Combinations for the treatment of cancer

Abstract

In one aspect, provided herein are methods of treating cancer with a combination therapy comprising an anti-human-B7-H3 antibody-drug conjugate and the anti-PD-1 antibody pembrolizumab, with or without 5 -fluorouracil and leucovorin, levoleucovorin, or oxaliplatin.

Description

Attorney Docket Number: 14463-359-228COMBINATIONS FOR THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 729,900, filed December 9, 2024, the disclosure of which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14463-359-228_SEQ_LISTING.xml”, was created on December 4, 2025, and is 30,930 bytes in size.BACKGROUND

[0003] Cancer is a significant cause of morbidity and mortality worldwide. While the standards of care for many different cancer types have greatly improved over the years, current standards of care still fail to meet the need for effective therapies to improve treatment of cancer. Accordingly, there is a need in the art for new therapies, including, for example, combination therapies for the treatment of cancers. Provided herein are solutions to these and other problems in the art.SUMMARY

[0004] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:1NAI-5007064122Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC). In some embodiments, the drug-linker of Formula I is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0005] In some embodiments, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula II2NAI-5007064122Formula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

[0006] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0007] In some embodiments of the method described herein, the method further comprises administering to the subject 5 -fluorouracil and leucovorin or levoleucovorin. In some embodiments of the method described herein, the method further comprises administering to the subject 5 -fluorouracil and oxaliplatin.

[0008] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:3NAI-5007064122(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin. In some embodiments, the drug-linker of Formula I is conjugated to the anti -human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0009] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula II4NAI-5007064122Formula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin.

[0010] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0011] Pharmaceutical compositions for use and uses according to the present combinational therapies are also provided herein.

[0012] In some embodiments of the methods, pharmaceutical compositions and uses provided herein, the cancer is a cancer associated with B7-H3. In some embodiments, the cancer is esophageal squamous cell carcinoma (ESCC). In some embodiments, the ESCC is unresectable or metastatic. In other embodiments, the subject has a histologically or5NAI-5007064122cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC. In some embodiments, the subject has not had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer. In some embodiments, the subject has received prior neoadjuvant or adjuvant therapy.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 depicts an exemplary study design. 5-FU=5-fluorouracil; lL=first-line of therapy, ADA=antidrug antibodies; AE=adverse event; BICR=blinded independent central review; BOIN=Bayesian Optimal Interval; DCR=disease control rate; DLT=dose-limiting toxicity; DOR=duration of response; ECOG=Eastern Cooperative Oncology Group; ESCC=esophageal squamous cell carcinoma; ICF=informed consent form; I- DXd=ifinatamab deruxtecan; IV=intravenous; LV= leucovorin or levoleucovorin; mFOLFOX6=oxaliplatin + 5-FU + LV; N=number; ORR=objective response rate; OS=overall survival; PD-Ll=programmed cell death ligand 1; PK=pharmacokinetic; PF S=progressi on-free survival; RECIST=Response Evaluation Criteria In Solid Tumors; Topo-l=topoisom erase I.DETAILED DESCRIPTION1. Definitions

[0014] Unless otherwise defined, terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art.

[0015] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0016] As used herein, the term “comprising” also specifically includes embodiments “consisting of’ and “consisting essentially of’ the recited elements, unless specifically indicated otherwise.

[0017] The term “about” or “approximately” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” or “approximately” indicates the designated value ± 10%. In certain embodiments, where6NAI-5007064122applicable, the term “about” or “approximately” indicates the designated value(s) ± one standard deviation of that value(s).

[0018] In some embodiments, the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first composition” and “second composition” are used to distinguish two compositions.

[0019] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodiments are described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.

[0020] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry,” 2ndEd., Thomas Sorrell, University Science Books, Sausalito: 2006, and "March’s Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference.

[0021] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0022] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain7NAI-5007064122constant region typically comprises three domains, abbreviated CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0023] “Antigen” refers to any molecule (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, portions thereof, or combinations thereof) that is capable of mediating an immune response. Exemplary immune responses include antibody production and activation of immune cells, such as T cells, B cells or NK cells.

[0024] “Antigen binding fragment” or “antigen binding domain” refers to a portion of a protein that binds the antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as a VH, a VL, the VH and the VL, Fab, Fab’, F(ab’)2, Fd and Fv fragments, single-domain antibodies (sdAb) consisting of one VH domain or one VL domain, camelized VH domains, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen binding fragments. Antigen binding fragments (such as the VH and the VL) may be linked together via a synthetic linker to form various types of single antibody designs in which the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and the VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins.

[0025] “Antibody” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. A “full length antibody” is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light8NAI-5007064122chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (1), based on the amino acid sequences of their constant domains. An antibody provided herein may include post-translational modifications thereof, e.g., C-terminal lysine clipping in the heavy chain or conversion of glutamine or glutamic acid to pyroglutamate or pyroglutamic acid, which may occur when recombinantly expressed in host cells (e.g., CHO cells), or during purifi cati on / storage .

[0026] “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. A “human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, a “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, a “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on9NAI-5007064122phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-396, and in Int. Patent Publ. No. W02009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody.”

[0027] “Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework region is derived from human immunoglobulin sequences. A humanized antibody may include substitutions in the framework regions so that the framework regions may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0028] The term “Fc region” means the C-terminal region of an immunoglobulin heavy chain that, in naturally occurring antibodies, interacts with Fc receptors and certain proteins of the complement system. The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art.

[0029] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD.

[0030] A “Complementary Determining Region (CDR)” refers to one of three hypervariable regions (Hl, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH [3-sheet framework, or one of three hypervariable regions (LI, L2 or L3) within the non-framework region of the antibody VL [3-sheet framework. CDRs are variable region sequences interspersed within the framework region sequences. CDRs are well recognized in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable (V) domains. See Kabat et al., J Biol Chem, 1977, 252:6609-6616 and Kabat, Adv Protein Chem, 1978, 32: 1-75.CDRs have also been defined structurally by Chothia as those residues that are not part of the conserved [3-sheet framework, and thus are able to adapt different conformations. See Chothia and Lesk, J Mol Biol, 1987, 196:901-917. Both the Kabat and Chothia nomenclatures are well known in the art. AbM, Contact and IMGT also define CDRs. CDR positions within a10NAI-5007064122canonical antibody variable domain have been determined by comparison of numerous structures. See Morea et al., Methods, 2000, 20:267-279 and Al-Lazikani et al., J Mol Biol, 1997, 273:927-48. Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable domain numbering scheme. Such terminology is well known to those skilled in the art.

[0031] A number of hypervariable region delineations are in use and are included herein. The Kabat CDRs are based on sequence variability and are the most commonly used. See Kabat et al. (1992) Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719. Chothia refers instead to the location of the structural loops (Chothia and Lesk, supra). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software. The Contact hypervariable regions are based on an analysis of the available complex crystal structures.

[0032] More recently, a universal numbering system ImMunoGeneTics (IMGT) Information System™ has been developed and widely adopted. See Lefranc et al., Dev Comp Immunol, 2003, 27:55-77. IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. The IMGT CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. Correspondence between the Kabat, Chothia and IMGT numbering is also well known in the art (Lefranc et al., supra). An exemplary system, shown herein, combines Kabat and Chothia CDR definitions.11NAI-5007064122

[0033] The light chain from any vertebrate species can be assigned to one of two types, called kappa (K) and lambda (1), based on the sequence of its constant domain.

[0034] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 8, a, y, and p, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0035] The term “constant region” or “constant domain” refers to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CHI, CH2 and CH3 domains of the heavy chain and the CL domain of the light chain.

[0036] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, / .<?., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population.Monoclonal antibody may be monospecific or multispecific such as bispecific or trispecific.

[0037] “Multispecific” refers to a molecule that binds two or more distinct antigens or two or more distinct epitopes within the same antigen. Multispecific molecule may have cross-reactivity to other related antigens, for example to the same antigen from other species (homologs), such as human or monkey, for example Macaca fascicularis (cynomolgus, cyno) o Pan troglodytes, or may bind an epitope that is shared between two or more distinct antigens.

[0038] As used herein, “pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab), alternatively referred to herein as “pembro,” is a humanized anti-PD-1 IgG4 monoclonal antibody with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain and CDR amino acid sequences shown in Table A. Pembrolizumab has been approved by the U.S. FDA as described in the Prescribing Information for KEYTRUDA® (Merck & Co., Inc., Rahway, NJ12NAI-5007064122USA; initial U.S. approval 2014, updated September 2024). The term pembrolizumab includes monoclonal antibodies having a structure as described above but which do not include the C-terminal lysine in the heavy chain.Table A. Exemplary Antibody Sequences for Pembrolizumab

[0039] “Polynucleotide” refers to a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is a typical example of a polynucleotide.13NAI-5007064122

[0040] “Protein” or “polypeptide” are used interchangeably herein to refer to a molecule that comprises one or more polypeptides each comprised of at least two amino acid residues linked by a peptide bond. Protein may be a monomer, or may be a protein complex of two or more subunits, the subunits being identical or distinct. Small polypeptides of less than 50 amino acids may be referred to as “peptides.” Protein may be a heterologous fusion protein, a glycoprotein, or a protein modified by post-translational modifications such as phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, citrullination, polyglutamylation, ADP-ribosylation, pegylation or biotinylation.

[0041] “Recombinant” refers to polynucleotides, polypeptides, vectors, viruses and other macromolecules that are prepared, expressed, created or isolated by recombinant means.

[0042] “Single chain Fv” or “scFv” refers to a single chain protein comprising a VH, a VL and a linker between the VH and the VL. The scFv may have the VL and VH variable regions in either orientation, e.g., with respect to the N- to C-terminal order of the VH and the VL. The scFv may thus be in the orientation VL-linker-VH or VH-linker-VL. In some embodiments, an scFv may be engineered to comprise disulfide bonds between the VH, the VL and the linker.

