Combination of zimberelimab and domvanalimab

Abstract

Described herein are treatments and preventions for Head and Neck Squamous Cell Carcinoma (HNSCC) using the combination of zimberelimab and domvanalimab, in addition to one or more chemotherapeutic agents.

Description

Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOCOMBINATION OF ZIMBERELIMAB AND DOMVANALIMABCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit under 35 U.S.C. 119(e) of United States Provisional Application Nos. 63 / 692,619, filed September 9, 2024, and 63 / 715,438, filed November 1, 2024, each of which is hereby incorporated by reference in its entirety.ELECTRONIC SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted in XML format via Patent Center and is hereby incorporated by reference in its entirety. Said XML copy, created September 5, 2025, is named 37JD-395214.xml and is 19,868 bytes in size.BACKGROUND

[0003] Head and neck cancer refers to a group of malignancies that arise in the head and neck region, including the oral cavity, nasopharynx, oropharynx, hypopharynx, paranasal sinuses, and larynx. Although diverse histological types of tumors are found in the head and neck regions, most head and neck cancers arise from the mucosa of squamous cell epithelium.

[0004] It has been reported that head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide. The risk factors most frequently associated with HNSCC are known to include smoking, alcohol consumption, human papillomavirus (HPV) infection (especially for oropharyngeal cancers), and Epstein-Barr virus infection (especially for nasopharyngeal cancer). Nasopharyngeal cancer is a rare presentation of HNSCC that differs from typical HNSCC in etiology, standard therapies, and treatment response.

[0005] Approximately 30% to 40% of patients with HNSCC present with early-stage disease (Stage I or II), which is commonly curable with either surgery or definitive radiation therapy. A large number of patients with HNSCC initially present with locoregionally advanced disease (Stage III or IV) and they are treated with combined modality approaches such as surgery,Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO radiation therapy, and / or chemotherapy. However, approximately 50% of patients with locoregionally advanced disease may develop a recurrence after definitive local therapies. A newly diagnosed Stage IV with distant metastasis is not common in HNSCC and approximately 10% of patients with HNSCC present with distant metastasis at initial diagnosis.

[0006] The prognosis of patients with recurrent or metastatic (r / m) HNSCC is generally poor, and they are treated with single-agent therapy or in combination with immune checkpoint inhibitors, conventional cytotoxic chemotherapies, and / or molecular targeted agents (e.g., epidermal growth factor receptor inhibitor). There are unmet medical needs in locoregionally advanced and r / m HNSCC which remain high and there are urgent needs for novel therapies to improve overall survival (OS) in the management of HNSCC.SUMMARY

[0007] In one aspect, the present disclosure provides a novel therapy to treat or manage Head and Neck Squamous Cell Carcinoma (HNSCC).

[0008] The present disclosure, in one embodiment, provides a method of treating Head and Neck Squamous Cell Carcinoma (HNSCC) in a subject in need thereof, comprising administering a therapeutically effective amount of zimberelimab, a therapeutically effective amount of domvanalimab, and one or more chemotherapeutic agent.

[0009] In some embodiments, the HNSCC is recurrent / metastatic (r / m) HNSCC. In some embodiments, the HNSCC is histologically or cytologically confirmed r / m squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies. In some embodiments, the HNSCC has programmed cell death ligand 1 (PD- Ll) expression, and has VENTANA PD-L1 (SP263) immunohistochemistry (IHC) TAP score of 20% or greater. In some embodiments, the HNSCC is HPV pl6 negative. In some embodiments, zimberelimab and domvanalimab are administered separately. In some embodiments, zimberelimab and domvanalimab are administered simultaneously (e.g., co-administration). In some embodiments, zimberelimab and domvanalimab are administered intravenously. In someAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO embodiments, domvanalimab is administered at a dose of about 1100 mg to about 1300 mg once every 3 weeks. In some embodiments, zimberelimab is administered at a dose of about 350 mg to about 400 mg once every 3 weeks. In some embodiments, said one or more chemotherapeutic agent comprises a platinum-based chemotherapeutic agent. In some embodiments, said one or more chemotherapeutic agents are one platinum-based chemotherapeutic agent and another chemotherapeutic agent. In some embodiments, the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, or nedaplatin. In some embodiments, said another chemotherapeutic agent is selected from paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan. In some embodiments, the method further comprises administering a therapeutically effective amount of carboplatin and a therapeutically effective amount of paclitaxel. In some embodiments, paclitaxel is administered at a dose of about 175 mg / m2once every 3 weeks. In some embodiments, carboplatin is administered at a dose of about AUC 5 once every 3 weeks. In some embodiments, zimberelimab, domvanalimab, carboplatin, and paclitaxel are administered on a same day. In some embodiments, zimberelimab and domvanalimab are administered for up to 35 treatment cycles. In some embodiments, carboplatin and paclitaxel are administered for up to 6 treatment cycles. In some embodiments, the subject did not have prior systemic therapy for r / m HNSCC. In some embodiments, the subject had had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum-containing therapy for locoregionally advanced disease. In some embodiments, the subject does not have nasopharyngeal cancer or squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, or salivary gland.

[0010] The present disclosure, in one embodiment, provides a method of treating recurrent / metastatic (r / m) head and neck squamous cell carcinoma (HNSCC) in a subject in need thereof, comprising administering: zimberelimab at a dose of about 360 mg once per 3 weeks; domvanalimab at a dose of about 1200 mg once every 3 weeks; and a platinum-doublet chemotherapy.

[0011] In some embodiments, the HNSCC is histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that isAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO considered incurable by local therapies. In some embodiments, the HNSCC has programmed cell death ligand 1 (PD-L1) expression, and has investigational VENTANA PD-L1 (SP263) immunohistochemistry (IHC) TAP score of 20% or greater. In some embodiments, the platinum- doublet chemotherapy comprises carboplatin and paclitaxel. In some embodiments, the platinum- doublet chemotherapy comprises carboplatin at about AUC 5 once every 3 weeks and paclitaxel at a dose of about 175 mg / m2once every 3 weeks. In some embodiments, zimberelimab and domvanalimab are administered separately. In some embodiments, zimberelimab and domvanalimab are administered simultaneously (e.g., co-administration). In some embodiments, zimberelimab and domvanalimab are administered intravenously. In some embodiments, zimberelimab, domvanalimab, carboplatin, and paclitaxel are administered on a same day. In some embodiments, the subject did not have prior systemic therapy for r / m HNSCC. In some embodiments, the subject had had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum-containing therapy for locoregionally advanced disease. In some embodiments, the subject does not have nasopharyngeal cancer, squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, and salivary gland. In some embodiments, zimberelimab and domvanalimab are administered for up to 35 treatment cycles. In some embodiments, the platinum-doublet chemotherapy is administered for up to 6 treatment cycles. In some embodiments, the HNSCC is HPV p!6 negative.BRIEF DESCRIPTION OF DRAWINGS

[0012] FIG. 1 is a plot showing flow cytometric gating strategy for identifying cell populations in human HNSCC tumor infiltrating leukocytes (TIL) suspensions.

[0013] FIG. 2A is a graph showing frequency of CD4+TCOnv (CD4+FoxP3“), CD4+Treg(CD4+FoxP3+), CD8+T, CD3"CD19+B, CD3"CD56+NK, CD3+CD56+NKT, CD14+and / or CD16+monocyte, Lineage" Side Scatter111(SSChl) myeloid / macrophage, and CD45" cancer or stromal subsets in HNSCC TIL suspensions.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0014] FIG. 2B is a set of graphs showing frequency (circles, left y-axis) and geometric mean fluorescence intensity (gMFI) (triangles, right y-axis) of TIG IT, PD-1, and CD226 in CD4+TConv, Treg, and CD8+T subsets or NK cells.

[0015] FIG. 2C is a set of graphs showing frequency of PD-1+TIGIT+CD226+triple positive cells in CD4+TCOnv, Treg, and CD8+T subsets or NK cells.

[0016] FIG. 2D is a graph showing frequency (circles, left y-axis) and gMFI (triangles, right y- axis) of CD155 or PD-L1 in CD4+TCOnv (CD4+FoxP3’), CD4+Treg(CD4+FoxP3+), CD8+T, CD3’ CD19+B, CD3 CD56+NK, CD3+CD56+NKT, CD14+and / or CD16+monocyte, Lineage- Side Scatter111(SSChl) myeloid / macrophage, and CD45’ cancer or stromal subsets.

[0017] FIG. 3A is a representative pseudocolor plot showing gating strategy for of Tpex- (TCF- 1+TIM-3") and Ttex-containing (TCF-TTIM-3+) populations in the CD8+T subset in HNSCC TIL suspensions.

[0018] FIG. 3B is a graph showing frequencies of TCF-1+TIM-3’ Tpexand TCF-T TIM-3+Ttexpopulations in the CD8+T subset.

[0019] FIG. 3C is a graph showing frequencies of PD1+TIGIT+CD226+triple-positive cells in Tpexand Ttexpopulations.DETAILED DESCRIPTIONDefinitions

[0020] The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0021] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise,

[0022] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to "the compound" includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0023] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0024] As used herein, “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0025] The “amount,” “level,” or “expression level,” used herein interchangeably, of a biomarker is a detectable level in a biological sample. “Expression” generally refers to the process by which information (e.g., gene-encoded and / or epigenetic) is converted into theAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO structures present and operating in the cell. Therefore, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide, or even polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide). Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and / or polypeptide modifications (e.g., posttranslational modification of a polypeptide) shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis. “Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs). Expression levels can be measured by methods known to one skilled in the art and also disclosed herein. The expression level or amount of a biomarker (e.g., CD155, CD226, PD-1, PD-L1, CD73) can be used to identify / characterize a cancer that may be likely to respond to, or benefit from, a particular therapy or to not experience clinical benefit.

[0026] The term “biomarker” as used herein refers to an indicator, e.g., predictive, diagnostic, and / or prognostic, which can be detected in a sample. The biomarker may serve as an indicator of a particular subtype of a disease or disorder characterized by certain, molecular, pathological, histological, and / or clinical features. Biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA, and / or RNA), polynucleotide copy number alterations (e.g., DNA copy numbers), polypeptide and polynucleotide modifications (e.g., methylation, acetylation, oxidation, glycosylation), carbohydrates, and / or glycolipid-based molecular markers.

[0027] The terms “detecting” and “detection” are used herein in the broadest sense to include both qualitative and quantitative measurements of a target molecule. Detecting includes identifying the mere presence of the target molecule in a sample as well as determining whether the target molecule is present in the sample at detectable levels. Detecting may be direct or indirect.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0028] The term “sample,” as used herein, refers to a composition that is obtained or derived from a subject that contains a biomarker that is to be identified and / or characterized, for example based on physical, biochemical, chemical and / or physiological characteristics. For example, the phrase “tumor sample,” “disease sample,” and variations thereof refers to any sample obtained from a subject of interest that would be expected or is known to contain the biomarker that is to be characterized. Other samples include, but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, stool, whole lymph nodes or lymph node biopsies, tissue from biopsies or resections, tumor biopsies, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, cellular extracts, and combinations thereof.

[0029] A “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue,” as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes. In one embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or nondiseased part of the body (e.g., tissue or cells) of the same subject. For example, healthy and / or non-diseased cells or tissue adjacent to the diseased cells or tissue (e.g., cells or tissue adjacent to a tumor). In another embodiment, a reference sample is obtained from an untreated tissue and / or cell of the body of the same subject. In yet another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and / or non-diseased part of the body (e.g., tissues or cells) of a subject who is not the subject. In even another embodiment, a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and / or cell of the body of an individual who is not the subject.

[0030] A “tumor sample” refers to a sample comprising tumor cells. Typically, a tumor sample obtained from a solid tumor (e.g., tissue from biopsies or resections) comprises tumor cells and other cells of the tumor microenvironment (e.g., immune cells, stromal cells, fibroblasts, etc.).Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0031] The term “positive cell fraction” is the percentage of viable cells showing positive staining for a protein of interest in one or more cellular location (e.g., membrane, cytoplasm) at any intensity in a sample, following staining of the sample, e.g., in an immunohistochemical (IHC) assay. A positive cell fraction may be reported for all cell types or a certain subtype or subtypes (e.g., tumor cells, immune cells, other cells of the tumor microenvironment, etc.). The term “positive tumor cell fraction”, which may be abbreviated “% TC” is the percentage of viable tumor cells showing positive staining for a protein of interest in one or more cellular location. A “tumor cell”, as used herein, refers to a cancerous cell. Accordingly, a positive tumor cell fraction may be calculated using the formula % TC=(number of positive viable tumor cells) / (number of positive + negative viable tumor cells) xlOO, wherein all positive- staining non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) are excluded from evaluation and scoring. The term “positive immune cell fraction”, which may be abbreviated “% IC” is the percentage of viable immune cells in a sample or specified area of a sample showing positive staining for a protein of interest in one or more cellular location.

