105517, V01. 3, 101111 Wiley and Sens, 1110, NY, NY, pp. 160.546.22.17; Sig111a~Aldric11, C0. (2001) Products jbr life Science Research, St. Leuis, MO; pp. ; Arnersliarn Pharmacia 1211111 (2001) 81(1,Direetnry, Piscataway, N1 ., pp. 384—391), 13101111131101}, puri?cation, and fragmentatinn nfpelycienal and, ninnccinnai antibndies are described (Celigan, er a1. (2001) Current is in Imrnzmalogy, V01. 1, 101111 Wiley and Sons, 1110., New York; Harlew and Lane (1999) Uring Antibodies, C0111 Spring Harbor Laberatory Press, C0111 Spring Harbor, NY; Ha1‘10w and Lane, 52mm"). Standard techniques fer characterizing ligand/’receptcr interactiens are ava11a111e (see, eg, Ceiigan, er a]. (2001) ! Protocols in Immunology, Vol. 4, 101111 Wi1ey, 111e,, New York). 1001511 31011001011111, polycinnal, and humanized antibndies can be prepared (see, eg, Sheperd and Dean (eds) (2000) 11101106101112! Antibodies, Oxfnrd Univ. Press, New Yerk, NY; Rentermann and Du’bei (eds) (2001)/1nzibcdy Engineering, Springer? ’erlag, New Yerk, Har10w and Lane (1988) Antibodies A Laboratmy Manual, (301d Spring, Earlier Lalinratery Press, (30111 Spring 1-1a1‘110r, NY, pp. ; Carpenter, et a]. (2000) J. Imnmnal. 16516205; He, at: a]. (1998) J; Immanal. 16011029; Tang et a}. (1999) 3. 13101. Chem. 27412737127378; Baca er a1. (1997) J; .8101. Chem. 2721067840684; (3110111121 12; a1. (1989) Nature 342:877—883; Footie and Winter (1992) J. Moi. Bio/7. 224:487~499; US. Pat. No. 6,329,511). {00152} An ailerriative 10 humanizarien is 10 use human antibcdy libraries disp1ayed 0n phage 0r human antibedy libraries in transgenic mice (Vaughan 6111!. (1990) Nature Bietechnel. 14; Barbas (1995) Nature 12701126 1037—839; Mendez er a1. (1997) Nature Genetics :146—156; Hengerrbnnni and Chanies (2000) Immunof. Today 21371—377; Barbas et ai. (2001) Phage Dispidy: 141 Laboraz’my Mam/mi. Cold, Spring Harbor iisabera‘mry Press, C0111 Spring Harbnr, New Yerk; Kay 61‘ a1. (1996) Phage Display Qf’Pegirides and g: 11 Labaramifv Alanna], Academic Press, San Diegn, CA; de Bruin 61111. (1999) Nature 1111101. 17397099). lfliii Puri?cation of antigen is not necessary for the generation of antibodies. Animals can he immunized with cells bearing the antigen of interest, Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridorna (see, eg, Meyaard er ai, (l9???) arly 7:283~290; Wright 6? ai, (2906) ’nl U1 l3:233—242; Preston 6! at, szgnm; Kaitharnana et ai. U999) J. [mmZ/MOZ, l63:5 l 5715 l64), iilltll?d? dies can be conjugated, cg, to small drug molecules, enzymes, liposomes, polyethylene glycol (PEG). Antibodies are useful for therapeutic, diagnostic, kit or other purposes, and include antibodies coupled, eg, to dyes, sotopes, enzymes, or metals, 6g, colloidal gold (see, eg, Le l 61' (ll, (l99l) J. Immunof. l46:l69ml75; Csihellini er ai. ll} (l998) J, inummoi, l6ll:389l—3898; lising and Bishop (l 999) J. Zmnmnoi. l62:2804~28ll; Everts ct al. (2002)1 [Ii/animal. ll’i8z883—889). ??l Methods for ?ow eytometw, including fluorescence activated cell sorting , are available (see, eg, Owens, el al. 0994) Flaw trjv Principles for minim! Laboratory Practice, John Wiley and Sons, lloboken, NJ; Givan (200D Flow l/y, 2w 6d,; Wiley—kiss, llobeken, NJ; Shapiro (2003) Practical Flow Cytomel‘ry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid s and probes, polypeptides, and antibodies, for use, eg, as diagnostic reagents, are available (Molecular sy (2003:} Catalogue, Molecular Probes, ine, Eugene, 0R; Sigma Aldrich (2003:} Catalogs/(e, St. Louis, MO). {@156} Standard methods of histology of the immune system are described (see, eg, Muller—Harmelink (ed) @986) Human us: Histapa?zoiagv and Pathology, Springer Verlag, New York, NY, Hiatt, er a3. (2009) Color Arias Qinstaiogy, Lippincott, ms, and Wilkins, Phila, PA; Louis, er a], (2002) Basic Histology: Text and Atlas, McGraW—Hill, New York, NY). {lllll57} Software packages and databases for determining, eg, antigenic li'aginents, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, ag, GenBank, Vector NTl® Suite (lnformax, lne, Bethesda, MD); GCG Wisconsin Package (Aecelws, inc, San Diego, CA), DeCypher® (i'il‘irneLogic Corp, Crystal Bay, Nevada); Menne, er a5. (2000) Bioiaformazics l6: "fill—742; Menne, er a5. (2000) crrma?cs Applications Note l6374l—742; Wren, er al. {2002) , lik?MdS Programs 3 (3 Bronzed. €58:l77—l8l; von Heijne U983) Eur. J, Biochem. l33:l7"2l; von Heijne (1986) Mailed? Acids Res. l4:4683—4690).