[0043] As used herein, the term “percent (%) amino acid sequence identity” with respect to a sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs or software such as EMBOSS MATCHER, EMBOSS WATER, EMBOSS STRETCHER, EMBOSS NEEDLE, EMBOSS LALIGN, BLAST, BLAST-2, ALIGN or Megalign (DNASTAR). Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0044] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope). The affinity of a molecule X for its partner Y can be14NAI-5007064122represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0045] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule.

[0046] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In some embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0047] The term “antibody-drug conjugate” or “ADC” refers to a conjugate comprising an antibody conjugated to one or more cytotoxic agents, optionally through one or more linkers. The terms “anti-human B7-H3 antibody-drug conjugate,” “anti-human B7-H3 ADC” are used interchangeably and refer to a conjugate comprising an anti-human B7-H3 antibody conjugated to one or more cytotoxic agents, optionally through one or more linkers.

[0048] As used herein, the term “functional fragment” of an antibody is also called “antigen binding fragment” of a human B7-H3 antibody, and is used to mean a partial fragment of the antibody having binding activity against human B7-H3, and includes, but not limited to, Fab, F(ab’)2, scFv, a diabody, a linear antibody and a multi-specific antibody formed from antibody fragments. In some embodiments, Fab’, which is a monovalent fragment of antibody variable regions obtained by treating F(ab’)2 under reducing conditions, is also included in the antigen-binding fragment of an antibody. The antigen-binding fragment of an antibody is not limited to these molecules, as long as the antigen-binding fragment has B7-H3-binding ability. These antigen-binding fragments include not only those15NAI-5007064122obtained by treating a full-length molecule of an antibody protein with an appropriate enzyme, but proteins produced in appropriate host cells using a genetically engineered antibody gene.

[0049] The term “cytotoxic agent,” as used herein, refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. The cytotoxic agent can be an anti-angiogenic agent, a pro-apoptotic agent, an anti-mitotic agent, an anti-kinase agent, an alkylating agent, a hormone, a hormone agonist, a hormone antagonist, a chemokine, a drug, a prodrug, a toxin, an enzyme, an antimetabolite, an antibiotic, an alkaloid, or a radioactive isotope. Exemplary cytotoxic agents include calicheamycin, camptothecin, carboplatin, irinotecan, SN-38, carboplatin, camptothecan, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, etoposide, idarubicin, topotecan, vinca alkaloid, maytansinoid, maytansinoid analog, pyrrolobenzodiazepine, taxoid, duocarmycin, dolastatin, auristatin, and derivatives thereof.

[0050] A “linker” refers to a molecule that connects one composition to another, e.g., an antibody to an agent. Linkers described herein can conjugate an antibody to a cytotoxic agent. Exemplary linkers include a labile linker, an acid labile linker, a photolabile linker, a charged linker, a disulfide-containing linker, a peptidase-sensitive linker, a P-glucuronide-linker, a dimethyl linker, a thio-ether linker, and a hydrophilic linker. A linker can be cleavable or non-cleavable.

[0051] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, the term “treating” or any grammatical variation thereof refers to reducing and / or ameliorating the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein).16NAI-5007064122

[0052] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans. Additionally or alternatively, the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit risk ratio.

[0053] The term “pharmaceutically acceptable carrier” includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the ingredients and that is not toxic to the patient to whom it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil / water emulsions, various types of wetting agents, and sterile solutions. Such carriers can be formulated by conventional methods and can be administered to the subject at a suitable dose. Preferably, the compositions are sterile. These compositions may also contain adjuvants such as preservative, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents.

[0054] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., those described herein individually or in combination) that is sufficient to reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto. A therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) improvement or enhancement of the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein). A “therapeutically effective amount” of a substance / molecule / agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule / agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term “therapeutically effective17NAI-5007064122amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.

[0055] As used herein, the term “concurrently” means at the same time. For example, if two treatment regimens for a single patient are being conducted concurrently, then they are being conducted at the same time. It will be understood that two treatment regimens happening at the same time, does not necessarily mean that actual delivery of two drugs happens at the same time, as each regimen may call for a different dosing schedule and / or different delivery modes.

[0056] As used herein, the terms “subject” or “patient” are used interchangeably and mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human. In some embodiments, the subject has a disease or condition that can be treated with an agent provided herein. In some embodiments, the disease or condition is a cancer.

[0057] Cancer” refers to any physiological condition in mammals characterized by unregulated cell growth; in particular, cellular-proliferative disease states. As used herein, “tumor” refers to any neoplastic cell growth or proliferation, whether malignant or benign, and to all pre-cancerous and cancerous cells and tissues.

[0058] The term “administering” refers to the act of delivering one or more combination or composition described herein into a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration may be local or systemic. Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).

[0059] As used herein, in some embodiments, the terms “administration in combination with” and “administered in combination” are used to represent a form of drug administration in which a plurality of active ingredients are contained or encapsulated in different preparations and administered simultaneously (a person skilled in the art would naturally understand that “simultaneously” or “at the same time” may be or may not be at about the same time) or separately or sequentially in any order at different times, or both contained or encapsulated in the same preparation and administered, unless the context otherwise requires and unless technically inconsistent.18NAI-5007064122

[0060] In the present disclosure, the term “anti-human-B7-H3 antibody” refers to an antibody which binds specifically to B7-H3 (also known as: B cell antigen #7 homolog 3, PD-L3, or CD276), and preferably has an activity of internalization in B7-H3-expressing cells by binding to B7-H3. In some embodiments, B7-H3 is human B7-H3.

[0061] Anti-human-B7-H3 antibody-drug conjugates used in the present disclosure are known in the art. Examples of such anti-human-B7-H3 antibody-drug conjugates include, but are not limited to, vobramitamab duocarmazine (MGC018), mirzotamab clezutoclax (ABBV- 155), BAT8009, HS-20093, MHB088C, 7MW3711, and DB-1311. Anti-human-B7-H3 antibody-drug conjugates are also described in WO2014 / 057687, WO2023 / 061457, US11,685, 742B2, US20210347894A, US20220233708A, WO2024 / 022372, WO2022 / 117040, W02024 / 061306, W02024 / 037503, WO2024 / 052685, WO2024 / 052684, WO2023 / 236949, US20240148892A, WO2023 / 241663, WO2024 / 140935, US20240108745A1 (or WO2022 / 170971), WO2024 / 140932, WO2024 / 140935, and WO2024 / 211235, each of which are incorporated herein by reference in its entirety.

[0062] As used herein, the term “I-DXd” is an antibody-drug conjugate (ADC) comprising a B7 homolog 3 (B7-H3) immunoglobulin G1 monoclonal antibody, which is covalently linked to a cytotoxic payload, exatecan, or more preferably, an exatecan derivative deruxtecan (“DXd”). Exatecan is a topoisomerase I inhibitor that leads to apoptosis of the target cells. In some embodiments, I-DXd is ifinatamab deruxtecan.

[0063] As used herein, the term “ifinatamab deruxtecan” is an antibody-drug conjugate (ADC) comprising the anti-B7-H3 antibody immunoglobulin G1 monoclonal antibody ifinatamab, which is covalently linked to deruxtecan. In pre-clinical models, ifinatamab deruxtecan exerted potent antitumor activity in high B7-H3 expressing tumors with an acceptable pharmacokinetic and safety profile (Yamato, M., et. al., (IC ). Mol Cancer Ther, 21(4), 635-646). Ifinatamab and ifinatamab deruxtecan are described, e.g., in WHO Drug Information, Vol. 36, No. 3, 2022 (Recommended INN: List 88). Deruxtecan is also described, e.g., in WHO Drug Information, Vol. 30, No. 4, 2016 (Proposed INN List 116).

[0064] The term “packaging material” refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, and the like).

[0065] In general, the nomenclature used in this application is based on naming conventions adopted by the international union of pure and applied chemistry (IUPAC). Any19NAI-5007064122open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.2. Methods of Treatment

[0066] Provided herein are combinational therapies comprising at least an anti-human- B7-H3 antibody-drug conjugate and an IO therapy, e.g., a PD-1 antagonist (e.g., an anti-PD-1 antibody) or a PD-L1 antagonist (e.g., an anti-PD-Ll antibody). In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody such as pembrolizumab.

[0067] In one aspect, provided herein is a method for treating unresectable or metastatic esophageal squamous cell carcinoma (ESCC) using the present combinational therapies.

[0068] Thus, in some embodiments, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and20NAI-5007064122(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC). In some embodiments, the drug-linker of Formula I is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0069] In some embodiments, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula IIFormula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

[0070] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of21NAI-5007064122drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0071] In some embodiments of the methods described herein, the method further comprises administering to the subject 5 -fluorouracil. In some embodiments of the methods described herein, the method further comprises administering to the subject leucovorin or levoleucovorin. In some embodiments of the methods described herein, the method further comprises administering to the subject leucovorin. In some embodiments of the methods described herein, the method further comprises administering to the subject levoleucovorin. In some embodiments of the methods described herein, the method further comprises administering to the subject 5 -fluorouracil and leucovorin or levoleucovorin. In some embodiments of the methods described herein, the method further comprises administering to the subject 5 -fluorouracil and leucovorin. In some embodiments of the methods described herein, the method further comprises administering to the subject 5 -fluorouracil and levoleucovorin. In some embodiments of the method described herein, the method further comprises administering to the subject 5 -fluorouracil and oxaliplatin.

[0072] In another aspect, provided herein is a method for treating cancer in a subject comprising administering to the subject specific combinations comprising the present anti- human-B7-H3 antibody drug conjugate, pembrolizumab, 5-fluorouracil, and one from the list consisting of leucovorin, levoleucovorin and oxaliplatin.

[0073] Thus, in some embodiments, provided herein is a method for treating cancer i a subject in need thereof comprising:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I22NAI-5007064122wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin. In some embodiments, the drug-linker of Formula I is conjugated to the anti -human B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0074] In some embodiments, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula IIFormula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:23NAI-5007064122(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin.