[0032] The term “protein,” as used herein, encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the subject (e.g., processing that may occur intracellularly or extracellularly within the body). The term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.

[0033] “Polynucleotide” or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length, and includes DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction. Thus, for instance, polynucleotides as defined herein include, without limitation, single- and double- stranded DNA, DNA including single- and double-stranded regions, single- and double- stranded RNA, and RNA including single- and double- stranded regions, hybrid molecules comprising DNA and RNA that may be single- stranded or, more typically, double-stranded or include single- and double- stranded regions. In addition, the term “polynucleotide” as used herein refers to triple-stranded regions comprising RNA or DNA orAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO both RNA and DNA. The strands in such regions may be from the same molecule or from different molecules. The regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules. One of the molecules of a triple-helical region often is an oligonucleotide. The terms “polynucleotide” and “nucleic acid” specifically includes mRNA and cDNAs.

[0034] As used herein, the “administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including but not limited to, orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), rectally, intrathecally, intratumorally or topically. Administration includes self-administration and the administration by another.

[0035] The term “antibody,” as used herein, is used in the broadest sense and encompasses various antibody and antibody-like structures that specifically bind to a single antigen or to multiple antigens (e.g., monospecific antibodies, multispecific antibodies, polyepitopic antibodies, etc.), including but not limited to full-length antibodies, antigen-binding fragments, heavy chain antibodies, single-chain antibodies, and higher order variants of single-chain antibodies. Thus, any reference to an antibody should be understood to refer to the antibody in intact form or an antigen-binding fragment (including an antigen-binding fragment derived from a full-length antibody) unless the context requires otherwise. Preferably, but not necessarily, antibodies useful herein are isolated and can be produced recombinantly. The term “isolated antibody” refers to an antibody that has been separated from a component of its natural environment. In some embodiments, an isolated antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis or chromatography (e.g., ion exchange or reverse phase HPLC).

[0036] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or having heavy chains that contain an Fc region.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0037] The term “antibody fragment” refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antigen-binding fragment include, without limitation, a diabody, a Fab, a Fab', a F(ab')2, a F(ab)c, an Fv fragment, a disulfide stabilized Fv fragment (dsFv), a (dsFv)2, a bispecific dsFv (dsFv-dsFv'), a disulfide stabilized diabody (ds diabody), a triabody, a tetrabody, a single-chain antibody, an scFv, an scFv dimer, a single domain antibody, a single-domain antibody, and a multivalent domain antibody. Typically, binding fragments compete with the intact antibody from which they were derived for specific binding. Binding fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulin s .

[0038] As used herein, the term “therapeutic agent” is intended to mean a compound that, when present in an effective amount, produces a desired therapeutic effect on a subject in need thereof.

[0039] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) is meant to encompass any non-proteinaceous (i.e., non-peptidic) chemical compound useful in the treatment of cancer.

[0040] Additionally, amounts, ratios, and other numerical values are sometimes presented herein in a range format. It is to be understood that such range format is used for convenience and brevity and should be understood flexibly to include numerical values explicitly specified as limits of a range, but also to include all individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly specified. For example, a value in the range of about 1 to about 200 should be understood to include the explicitly recited limits of about 1 and about 200, but also to include individual values such as about 2, about 3, and about 4, and sub-ranges such as about 10 to about 50, about 20 to about 100, and so forth.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOCompoundsZimberelimab

[0041] Zimberelimab is also known as AB 122. Zimberelimab is a fully human immunoglobulin (Ig) G4 monoclonal antibody targeting human programmed cell death protein 1 (PD-1). Zimberelimab has demonstrated the ability to block the interaction of PD-1 with PD-L1 and PD-L2. In vitro binding studies showed that zimberelimab binds to PD-1 from both humans and cynomolgus monkeys to a similar extent and without cross-reactivity toward other CD28 family members (e.g., CD28, inducible T cell costimulator-, or cytotoxic T lymphocyte-associated antigen 4). In addition, zimberelimab did not mediate antibodydependent cellular cytotoxicity (ADCC) on human PD-1+ CD4+ T cells upon exposure to peripheral blood mononuclear cells or any complement-dependent cytotoxicity (CDC) on human PD-1+ CD4+ T cells upon exposure to human complement.

[0042] Zimberelimab comprises a heavy chain complementarity-determining region (CDR) 1 (CDRH1) comprising the amino acid sequence of STTYYWV (SEQ ID NO. 1), a heavy chain CDR2 (CDRH2) comprising the amino acid sequence of SISYSGSTYYNPSLKS (SEQ ID NO: 2), a heavy chain CDR3 (CDRH3) comprising the amino acid sequence of HLGYNGRYLPFDY (SEQ ID NO: 3), a light chain CDR1 (CDRL1) comprising the amino acid sequence of TGTSSDVGFYNYVS (SEQ ID NO: 4), a light chain CDR2 (CDRL2) comprising the amino acid sequence of DVSNRPS (SEQ ID NO: 5), and a light chain CDR3 (CDRL3) comprising the amino acid sequence of SSYTSISTWV (SEQ ID NO: 6).

[0043] Zimberelimab comprises a variable heavy chain (VH) domain comprising the amino acid sequence of: QLQLQESGPGLVKPSETLTLTCTVSADSISSTTYYWVWIRQPPGKGLEWIGSISYSGSTYY NPSLKSRVTVSVDTSKNQFSLKLNSVAATDTALYYCARHLGYNGRYLPFDYWGQGTLV TVSS (SEQ ID NO: 7) andAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO a variable light chain (VL) domain comprising the amino acid sequence of: QSALTQPASVSGSPGQSITISCTGTSSDVGFYNYVSWYQQHPGKAPELMIYDVSNRPSGV SDRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSISTWVFGGGTKLTVL (SEQ IDNO: 8).

[0044] The mature gamma heavy chain amino acid sequence of zimberelimab is:QLQLQESGPGLVKPSETLTLTCTVSADSISSTTYYWVWIRQPPGKGLEWIGSISYSGSTYY NPSLKSRVTVSVDTSKNQFSLKLNSVAATDTALYYCARHLGYNGRYLPFDYWGQGTLV TVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLG GPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQ FNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGEPSS1EKT1SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVD KSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 9); and the mature kappa light chain amino acid sequence of zimberelimab is:QSALTQPASVSGSPGQSITISCTGTSSDVGFYNYVSWYQQHPGKAPELMIYDVSNRPSGV SDRFSGSKSGNTASLTISGLQAEDEADYYCSSYTSISTWVFGGGTKLTVLGQPKAAPSVT LFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS (SEQ ID NO: 10).Domvanalimab

[0045] Domvanalimab is also known as AB 154 or GS-0154. Domvanalimab is a humanized IgGl monoclonal antibody that targets T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine -based inhibitory motif domains (TIGIT), which functions as an immune checkpoint. Domvanalimab comprises 2 heavy chains of the IgGl isotype and 2 light chains of the kappa (K) subclass. The 4 chains are stabilized by multiple disulfide bonds, with a single glycosylation site (Asn299) located on the heavy chain. The fragment crystallizable (Fc)Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO domain sequence of the heavy chain contains 2 amino acid mutations to silence the effector function.

[0046] Domvanalimab comprises a CDRH1 comprising the amino acid sequence of NFGMH (SEQ ID NO. 11), a CDRH2 comprising the amino acid sequence of FISSGSSSIYYADTVKG (SEQ ID NO: 12), a CDRH3 comprising the amino acid sequence of MRLDYYAMDY (SEQ ID NO: 13), a CDRL1 comprising the amino acid sequence of RASKSISKYLA (SEQ ID NO: 14), a CDRL2 comprising the amino acid sequence of SGSTLQS (SEQ ID NO: 15), and a CDRL3 comprising the amino acid sequence of QQHNEYPWT (SEQ ID NO: 16).

[0047] Domvanalimab comprises a variable heavy chain (VH) domain comprising the amino acid sequence of:EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAF1SSGSSS1Y YADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMV TVSS (SEQ ID NO: 17) and a variable light chain (VL) domain comprising the amino acid sequence of:DIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIK (SEQ ID NO: 18).

[0048] The mature gamma heavy chain amino acid sequence of domvanalimab is:EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAFISSGSSSIY YADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPE AAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 19);Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO and the mature kappa light chain amino acid sequence of domvanalimab is:DIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 20).Carboplatin

[0049] Carboplatin is an anticancer platinum coordination compound that produces intrastrand DNA crosslinks. Carboplatin is indicated for the treatment of solid tumors, including first-line advanced head and neck squamous cell carcinoma (HNSCC). Use of carboplatin may decrease risk for several of the AEs associated with cisplatin, including renal toxicity, ototoxicity, and peripheral neuropathy, but has a greater degree of myelotoxicity, especially thrombocytopenia.Paclitaxel

[0050] Paclitaxel is a natural product (obtained via a semisynthetic process from the Pacific yew tree [Taxus brevifolia]) with antitumor activity. It promotes the assembly and stabilization of microtubules, while inhibiting their depolymerization, and thus results in mitosis inhibition and cell death. Common side effects include nausea and vomiting, loss of appetite, neutropenia, alopecia, anemia, arthralgia / myalgia, diarrhea, leukopenia, opportunistic infections, peripheral neuropathy, thrombocytopenia, mucositis, hypersensitivity, renal impairment, and hypotension. Dexamethasone may be administered prior to paclitaxel infusion to mitigate some of the side effects.Treatment Methods and Uses

[0051] Provided herein is use of zimberelimab in combination with domvanalimab to treat cancer.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0052] ‘ ‘Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0053] “ Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0054] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human. The terms “patient” or “subject” may be used interchangeably to refer to a human.10055] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition of cancer. The therapeutically effective amount may vary depending on the subject, and disease or conditionAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art.

[0056] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine the optimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0057] The combinations disclosed herein are useful for the treatment of a cancer. In further embodiments, the methods are provided for treating a cancer.

[0058] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC), breast cancer, colorectal cancer (CRC), melanoma, bladder cancer, ovarian cancer, endometrial cancer, Merkel Cell, or gastroesophageal cancer.

[0059] In some embodiments, the cancer is head and neck squamous cell carcinoma (HNSCC). In some embodiments, a patient in need of the treatments, prophylaxis, or methods describedAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO herein may be a human subject with head and neck squamous cell carcinoma (HNSCC). In some embodiments, the HNSCC is recurrent / metastatic (r / m) HNSCC. In some embodiments, the HNSCC is histologically or cytologically confirmed r / m squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies.