{MISS} Exam Tile l: Treatment of Fatients with Renal Cell Carcinoma with a Combination ofoitiriib and MKn3475 - 36 .. fl?‘ll This study will evaluate the efficacy of a combination of axitinih and lle—3475 in human ts with RCC. Patients will he treated with axitinih at 5 mg or 3 mg Bil) and with MKéléWS at l mg/lcg or ’2 mg/lcg every three weeks by intravenous infusion for a period of l 8 months. {salsa} Table 3 provides exemplary dosing information for the coinhinationofaxitinih and Mia—3475. 3m [mo BID: twice daily; q3wlr: every 3 weeks. ltlllloll it is expected that the combination ot‘aaitinih and l‘let—347S will he more ef?cacious than either treatrnent alone according to at least one ol" the tollowing e measures: ll) {tltlltiZl Duration of Response (DR) E Time Frame: l8 months l - Time in weeks from the first documentation of obj ective tumor response to ohj ective tumor progression or death due to any cancer. on of tumor response will be calculated as {the date of the ?rst ntation ofohjective tumor progression or death due to cancer minus the date or" the first CR or PR that will be subsequently con?rmed plus l) divided by 7. DR will be calculated for the subgroup of participants with a con?rmed obj ective tumor response. {@163} Percentage of Participants With Objective esponse { Time Frame: l8 months ] n Percentage of participants with OR hased assessment of confirmed complete remission (CR) or confirmed partial remission (PR) according to Response Evaluation Criteria in Solid Tumors {RliltiilS’l'}. ed remission are those with repeat hone marrow showing less than 5 t (ll/El) myelohlasts with normal maturation of all cell lines and absolute values of the peripheral blood lasting at least 2 months. PR are those with all CR. criteria except at least 50(375 decrease in, the blasts over the pretreatment {salsa} Progression—Free Survival (PFS) { Time Frame: l8 months ] n Median time from the first dose of study treatment to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first. PPS calculated as (Weeks) = (first event date minus first dose date plus l) divided by 7. ltltlthl Overall Survival (OS) { Time Frame: live years l ~ Overall survival will be the duration from nent to death. For participants who are alive, overall survival will he censored at the last contact" liiiil Eastern Cooperative Oncology Group {ECOG} performance status [ ,_l‘irne Frame: Up to 2.5 years ] — liltilt?lG—PS measured tin—therapy (time between first dose and last close date with a 3t)~day lag) assessed participant‘s performance status on 5 point scale: tl===llully active/able to carry on all premdisease activities without restriction; lJ‘i {?lllo’ll’l l=restricted in ally strenuous activity, ambulatory/able to carry out light or sedentary work; 2=anibulatory (>509?) ofwalring lirs), e of all self caret unable to carry out any worl: activities; 3=capalile of only limited self care, confined to lied/chair >50% of waking hrs; 4=cornpletely disabled, cannot carry on any self care," totally confined to lied/chair; 5=rlead. {?lling} Presence (rate) or absence of blood hiornarkers { Time Frame: Up to 235 years ] — l0 To identify bion'iarkers (FOR list}, VE6 Fm) of complete response and relawe/progression i f occurs. {earns} Patient eligibility for the study will be determined according to the following criteria: Ages le for Study: l8 Years and older: s Eligible for Study: Both.