[0075] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0076] In some embodiments, the combinational therapies provided herein are for treating a cancer associated with B7-H3. In some embodiments, the cancer is esophageal squamous cell carcinoma (ESCC). In some embodiments, the ESCC is unresectable or metastatic. In some embodiments, the ESCC is locally advanced unresectable ESCC. In some embodiments, the ESCC is metastatic ESCC. In other embodiments, the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC. In some embodiments, the subject has not had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer. In some embodiments, the subject has received prior neoadjuvant or adjuvant therapy.Dosage and Administration of Anti-human-B7-H3 Antibody-Drug Conjugate

[0077] Any suitable dose(s) of the anti-human-B7-H3 ADC may be used in the methods, compositions, and kits described herein. In some embodiments, the anti-human-B7-H3 ADC is administered at a dose of about 4 mg / kg, about 6 mg / kg, about 8 mg / kg, or about 12 mg / kg of the subject’s body weight. In some embodiments, the anti-human-B7-H3 ADC is administered at a dose of about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, or about 12.0 mg / kg. In some embodiments, the anti-human-B7-H3 ADC is administered at a dose of 8 mg / kg. In some embodiments, the anti-human-B7-H3 ADC is administered at a dose of 12 mg / kg.24NAI-5007064122

[0078] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-B7-H3 ADC is administered intravenously (IV). In some embodiments, the anti-human-B7-H3 ADC is administered via IV infusion, for example for about 20 minutes to about 120 minutes. In some embodiments, the dose of the anti-human-B7-H3 ADC is administered via a 30 ± 5 minute IV infusion. In some embodiments, the pembrolizumab is administered intravenously using a 30-minute IV infusion. In some embodiments, pembrolizumab is administered intravenously using a 30-minute IV infusion (-5 minutes / +10 minutes).

[0079] In certain embodiments, the anti-human-B7-H3 ADC dose is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the anti-human-B7-H3 ADC dose is administered every three weeks (±3 days). In some embodiments, the anti-human-B7-H3 ADC dose is administered once every three weeks until progressive disease (PD) or toxicity.Dosage and Administration of Pembrolizumab

[0080] Any suitable dose(s) of pembrolizumab may be used in the methods, compositions, and kits described herein. In some embodiments, pembrolizumab is administered at a dose of about 200 mg. In some embodiments, pembrolizumab is administered at a dose of about 400 mg.

[0081] In some embodiments, for example, relevant to any method as disclosed herein, the pembrolizumab is administered intravenously (IV). In some embodiments, the pembrolizumab is administered via IV infusion, for example for about 20 minutes to about 120 minutes. In some embodiments, the pembrolizumab is administered via a 30 (- 5 minute or + 10 minute) IV infusion. In some embodiments, the pembrolizumab is administered via a 30 minute IV infusion. In some embodiments, for example, relevant to any method as disclosed herein, the pembrolizumab is administered subcutaneously.

[0082] In some embodiments, for example, relevant to any method as disclosed herein, the target dose is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the target dose is administered every three weeks (±3 days). In some embodiments, for example, relevant to any method as disclosed herein, the target dose is administered for about 1 week to about 35 weeks. In some embodiments, the pembrolizumab is administered every three weeks for up to about 35 weeks.25NAI-5007064122

[0083] In some embodiments, pembrolizumab is administered subcutaneously or intravenously, on a weekly, biweekly, triweekly, every 4 weeks, every 5 weeks, every 6 weeks, monthly, bimonthly, or quarterly basis at about 10, about 20, about 50, about 80, about 100, about 200, about 300, about 400, about 500, about 1000 or about 2500 mg / subject.

[0084] In some specific methods, the dose of pembrolizumab is from about 0.01 mg / kg to about 50 mg / kg, from about 0.05 mg / kg to about 25 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, from about 0.2 mg / kg to about 9 mg / kg, from about 0.3 mg / kg to about 8 mg / kg, from about 0.4 mg / kg to about 7 mg / kg, from about 0.5 mg / kg to about 6 mg / kg, from about 0.6 mg / kg to about 5 mg / kg, from about 0.7 mg / kg to about 4 mg / kg, from about 0.8 mg / kg to about 3 mg / kg, from about 0.9 mg / kg to about 2 mg / kg, from about 1.0 mg / kg to about 1.5 mg / kg, from about 1.0 mg / kg to about 2.0 mg / kg, from about 1.0 mg / kg to about 3.0 mg / kg, or from about 2.0 mg / kg to about 4.0 mg / kg.

[0085] In some specific methods, the dose of pembrolizumab is from about 10 mg to about 500 mg, from about 25 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 150 mg to about 250 mg, from about 175 mg to about 250 mg, from about 200 mg to about 250 mg, from about 150 mg to about 240 mg, from about 175 mg to about 240 mg, or from about 200 mg to about 240 mg. In some embodiments, the dose of pembrolizumab is about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 240 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg.

[0086] In another embodiment of the disclosure, pembrolizumab is administered in a liquid medicament at a dose selected from the group consisting of 1 mg / kg Q2W, 2 mg / kg Q2W, 3 mg / kg Q2W, 5 mg / kg Q2W, 10 mg / kg Q2W, 1 mg / kg Q3W, 2 mg / kg Q3W, 3 mg / kg Q3W, 5 mg / kg Q3W, or 10 mg / kg Q3W. In other embodiments, pembrolizumab is administered in a liquid medicament at a flat dose such as 200 mg Q3W or 400 mg Q6W.

[0087] In some embodiments of the methods, compositions, kits and uses described herein, the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg pembrolizumab once every three or six weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered 2 mg / kg pembrolizumab once every three weeks. In one embodiment, the human patient is administered 400 mg pembrolizumab once every three weeks.26NAI-5007064122

[0088] In certain embodiments of the methods, compositions, kits and uses described herein, the human patient is administered 400 mg pembrolizumab once every six weeks.

[0089] In some embodiments of the methods, compositions, kits and uses described herein, the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 400 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 480 mg pembrolizumab once every six weeks.

[0090] In some embodiments, pembrolizumab is provided as a liquid medicament that comprises 25 mg / ml pembrolizumab, 7% (w / v) sucrose, 0.02% (w / v) polysorbate 80 in 10 mM histidine buffer pH 5.5. In other embodiments, pembrolizumab is provided as a liquid medicament that comprises about 125 to about 200 mg / mL of pembrolizumab, or an antigen binding fragment thereof; about 10 mM histidine buffer; about 10 mM L-methionine, or a pharmaceutically acceptable salt thereof; about 7% (w / v) sucrose; and about 0.02 % (w / v) polysorbate 80.

[0091] In some embodiments, the selected dose of pembrolizumab is administered by IV infusion. In one embodiment, the selected dose of pembrolizumab is administered by IV infusion over a time period of between 25 and 40 minutes, or about 30 minutes. In other embodiments, the selected dose of pembrolizumab is administered by subcutaneous injection.

[0092] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In embodiments of the disclosure, the amount of pembrolizumab administered subcutaneously to the patient is from 320 mg to 420 mg, from 340 mg to 420 mg, from 345 mg to 415 mg, from 350 mg to 410 mg, from 355 mg to 405 mg, from 360 mg to 400 mg, from 365 mg to 395 mg, from 370 mg to 390 mg, from 375 mg to 385 mg, or from 379 mg to 381 mg. In one embodiment, pembrolizumab is administered by subcutaneous injection at a dose of about 280 mg to about 450 mg. In a further embodiment of the disclosure, pembrolizumab is administered by subcutaneous injection at a dose of about 300 mg to about 450 mg. In yet a further embodiment of the disclosure, pembrolizumab is administered subcutaneously at a dose of about 320 mg to about 450 mg.

[0093] In embodiments of the disclosure, pembrolizumab is administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 130 mg / mL. In embodiments of the disclosure, pembrolizumab administered subcutaneously to the patient, wherein the pembrolizumab is part of a composition and is present in the composition at a concentration of 165 mg / mL. In27NAI-5007064122embodiments of the disclosure, pembrolizumab is administered subcutaneously to the patient in two injections. In embodiments of the disclosure, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in one pre-filled syringe. In embodiments of the disclosure, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in two pre-filled syringes.

[0094] In one embodiment, the selected dose of pembrolizumab is administered by subcutaneous injection at a dose that is at least about 1.6 times higher than a 200 mg or a 2 mg / kg dose. In one embodiment, the subcutaneous dose is administered once every three weeks. In one embodiment, the subcutaneous dose is administered once every six weeks. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 63%. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 64%. In one embodiment, the bioavailability of the pembrolizumab subcutaneous dose is at least 66%.Dosage and Administration of 5-Fluorouracil (5-FU)

[0095] Any suitable dose(s) of 5 -fluorouracil may be used in the methods, compositions, and kits described herein. In some embodiments, the 5 -fluorouracil is administered to the subject at a dose of about 400 mg / m2, about 800 mg / m2, about 1200 mg / m2, about 1600 mg / m2, about 2000 mg / m2, about 2400 mg / m2, or about 2800 mg / m2. In some embodiments, the 5 -fluorouracil is administered to the subject at a dose of about 400 mg / m2. In some embodiments, the 5 -fluorouracil is administered to the subject at a dose of about 2000 mg / m2. In some embodiments, the 5 -fluorouracil is administered to the subject at a dose of about 2400 mg / m2. In some embodiments, the 5 -fluorouracil is administered to the subject at a dose of about 2800 mg / m2.

[0096] In certain embodiments, the 5-FU is administered intravenously (IV). In some embodiments, the 5-FU is administered via IV infusion. In certain embodiments, the 5-FU is administered via bolus IV administration. In certain embodiments, the 5-FU is administered at a dose of about 400 mg / m2via bolus IV administration followed by about 2400 mg / m2via continuous IV administration.