[0060] In some embodiments, the HNSCC may be PD-L1 positive and / or the patient has PD- L1 expression. In some embodiments, the HNSCC may be PD-L1 positive and / or the patient has PD-L1 expression as measured by a clinically validated PD-L1 IHC assay or other FDA- approved tests, such as 22C3 pharmDx assay (Dako), 28-8 pharmDx assay (Dako), 73-10 pharmDx assay (Dako), SP263 assay (Ventana), or SP142 assay (Ventana). In some embodiments, the HNSCC tumor of the patient has Tumor Area Positivity (TAP) of > 1%, > 2%, > 3%, > 5%, > 10%, > 15%, > 20%, > 30%, or > 50%, as measured by a SP263 assay or other FDA-approved tests (i.e., 22C3 pharmDx, 28-8 pharmDx, or SP142 assay). A HNSCC tumor of the patient may have a combined positive score (CPS) of > 1, > 2, > 3, > 5, > 10, > 15, > 20, > 30, or > 50 as measured by as measured by a SP263 assay, a clinically validated PD-L1 IHC assay, or other FDA-approved PD-L1 IHC assay or test. In some embodiments, a HNSCC tumor of the patient has a tumor proportion score (TPS) of > 1%, > 2%, > 3%, > 5%, > 10%, > 15%, > 20%, > 30%, or > 50%, as measured by a SP263 assay, a clinically validated PD-L1 IHC assay, or other FDA-approved PD-L1 IHC assay or test. In some embodiments, a HNSCC tumor has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or more, about 2% or more, about 3% or more, about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 30% or more, or about 50% or more of the tumor sample by area, as measured by a SP263 assay or other FDA-approved tests (i.e., 22C3 pharmDx, 28-8 pharmDx, or SP142 assay). In some embodiments, a HNSCC tumor has a detectable expression level of PD-L1 in about 1% or more, about 2% or more, about 3% or more, about 5% or more, about 10% or more, about 15% or more, about 20% or more, about 30% or more, or about 50% or more of the tumor sample, as measured by a SP263 assay or other FDA-approved tests (i.e., 22C3 pharmDx, 28-8 pharmDx, or SP142 assay).Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0061] In some embodiments, a HNSCC tumor of the patient may have Tumor Area Positivity (TAP) of < 1%, < 2%, < 3%, < 5%, <10%, < 15%, < 20%, < 30%, < 50%, as measured by a SP263 assay, a clinically validated PD-L1 IHC assay, or other FDA-approved PD-L1 IHC assay or test. A HNSCC tumor of the patient may have a combined positive score (CPS) of < 1, < 2, < 3, < 5, < 10, < 20, < 30, or < 50„ as measured by a SP263 assay, a clinically validated PD-L1 IHC assay, or other FDA-approved PD-L1 IHC assay or test. In some embodiments, a HNSCC tumor of the patient has a tumor proportion score (TPS) of < 1%, < 2%, < 3%, < 5%, <10%, < 15%, < 20%, < 30%, < 50%, as measured by as measured by a SP263 assay, a clinically validated PD-L1 IHC assay, or other FDA-approved PD-L1 IHC assay or test. In some embodiments, a HNSCC tumor has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise about 1% or less, about 2% or less, about 3% or less, about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 30% or less, or about 50% or less of the tumor sample by area of the tumor sample by area, as measured by a SP263 assay or other FDA-approved tests (i.e., 22C3 pharmDx, 28-8 pharmDx, or SP142 assay). In some embodiments, a HNSCC tumor has a detectable expression level of PD-L1 in about 1% or less, about 2% or less, about 3% or less, about 5% or less, about 10% or less, about 15% or less, about 20% or less, about 30% or less, or about 50% or less of the tumor sample, as measured by a SP263 assay or other FDA-approved tests (i.e., 22C3 pharmDx, 28-8 pharmDx, or SP142 assay).

[0062] In some embodiments, the cancer may be tumor mutational burden-high (TMB-H; >10 mutations / megabase (mut / Mb), as determined by an FDA-approved test). The cancer may or may not have a genomic mutation for which a targeted therapy has received marketing approval by a regulatory authority, non-limiting examples of genes with such mutation include ALK fusion oncogene, EGFR, ROS, BRAF, and NTRK. In the foregoing embodiments, the cancer may be positive or overexpressing or down-regulating a biomarker selected from the group consisting of CD73, DNAM-1, PVR, TIGIT, and CD8-Ki67, or any combination thereof.

[0063] In some embodiments, the cancer may be human papillomavirus (HPV) negative and / or pl6 negative. The tumor HPV status may be determined by tumor pl6 status assay. Tumor pl6 status is known to be indicative of tumor HPV status, and tumor pl6 status may be evaluatedAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO locally by IHC analysis with CINtec Histology (p 16) assay (Ventana). The local results of HPV status by PCR and ISH may be also acceptable. In some embodiments, the cancer is oropharyngeal cancer and HPV pl6 negative. In some embodiments, HNSCC which is not an oropharyngeal cancer may be considered HPV pl6 negative.

[0064] In some embodiments, the patients may have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. In some embodiments, the patients may have Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0065] In some embodiments, the patients may have adequate organ function. In some embodiments, the patients may have adequate hematologic counts without transfusional or growth factor support within 2 weeks of study drug initiation. For example, the patients may have hemoglobin greater than or equal to about 5, 6, 7, 8, 9, 10, 11, or 12 g / dL. The patients may have ANC (absolute neutrophil count) greater than or equal to 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 / mm3. The patients may have platelets level greater than or equal to 80,000, 90,000, 100,000, 110,000, or 120,000 / pL.

[0066] In some embodiments, the patients may have adequate hepatic function. Specifically, the patients may have total bilirubin less than or equal to 1.5 ULN (upper limit of normal), 2 ULN, 2.5 ULN, or 3 ULN. The bilirubin may be primarily unconjugated if subject has a documented history of Gilbert’s syndrome or a genetic equivalent. The patient may have AST (aspartate aminotransferase) less than or equal to 1.5 ULN (upper limit of normal), 2 ULN, 2.5 ULN, 3 ULN, 3.5 ULM, 4 ULN, 4.5 ULN, or 5 ULN. The patient have ALT (alanine aminotransferase) less than or equal to 1.5 ULN (upper limit of normal), 2 ULN, 2.5 ULN, 3 ULN, 3.5 ULM, 4 ULN, 4.5 ULN, or 5 ULN. If the patient has known liver metastases, the AST and / or ALT may be less than or equal to 5 ULN.

[0067] In some embodiments, the patients have normal creatine clearance. Lor example, the patients may have creatinine clearance of greater than or equal to 35 mL / min, 40 mL / min, 45 mL / min, 50 mL / min, or 55 ml / min, for example as assessed by the Cockcroft-Gault method.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0068] In some embodiments, the patients may not have cancers other than HNSCC. In some embodiments, the patient may not have nasopharyngeal cancer (any histology), or squamous cell carcinoma of unknown primary tumors at skin (cutaneous squamous cell carcinoma), paranasal sinuses, and salivary gland.

[0069] In some embodiments, the patients may not have other disease that may interfere with the treatment provided herein. For example, the patients may not have disease that is suitable for any local therapies with curative intent. In some embodiments, the patients may not have a history of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. In some embodiments, the patients may not have an active autoimmune disease that required systemic treatment in the past 2 years, (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) may not be considered a form of systemic treatment. The patients may have not received major surgery for any cause or significant traumatic injury within 4 weeks prior to the first dose of study drug. The patients may have recovered adequately from the toxicity and / or complications from the intervention prior to starting study drug.

[0070] The patients may not have received any anticancer therapy (chemotherapy, biologic therapy, targeted therapy, hormone therapy, or immunotherapy, etc.) other than the therapy provided herein (e.g., combination of zimberelimab and domvanalimab), within 4 weeks prior to the first dose of the therapy provided herein (e.g., combination of zimberelimab and domvanalimab). Concurrent use of drugs for noncancer related condition (e.g., hormone replacement therapy) is acceptable. The patients may have not been administered any drugs not marketed for any indication within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of the therapy provided herein. The patients may have not received radiation therapy within 2 weeks prior to the first dose of the therapy provided herein (e.g., combination of zimberelimab and domvanalimab). The patients must have recovered to Grade < 1 from all radiation-related toxicides, not requiring corticosteroid, and have not experienced radiation pneumonitis.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0071] In some embodiments, the patients may have not received prior treatment with any anti- PD-1 / PD-L1, anti-TIGIT, or other immune checkpoint inhibitors. The patients may not be currently receiving chronic systemic steroids (e.g., > 10 mg / day prednisone or its equivalent). The patients may use topical, inhalational, intranasal, intraocular steroids, and use as premedication for hypersensitivity reactions (e.g., IV contrast allergy). In some embodiments, the patients may not show any unresolved toxicity (Grade 2) per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 from prior anticancer therapy or surgical intervention, with the exception of alopecia, vitiligo, and the laboratory toxicities if the laboratory thresholds defined in the inclusion criteria are met. In some embodiments, the patients may have Grade 2 neuropathy.

[0072] In some embodiments, the subjects may not have shown an active second malignancy or have had an active second malignancy within 3 years prior to enrollment. The patients with a history of malignancy that has been completely treated, with no evidence of active cancer for at least 3 years prior to enrollment, or with surgically cured tumors with low risk of recurrence (e.g., nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) may receive the treatment provided herein (e.g., combination of zimberelimab and domvanalimab).

[0073] In some embodiments, the patients may not have known active central nervous system (CNS) metastases. Patients with previously treated brain metastases may receive the treatment provided herein, provided they have stable CNS disease for at least 4 weeks prior to enrollment and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastasis and are not requiring use of steroid for at least 14 days prior to the first dose of study drugs.

[0074] Measures for determining efficacy of treatment of the cancer (e.g., HNSCC) have been described and include, for example, the following: computed tomography (CT) or MRI scans with IV contrast of the head, neck, chest, abdomen, pelvis, and any other involved disease sites.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOImprovements in any of the foregoing response criteria are specifically provided by the methods of the present disclosure.Combination Therapies

[0075] Provided herein is use of zimberelimab in combination with domvanalimab for treating a cancer (e.g., HNSCC).

[0076] HNSCC tumors have been reported to have immune infiltrates which fail to mount productive immune responses due to suppressive mechanisms within the tumor microenvironment. Chronic exposure to antigen drives development of a hypo-responsive T cell state termed “exhaustion” which is characterized by transcriptional, epigenetic, and metabolic reprograming and increased expression of inhibitory receptors such as PD-1, TIGIT, CTLA4, LAG3, and TIM-3. The T cell exhaustion program encompasses T cells across various states ranging from pre-dysfunctional to terminally exhausted (Ttex). The progenitor exhausted CD8+subset (Tpex) has self-renewal capacity and sustains effector and exhausted T cell differentiation. PD-1 / PD-L1 blockade mobilizes the Tpexsubset to proliferate and differentiate into T cells with anti-tumor effector potential.

[0077] Blockade of the PD-1 / PD-L1 axis has demonstrated clinical benefit in a subset of HNSCC patients which necessitates the search for additional combination partners to improve responses. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) is an inhibitory receptor expressed primarily on NK and T cell subsets that negatively regulates immune responses by outcompeting the co-stimulatory receptor, CD226, for a shared ligand, CD155. PD-1 can also regulate this axis by dephosphorylating the intracellular- domain of CD226. Because both TIGIT and PD-1 can restrain T cell responses via suppression of CD226, T cells co-expressing both inhibitory receptors may require co-blockade for superior therapeutic benefit. Further, blockade of PD-1 and TIGIT may induce maximal effector cell functionality through CD226 activation on target cells that co-express all three receptors, particularly pre-exhausted or pre-dysfunctional T cells (TPEX).Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0078] As shown in Examples, inventors of the present disclosure have discovered that TIGIT, CD226, and PD-1 are co-expressed in human HNSCC tumor infiltrating leukocytes including TpeXand TtexCD8+T cell subsets, and thus co-blockade of TIGIT (e.g., with domvanalimab) and PD-1 (e.g., with zimberelimab) can provide superior therapeutic benefit.

[0079] In some embodiments, zimberelimab and domvanalimab may be administered with one or more additional therapy. The additional therapy can be a therapeutic agent or another treatment modality. The additional therapeutic agents can be small chemical molecules; macromolecules such as proteins, antibodies, peptibodies, peptides, DNA, RNA or fragments of such macromolecules; or cellular or gene therapies. Non-limiting examples of additional treatment modalities include surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. In some embodiments, the additional therapy may be one or more chemotherapeutic agents (i.e., chemotherapy). For example, a therapeutically effective amount of zimberelimab, a therapeutically effective amount of domvanalimab, and one or more chemotherapeutic agents or chemotherapy may be administered to treat a cancer (e.g., HNSCC).

[0080] In some embodiments, the one or more chemotherapeutic agents may include one or more platinum-based chemotherapeutic agents. In some embodiments, the one or more chemotherapeutic agents may include one platinum-based chemotherapeutic agent and another chemotherapeutic agent, which may not be platinum-based. In some embodiments, the chemotherapy is platinum-based doublet chemotherapy, and the one or more chemotherapeutic agents may include one platinum-based chemotherapeutic agent (e.g., cisplatin, carboplatin, and nedaplatin) and one of the third-generation chemotherapeutic agents (e.g., paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan). For example, said additional therapy may be a combination of carboplatin and paclitaxel, and carboplatin and paclitaxel may be used in combination with zimberelimab and domvanalimab.