Accepts Healthy Volunteers: No. llistologically or cytologieally confirmed, ed RCC with predominantly clear—cell subtype with primary tumor resccted; at least one measureahle lesion as defined by Response Evaluation Criteria in Solid Tumors (REClS'l‘) version l .l; Eastern Cooperative Oncology Group performance status (l or l; and controlled hypertension. {lltll’i’tll Table 4 provides a bri efdeseription of the sequences in the sequence g anon toss light chain cost 2: hPD—l .GSA light chain CDRIZ ' hPD—l ~08A light chain CDR3 hl?’l)d .(lSA heavy chain CDRl hPD—l .flSA heavy chain CDRZ’; liPD—l «GSA heavy chain CDRS l 09A light chain (IDRl lil’D-l .09A light chain CDRE hPD—lllElA light chain CDRB K09AnLnl7 light chain variable regien KQQA—L—ll light chain full length $109} arm light Chain full length K09A~L~l7 light chain full length Mtg—3475 Heavy chain Mii-Bl?? Light Chain Nivelninab Heavy eliain inab light chain Human PD—Ll REFERENCES l Sharpe, All, Wherry, Ell, Ahmed R, and Ei‘reeman (Ill The ?tnetinn ef’ prngrammed cell death l and, its ligands in regulating alvlti‘lll'i’ll?ul‘llly and, iehi Naz‘zrzre immzmalagy (2607); 8:239~245. 2. Dong ll ei‘ ai. Tunmnasseeiated B7—l’ll promotes T—eell apeptosis: a petential mechanism of immune evasinn, Nat Med. 2.092 8):793—8QG. l0 3 Yang a all. l’D-l interactien centiibutes tn the functional suppressien 0f 'l'wcell responses to lnnnan uveal melanoma cells in Vltl‘?. Invest Ophthaimoi ViS Sci. 2068 .lun;49(6 : 49: l 8-2525. 4‘ Ghebeh er al. The B7-l—ll (PD—Ll) T lymplineyte~inhibitnry molecule is expressed in breast cancer patients with in?ltrating duetal neina: cori‘elatieh with impm'tant higlnrisk 'propgnnstie factors; Neapiasia (2006) 8: @3498. - 39 ..

. Harnanishi 1 62‘ a5. Programmed ce1l death l ligand 1 and tnmcr—in?1trating CD8+ ’1‘ lymphocytes are prognnstic factors cf nunian cvarian cancer. Praccedz‘ng Qf‘z‘ne l .laz‘z'cnai Academy q?S’cz'ences (20(17): 104: 336045365.