[0097] In certain embodiments, the 5-FU dose is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the 5-FU dose is administered every three weeks (±3 days).

[0098] In certain embodiments, the 5-FU and oxaliplatin are administered intravenously (IV). In some embodiments, the 5-FU and oxaliplatin are administered via IV infusion. In28NAI-5007064122certain embodiments, the 5-FU is administered via continuous IV administration. In certain embodiments, the 5-FU is administered in a dose of about 2400 mg / m2and the oxaliplatin is administered in a dose of about 60 mg / m2. In certain embodiments, the 5-FU and oxaliplatin doses are administered once every week, once every two weeks or once every three weeks. In certain embodiments, the 5-FU dose is administered every two weeks (±3 days) and the oxaliplatin dose is administered every two weeks (±3 days).Dosage and Administration of Leucovorin or Levoleucovorin

[0099] Any suitable dose(s) of leucovorin or levoleucovorin may be used in the methods, compositions, and kits described herein. In some embodiments, the leucovorin is administered to the subject at a dose of about 400 mg / m2. In some embodiments, the levoleucovorin is administered to the subject at a dose of about 200 mg / m2.

[0100] In certain embodiments, the leucovorin or levoleucovorin dose is administered once every week, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, the leucovorin or levoleucovorin dose is administered every two weeks (±3 days).

[0101] In certain embodiments the leucovorin or levoleucovorin is administered intravenously (IV). In some embodiments, the leucovorin or levoleucovorin is administered via IV infusion. In some embodiments, the leucovorin or levoleucovorin is administered once every three weeks until progressive disease (PD) or toxicity.Dosage and Administration of Oxaliplatin

[0102] Any suitable dose(s) of oxaliplatin may be used in the methods, compositions, and kits described herein. In some embodiments, the oxaliplatin is administered to the subject at a dose of about 60 mg / m2, about 65 mg / m2, about 70 mg / m2, about 75 mg / m2, about 80 mg / m2, or about 85 mg / m2. In some embodiments, the oxaliplatin is administered to the subject at a dose of about 60 mg / m2. In certain embodiments, the oxaliplatin dose is administered once every week, once every two weeks or once every three weeks. In certain embodiments, the oxaliplatin dose is administered every two weeks (±3 days). In certain embodiments, the oxaliplatin dose is administered every two weeks until progressive disease (PD) or toxicity.

[0103] In certain embodiments, the oxaliplatin is administered intravenously (IV). In some embodiments, the oxaliplatin is administered via IV infusion.Dose Modification

[0104] Dose Modification for Anti-human-B7-H3 antibody-drug conjugate29NAI-5007064122

[0105] In some embodiments, the dose of the anti-human-B7-H3 antibody-drug conjugate described herein can be modified. Non-limiting examples of dose modifications are interruption, delay, reduction, and discontinuation.

[0106] In some embodiments, the dose of the anti-human-B7-H3 antibody-drug conjugate can be modified based on dose modification criteria (e.g., the presence of one or more adverse events). In some embodiments, the adverse event is a hematologic toxicity selected from decreased neutrophil count, decreased white blood cell count, decreased lymphocyte count, anemia, or decreased platelet count. In some embodiments, the adverse event is a non- hematologic toxicity. In some embodiments, the adverse event is a hematologic toxicity. In some embodiments, the adverse event is a non-hematologic toxicity selected from cardiac toxicity or electrocardiogram QT interval prolongation.

[0107] In some embodiments, the adverse event is an interstitial lung disease or pneumonitis. In some embodiments, the adverse event is an ocular toxicity. In some embodiments, the adverse event is increased blood creatinine (e.g., Grade 3 (>3.0 x baseline or >3.0 to 6.0 x ULN) or Grade 4 (>6.0 x ULN)). In some embodiments, the adverse event is a hepatotoxicity (e.g., AST / ALT >3.0 x ULN with simultaneous TBL >2.0 x ULN). In some embodiments, the adverse event is a gastrointestinal event selected from nausea, vomiting, diarrhea, or colitis. In some embodiments, the adverse event(s) is one or more from those listed in Tables 7, 8 and 10-14.

[0108] In some embodiments, the dose of the anti-human-B7-H3 antibody-drug conjugate can be modified from about 12 mg / kg of the subject’s body weight to about 10 mg / kg of the subject’s body weight. In some embodiments, the dose of the anti-human-B7-H3 antibodydrug conjugate can be modified from about 10 mg / kg of the subject’s body weight to about 8 mg / kg of the subject’s body weight. In some embodiments, the dose of the anti-human-B7- H3 antibody-drug conjugate can be modified from about 8 mg / kg of the subject’s body weight to about 6.4 mg / kg of the subject’s body weight. In some embodiments, the dose of the anti-human-B7-H3 antibody-drug conjugate can be modified from about 6.4 mg / kg of the subject’s body weight to about 4.8 mg / kg of the subject’s body weight.

[0109] Dose Modification for Pembrolizumab

[0110] In some embodiments, the dose of the pembrolizumab described herein can be modified (e.g., by interruption, delay, reduction, and / or discontinuation). In some embodiments, the dose of the pembrolizumab can be modified based on dose modification criteria (e.g., the presence of one or more adverse events).30NAI-5007064122

[0111] In some embodiments, the adverse event is an infusion reaction. In some embodiments, the adverse event is an overlapping toxicity (e.g., an overlapping toxicity related to the anti-human-B7-H3 antibody-drug conjugate and pembrolizumab). In some embodiments the adverse event is an immune-related adverse events associated with pembrolizumab monotherapy, coformulations, or immuno-oncology (IO) combinations. In some embodiments, the adverse event is an immune-related event. Non-limiting examples of immune-related adverse events include pneumonitis, diarrhea / colitis, AST or ALT elevation or increased bilirubin, type 1 diabetes mellitus (T1DM) or hyperglycemia, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, neurological toxicities, myocarditis, and exfoliative dermatologic conditions. In some embodiments, the dose modification and / or adverse event(s) is one or more from those listed in Tables 12-14.

[0112] Dose Modification for 5 -fluorouracil

[0113] In some embodiments, the dose of the 5 -fluorouracil described herein can be modified (e.g., by interruption, delay, reduction, and / or discontinuation). In some embodiments, the dose of the pembrolizumab can be modified based on dose modification criteria (e.g., the presence of one or more adverse events).

[0114] In some embodiments, the dose of the 5 -fluorouracil can be modified from about 400 mg / m2(bolus) plus about 2400 mg / m2(continuous) to about 2400 mg / m2(continuous). In some embodiments, the dose of the pembrolizumab can be modified from about 2400 mg / m2(continuous) to about 2000 mg / m2(continuous). In some embodiments, the dose of the pembrolizumab can be modified from about 2000 mg / m2(continuous) until discontinued.

[0115] In some embodiments, the adverse event is a hematologic toxicity (e.g., neutropenia, febrile neutropenia, and thrombocytopenia). In some embodiments, the adverse event is a non-hematologic toxicity (e.g., diarrhea, mucositis, and hand-foot syndrome).Exemplary Combinational Treatments

[0116] In some specific embodiments, provided herein is provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:31NAI-5007064122Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC). In some embodiments, the drug-linker of Formula I is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the anti-human-B7-H3 ADC and the pembrolizumab are administered intravenously (IV). In some embodiments, the ADC and the pembrolizumab are administered via IV infusion. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 200 mg. In some embodiments, the ADC is administered at a dose of about 8 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 200 mg. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the ADC is administered at a dose of about 832NAI-5007064122mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 200 mg every three weeks. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 400 mg every six weeks. In some embodiments, the ADC is administered at a dose of about 8 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 200 mg every three weeks. In some embodiments, the ADC is administered at a dose of about 8 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 400 mg every six weeks. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, and the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day, and the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day. In other embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, and the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day, and the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day. In some embodiments, the dose of the ADC is administered concurrently with pembrolizumab. In some embodiments, the ADC is administered after completion of the pembrolizumab infusion.

[0117] In some embodiments, provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula II33NAI-5007064122Formula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC). In some embodiments, the anti-human-B7-H3 ADC and the pembrolizumab are administered intravenously (IV). In some embodiments, the ADC and the pembrolizumab are administered via IV infusion. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight and the pembrolizumab is administered to the subject at a dose of about 200 mg. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, and the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day, and the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day. In some34NAI-5007064122embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day, and the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, every six weeks + / - 2 days, or every six weeks + / - 1 day. In some embodiments, the dose of the ADC is administered concurrently with pembrolizumab. In some embodiments, the ADC is administered after completion of the pembrolizumab infusion.

[0118] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0119] In some embodiments, provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ35NAI-5007064122ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin or levoleucovorin. In some embodiments, the drug-linker of Formula I is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the ADC, pembrolizumab, 5- FU and leucovorin (or levoleucovorin) are administered intravenously (IV). In some embodiments, the ADC, pembrolizumab, 5-FU and leucovorin (or levoleucovorin) are administered to the subject via IV infusion. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 200 mg, the 5-FU is administered at a dose of about 400 mg / m2bolus IV infusion followed by 2400 mg / m2continuous IV infusion, and the leucovorin is administered at a dose of about 400 mg / m2(or the levoleucovorin is administered at a dose of about 200 mg / m2). In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 400 mg, the 5- FU is administered at a dose of about 400 mg / m2bolus IV infusion followed by 2400 mg / m2continuous IV infusion, and the leucovorin is administered at a dose of about 400 mg / m2(or the levoleucovorin is administered at a dose of about 200 mg / m2). In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, the 5-FU is administered by intravenous administration every two weeks + / - 3 days, and the leucovorin (or levoleucovorin) is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day, and the 5-FU is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, the 5- FU is administered by intravenous administration every two weeks + / - 3 days, and the leucovorin (or levoleucovorin) is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day, and the 5-FU is administered to the subject by intravenous36NAI-5007064122administration every six weeks + / - 3 days, every six weeks + / - 2 days, or every six weeks + / - 1 day. In some embodiments, the ADC is administered after completion of the pembrolizumab infusion. In some embodiments, the antibody-drug conjugate is administered after pembrolizumab and before the chemotherapy (i.e., 5 -fluorouracil and leucovorin (or levoleucovorin)).