[0081] Further examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa;Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiopho sphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2’, 2” -trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin, carboplatin and oxaliplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorclbinc; navclbinc; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomeraseAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylomithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above. In one embodiment, combination therapy comprises a chemotherapeutic regimen comprising FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (folinic acid, fluorouracil, and irinotecan), a taxane (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), CAPOX (capecitabine and oxaliplatin), XELOX (capecitabine and oxaliplatin), irinotecan, a fluoropyrimidine-containing chemotherapy (e.g., fluorouracil, capecitabine, floxuridine), a platinum-based chemotherapeutic agent, or gemcitabine.Kits

[0082] Provided herein are also kits that include zimberelimab and / or domvanalimab, additional chemotherapy, and suitable packaging. In one embodiment, a kit further includes instructions for use.

[0083] Provided herein arc also articles of manufacture that include zimberelimab and / or domvanalimab. The container may be a vial, jar, ampoule, preloaded syringe, and intravenous bag.Pharmaceutical Compositions and Modes of Administration

[0084] Compounds and antibodies provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that contain one or more of the compounds and antibodies described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences,Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOMace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0085] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0086] In embodiments comprising one or more additional therapeutic agents, the therapeutic agent(s) used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times. Furthermore, the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and / or resumed during a patient’s course of therapy. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0087] In some embodiments, zimberelimab may be formulated as a solution, for example in a buffer solution (e.g., histidine / histidine-HCl buffer). The composition may include one or more excipients, such as sucrose, sodium chloride, and / or polysorbate 80. The concentration of zimberelimab may be between about 5 mg / mL and 100 mg / mL, between 5 mg / mL and 50 mg / mL, between 10 mg / mL and 50 mg / mL, or between 20 mg / mL and 40 mg / mL. The concentration of zimberelimab may be about 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, or 50 mg / mL. The composition may have pH at 5.0, 5.5, or 6.0. In some embodiments, zimberelimab may be formulated at 30 mg / mL in a histidine / histidine-HCl buffer solution (pHAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO5.5), further containing sucrose, sodium chloride, and polysorbate 80. The composition may be contained in a glass vial or an IV bag. Zimberelimab may be administered by intravenous (IV) infusion.

[0088] In some embodiments, domvanalimab is formulated as a solution, for example in a buffer solution (e.g., histidine / histidine-HCl buffer). The composition may include one or more excipients, such as sucrose, sodium chloride, and / or polysorbate 80. The concentration of domvanalimab may be between about 5 mg / mL and about 200 mg / mL, between about 10 mg / mL and about 200 mg / mL, between about 20 mg / mL and about 150 mg / mL, or between about 30 mg / mL and about 100 mg / mL. The concentration of domvanalimab may be about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, or about 100 mg / mL. In some embodiments, the domvanalimab may be formulated in 20mM histidine / histidine-HCl buffer solution (pH 5.8), further containing sucrose and polysorbate 80. The composition may be contained in a glass vial or an IV bag. Domvanalimab may be administered by intravenous (IV) infusion.

[0089] In some embodiments, zimberelimab and domvanalimab may be administered separately. For example, zimberelimab may be administered first, and then domvanalimab may be administered. Or domvanalimab may be administered first, and then zimberelimab may be administered. In some embodiments, there may be some time period or break between administration of zimberelimab and domvanalimab. For example, there may be a break or interval for about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, or about 60 minutes between administration of zimberelimab and administration of domvanalimab.

[0090] In some embodiments, zimberelimab and domvanalimab may be administered simultaneously. In some embodiments, zimberelimab and domvanalimab may be contained together in a composition, and the composition may be administered.

[0091] As described herein, additional anti-cancer therapy (e.g., chemotherapy) may be administered in addition to zimberelimab. In some embodiments, said additional chemotherapy or chemotherapeutic agent may be administered separately from zimberelimab and / orAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO domvanalimab. For example, the additional chemotherapy or chemotherapeutic agent may be administered after zimberelimab and / or domvanalimab. In some embodiments, the additional chemotherapy or chemotherapeutic agent may be administered after an interval or break after administration of zimberelimab and / or domvanalimab. For example, zimberelimab may be administered first, subsequently domvanalimab may be administered about 30 minutes after zimberelimab administration is finished, and then the additional chemotherapy or chemotherapeutic agent is administered about 30 minutes after domvanalimab is administered. In another example, domvanalimab may be administered first, subsequently zimberelimab may be administered about 30 minutes after domvanalimab administration is finished, and then the additional chemotherapy or chemotherapeutic agent is administered about 30 minutes after zimberelimab is administered.

[0092] In some embodiments, the additional chemotherapy or chemotherapeutic agent may be paclitaxel and carboplatin. In some embodiments, paclitaxel may be administered before carboplatin.Dosing

[0093] The specific dose level of zimberelimab and domvanalimab of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy.

[0094] For example, when zimberelimab is administered to human patients intravenously, the dose of zimberelimab can be selected from within the range of 0.01 to 100 mg / kg body weight, preferably 0.05 to 100 mg / kg body weight, or more preferably 0.1 to 100 mg / kg. In some embodiments, zimberelimab is administered at a dose of, for example, about 0.01 to about 50 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to 50 mg / kg, about 0.3 mg / kg to about 40 mg / kg, about 0.3 mg / kg to 30 mg / kg,Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO about 0.3 mg / kg to about 20 mg / kg, about 0.4 mg / kg to 50 mg / kg, about 0.4 mg / kg to about 40 mg / kg, about 0.4 mg / kg to 30 mg / kg, about 0.4 mg / kg to about 20 mg / kg, about 0.5 mg / kg to 50 mg / kg, about 0.5 mg / kg to about 40 mg / kg, about 0.5 mg / kg to 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg body weight of zimberelimab. In preferred embodiments, zimberelimab may be administered at a dose in the range of 0.1 mg / kg to 30 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 10 mg / kg, 1.0 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 10 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg. Accordingly, the administered dose may be 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / lg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg or any dose in between the foregoing doses. In particular embodiments, the effective amount of zimberelimab or a fragment or variant thereof is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, about 10.0 mg / kg, about 15.0 mg / kg, or about 20.0 mg / kg. For the purposes of the forgoing doses, these amounts may be administered as appropriate, such as weekly, once every other week (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, for example, zimberelimab may be administered at a dose of 3 mg / kg Q2W, Q3W, or Q4W. In some embodiments, zimberelimab may be administered at a dose of 5 mg / kg Q2W, Q3W, or Q4W. In some embodiments, zimberelimab may be administered at a dose of 10 mg / kg Q2W, Q3W, or Q4W.[00951 In some embodiments, a dose of zimberelimab can be selected irrespective of a subject’s body weight. For example, in some embodiments, a dose of zimberelimab can be selected from within the range of 100 mg to 1000 mg of zimberelimab, irrespective of a subject’s body weight. In some embodiments, a dose of zimberelimab can be selected from within the range of 200 mg to 800 mg. In some embodiments, a dose of zimberelimab can be selected from within the range of 200 mg to 700 mg, or 200 mg to 600 mg. In some embodiments, a dose of zimberelimab can be selected from within the range of 200 mg to 500 mg. In some embodiments, a dose of zimberelimab can be selected from within the range of 100 mg to 500 mg. In some embodiments, the dose of zimberelimab may be about 200 mg, about 220 mg, about 240 mg,Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO about 260 mg, about 280 mg, about 300 mg, about 320 mg, about 340 mg, about 360 mg, about 380 mg, about 400 mg, about 420 mg, about 440 mg, about 460 mg, about 480 mg, about 500 mg, about 520 mg, about 540 mg, about 560 mg, about 580 mg, or about 600 mg.

[0096] For the purposes of any of the foregoing methods of treatment, a dose cycle may comprise, for example, dosing twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. Subjects may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more dosing cycles. For example, a subject may be administered a plurality of dosing cycles until a suitable clinical endpoint is reached, for example disease progression, remission, or other clinical endpoint suitable based on the subject’s cancer or intolerance.

[0097] In particular embodiments, a dose cycle may comprise about 3 mg / kg to about 20 mg / kg of zimberelimab administered Q2W (once every 2 weeks), Q3W (once every 3 weeks) or Q4W (once every 4 weeks). In a specific example, a dose cycle may comprise about 3 to 10 mg / kg of zimberelimab administered Q2W. In another specific example, a dose cycle may comprise about 5 to 7 mg / kg of zimberelimab administered Q2W. In another specific example, a dose cycle may comprise about 3 to 10 mg / kg of zimberelimab administered Q3W. In another specific example, a dose cycle may comprise about 5 to 7 mg / kg of zimberelimab administered Q3W. In some embodiments, a dose cycle may comprise about 100 mg to about 1000 mg of zimberelimab administered Q2W, Q3W, or Q4W. In some embodiments, a dose cycle may comprise about 100 mg to about 800 mg of zimberelimab administered Q2W, Q3W, or Q4W. In some embodiments, a dose cycle may comprise about 200 mg to about 800 mg of zimberelimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 200 mg to about 600 mg of zimberelimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 200 mg to about 400 mg of zimberelimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 300 mg to about 400 mg of zimberelimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 300 mg to about 400 mg of zimberelimab administered Q2W. In a specific example, a dose cycle may comprise about 300 mg to about 400 mg of zimberelimabAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO administered Q3W. In a specific example, a dose cycle may comprise about 300 mg to about 400 mg of zimberelimab administered Q4W. In a specific example, a dose cycle may comprise about 240 mg of zimberelimab administered Q2W. In another specific example, a dose cycle may comprise about 360 mg of zimberelimab administered Q2W. In a specific example, a dose cycle may comprise about 720 mg of zimberelimab administered Q2W. In another specific example, a dose cycle may comprise about 360 mg of zimberelimab administered Q3W. In another specific example, a dose cycle may comprise about 450 mg of zimberelimab administered Q3W. In another specific example, a dose cycle may comprise about 720 mg of zimberelimab administered Q3W. In another specific example, a dose cycle may comprise about 360 mg of zimberelimab administered Q4W. In another specific example, a dose cycle may comprise about 720 mg of zimberelimab administered Q4W. In one or more of the foregoing embodiments, the zimberelimab may be administered intravenously, for example by an IV infusion.

[0098] In one or more of the foregoing embodiments, the zimberelimab may be administered intravenously, for example by an IV infusion, over about 20 minutes to about 60 minutes, about 20 minutes to about 45 minutes, or about 25 minutes to about 45 minutes. In one or more of the foregoing embodiments, the zimberelimab may be administered intravenously, for example by an IV infusion, over about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 minutes. In one or more of the foregoing embodiments, the zimberelimab may be administered intravenously, for example by an IV infusion, over about 30 minutes.

[0099] In some embodiments, when domvanalimab is administered to human patients intravenously, the dose of domvanalimab can be selected from within the range of 0.01 to 100 mg / kg body weight, preferably 0.05 to 100 mg / kg body weight, or more preferably 0.1 to 100 mg / kg. In some embodiments, domvanalimab is administered at a dose of, for example, about 0.01 to about 50 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to 50 mg / kg, about 0.3 mg / kg to about 40 mg / kg, about 0.3 mg / kg to 30 mg / kg, about 0.3 mg / kg to about 20 mg / kg, about 0.4 mg / kg to 50 mg / kg, about 0.4 mg / kg to about 40 mg / kg, about 0.4 mg / kg to 30 mg / kg, about 0.4 mg / kg to about 20 mg / kg,Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO about 0.5 mg / kg to 50 mg / kg, about 0.5 mg / kg to about 40 mg / kg, about 0.5 mg / kg to 30 mg / kg, about 0.5 mg / kg to about 20 mg / kg body weight of domvanalimab. In preferred embodiments, domvanalimab may be administered at a dose in the range of 0.1 mg / kg to 30 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 10 mg / kg, 1.0 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 10 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg. Accordingly, the administered dose may be 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / lg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg or any dose in between the foregoing doses. In particular embodiments, the effective amount of domvanalimab is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 5.0 mg / kg, about 10.0 mg / kg, about 15.0 mg / kg, or about 20.0 mg / kg. For the purposes of the forgoing doses, these amounts may be administered as appropriate, such as weekly, once every other week (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, for example, domvanalimab may be administered at a dose of 10 mg / kg Q2W, Q3W, or Q4W. In some embodiments, domvanalimab may be administered at a dose of 15 mg / kg Q2W, Q3W, or Q4W. In some embodiments, domvanalimab may be administered at a dose of 20 mg / kg Q2W, Q3W, or Q4W.