U"! (3. 'fi‘iinnipscn RB et al. cance city—1311 cverexpressinn in kidney cancer. C1inical genitcnrin Cancer (20(16): 5; 2064211. 7. Nomi, T. Site. 1%., Alcahnri. T... at (If. Clinicai signi?cance and therapeutic 'pntmrtial cf the pregrannned death" 1 tigand/programmed deatnml pathway in human pancreatic cancer. Clinical! l0 Cancer ch ;13:2l5 141157. 8. Ohigasni Y et a1. Ciinicai signi?cance nfprngrannned death—1 1igand— 1 and pregrann‘ned death-1 1igand 2 sinn in human esophageal cancer. Clin. (Tamer Research (2005): 1 1 : 29473953. 9. innian er ai, PDJA (B72111) expression by urctheii a1 carcincina cfthe bladder and, ECG— indnced granuletnata: ations with incatized stage pregressinn. Cancer (29(17): 109: 1499- 1t). Shiinauchi T ct at. ted expression cfprcgramnred death—1 in both necpiasinatic and, plastic CD4+ ’1‘—cel1s in adult T—celi Leukemia" Lyniphcrna. Int. J. Cancer (2007): 12112585—2590. 11. Gan er a1. Overexpressicn nt‘PD-U significantly associates with turner aggressiveness and NU1 pcstcperative recurrence in human liepatccelhilar carcinoma. Clinical Cancer Research (2009) : 971—979. 12. Nakanishi .1. pression 01987411 (P1111) signi?cantly assnciates with turner grade and erative prognnsis in human nrotheliai cancers. Cancer In/zrnzmoi Immunafner. {2007) 56: 1173—1182. 13. Hinn e! a]. 'l‘nrnor celi expression cf prcgrarnnied ceil l is a prognnstic factm‘ for malignant ma. Cancer (2010): ()0: 1—9. 14. (:i'nebeli 1-1. chpii" tregs and 1&7—1l-'/1’D—1~t- ’1‘ tyinpnccytes cit—infiltrate the turner tissues of tiigti~risk breast cancer patitnits: intnlicatien for innnnnntl'ierapy. BMC Cancer. 2008 Feb 23;8:57. l5. Ahmadzadeh lvl et all "l‘uinor antigen—specific C138 T cells in?ltrating the tumor express high levels of l’B-l and are functionally ed. Blood {2%9) ilél: l537—l 544.

U1 l6. Thompson Rl-i et alt l’D—l is expressed by tumor infiltrating cells and is associated with poor outcome for ts with renal carcinoma. Clinical Cancer Research (2007) l5: l757sl 7(3l. {@171} All references cited herein are incorporated by reference to the same extent as if each individual publication database entry (eg. h sequences or GenelD entries), patent application, or patent, was speci?cally and dually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants, nt to 37 {Lilli §ii57(b){l), to relate to each and every individual publication, database entry (erg.

Genbanl: ces or (:i'enell) entries), patent application, or patent, each of which is clearly identi?ed in compliance with 37 CESR‘ §l,357{b)(2), even if such on is not innnediately adjacent to a dedicated statement of incorporation by nce. The inclusion of dedicated statements of incorporation by reference, if any within the speci?cation does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the re "erenee is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.

Claims (7)

CLAIMS :

1. Use of pembrolizumab and axitinib for the manufacture of a ment for combination therapy treatment of renal cell carcinoma in an individual.

2. Use of pembrolizumab for the manufacture of a medicament for the treatment of renal cell carcinoma in an individual wherein the pembrolizumab is to be administered in combination with axitinib.

3. Use of axitinib for the manufacture of a medicament for the treatment of renal cell carcinoma in an individual wherein the axitinib is to be administered in combination with pembrolizumab.

4. A ment comprising a ation of lizumab and axitinib for use in treating renal cell carcinoma in an individual.

5. The medicament of claim 4, wherein pembrolizumab is formulated as a liquid medicament which comprises 25 mg/ml pembrolizumab, 7% (w/v) sucrose, 0.02% (w/v) polysorbate 80 in 10 mM histidine buffer pH 5.5 and axitinib is formulated as a 1 mg tablet or a 5 mg tablet.

6. A use according to any one of claims 1 to 3 substantially as herein described with nce to any one or more of the examples but excluding comparative es.

7. A medicament according to claim 4 ntially as herein described with reference to any one or more of the examples but excluding comparative examples. PCFC-956 -