[0120] In some embodiments, provided is a method for treating cancer in a subject in need thereof. The method comprises(i) administering to the subject an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula IIFormula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin or levoleucovorin. In some embodiments, the37NAI-5007064122ADC, pembrolizumab, 5-FU and leucovorin (or levoleucovorin) are administered intravenously (IV). In some embodiments, the ADC, pembrolizumab, 5-FU and leucovorin (or levoleucovorin) are administered to the subject via IV infusion. In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 200 mg, the 5-FU is administered at a dose of about 400 mg / m2bolus IV infusion followed by 2400 mg / m2continuous IV infusion, and the leucovorin is administered at a dose of about 400 mg / m2(or the levoleucovorin is administered at a dose of about 200 mg / m2). In some embodiments, the ADC is administered at a dose of about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 400 mg, the 5-FU is administered at a dose of about 400 mg / m2bolus IV infusion followed by 2400 mg / m2continuous IV infusion, and the leucovorin is administered at a dose of about 400 mg / m2(or the levoleucovorin is administered at a dose of about 200 mg / m2). In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, the 5-FU is administered by intravenous administration every two weeks + / - 3 days, and the leucovorin (or levoleucovorin) is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the 5-FU is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day; and the leucovorin (or levoleucovorin) is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, the 5-FU is administered by intravenous administration every two weeks + / - 3 days, and the leucovorin (or levoleucovorin) is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, every six weeks + / - 2 days, or every six weeks + / - 1 day; the 5-FU is administered to the subject by intravenous administration every two weeks38NAI-5007064122+ / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day; and the leucovorin (or levoleucovorin) is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day. In some embodiments, the ADC is administered after completion of the pembrolizumab infusion. In some embodiments, the antibody-drug conjugate is administered after pembrolizumab and before the chemotherapy (i.e., 5 -fluorouracil and leucovorin (or levoleucovorin)).

[0121] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0122] In some embodiments, provided is a method for treating cancer in a subject in need thereof. The method comprises(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ39NAI-5007064122ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject oxaliplatin. In some embodiments, the drug-linker of Formula I is conjugated to the anti-human B7-H3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the ADC, pembrolizumab, 5-FU and oxaliplatin are administered intravenously (IV). In some embodiments, the ADC, pembrolizumab, 5-FU and oxaliplatin are administered to the subject via IV infusion. In some embodiments, the ADC is administered at a dose of about 8 mg / kg to about 12 mg / kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 8 mg / kg or about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 200 mg, the 5-FU is administered at a dose of about 2400 mg / m2continuous IV infusion, and the oxaliplatin is administered at a dose of about 60 mg / m2. In some embodiments, the ADC is administered at a dose of about 8 mg / kg or about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 400 mg, the 5-FU is administered at a dose of about 2400 mg / m2continuous IV infusion, and the oxaliplatin is administered at a dose of about 60 mg / m2. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, the 5-FU is administered by intravenous administration every two weeks + / - 3 days, the oxaliplatin is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the 5-FU is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day; and the oxaliplatin is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, the 5- FU is administered by intravenous administration every two weeks + / - 3 days, the oxaliplatin is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every40NAI-5007064122three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, every six weeks + / - 2 days, or every six weeks + / - 1 day; the 5-FU is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day; and the oxaliplatin is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day. In some embodiments, the antibody-drug conjugate is administered after pembrolizumab and before the chemotherapy (i.e., 5-fluorouracil, and oxaliplatin).

[0123] In some embodiments, provided is a method for treating cancer in a subject in need thereof. The method comprises(i) administering to the subject an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a drug-linker of Formula IIFormula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;41NAI-5007064122(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject oxaliplatin. In some embodiments, the ADC, pembrolizumab, 5-FU and oxaliplatin are administered intravenously (IV). In some embodiments, the ADC, pembrolizumab, 5-FU and oxaliplatin are administered to the subject via IV infusion. In some embodiments, the ADC is administered at a dose of about 8 mg / kg to about 12 mg / kg of the subject’s body weight. In some embodiments, the ADC is administered at a dose of about 8 mg / kg or about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 200 mg, the 5-FU is administered at a dose of about 2400 mg / m2continuous IV infusion, and the oxaliplatin is administered at a dose of about 60 mg / m2. In some embodiments, the ADC is administered at a dose of about 8 mg / kg or about 12 mg / kg of the subject’s body weight, the pembrolizumab is administered at a dose of about 400 mg, the 5-FU is administered at a dose of about 2400 mg / m2continuous IV infusion, and the oxaliplatin is administered at a dose of about 60 mg / m2. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, the 5-FU is administered by intravenous administration every two weeks + / - 3 days, and the oxaliplatin is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the pembrolizumab is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the 5-FU is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day; and the oxaliplatin is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, the 5-FU is administered by intravenous administration every two weeks + / - 3 days, and the oxaliplatin is administered by intravenous administration every two weeks + / - 3 days. In some embodiments, the ADC is administered to the subject by intravenous administration every three weeks + / - 3 days, every three weeks + / - 2 days, or every three weeks + / - 1 day; the pembrolizumab is administered to the subject by intravenous administration every six weeks + / - 3 days, every six weeks + / - 242NAI-5007064122days, or every six weeks + / - 1 day; the 5-FU is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day; and the oxaliplatin is administered to the subject by intravenous administration every two weeks + / - 3 days, every two weeks + / - 2 days, or every two weeks + / - 1 day. In some embodiments, the antibody-drug conjugate is administered after pembrolizumab and before the chemotherapy (i.e., 5 -fluorouracil and oxaliplatin).

[0124] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0125] In some embodiments, pembrolizumab is administered at a dose of 200 mg every three weeks.

[0126] In other embodiments, pembrolizumab is administered at a dose of 400 mg every six weeks.Methods or Uses for Cancer Treatment

[0127] In some embodiments, the method provided herein is for treating a neoplastic condition. Neoplastic conditions, in some embodiments, are benign or malignant; solid tumors or blood neoplasia. In one embodiment, the neoplastic condition is a cancer. In one embodiment, the neoplastic condition is squamous cell carcinoma of the esophagus. In some embodiments, the neoplastic condition (e.g., cancer) is associated with B7-H3 expression.

[0128] In some embodiments, the method provided herein is for treating a cancer. In some embodiments, the cancer is a cancer associated with B7-H3 expression. In one aspect, the method provided herein is for treating esophageal squamous cell carcinoma (ESCC). In one aspect, the method provided herein is for treating ESCC that is unresectable or metastatic. In some embodiments, the ESCC is locally advanced unresectable ESCC. In some embodiments, the ESCC is metastatic ESCC. In another aspect, the method provided herein is for treating a histologically or cytologically confirmed locally advanced unresectable or metastatic ESCC.

[0129] In certain embodiments, the combination therapy provided herein is used to treat a subject that has not previously been treated (with anti-cancer agent(s)). In some embodiments, the subject has had no prior systemic anticancer therapy. In certain embodiments, the combination therapy provided herein is used to treat a subject as a first-line therapy. In certain embodiments, the combination therapy provided herein is used to treat a43NAI-5007064122subject that has not previously been treated with an anti-PD-1, anti-PD-Ll, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD 137). In certain embodiments, the combination therapy provided herein is used to treat a subject that has not previously been treated with orlotamab, enoblituzumab, or other B7-H3 -targeted agents.

[0130] In certain embodiments, the subject has not received prior treatment with a topoisomerase-I inhibitor (including ADC) and has not received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of treatment intervention.

[0131] In certain embodiments, the combination therapy provided herein is used to treat a subject that has not received prior radiotherapy within 2 weeks of start of treatment intervention.

[0132] In certain embodiments, the combination therapy of the disclosure reduces the growth of tumor cells in vivo when administered to a subject who has tumor cells that express B7-H3. Measurement of the reduction of the growth of tumor cells can be determined by multiple different methodologies well known in the art. Non-limiting examples include direct measurement of tumor dimension, measurement of excised tumor mass and comparison to control subjects, measurement via imaging techniques (e.g., CT or MRI) that may or may not use isotopes or luminescent molecules (e.g., luciferase) for enhanced analysis, and the like.

[0133] In specific embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, with an about 100% reduction in tumor growth indicating a complete response and disappearance of the tumor. In further embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-100%, about 75-100% or about 90-100%. In further embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100%.

[0134] In one embodiment, the subject is a human subject. In some embodiments, the human subject is an adult human subject, e.g., greater than or equal to 18 years of age.

[0135] In one aspect, provided herein is use of pembrolizumab and an anti-human-B7-H3 antibody-drug conjugate (e.g., an anti-human B7-H3 antibody-drug conjugate) for the manufacture of a medicament for treating ESCC. In another aspect, provided herein is use of44NAI-5007064122pembrolizumab for the manufacture of a medicament in combination with an anti-B7-H3 antibody-drug conjugate for treating ESCC. In yet another aspect, provided herein is use of an anti-human-B7-H3 antibody-drug conjugate for the manufacture of a medicament in combination with pembrolizumab for treating ESCC.

[0136] In one aspect, provided herein is pembrolizumab for use in combination with an anti-human-B7-H3 antibody-drug conjugate in treating cancer in a subject. In one aspect, provided herein is pembrolizumab for use in combination with an anti-human-B7-H3 antibody-drug conjugate in treating ESCC in a subject.