[0100] In some embodiments, a dose of domvanalimab can be selected irrespective of a subject’s body weight. For example, in some embodiments, a dose of domvanalimab can be selected from within the range of 500 mg to 2000 mg of domvanalimab, irrespective of a subject’s body weight. In some embodiments, a dose of domvanalimab can be selected from within the range of 700 mg to 1800 mg. In some embodiments, a dose of domvanalimab can be selected from within the range of 700 mg to 1500 mg, or 700 mg to 1400 mg. In some embodiments, a dose of domvanalimab can be selected from within the range of 1000 mg to 1500 mg. In some embodiments, a dose of domvanalimab can be selected from within the range of 1200 mg to 1500 mg. In some embodiments, the dose of domvanalimab may be about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, or about 1800 mg.

[0101] For the purposes of any of the foregoing methods of treatment, a dose cycle may comprise, for example, dosing twice a week, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. Subjects may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more dosing cycles. For example, a subject may be administered a plurality of dosing cycles until a suitable clinical endpoint is reached, for example disease progression, remission, or other clinical endpoint suitable based on the subject’s cancer or intolerance.

[0102] In particular embodiments, a dose cycle may comprise about 10 mg / kg to about 20 mg / kg of domvanalimab administered Q2W, Q3W or Q4W. In a specific example, a dose cycle may comprise about 10 mg / kg of domvanalimab administered Q2W. In another specific example, a dose cycle may comprise about 15 mg / kg of domvanalimab administered Q2W. In another specific example, a dose cycle may comprise about 15 mg / kg of domvanalimab administered Q3W. In another specific example, a dose cycle may comprise about 20 mg / kg of domvanalimab administered Q3W. In another specific example, a dose cycle may comprise about 20 mg / kg of domvanalimab administered Q4W. In some embodiments, a dose cycle may comprise about 500 mg to about 2000 mg of domvanalimab administered Q2W, Q3W, or Q4W. In some embodiments, a dose cycle may comprise about 600 mg to about 1600 mg of domvanalimab administered Q2W, Q3W, or Q4W. In some embodiments, a dose cycle may comprise about 1000 mg to about 1500 mg of domvanalimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 600 mg to about 800 mg of domvanalimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle mayAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO comprise about 900 mg to about 1200 mg, about 1100 mg to about 1300 mg, or about 1000 mg to about 1400 mg of domvanalimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 1200 mg to about 1600 mg of domvanalimab administered Q2W, Q3W, or Q4W. In a specific example, a dose cycle may comprise about 600 mg to about 800 mg of domvanalimab administered Q2W. In a specific example, a dose cycle may comprise about 900 mg to about 1200 mg of domvanalimab administered Q3W. In a specific example, a dose cycle may comprise about 1000 mg to about 1400 mg of domvanalimab administered Q3W. In a specific example, a dose cycle may comprise about 1100 mg to about 1300 mg of domvanalimab administered Q3W. In a specific example, a dose cycle may comprise about 1200 mg to about 1600 mg of domvanalimab administered Q4W. In a specific example, a dose cycle may comprise about 1000 mg of domvanalimab administered Q2W. In another specific example, a dose cycle may comprise about 1200 mg of domvanalimab administered Q2W. In another specific example, a dose cycle may comprise about 1200 mg of domvanalimab administered Q3W. In another specific example, a dose cycle may comprise about 1500 mg of domvanalimab administered Q3W. In another specific example, a dose cycle may comprise about 1500 mg of domvanalimab administered Q4W. In one or more of the foregoing embodiments, domvanalimab may be administered intravenously, for example by an IV infusion.

[0103] In one or more of the foregoing embodiments, the domvanalimab may be administered intravenously, for example by an IV infusion, over about 20 minutes to about 60 minutes, about 20 minutes to about 45 minutes, or about 25 minutes to about 45 minutes. In one or more of the foregoing embodiments, the domvanalimab may be administered intravenously, for example by an IV infusion, over about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 minutes. In one or more of the foregoing embodiments, the domvanalimab may be administered intravenously, for example by an IV infusion, over about 30 minutes.

[0104] For a combination of domvanalimab and zimberelimab, any appropriate dose of each of domvanalimab and zimberelimab may be chosen from doses described herein. For example, about 300 mg to about 400 mg of zimberelimab Q3W and about 1000 mg to about 1400 mg of domvanalimab Q3W; about 300 mg to about 400 mg of zimberelimab Q3W and about 1100 mgAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO to about 1300 mg of domvanalimab Q3W; about 350 mg to about 400 mg of zimberelimab Q3W and about 1000 mg to about 1400 mg domvanalimab Q3W; or about 350 mg to about 400 mg of zimberelimab Q3W and about 1100 mg to about 1300 mg of domvanalimab Q3W may be administered. In some embodiments, about 360 mg of zimberelimab Q3W and about 1200 mg of domvanalimab Q3W may be administered.

[0105] In some embodiments, The combination of zimberelimab and domvanalimab may be administered for a prolonged period. For example, zimberelimab and domvanalimab may be administered once in a 3 week cycle (Q3W), and zimberelimab and domvanalimab may be administered for up to 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 cycles. In some embodiments, zimberelimab and domvanalimab may be administered for 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 cycles or more. In some embodiments, zimberelimab and domvanalimab may be administered for up to 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 52, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 1 11 , 1 14, 117, or 120 weeks. In some embodiments, zimberelimab and domvanalimab may be administered for 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 52, 54, 57, 60, 63, 66, 69, 72, 75, 78, 81, 84, 87, 90, 93, 96, 99, 102, 105, 108, 111, 114, 117, or 120 weeks or more.

[0106] In some embodiments, the additional chemotherapy or chemotherapeutic agent may be paclitaxel and carboplatin. Any appropriate dose for paclitaxel and carboplatin may be administered. For example, about 100 mg / m2to about 300 mg / m2, about 120 mg / m2to about 200 mg / m2, about 150 mg / m2to about 200 mg / m2Q3W of paclitaxel may be administered intravenously. In some embodiments, about 150 mg / m2, about 155 mg / m2, about 165 mg / m2, about 170 mg / m2, about 175 mg / m2, about 180 mg / m2, about 185 mg / m2, about 190 mg / m2, about 195 mg / m2, or about 200 mg / m2Q3W of paclitaxel may be administered. In some embodiments, about 175 mg / m2Q3W of paclitaxel may be administered. Each dose of paclitaxel may be administered over about 3, about 4, about 5, about 6, about 7, about 8, or about 9 hours.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0107] In some embodiments, about AUC 4, 5, or 6 of carboplatin, which may be calculated under Calvert formula, may be administered once every three weeks (Q3W). Each dose of carboplatin may be administered over 15 to 60 minutes, for example about 15, about 30, about 45, or about 60 minutes.

[0108] In some embodiments, about 175 mg / m2of paclitaxel and about AUC 5 of carboplatin may be administered Q3W.

[0109] In some embodiments, the additional chemotherapy or chemotherapeutic agent (e.g., paclitaxel and carboplatin) may be administered for a prolonged period. For example, paclitaxel and carboplatin may be administered once in a 3 week cycle (Q3W), and paclitaxel and carboplatin may be administered for up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cycles. In some embodiments, paclitaxel and carboplatin may be administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 cycles. In some embodiments, paclitaxel and carboplatin may be administered for up to 3, 6, 9, 12, 15, 18, 21, 24, 27, or 30 weeks. In some embodiments, zimberelimab and domvanalimab may be administered for 3, 6, 9, 12, 15, 18, 21 , 24, 27, or 30 weeks or more.

[0110] In some embodiments, zimberelimab, domvanalimab, and the additional chemotherapy or chemotherapeutic agent are administered on the same day. For example, zimberelimab, domvanalimab, and the additional chemotherapy or chemotherapeutic agent (e.g., paclitaxel and carboplatin) may be administered on Day 1 of each of treatment cycle. In some embodiments, any one or more of zimberelimab, domvanalimab, and the additional chemotherapy or chemotherapeutic agent may be administered on a different day.

[0111] In some embodiments, for the treatment of HNSCC, about 1100 mg to about 1300 mg of domvanalimab, and about 350 mg to 400 mg of zimberelimab may be administered once every three weeks. In some embodiments, about 150 mg / m2to about 200 mg / m2of paclitaxel and about AUC 5 of carboplatin are also administered once every three weeks.

[0112] In some embodiments, for the treatment of HNSCC, about 1200 mg of domvanalimab, and about 360 mg of zimberelimab may be administered once every three weeks. In someAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO embodiments, about 175 mg / m2of paclitaxel and about AUC 5 of carboplatin are also administered once every three weeks.Embodiments

[0113] Embodiment 1. A method of treating Head and Neck Squamous Cell Carcinoma (HNSCC) in a subject in need thereof, comprising administering a therapeutically effective amount of zimberelimab, a therapeutically effective amount of domvanalimab, and one or more chemotherapeutic agents.

[0114] Embodiment 2. The method of Embodiment 1, wherein the HNSCC is recurrent / metastatic (r / m) HNSCC.

[0115] Embodiment 3. The method of Embodiment 1 or 2, wherein the HNSCC is histologically or cytologically confirmed r / m squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies.

[0116] Embodiment 4. The method of any one of Embodiments 1 to 3, wherein the HNSCC has programmed cell death ligand 1 (PD-L1) expression, and has VENTANA PD-L1 (SP263) immunohistochemistry (IHC) TAP score of 20% or greater.

[0117] Embodiment 5. The method of any one of Embodiments 1 to 4, wherein the HNSCC is HPV pl6 negative.

[0118] Embodiment 6. The method of any one of Embodiments 1 to 5, wherein zimberelimab and domvanalimab are administered separately.

[0119] Embodiment 7. The method of any one of Embodiments 1 to 6, wherein zimberelimab and domvanalimab are administered intravenously.

[0120] Embodiment 8. The method of any one of Embodiments 1 to 7, wherein domvanalimab is administered at a dose of about 1100 mg to about 1300 mg once every 3 weeks.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0121] Embodiment 9. The method of any one of Embodiments 1 to 8, wherein zimberelimab is administered at a dose of about 350 mg to about 400 mg once every 3 weeks.

[0122] Embodiment 10. The method of any one of Embodiments 1 to 9, wherein said one or more chemotherapeutic agents comprise a platinum-based chemotherapeutic agent.

[0123] Embodiment 11. The method of any one of Embodiments 1 to 10, wherein said one or more chemotherapeutic agents are one platinum-based chemotherapeutic agent and another chemotherapeutic agent.

[0124] Embodiment 12. The method of Embodiment 10 or 11, wherein the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, or nedaplatin.

[0125] Embodiment 13. The method of Embodiment 11 or 12, wherein said another chemotherapeutic agent is selected from paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan.

[0126] Embodiment 1 . The method of any one of Embodiments 1 to 13, further comprising administering a therapeutically effective amount of carboplatin and a therapeutically effective amount of paclitaxel.

[0127] Embodiment 15. The method of Embodiment 14, wherein paclitaxel is administered at a dose of about 175 mg / m2once every 3 weeks.

[0128] Embodiment 16. The method of Embodiment 14 or 15, wherein carboplatin is administered at a dose of about AUC 5 once every 3 weeks.

[0129] Embodiment 17. The method of any one of Embodiments 14 to 16, wherein zimberelimab, domvanalimab, carboplatin, and paclitaxel are administered on a same day.

[0130] Embodiment 18. The method of any one of Embodiments 1 to 17, wherein zimberelimab and domvanalimab are administered for up to 35 treatment cycles.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0131] Embodiment 19. The method of any one of Embodiments 14 to 18, wherein carboplatin and paclitaxel arc administered for up to 6 treatment cycles.

[0132] Embodiment 20. The method of any one of Embodiments 1 to 19, wherein the subject did not have prior systemic therapy for r / m HNSCC.

[0133] Embodiment 21. The method of any one of Embodiments 1 to 20, wherein the subject had had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum-containing therapy for locoregionally advanced disease.