[0137] In certain embodiments, provided herein is a method of treating cancer in a subject comprising administering pembrolizumab for use in combination with an anti-human- B7-H3 antibody-drug conjugate, 5 -fluorouracil, and leucovorin or levoleucovorin. In certain embodiments, provided herein is a method of treating cancer in a subject comprising administering pembrolizumab for use in combination with an anti-human-B7-H3 antibodydrug conjugate, 5-fluorouracil, and oxaliplatin.3. Anti-human-B7-H3 antibody-drug conjugate

[0138] B7-H3, one of the B7 family members expressed in antigen-presenting cells as a co-stimulator, is considered to act on receptors on T cells and enhance or suppress immune effect. B7-H3 is a single transmembrane protein and has two variants. B7-H3 variant 1 (41g- B7-H3) contains two each of V- or C- like Ig domains, and B7-H3 variant 2 (2Ig-B7-H3) contains one each of V- or C -like Ig domain. Amino acid sequences of these variants are known in the art. The amino acid sequence of human 4Ig-B7-H3 is for example shown in UniProt accession number Q5ZPR3-1 (2004-11-23 vl) or GenBank accession number: NP 001019907.1. The N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP 001019907.1. The amino acid sequence of human 2Ig-B7-H3 is for example shown in UniProt accession number Q5ZPR3-2, or GenBank accession number: NP 001316557.1 or NP 079516.1. The N-terminal amino acid residues 1 to 28 are explained to correspond to a signal sequence under the definition of GenBank accession number: NP 001316557.1 or NP 079516.1. B7- H3 protein has a very limited expression on normal tissues because of its post-transcriptional regulation by microRNAs. However, B7-H3 protein is expressed at high frequency on many different cancer types.45NAI-5007064122

[0139] In one aspect of the method provided herein, the method comprises administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human-B7-H3 antibody or a functional fragment thereof and the druglinker of Formula I is conjugated to the anti-human-B7-H3 antibody or the functional fragment thereof via a thioether bond. In Formula I, n represents the drug to antibody ratio. Drug to antibody ratio (DAR) as used herein: (i) when referring to a composition of the antibody-drug conjugates, is the average number of drug molecules (or units of a drug-linker) that are conjugated to the anti-human-B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate, and (ii) when referring to a single antibody-drug conjugate, is the discrete integer of drug molecules (or units of a drug-linker) that are conjugated to the anti- human-B7-H3 antibody or functional fragment thereof in the antibody-drug conjugate. Methods to determine DAR are well known to the skilled person and include methods using reverse phase chromatography, or HPLC-MS.

[0140] In some embodiments of the method provided herein, with respect to a composition of antibody-drug conjugates, n is from about 2 to about 8, from about 3 to about 5, from about 3.5 to about 4.5, or about 4. In the present disclosure, the term “about 4” is from 3.8 to 4.2, from 3.9 to 4.1, or 4. In other embodiments, the number of the drug or the drug-linker conjugated per antibody molecule in the anti-human-B7-H3 antibody-drug conjugate in the instant method is an integer in the range from 2 to 8, for example, 2, 4, 6, or 8. In a specific embodiment, the number of the drug or the drug-linker conjugated per antibody molecule in the anti-human-B7-H3 antibody-drug conjugate is 4.46NAI-5007064122

[0141] In one aspect of the present disclosure, the anti-human-B7-H3 antibody-drug conjugate is an anti-human-B7-H3 antibody-drug conjugate, in which a drug-linker represented by the following formula:Formula II wherein A represents a connecting position to an anti-human-B7-H3 antibody or a functional fragment thereof; is conjugated to the anti-human-B7-H3 antibody or the functional fragment thereof via a thioether bond.

[0142] In the present disclosure, the partial structure consisting of a linker and a drug in the anti-human-B7-H3 antibody-drug conjugate is referred to as a “drug-linker.” The druglinker is connected to a thiol group (i.e., the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[0143] In particular embodiments, the drug-linker of the present disclosure includes exatecan (IUPAC name: (lS,9S)-l-amino-9-ethyl-5-fhioro-l,2,3,9,12,15-hexahydro-9- hydroxy-4-methyl- 1 OH, 13H-benzo[de]pyrano[3 ',4' :6,7]indolizino[ 1 ,2-b]quinolin- 10,13- dione, (also expressed as chemical name: (lS,9S)-l-amino-9-ethyl-5-fhioro-2,3-dihydro-9- hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin- 10,13(9H,15H)-dione)), which is a topoisomerase I inhibitor, as a component.

[0144] Exatecan is a camptothecin derivative having an antitumor effect, represented by the following formula:47NAI-5007064122Formula III

[0145] After internalization into cancer cells, the anti-human-B7-H3 antibody-drug conjugate used in the present disclosure releases the compound represented by the following formula IV, and thereby exerts an antitumor effect.Formula IV

[0146] The aforementioned compound is inferred to be the original source of the antitumor activity of the anti-human-B7-H3 antibody-drug conjugate used in the present disclosure, and has a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016; 22(20):5097-5108).

[0147] In some embodiments, the anti-human-B7-H3 antibody-drug conjugate used in the present disclosure has a bystander effect (Ogitani Y. et al., Cancer Science, 2016; 107, 1039- 1046). The bystander effect is considered to be exerted through a process such that the anti- human-B7-H3 antibody-drug conjugate used in the present invention is internalized in cancer cells expressing the target and the aforementioned compound is released and then exerts an antitumor effect also on nearby cancer cells not expressing the target.

[0148] Relevant to any method as disclosed herein, the anti-human-B7-H3 antibody (e.g., anti-human B7-H3 antibody) or a functional fragment thereof in the anti-human-B7-H3 antibody-drug conjugate used in the present invention may be derived from any species, but is preferably an antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the48NAI-5007064122antibody is derived from species other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the present invention may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. Examples of anti-human-B7-H3 antibodies include, but are not limited to, M30-H1-L4 described in WO2014 / 057687 or those described in W02024 / 061306.

[0149] In the anti-human-B7-H3 antibody in the anti-human-B7-H3 antibody-drug conjugate relevant to any method as disclosed herein, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of the chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or O- linked carbohydrate chain, and the like. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and others known in the art), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant.

[0150] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell can be deleted or “clipped” (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell can be deleted and a proline residue newly located at the carboxyl terminus can be amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence typically do not affect the antigenbinding affinity and the effector function (e.g., complement activation or antibody-dependent cellular cytotoxicity) of the antibody. Therefore, in the anti-human-B7-H3 antibody according to the present methods, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by49NAI-5007064122amidation of the deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present disclosure is not limited to the above variants as long as the antigenbinding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present invention may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom.

[0151] In some embodiments, an N-terminal E or Q of the anti-human-B7-H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K of the anti-human-B7-H3 antibody provided herein is removed. In other embodiments, an N-terminal E or Q of the anti-human-B7-H3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K (e.g., heavy chain C terminal amino acid) of the anti-human-B7-H3 antibody is removed. The present disclosure includes any of the above described post-translational modifications of any of the anti-human-B7-H3 antibody provided herein.

[0152] All isotypes of the antibody according to the present disclosure, for example, IgG(IgGl, IgG2, IgG3, IgG4) are exemplified, and IgGl or IgG2 are exemplified preferably.

[0153] In an embodiment, the anti-human-B7-H3 antibody comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided herein, or a sequence with 95-99% identity with an amino acid sequence provided herein; and / or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided herein, or a sequence with 95-99% identity to an amino acid sequence provided herein. In some embodiments, for example, relevant to any method as disclosed herein, the anti-B7-H3 binding domain comprises three heavy chain CDRs (VH-CDR1, VH-CDR2, and VH-CDR3), and three light chain CDRs (VL-CDR1, VL-CDR2, and VL-CDR3). In some embodiments, the VH-CDR1 of the anti-human-B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 1, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 1. In some embodiments, the VH-CDR2 of the anti-human-B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 2, or a sequence comprising one or more50NAI-5007064122modifications or substitutions in SEQ ID NO: 2. In some embodiments, the VH-CDR3 of the anti-human-B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 3, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 3. In some embodiments, the VL-CDR1 of the anti-human-B7-H3 antibody comprises the amino acid sequence of SEQ ID NO: 4, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 4. In some embodiments, the VL-CDR2 of the anti-human-B7- H3 antibody comprises the amino acid sequence of SEQ ID NO: 5, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 5. In some embodiments, the VL- CDR3 of the anti-human-B7-H3 antibody comprises the amino acid sequence of SEQ ID NO:6, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 6.

[0154] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-B7-H3 antibody comprises as a VH, the amino acid sequence of SEQ ID NO:7, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 7. In some examples, the anti-human-B7-H3 antibody comprises as a VL, the amino acid sequence of SEQ ID NO: 8, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 8. In some examples, the anti-human-B7-H3 antibody comprises as a VL, the amino acid sequence of SEQ ID NO: 16, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16.

[0155] In one aspect, for example, relevant to any method as disclosed herein, the anti- human-B7-H3 antibody comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 7. In one aspect, for example, relevant to any method as disclosed herein, the anti-human-B7-H3 antibody comprises: a VL-CDR1, a VL-CDR2, and a VL- CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8, or a sequence that is at least about 60%, about 70%,51NAI-5007064122about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-human-B7-H3 antibody comprises: a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 16, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 16.

[0156] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-B7-H3 antibody comprises as a heavy chain (HC), the amino acid sequence of SEQ ID NO: 11, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 11. In some examples, the anti-human-B7-H3 antibody comprises as a light chain (LC), the amino acid sequence of SEQ ID NO: 12, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 12.

[0157] In some embodiments, the HC of the anti-human-B7-H3 antibody of the present disclosure comprises a signal sequence at the N-terminus. In one embodiment, the signal sequence comprises the amino acid sequence of SEQ ID NO: 14. In some embodiments, the LC of the anti-human-B7-H3 antibody of the present disclosure comprises a signal sequence at the N-terminus. In one embodiment, the signal sequence comprises the amino acid sequence of SEQ ID NO: 15.