[0134] Embodiment 22. The method of any one of Embodiments 1 to 21, wherein the subject does not have nasopharyngeal cancer or squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, or salivary gland.

[0135] Embodiment 23. A method of treating recurrent / metastatic (r / m) head and neck squamous cell carcinoma (HNSCC) in a subject in need thereof, comprising administering: zimbcrclimab at a dose of about 360 mg once per 3 weeks; domvanalimab at a dose of about 1200 mg once every 3 weeks; and a platinum-doublet chemotherapy.

[0136] Embodiment 24. The method of Embodiment 23, wherein the HNSCC is histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies.

[0137] Embodiment 25. The method of Embodiment 23 or 24, wherein the HNSCC has programmed cell death ligand 1 (PD-L1) expression, and has investigational VENTANA PD-L1 (SP263) immunohistochemistry (IHC) TAP score of 20% or greater.

[0138] Embodiment 26. The method of any one of Embodiments 23 to 25, wherein the platinum-doublet chemotherapy comprises carboplatin and paclitaxel.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0139] Embodiment 27. The method of any one of Embodiments 23 to 26, wherein the platinum-doublet chemotherapy comprises carboplatin about AUC 5 once every 3 weeks and paclitaxel at a dose of about 175 mg / m2once every 3 weeks.

[0140] Embodiment 28. The method of any one of Embodiments 23 to 27, wherein zimberelimab and domvanalimab are administered separately.

[0141] Embodiment 29. The method of any one of Embodiments 23 to 28, wherein zimberelimab and domvanalimab are administered intravenously.

[0142] Embodiment 30. The method of any one of Embodiments 23 to 29, wherein zimberelimab, domvanalimab, carboplatin, and paclitaxel are on a same day.

[0143] Embodiment 31. The method of any one of Embodiments 23 to 30, wherein the subject did not have prior systemic therapy for r / m HNSCC.

[0144] Embodiment 32. The method of any one of Embodiments 23 to 31, wherein the subject had had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum-containing therapy for locoregionally advanced disease.

[0145] Embodiment 33. The method of any one of Embodiments 23 to 32, wherein the subject does not have nasopharyngeal cancer, squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, and salivary gland.

[0146] Embodiment 34. The method of any one of Embodiments 23 to 33, wherein zimberelimab and domvanalimab are administered for up to 35 treatment cycles.

[0147] Embodiment 35. The method of any one of Embodiments 23 to 34, wherein the platinum-doublet chemotherapy is administered for up to 6 treatment cycles.

[0148] Embodiment 36. The method of any one of Embodiments 23 to 35, wherein the HNSCC is HPV pl6 negative.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOEXAMPLES

[0149] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the ail that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the ail should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.Example 1: Preclinical Study for Expression Profile of HNSCC tumor cells

[0150] To assess the expression of TIG IT, PD-1, and associated ligands on immune cell infiltrates in human HNSCC tumors, dissociated human HNSCC tumor biopsies were stained with fluorophore-conjugated antibodies specific for immune cell populations, CD226, TIGIT, CD 155, PD-1 , and PD-L1 . Receptor and ligand expression was evaluated by flow cytometric analysis using a LSRFortcssa X-20 for acquisition and FlowJo for analysis.

[0151] Dissociated human HNSCC tumor biopsy cells from seven patients were thawed and resuspended in DPBS containing Human Fc Block and LIVE / DEAD Fixable Aqua Dead dye. 50 pL of cells each was plated into 3 wells of a 96- well round bottom plate and incubated for 15- 20 minutes. Plating in triplicate was necessary to obtain a fully stained sample, a sample with extracellular' isotype controls, and a sample with intracellular isotype controls.

[0152] 50 pL of master-mix containing fluorophore-conjugated antibodies specific for extracellular surface receptors or extracellular isotype controls was added to the cells and incubated at 4 °C for 30 minutes. 100 pL FSB was added to the cells followed by centrifugating at 400 x g for 5 minutes at 4 °C followed by an additional wash using FSB. Washed cells were fixed / permeabilized by incubation with 100 pL Foxp3 Fixation / Permeabilization working solution at room temperature for 45 minutes. Fixed / permeabilized cells were washed twice using 100 pL lx permeabilization buffer and pelleted at 400 x g for 5 minutes at 4°C. Cells wereAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO blocked intracellularly for 15 minutes at room temperature with 50 pL of lx permeabilization buffer containing 20% each of normal serum. Samples interrogated for CD8 subsets were incubated with normal rabbit serum and normal mouse serum. Samples interrogated for broad immune lineages were incubated with normal rat serum.

[0153] Cells were stained intracellularly by incubation with 50 pL lx permeabilization buffer containing fluoro phore-conjugated antibodies or isotype controls for 30 minutes at 4 °C. Stained cells were washed twice with 100 pL lx permeabilization buffer followed by resuspension in 120 pL FSB. Compensation controls were prepared by staining UltraComp eBeads with 1 pL of fluorophore-conjugated antibody for 10 minutes at 4 °C followed by centrifugation at 400 x g for 5 minutes at 4 °C and final resuspension in FSB. Samples were acquired on an LSRFortessa-X20 and analyzed using FlowJo software.

[0154] FIG. 1 illustrates gating strategy for identifying cell populations in human HNSCC tumor infiltrating leukocytes (TIL) suspensions. As shown in FIG. 1, HNSCC samples from Subjects 1-3 were stained with a broad panel of lineage markers to assess the composition of the tumor. Cellular composition and expression of TIGIT, PD-1, CD226 and associated ligands was evaluated by flow cytometry in human HNSCC TIL suspensions.

[0155] FIG. 2A and Table 1 show frequency of CD4+TCOnv (CD4+FoxP3"), CD4+Treg (CD4+FoxP3+), CD8+T, CD3"CD19+B, CD3"CD56+NK, CD3+CD56+NKT, CD14+and / or CD16+monocyte, Lineage" Side Scatter111(SSChl) myeloid / macrophage, and CD45" cancer or stromal subsets in HNSCC TIL suspensions. The receptor ligand, CD155, was expressed on a larger proportion of myeloid cells (CD14+classical monocytes, CD14+CD16+intermediate monocytes, and the lineage negative SSChi subset) and CD45" cells whereas PD-L1 was more variably expressed across CD4 T cell, myeloid, and CD45" subsets.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOTable 1

[0156] As shown in FIG. 2A and Table 1, samples primarily consisted of T cell populations (CD4+ Tregs, conventional CD4+, and CD8+), monocytes, and a CD45- population (representing cancer and stromal cells) with B, NK, NKT, and SSChi myeloid / macrophage populations making up a minority of the fraction.

[0157] FIG. 2B illustrates frequency (circles, left y-axis) and geometric mean fluorescence intensity (gMFI) (triangles, right y-axis) of TIGIT, PD-1, and CD226 in CD4+TCOnv, Treg, and CD8+T subsets or NK cells. Frequency of TIGIT, PD-1, and CD226 in CD4+TCOnv, Treg, and CD8+T subsets or NK cells is shown in Table 2, and geometric mean fluorescence intensity (gMFI) of TIGIT, PD-1, and CD226 in CD4+Tconv, Treg, and CD8+T subsets or NK cells is shown in Table 3.Table 2Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOTable 3

[0158] FIG. 2C and Table 4 show frequency of PD-1+TIGIT+CD226+triple positive cells in CD4+TConv, Treg, and CD8+T subsets or NK cells.Table 4

[0159] As shown in FIG. 2B-2C and Table 4, TIGIT, PD-1, and CD226 were co-expressed on all three broad T cell populations (CD4+Treg, CD4+conventional, and CD8+) with the highest frequency of T1G1T+ cells being TregS. Whereas NK cells had a lower frequency of cells expressing either TIGIT, PD-1, or CD226 compared to the broad T cell populations and had no co-expression of all three receptors.

[0160] FIG. 2D and Tables 5-6 illustrate frequency (circles, left y-axis) and gMFI (triangles, right y-axis) of CD155 or PD-L1 in CD4+TCOnv (CD4+FoxP3 ), CD4+Treg(CD4+FoxP3+), CD8+T, CD3 CD19+B, CD3'CD56+NK, CD3+CD56+NKT, CD14+and / or CD16+monocyte, Lineage' Side Scatter111(SSChl) myeloid / macrophage, and CD45' cancer or stromal subsets.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOTable 5Table 6

[0161] Expression of TIGIT, PD-1, and CD226 (DNAM-1) on CD8+T cell Tpex / Ttexsubsets was evaluated by flow cytometry in human HNSCC TIL suspensions. CD8+ Tpexand Ttexsubsets were identified using antibodies specific for the transcription factor TCF- 1 or the inhibitory receptor TIM-3. Gating strategy for identification of Tpex- (TCF-1+TIM-3") and Ttex-containing (TCF-l"TIM-3+) populations in HNSCC TIL suspensions from Subjects 4-7 is shown in FIG. 3A. FIG. 3A shows a representative pseudocolor plot of these two populations in the CD8+T subset.

[0162] FIG. 3B and Table 7 show frequencies of TCF-1+TIM-3" Tpexand TCF-1" TIM-3+Ttexpopulations in the CD8+T subset.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOTable 7

[0163] FIG. 3C and Table 8 show frequencies of PD1+TIGIT+CD226+triple-positive cells in Tpcx and Ttcxpopulations.Table 8

[0164] As shown in FIG. 3C and Table 8, co-expression of TIGIT, PD-1, and CD226 was observed in both CD8+ T cell subsets in HNSCC samples.

[0165] In conclusion, it was found that members of the TIGIT, PD-1, and CD226 signaling axis are expressed on human HNSCC tumor infiltrating leukocytes including Tpexand TtexCD8+ T cell subsets, and thus it is suggested that co-blockade of TIGIT (e.g., with domvanalimab) and PD-1 (e.g., with zimberelimab) may provide superior therapeutic benefit.Example 2: Phase 2 Study with Zimberelimab and Domvanalimab

[0166] This example relates to a Phase 2 study with zimberelimab alone in combination with chemotherapy, or zimberelimab and domvanalimab in combination with chemotherapy, in subjects with recurrent or metastatic (r / m) head and neck squamous cell carcinoma (HNSCC), with any PD-L1 expression status who have not received any prior systemic therapies for r / m HNSCC.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOCohorts / Groups

[0167] Cohort 1 is a randomization cohort to assess the efficacy and safety of domvanalimab and zimberelimab in combination with platinum-doublet chemotherapy (Treatment Group A, N=50) as compared with zimberelimab in combination with platinum-doublet chemotherapy (Treatment Group B, N=50). The 100 subjects are randomized in a 1:1 ratio to domvanalimab and zimberelimab in combination with paclitaxel and carboplatin (treatment group A) or zimberelimab in combination with paclitaxel and carboplatin (treatment group B). Subjects will be stratified by PD-L1 expression (VENTANA PD-L1 (SP263) assay TAP score < 20% vs > 20% determined by central laboratories) and HPV pl6 status for oropharyngeal cancer (positive vs negative). Subjects with non-oropharyngeal tumors are considered pl6 negative. Crossover between different treatment groups is not permitted. PD-L1 expression is monitored as subject accrual occurs, and if there is a significant difference from the published prevalence, certain PD- L1 expression groups may be prioritized to enroll in the study.

[0168] Study treatments are administered via an intravenous (IV) infusion in 3-week (21 days) cycles.

[0169] In Cohort 1, first 8 subjects randomized in treatment group A completes at least 1 full study treatment cycle. Additional subjects are only enrolled after the completion of a formal safety data review if no new safety concerns are identified that detrimentally change the benefit / risk profile.

[0170] Cohort 2 is a biomarker cohort to assess the mechanism of action of domvanalimab and zimberelimab in combination with platinum-doublet chemotherapy as well as the efficacy and safety of the treatments (N=20). Tumor tissue samples are required at baseline (fresh tissue sample only) and on-treatment. Domvanalimab and zimberelimab will be administered for the first 2 cycles, followed by domvanalimab and zimberelimab in combination with paclitaxel and carboplatin.

[0171] Groups and cohorts are shown in Table 9 below:Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOTable 9Subjects

[0172] Subjects are 18 years old or older.

[0173] Subjects have histologically or cytologically confirmed r / m squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies;

[0174] Subjects do not have prior systemic therapy for r / m HNSCC. Subjects who had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum- containing therapy for locoregionally advanced disease are eligible;

[0175] Subjects have at least 1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) that qualifies as a RECIST vl.l target lesion at baseline, (tumor lesions located in a previously irradiated field may be considered measurable if disease progression has been demonstrated in such lesions);

[0176] Subjects have adequate tumor tissue samples preferably from lesions not irradiated prior to biopsy (acceptable from irradiated lesions if disease progression has been demonstrated in such lesions) to submit for central testing of PD-L1 status by investigational VENTANA PD-L1 (SP263) assay for stratification at randomization (Cohort 1 only) and biomarker assessment.Archived tumor tissue samples that were obtained preferably within 24 months prior to the initial dosing (Cycle 1 Day 1) are acceptable but newly acquired samples at baseline are required if archived samples are not available. In Cohort 1, PD-L1 expression will be monitored as subject accrual occurs, and if there is a significant difference from the published prevalence, certain PD-Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOLI expression groups may be prioritized to enroll in the study. In Cohort 2, newly acquired samples at baseline are required (archival tissue samples can be additionally submitted).

[0177] Subjects have Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0178] Subjects have known results from HPV status test (pl 6 expression) for oropharyngeal carcinoma defined as pl6 testing with CINtec IHC assay (see Section 6.1.4.2). HPV testing by polymerase chain reaction (PCR) and in situ hybridization (ISH) can be accepted. If local results by above methods are not available, a tumor tissue sample must be submitted to the designated central laboratory to be tested and pl6 status is required prior to randomization. In Cohort 1, documentation of HPV pl6 status is required prior to randomization.

[0179] Subjects have adequate hematologic counts without transfusional or growth factor support within 2 weeks of study drug initiation. Specifically, subjects have hemoglobin > 9 g / dL and ANC (absolute neutrophil count) > 1500 / mm3 and platelets > 100,000 / pL. Subjects have adequate hepatic function. Specifically, subjects have total bilirubin < 1.5 ULN (upper limit of normal) or < 3 ULN and primarily unconjugated if subject has a documented history of Gilbert’s syndrome or a genetic equivalent AST (aspartate aminotransferase) and ALT (alanine aminotransferase) < 2.5 ULN or < 5 ULN if known liver metastases. Subjects have creatinine clearance of at least CLcr > 45 mL / min as assessed by the Cockcroft-Gault method.

[0180] Subjects have life expectancy of 3 month or greater in the opinion of the investigator.

[0181] Subjects may not have nasopharyngeal cancer (any histology), squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, and salivary gland.

[0182] Subjects may not have disease that is suitable for any local therapies with curative intent.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0183] Subject might not have disease progression or recurrence within 6 months after the last dose of curative intent systemic platinum-containing therapy for locoregionally advanced disease.

[0184] Subjects may not have a history of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.

[0185] Subjects may not have an active autoimmune disease that required systemic treatment in the past 2 years, (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

[0186] Subjects may have not received major surgery for any cause or significant traumatic injury within 4 weeks prior to the first dose of study drug. Subjects must have recovered adequately from the toxicity and / or complications from the intervention prior to starting study drug. Subjects may have not received any non-invcstigational anticanccr therapy (chemotherapy, biologic therapy, targeted therapy, hormone therapy, or immunotherapy, etc.) within 4 weeks prior to the first dose of study drug. Concurrent use for noncancer related condition (e.g., hormone replacement therapy) is acceptable. Subjects may have not been administered any investigational drugs (drugs not marketed for any indication) within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of study drug. Subjects may have not received radiation therapy within 2 weeks prior to the first dose of study drug. Subjects must have recovered to Grade < 1 from all radiation-related toxicities, not requiring corticosteroid, and have not experienced radiation pneumonitis.

[0187] Subjects may have not received prior treatment with any anti-PD-l / PD-Ll, anti-TIGIT, or other immune checkpoint inhibitors.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0188] Subjects may not be currently receiving chronic systemic steroids (> 10 mg / day prednisone or its equivalent). Use of topical, inhalational, intranasal, intraocular steroids, and use as premedication for hypersensitivity reactions (e.g., IV contrast allergy) are permitted.

[0189] Subjects may not show any unresolved toxicity (Grade > 2) per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 from prior anticancer therapy or surgical intervention, with the exception of alopecia, vitiligo, and the laboratory toxicities if the laboratory thresholds defined in the inclusion criteria are met. Subjects with Grade A 2 neuropathy are eligible for this study.

[0190] Subjects may not have shown an active second malignancy or have had an active second malignancy within 3 years prior to enrollment. Subjects with a history of malignancy that has been completely treated, with no evidence of active cancer for at least 3 years prior to enrollment, or with surgically cured tumors with low risk of recurrence (e.g., nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll.

[0191] Subjects may not have known active central nervous system (CNS) metastases. Subjects with previously treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to enrollment and all neurologic symptoms have returned to baseline, have no evidence of new or enlarging brain metastasis and are not requiring use of steroid for at least 14 days prior to the first dose of study drugs.Treatment

[0192] The dosage, schedule, order of administration, and treatment duration for Cohorts 1 and 2 are described in Table 10.

[0193] Study drugs should be administered on Day 1 of each cycle after scheduled procedures / assessments have been completed. Study drugs can be administered ± 3 days of theAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO targeted Day 1 for each cycle, except Cycle 1 where treatment must be administered within 5 days after randomization.Table 10D = Day; IV = intravenous; PD = progressive disease a Up to 35 treatment cycles, until PD, death, unacceptable toxicity, or another treatment discontinuation criterion is met. b Up to 6 treatment cycles (Cycle 3-Cycle 8), until PD, death, unacceptable toxicity, or another treatment discontinuation criterion is met.

[0194] For Cohort 1, Treatment Group A (domvanalimab + zimberelimab + platinum doublet chemotherapy), zimberelimab is administered intravenously (IV) over 30 (-5 / + 15) minutes followed by a 30-to-60-minute observation period, followed by domvanalimab IV over 30 (-5 / +15) minutes followed by a 30- to 60-minute observation period, followed by platinum doublet chemotherapy. Domvanalimab and zimberelimab are administered for a maximum of 35 treatment cycles. Paclitaxel and carboplatin, as platinum doublet chemotherapy, are administered for a maximum of 6 treatment cycles from Cycle 1 to Cycle 6. Treatment is given until PD, death, unacceptable toxicity, or another treatment discontinuation criterion is met .Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0195] For Cohort 1 , Treatment Group B (zimberelimab + platinum-doublet chemotherapy), zimberelimab is administered intravenously (IV) over 30 (—5 / 4-15) minutes followed by a 30- to 60-minute observation period, followed by chemotherapy. Zimberelimab will be administered for a maximum of 35 treatment cycles. Paclitaxel and carboplatin will be administered for a maximum of 6 treatment cycles from Cycle 1 to Cycle 6. Treatment will be given until PD, death, unacceptable toxicity, or another treatment discontinuation criterion is met.

[0196] For Cohort 2 (Biomarker Cohort), zimberelimab is administered intravenously (IV) over 30 (-5 / +15) minutes followed by a 30-to-60-minute observation period, followed by domvanalimab IV over 30 (-5 / 4-15) minutes followed by a 30- to 60-minute observation period, followed by platinum doublet chemotherapy. For the first 2 cycles, only domvanalimab and zimberelimab are administered. Domvanalimab and zimberelimab are administered for a maximum of 35 treatment cycles. Platinum-doublet chemotherapy are administered for a maximum of 6 treatment cycles from Cycle 3 to Cycle 8. Treatment is given until PD, death, unacceptable toxicity, or another treatment discontinuation criterion is met.

[0197] Study drugs should be administered on Day 1 of each cycle after scheduled procedures / assessments have been completed. Study drugs can be administered ± 3 days of the targeted Day 1 for each cycle, except for the Cycle 1 where treatment must be administered within 5 days after subject enrollment.

[0198] For all cohorts / groups, paclitaxel 175 mg / m2is administered as an IV infusion over 3 hours on Day 1 of each 21-day cycle. All subjects may be premedicated prior to paclitaxel administration to prevent severe hypersensitivity reactions. Paclitaxel is completely administered before initiating carboplatin dose.

[0199] For all cohorts / groups, carboplatin AUC 5 is administered as an IV infusion over 15 to 60 minutes on Day 1 of each 21-day cycle after paclitaxel. The carboplatin dose is calculated using the Calvert formula. Each carboplatin dose does not exceed 750 mg.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WODuration of Treatment

[0200] Study drugs will be given until PD as determined by investigators per RECIST vl.l, death, unacceptable toxicities, or another treatment discontinuation criterion is met.Domvanalimab and zimberelimab can be administered for a maximum of 35 treatment cycles and platinum-doublet chemotherapy can be administered for up to 6 cycles (Cycle 1 to Cycle 6 in Cohort 1, Cycle 3 to Cycle 8 in Cohort 2).

[0201] Treatment beyond the initial radiological PD as determined by investigators per RECIST vl.l may be permitted if there is evidence of clinical benefit as assessed by the investigator and the subject is tolerating study drug. The following clinical criteria should be met for subjects to continue to receive treatment beyond the investigator-assessed progression: Absence of symptoms and signs indicating clinically significant PD; no decline in performance status; absence of symptomatic rapid disease progression requiring urgent medical intervention (e.g., symptomatic pleural effusion, spinal cord compression).Cohort 1 Endpoints

[0202] To assess the efficacy of (domvanalimab and zimberelimab in combination with chemotherapy) vs (zimberelimab in combination with chemotherapy), the following primary endpoints are analyzed: objective response rate (ORR), defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) vl.l; and progression-free survival (PFS), defined as the time from the date of randomization until the first date of documented progressive disease (PD) or death from any cause, whichever occurs first, as measured by RECIST vl.l.

[0203] To assess the effect of domvanalimab and zimberelimab in combination with chemotherapy vs zimberelimab in combination with chemotherapy, the following secondary endpoints are analyzed: duration of response (DOR), defined as the time from the date of the first documented response until the first date of documented PD or death from any cause, whichever occurs first, as measured by RECIST vl.l; PFS rate at 6 months (PFS6), defined as theAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO proportion of subjects alive and PD-free from date of randomization until 6 months as measured by RECIST vl.l; overall survival (OS), defined as the time from the date of randomization until the date of death from any cause; OS rate at 6 months and 12 months (OS6 and OS 12), defined as the proportion of subjects alive at 6 months and 12 months from the date of randomization, respectively; disease control rate (DCR) defined as the proportion of subjects who achieve a CR, PR, or stable disease (SD) as measured by RECIST vl.l; Time to progression (TTP), defined as the time from randomization until the first date of documented PD as measured by RECIST vl.l; and safety and tolerability.[02041 To assess the efficacy of domvanalimab and zimberelimab in combination with chemotherapy vs zimberelimab in combination with chemotherapy in the population by programmed cell death ligand 1 (PD-L1) expression, efficacy within PD-L1 subgroups expression using VENTANA PD-L1 (SP263) assay is analyzed. To characterize the pharmacokinetics (PK) and immunogenicity of domvanalimab and zimberelimab in combination with chemotherapy, domvanalimab and zimberelimab concentrations in serum and immunogenicity is analyzed. To assess predictive, prognostic, or pharmacodynamic biomarkers in tumor tissue or blood that may be associated with disease status or mechanisms of response and / or resistance to domvanalimab and zimberelimab in combination with chemotherapy, following exploratory endpoints are analyzed: relationship between baseline biomarkers (e.g., PD-L1, T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine- based inhibitory motif domains [TIGIT], circulating tumor DNA [ctDNA], tumor mutation burden [TMB], and others) in tumor tissue and / or blood and efficacy, disease status, resistance, or other biomarker endpoints will be conducted; and association of baseline tissue-based biomarkers such as TIGIT, CD8, regulatory T cells, and natural killer (NK) cells with the following efficacy parameters will be conducted: OS, OS6, OS 12, PFS, PFS6, ORR, DOR, DCR, and TTP as measured by RECIST vl.l.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOCohort 2 Endpoints

[0205] To assess the efficacy of domvanalimab and zimberelimab in combination with chemotherapy vs zimberelimab in combination with chemotherapy, ORR, defined as the proportion of subjects who achieve a CR or PR as measured by RECIST vl.l is analyzed.