[0158] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising the anti-human-B7-H3 ADC (e.g., ifinatamab deruxtecan) described herein. The pharmaceutical composition of the present disclosure may comprise a plurality of anti-human-B7-H3 ADCs as disclosed herein.

[0159] The pharmaceutical composition of the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection or a lyophilized injection, and can be even more preferably used as a lyophilized injection. In the case that the pharmaceutical composition of the present invention is an aqueous injection, it can be preferably diluted with a suitable diluent and then given as an intravenous infusion. For the52NAI-5007064122diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified.

[0160] In the case that the pharmaceutical composition of the present disclosure is a lyophilized injection, it can be preferably dissolved in water for injection, subsequently a required amount can be diluted with a suitable diluent and then given as an intravenous infusion. For the diluent, a dextrose solution, physiological saline, and the like, can be exemplified, and a dextrose solution can be preferably exemplified, and a 5% dextrose solution can be more preferably exemplified.4. Pembrolizumab and other anti-PD-1 antibodies

[0161] In some cases, an IO therapy includes an immune checkpoint inhibitor, e.g., a PD- 1 antagonist (e.g., an anti-PD-1 antibody) or a PD-L1 antagonist (e.g., an anti-PD-Ll antibody). In various embodiments, the anti-PD-1 antibody is pembrolizumab, cemiplimab, dostarlimab, toripalimab, retifanlimab, tislelizumab, camrelizumab, sintilimab, vopratelimab, spartalizumab, INCMGA00012 (MGA012), AMP-514 (MEDI0680), acrixolimab, or nivolumab. In various embodiments, the anti-PD-Ll antibody is atezolizumab, durvalumab, KN035, cosibelimab, or avelumab. The anti-PD-1 antibody used in the present invention is not particularly limited as long as the clinical efficacy and safety thereof have been confirmed, and nivolumab (International Publication No. WO 2006 / 121168, etc.), atezolizumab (International Publication No. WO 2010 / 077634, etc.), durvalumab (International Publication No. WO 2011 / 066389, etc.), avelumab (International Publication No. WO 2013 / 079174, etc.), and pembrolizumab (International Publication No. WO 2008 / 156712, etc.) can be preferably exemplified. In one aspect, for example, relevant to any method or composition as disclosed herein, the anti-PD-1 antibody (e.g., anti-human PD- 1 antibody) used in the present disclosure refers to an antibody which specifically binds to PD-1 (Programmed cell death-1; CD279; PDCD1), and has an activity of reducing, inhibiting, and / or interfering with signal transduction caused by interaction between PD-1 and PD-L1 or PD-L2 as a binding partner. In one aspect, the anti-PD-1 antibody used in the present disclosure is pembrolizumab (see, e.g., International Publication No. WO 2008 / 156712, which is incorporated by reference herein in its entirety).

[0162] Examples of monoclonal antibodies that bind to human PD-1, useful in the treatment methods, compositions, and uses of the disclosure, are described in US 7,521,051, US 8,008,449, and US 8,354,509.53NAI-5007064122

[0163] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising the pembrolizumab described herein, and at least one pharmaceutically acceptable carrier. A further embodiment provides the pembrolizumab packaged in lyophilized form, or packaged in an aqueous medium.

[0164] In some embodiments of the pharmaceutical compositions, the pembrolizumab described herein are encapsulated in nanoparticles. In some embodiments, the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots, superparamagnetic nanoparticles, dendrimers, or nanorods. In other embodiments of the pharmaceutical compositions, pembrolizumab is attached to liposomes. In some instances, the pembrolizumab is conjugated to the surface of liposomes. In some instances, the pembrolizumab is encapsulated within the shell of a liposome. In some instances, the liposome is a cationic liposome.5. Kits

[0165] Also provided herein is a kit comprising (i) an anti-human-B7-H3 ADC as disclosed herein (such as I-DXd), or a pharmaceutically acceptable salt thereof, or thae pharmaceutical composition comprising same, and (ii) pembrolizumab, or a pharmaceutical composition comprising the same.

[0166] Also provided herein are kits comprising (i) an anti-human-B7-H3 ADC as disclosed herein (such as I-DXd), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, and (ii) pembrolizumab, or a pharmaceutical composition comprising the same, and optionally, (iii) 5-fluorouracil, and leucovorin or levoleucovorin, or a pharmaceutical composition comprising same, or (iv) 5-fluorouracil and oxaliplatin, or a pharmaceutical composition comprising same.

[0167] Provided herein is a kit comprising (i) an anti-human-B7-H3 ADC as disclosed herein (such as I-DXd), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, (ii) pembrolizumab, or a pharmaceutical composition comprising the same, optionally (iii) 5-fluorouracil, and leucovorin or levoleucovorin, or a pharmaceutical composition comprising same, or optionally, (iv) 5-fluorouracil and oxaliplatin, or a pharmaceutical composition comprising same, and (v) instructions for use, e.g., for treating cancer (e.g., ESCC) in a subject in need thereof.

[0168] Also provided herein are kits comprising (i) an anti-human-B7-H3 ADC as disclosed herein (such as I-DXd), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, and (ii) pembrolizumab, or a pharmaceutical composition comprising the same, and optionally (iii) 5-fluorouracil, and leucovorin or54NAI-5007064122levoleucovorin, or a pharmaceutical composition comprising same, or optionally, (iv) 5- fluorouracil and oxaliplatin, or a pharmaceutical composition comprising same, any or all of which are packaged into suitable packaging material. A kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.

[0169] Any of the kits disclosed herein may further include (iii) 5-fluorouracil, and leucovorin or levoleucovorin, or the pharmaceutical composition comprising same, or (iv) 5- fluorouracil and oxaliplatin, or the pharmaceutical composition comprising same.

[0170] Kits provided herein can include labels or inserts. Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g., a box), or attached to, for example, an ampoule, tube, or vial containing a kit component. Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic / optical storage media, FLASH media, or memory type cards. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location, and date.

[0171] Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Kits can also be designed for cold storage.6. Illustrative Embodiments

[0172] Provided below is a list of non-limiting illustrative embodiments according to the present disclosure:

[0173] Embodiment 1. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:55NAI-5007064122Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

[0174] Embodiment 2. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II56NAI-5007064122Formula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC). In some further embodiments, the antibody-drug conjugate comprises an anti- human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0175] Embodiment 3. The method of embodiment 1 or 2, wherein the unresectable or metastatic ESCC is locally advanced unresectable or metastatic ESCC.

[0176] Embodiment 4. The method of embodiment 3, wherein the unresectable or metastatic ESCC is locally advanced unresectable ESCC.

[0177] Embodiment 5. The method of embodiment 3, wherein the unresectable or metastatic ESCC is metastatic ESCC.57NAI-5007064122

[0178] Embodiment 6. The method of any one of embodiments 1-5, wherein the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC.

[0179] Embodiment 7. The method of any one of embodiments 1-6, wherein the subject has not had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.

[0180] Embodiment 8. The method of any one of embodiments 1-7, wherein the subject has received prior neoadjuvant or adjuvant therapy.

[0181] Embodiment 9. The method of any one of embodiments 1-8, wherein the antihuman B7-H3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 2,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 3,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 4,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

[0182] Embodiment 10. The method of any one of embodiments 1-9, wherein the antihuman B7-H3 antibody or the functional fragment thereof comprises a VH comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 7, and a VL comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 8.

[0183] Embodiment 11. The method of any one of embodiments 1-10, wherein the antihuman B7-H3 antibody is an IgGl.

[0184] Embodiment 12. The method of any one of embodiments 1-11, wherein the antihuman B7-H3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 7, and a VL comprising the amino acid sequence of SEQ ID NO: 8.

[0185] Embodiment 13. The method of any one of embodiments 1-12, wherein the antihuman B7-H3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11, and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0186] Embodiment 14. The method of any one of embodiments 1-13, wherein the antibody-drug conjugate is ifinatamab deruxtecan.

[0187] Embodiment 15. The method of any one of embodiments 1-14, further comprising:58NAI-5007064122(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject leucovorin or levoleucovorin.

[0188] Embodiment 16. The method of any one of embodiments 1-14, further comprising:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject oxaliplatin.

[0189] Embodiment 17. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5-fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin.59NAI-5007064122

[0190] Embodiment 18. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin. In some further embodiments, the antibody-drug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of drug-linkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.60NAI-5007064122

[0191] Embodiment 19. The method of embodiment 17 or 18, wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

[0192] Embodiment 20. The method of embodiment 19, wherein the unresectable or metastatic ESCC is locally advanced unresectable or metastatic ESCC.

[0193] Embodiment 21. The method of embodiment 20, wherein the unresectable or metastatic ESCC is locally advanced unresectable ESCC.

[0194] Embodiment 22. The method of embodiment 20, wherein the unresectable or metastatic ESCC is metastatic ESCC.

[0195] Embodiment 23. The method of any one of embodiments 17-22, wherein the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC.

[0196] Embodiment 24. The method of any one of embodiments 17-23, wherein the subject has not had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.

[0197] Embodiment 25. The method of any one of embodiments 17-24, wherein the subject has received prior neoadjuvant or adjuvant therapy.

[0198] Embodiment 26. The method of any one of embodiments 17-25, wherein the method comprises:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject leucovorin or levoleucovorin.

[0199] Embodiment 27. The method of any one of embodiments 17-25, wherein the method comprises:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject oxaliplatin.

[0200] Embodiment 28. The method of any one of embodiments 1-27, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a dose of about 12 mg / kg of the subject’s body weight; and(ii) administering to the subject pembrolizumab at a dose of about 200 mg or about 400 mg.

[0201] Embodiment 29. The method of embodiment 28, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days; and61NAI-5007064122(ii) administering to the subject pembrolizumab by intravenous administration every three weeks + / - 3 days or every six weeks + / - 3 days.