[0206] To assess the effect of domvanalimab and zimberelimab in combination with chemotherapy vs zimberelimab in combination with chemotherapy, the following secondary endpoints are analyzed: DOR defined as the time from the date of the first documented response until the first date of documented PD or death from any cause, whichever occurs first, as measured by RECIST vl.l; PFS, defined as the time from the dose initiation until the first date of documented PD or death from any cause, whichever occurs first, as measured by RECIST vl.l; PFS6, defined as the proportion of subjects alive and PD-free from dose initiation until 6 months as measured by RECIST vl.l; OS, defined as the time from the dose initiation until the date of death from any cause; OS6 and OS 12, defined as the proportion of subjects alive at 6 months and 12 months from the dose initiation, respectively; DCR, defined as the proportion of subjects who achieve a CR, PR, or SD as measured by RECIST vl.l; and TTP, defined as the time from dose initiation until the first date of documented PD as measured by RECIST vl.l. To assess the safety of domvanalimab and zimberelimab in combination with chemotherapy as compared with zimberelimab in combination with chemotherapy, safety and tolerability is evaluated.

[0207] To assess the efficacy of domvanalimab and zimberelimab in combination with chemotherapy vs zimberelimab in combination with chemotherapy in the population by PD-L1 expression, efficacy assessments within PD-L1 subgroups expression using the VENTANA PD- L1 (SP263) assay is analyzed. To characterize the PK and immunogenicity of domvanalimab and zimberelimab in combination with chemotherapy, summary of domvanalimab and zimberelimab concentrations in serum and immunogenicity is analyzed. To assess predictive, prognostic, or pharmacodynamic biomarkers in tumor tissue or blood that may be associated with disease status or mechanisms of response and / or resistance to domvanalimab and zimberelimab in combinationAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO with chemotherapy, following exploratory endpoints are analyzed: relationship between baseline biomarkers (e.g., PD-L1, TIGIT, ctDNA, TMB, and others) in tumor tissue and / or blood and efficacy, disease status, resistance, or other biomarker endpoints; association of baseline tissuebased biomarkers such as TIGIT, CD8, regulatory T cells, and NK cells with the following efficacy parameters: OS, OS6, OS 12, PFS, PFS6, ORR, DOR, DCR, and TTP as measured by RECIST vl.l; assessment of pharmacodynamic biomarkers including but not limited to effector T cell gene signature, regulatory T cells, and PD-L1 in tumor tissue to evaluate the mechanism of action of domvanalimab.Efficacy Assessments

[0208] To assess efficacy of the treatment, computed tomography or MRI scans with IV contrast of the head, neck, chest, abdomen, pelvis, and any other involved disease sites are obtained in all subjects according to the study procedures tables. If the use of IV contrast is medically contraindicated, one of the following options may be used: CT without contrast, MRI without contrast, or attempt to desensitize the subjects with steroids.

[0209] Target and nontarget lesions must be determined by the clinical site at baseline according to the RECIST vl.l for subject eligibility. During the study, tumor response and progression is determined using the RECIST vl.l. Additional CT or MRI scans at an unscheduled time point may be performed at the discretion of the investigator to assess disease status as medically indicated. Clinical progression leading to treatment discontinuation should be documented also by CT or MRI scan if clinically feasible.

[0210] For each subject, the same imaging technique used at screening is used throughout the study to ensure comparability.Pharmacokinetics and Immunogenicity Assessment

[0211] Serum samples are collected for study drug concentration and immunogenicity as outlined in the study procedures tables for each experimental treatment group. Additionally, ad hoc samples may be collected at any time if there is a suspected safety issue. Samples collectedAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO for analysis of study drug concentration and immunogenicity may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.Biomarker Testing

[0212] Before treatment, PD-L1 expression is tested; the TAP score of PD-L1 staining is used for stratification at randomization. PD-L1 testing is performed using the VENTANA PD-L1 (SP263) assay.

[0213] For subjects with oropharyngeal carcinoma, if local HPV assessment results are not available, pl6 status is tested.

[0214] Blood specimens are collected and may be used to evaluate blood-based biomarkers and correlate them with treatment efficacy, including evaluation of various predictive cutoffs for novel blood-based assays. Blood samples are collected at screening and / or baseline, during therapy, and end of therapy (EOT) to better understand the changes in blood-based biomarker profiles and potential mechanisms of resistance upon progression. Blood samples may also be evaluated for additional exploratory biomarkers that may be associated with the therapeutic effects of this combination or the pathogenesis of HNSCC. Methods for exploratory analysis include, but are not limited to, digital PCR, quantitative reverse transcriptase PCR, next generation sequencing (NGS), immunoassays, and proteomics-based approaches. In addition, potential correlations of these biomarkers with the safety and activity of this combination may be explored.

[0215] For Cohort 1, a mandatory tumor sample is collected for each subject at screening. Either an archival or fresh tumor tissue sample will be used for PD-L1 testing to stratify subjects across treatments to confirm study eligibility. In addition to the testing for PD-L1, the tumor samples may be evaluated for other exploratory biomarkers that include, but are not limited to, IHC staining for expression of TIGIT family proteins (poliovirus receptor [CD155], CD226, etc.), RNA- sequencing for gene expression profiles, and / or whole exome sequencing for tumor mutations. For subjects with PD during the study, a progression tumor tissue sample may beAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO collected at the end of treatment visit unless a tumor biopsy is not clinically feasible or advisable. If PD occurs and the subject is continuing the study drug, a tumor biopsy is strongly recommended unless not clinically feasible or advisable.

[0216] For Cohort 2, tumor tissue samples on-treatment will be also required for evaluation of domvanalimab-specific mechanism of action pharmacodynamic biomarkers including but not limited to T-effector genes, CD8 T cells, regulatory T cells, NK cells, and the other exploratory biomarkers listed above.

[0217] Subjects with oropharyngeal cancer are stratified by tumor HPV status (positive vs negative) in Cohort 1. Tumor p 16 status has been established as a surrogate of tumor HPV status and Tumor p 16 status may be evaluated locally by IHC analysis with CINtec Histology (pl 6) assay (VENTANA Medical Systems, Inc., Tucson, AZ). The local results of HPV status by PCR and ISH is also acceptable. If HPV status was previously tested by above methods, no additional testing is required. If local pl6 testing result is not available or it cannot be evaluated by methods specified above, a tumor tissue sample must be submitted prior to randomization. HPV testing by pl6 IHC is not required for subjects with oral cavity, hypopharyngeal, and laryngeal cancer as HPV status in these subjects is deemed negative by convention.

[0218] Exploratory biomarkers (including, but not limited to PD-L1, TIGIT, regulatory T cells, NK cells and T-effector gene expression, mutational load, and other biomarkers related to immune or HNSCC biology, such as T cell biomarkers or noninherited biomarkers identified through NGS on extracted DNA and / or RNA) may also be evaluated.* * *

[0219] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0220] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, forAttorney Docket No.: P0068-WO-PCT / 37JD-395214-WO example, the terms “comprising”, “including,” “containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed.

[0221] Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this invention. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the invention.

[0222] The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0223] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0224] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety, to the same extent as if each were incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO

[0225] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WOCLAIMS:

1. A method of treating Head and Neck Squamous Cell Carcinoma (HNSCC) in a subject in need thereof, comprising: administering a therapeutically effective amount of zimberelimab, a therapeutically effective amount of domvanalimab, and one or more chemotherapeutic agents.

2. The method of claim 1, wherein the HNSCC is rccurrcnt / mctastatic (r / m) HNSCC.

3. The method of claim 1 or 2, wherein the HNSCC is histologically or cytologically confirmed r / m squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies.

4. The method of any one of claims 1 to 3, wherein the HNSCC has programmed cell death ligand 1 (PD-L1) expression, and has VENTANA PD-L1 (SP263) immunohistochemistry (IHC) TAP score of 20% or greater.

5. The method of any one of claims 1 to 4, wherein the HNSCC is HPV pl6 negative.

6. The method of any one of claims 1 to 5, wherein zimberelimab and domvanalimab are administered separately.

7. The method of any one of claims 1 to 6, wherein zimberelimab and domvanalimab are administered intravenously.

8. The method of any one of claims 1 to 7, wherein domvanalimab is administered at a dose of about 1100 mg to about 1300 mg once every 3 weeks.

9. The method of any one of claims 1 to 8, wherein zimberelimab is administered at a dose of about 350 mg to about 400 mg once every 3 weeks.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO10. The method of any one of claims 1 to 9, wherein said one or more chemotherapeutic agents comprise a platinum-based chemotherapeutic agent.

11. The method of any one of claims 1 to 10, wherein said one or more chemotherapeutic agents are one platinum-based chemotherapeutic agent and another chemotherapeutic agent.

12. The method of claim 10 or 11, wherein the platinum-based chemotherapeutic agent is selected from cisplatin, carboplatin, or nedaplatin.

13. The method of claim 11 or 12, wherein said another chemotherapeutic agent is selected from paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan.

14. The method of any one of claims 1 to 13, wherein said one or more chemotherapeutic agent is a therapeutically effective amount of carboplatin and a therapeutically effective amount of paclitaxel.

15. The method of claim 14, wherein paclitaxel is administered at a dose of about 175 mg / m2once every 3 weeks.

16. The method of claim 14 or 15, wherein carboplatin is administered at a dose of about AUC 5 once every 3 weeks.

17. The method of any one of claims 14 to 16, wherein zimberelimab, domvanalimab, carboplatin, and paclitaxel are administered on a same day.

18. The method of any one of claims 1 to 17, wherein zimberelimab and domvanalimab are administered for up to 35 treatment cycles.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO19. The method of any one of claims 14 to 18, wherein carboplatin and paclitaxel are administered for up to 6 treatment cycles.

20. The method of any one of claims 1 to 19, wherein the subject did not have prior systemic therapy for r / m HNSCC.

21. The method of any one of claims 1 to 20, wherein the subject had had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum- containing therapy for locoregionally advanced disease.

22. The method of any one of claims 1 to 21, wherein the subject does not have nasopharyngeal cancer or squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, or salivary gland.

23. A method of treating recurrent / metastatic (r / m) head and neck squamous cell carcinoma (HNSCC) in a subject in need thereof, comprising administering: zimberelimab at a dose of about 360 mg once per 3 weeks; domvanalimab at a dose of about 1200 mg once every 3 weeks; and a platinum-doublet chemotherapy.

24. The method of claim 23, wherein the HNSCC is histologically or cytologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx that is considered incurable by local therapies.

25. The method of claim 23 or 24, wherein the HNSCC has programmed cell death ligand 1 (PD-L1) expression, and has investigational VENTANA PD-L1 (SP263) immunohistochemistry (IHC) TAP score of 20% or greater.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO26. The method of any one of claims 23 to 25, wherein the platinum-doublet chemotherapy comprises carboplatin and paclitaxel.

27. The method of any one of claims 23 to 26, wherein the platinum-doublet chemotherapy comprises carboplatin about AUC 5 once every 3 weeks and paclitaxel at a dose of about 175 mg / m2once every 3 weeks.

28. The method of any one of claims 23 to 27, wherein zimberelimab and domvanalimab are administered separately.

29. The method of any one of claims 23 to 28, wherein zimberelimab and domvanalimab are administered intravenously.

30. The method of any one of claims 23 to 29, wherein zimberelimab, domvanalimab, carboplatin, and paclitaxel are on a same day.

31. The method of any one of claims 23 to 30, wherein the subject did not have prior systemic therapy for r / m HNSCC.

32. The method of any one of claims 23 to 31, wherein the subject had had disease progression or recurrence more than 6 months after the last dose of curative intent systemic platinum-containing therapy for locoregionally advanced disease.

33. The method of any one of claims 23 to 32, wherein the subject does not have nasopharyngeal cancer, squamous cell carcinoma of unknown primary tumors, skin (cutaneous squamous cell carcinoma), paranasal sinuses, and salivary gland.

34. The method of any one of claims 23 to 33, wherein zimberelimab and domvanalimab arc administered for up to 35 treatment cycles.Attorney Docket No.: P0068-WO-PCT / 37JD-395214-WO35. The method of any one of claims 23 to 34, wherein the platinum-doublet chemotherapy is administered for up to 6 treatment cycles.

36. The method of any one of claims 23 to 35, wherein the HNSCC is HPV pl6 negative.

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