[0202] Embodiment 30. The method of embodiment 15 or 26, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a dose of about 12 mg / kg of the subject’s body weight;(ii) administering to the subject pembrolizumab at a dose of about 200 mg;(iii) administering to the subject 5 -fluorouracil at a dose of about 400 mg / m2followed by about 2400 mg / m2;(iv) administering to the subject leucovorin at a dose of about 400 mg / m2or levoleucovorin at a dose of about 200 mg / m2.

[0203] Embodiment 31. The method of embodiment 30, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days; and(ii) administering to the subject pembrolizumab by intravenous administration every three weeks + / - 3 days;(iii) administering to the subject 5 -fluorouracil at a dose of about 400 mg / m2by bolus intravenous administration followed by about 2400 mg / m2by continuous intravenous administration every two weeks + / - 3 days; and(iv) administering to the subject leucovorin or levoleucovorin by intravenous administration every two weeks + / - 3 days.

[0204] Embodiment 32. The method of embodiment 16 or 27, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a dose of about 8 mg / kg or about 12 mg / kg of the subject’s body weight;(ii) administering to the subject pembrolizumab at a dose of about 200 mg;(iii) administering to the subject 5 -fluorouracil at a dose of about 2400 mg / m2; and(iv) administering to the subject oxaliplatin at a dose of about 60 mg / m2of the subject’s body weight.

[0205] Embodiment 33. The method of embodiment 32, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days;(ii) administering to the subject pembrolizumab by intravenous administration every three weeks + / - 3 days;62NAI-5007064122(iii) administering to the subject 5 -fluorouracil at a dose of about 2400 mg / m2by continuous intravenous administration every two weeks + / - 3 days; and(iv) administering to the subject oxaliplatin by intravenous administration every two weeks + / - 3 days.

[0206] Embodiment 34. The method of any one of embodiments 1-27, wherein the method comprises administering to the subject the antibody-drug conjugate at a dose of about 4 mg / kg, about 6 mg / kg, about 8 mg / kg, or about 12 mg / kg of the subject’s body weight.

[0207] Embodiment 35. The method of embodiment 34, wherein the dose of the antibody-drug conjugate is a dose of about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, 8 mg / kg, about8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, or about 12.0 mg / kg.

[0208] Embodiment 36. The method of embodiment 34 or 35, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days.

[0209] Embodiment 37. The method of any one of embodiments 1-27, wherein if the method comprises administering to the subject 5-fluorouracil, the dose of the 5 -fluorouracil is a dose of about 2800 mg / m2, about 2400 mg / m2, or about 2000 mg / m2.

[0210] Embodiment 38. The method of any one of embodiments 1 to 37, wherein the subject is greater than or equal to 18 years of age.

[0211] Embodiment 39. A pharmaceutical composition for use in treating unresectable or metastatic ESCC in a subject in need thereof, comprising:(A)(i) an antibody-drug conjugate, as defined in any one of embodiments 1-14, and(ii) pembrolizumab optionally in combination, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 28, 29, and 34-36 and pembrolizumab is administered as defined in any one of embodiments 28 or 29;(B)(i) the antibody-drug conjugate, as defined in any one of embodiments 1-14,(ii) pembrolizumab optionally in combination,(iii) 5-fluorouracil, and(iv) leucovorin or levoleucovorin,63NAI-5007064122wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 30, 31, and 34-36, pembrolizumab is administered as defined in embodiment 30 or 31, 5 -fluorouracil is administered as defined in embodiment 30 or 31, and leucovorin or levoleucovorin is administered as defined in embodiment 30 or 31;(C)(i) the antibody-drug conjugate, as defined in any one of embodiments 1-14,(ii) pembrolizumab optionally in combination,(iii) 5-fluorouracil, and(iv) oxaliplatin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 32-36, pembrolizumab is administered as defined in embodiment 32 or 33, 5-fluorouracil is administered as defined in embodiment 32 or 33, and oxaliplatin is administered as defined in embodiment 32 or 33.

[0212] Embodiment 40. A pharmaceutical composition for use in treating unresectable or metastatic ESCC in a subject in need thereof, comprising:(A)(i) an antibody-drug conjugate, as defined in any one of embodiments 1-14, in combination with (ii) pembrolizumab, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 28, 29, and 34-36 and pembrolizumab is administered as defined in any one of embodiment 28 or 29;(B)(i) the antibody-drug conjugate, as defined in any one of embodiments 1-14, in combination with (ii) pembrolizumab, (iii) 5-fluorouracil, and (iv) leucovorin or levoleucovorin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiment 30, 31, and 34-36, pembrolizumab is administered as defined in embodiment 30 or 31, 5-fluorouracil is administered as defined in embodiment 30 or 31, and leucovorin or levoleucovorin is administered as defined in embodiment 30 or 31; or(C)(i) the antibody-drug conjugate, as defined in any one of embodiments 1-14, in combination with (ii) pembrolizumab, (iii) 5-fluorouracil, and (iv) oxaliplatin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 32-36, pembrolizumab is administered as defined in embodiment 32 or64NAI-500706412233, 5-fluorouracil is administered as defined in embodiment 32 or 33, and oxaliplatin is administered as defined in embodiment 32 or 33.

[0213] Embodiment 41. A pharmaceutical composition for use in treating unresectable or metastatic ESCC in a subject in need thereof, comprising:(A)(ii) pembrolizumab, in combination with (i) an antibody-drug conjugate, as defined in any one of embodiments 1-14, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 28, 29, and 34-36 and pembrolizumab is administered as defined in any one of embodiment 28 or 29;(B)(ii) pembrolizumab, in combination with (i) the antibody-drug conjugate, as defined in any one of embodiments 1-14, (iii) 5-fluorouracil, and (iv) leucovorin or levoleucovorin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 30, 31, and 34-36, pembrolizumab is administered as defined in embodiments 30 or 31, 5-fluorouracil is administered as defined in embodiment 30 or 31, and leucovorin or levoleucovorin is administered as defined in embodiment 30 or 31; or(C)(ii) pembrolizumab, in combination with (i) the antibody-drug conjugate, as defined in any one of embodiments 1-14, (iii) 5-fluorouracil, and (iv) oxaliplatin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of embodiments 32-36, pembrolizumab is administered as defined in embodiment 32 or 33, 5-fluorouracil is administered as defined in embodiment 32 or 33, and oxaliplatin is administered as defined in embodiment 32 or 33.

[0214] Embodiment 42. The pharmaceutical composition of any one of embodiments 39- 41, wherein the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC.

[0215] Embodiment 43. Use of the antibody-drug conjugate as defined in any one of embodiments 1-14 for the preparation of a medicament for treating unresectable or metastatic ESCC, by administration in combination with pembrolizumab, optionally wherein the use further comprises administration of(i) 5-fluorouracil, and leucovorin or levoleucovorin; or(ii) 5-fluorouracil and oxaliplatin.65NAI-5007064122

[0216] Embodiment 44. The antibody-drug conjugate as defined in any one of embodiments 1-14 for use in combination with pembrolizumab in treating unresectable or metastatic ESCC in a subject, optionally wherein the antibody-drug conjugate is for use with(i) 5 -fluorouracil, and leucovorin or levoleucovorin; or(ii) 5 -fluorouracil and oxaliplatin.

[0217] Embodiment 45. A kit for treating unresectable or metastatic ESCC comprising:(i) antibody-drug conjugate as defined in any one of embodiments 1-14 , or a pharmaceutical composition comprising the same; and(ii) pembrolizumab, or a pharmaceutical composition comprising the same; optionally wherein the kit further comprises:(iii) 5-fluorouracil, and leucovorin or levoleucovorin; or(iv) 5-fluorouracil and oxaliplatin.

[0218] Embodiment 46. The method of any one of embodiments 1-38, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a first dose;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present, administering to the subject the antibody-drug conjugate at a second dose; wherein:(a) the first dose is about 12 mg / kg of the subject’s body weight and the second dose is about 10 mg / kg of the subject’s body weight;(b) the first dose is about 10 mg / kg of the subject’s body weight and the second dose is about 8 mg / kg of the subject’s body weight;(c) the first dose is about 8 mg / kg of the subject’s body weight and the second dose is about 6.4 mg / kg of the subject’s body weight; or(d) the first dose is about 6.4 mg / kg of the subject’s body weight and the second dose is about 4.8 mg / kg of the subject’s body weight.

[0219] Embodiment 47. The method of embodiment 46, wherein:(i) the adverse event is a hematologic toxicity selected from decreased neutrophil count, decreased white blood cell count, decreased lymphocyte count, anemia, or decreased platelet count;(ii) the adverse event is a non-hematologic toxicity selected from cardiac toxicity or electrocardiogram QT interval prolongation;(iii) the adverse event is an interstitial lung disease or pneumonitis;66NAI-5007064122(iv) the adverse event is an ocular toxicity;(v) the adverse event is increased blood creatinine;(vi) the adverse event is a hepatotoxicity; or(vii) the adverse event is a gastrointestinal event selected from nausea, vomiting, diarrhea, or colitis.

[0220] Embodiment 48. The method of any one of embodiments 1-38 wherein, if the method comprises administering to the subject 5-fluorouracil, the method further comprises:(i) administering to the subject 5-fluorouracil at a first dose;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present, administering to the subject 5-fluorouracil at a second dose; wherein:(a) the first dose is about 400 mg / m2by bolus intravenous administration followed by about 2400 mg / m2by continuous intravenous administration and the second dose is about 2400 mg / m2by continuous intravenous administration;(b) the first dose is about 2400 mg / m2by continuous intravenous administration and the second dose is about 2000 mg / m2by continuous intravenous administration; or(c) the first dose is about 2000 mg / m2by continuous intravenous administration and the second dose is discontinued.

[0221] Embodiment 49. The method of embodiment 48, wherein:(i) the adverse event is a hematologic toxicity selected from neutropenia, febrile neutropenia, and thrombocytopenia; or(ii) the adverse event is a non-hematologic toxicity selected from diarrhea, mucositis, and hand-foot syndrome.

[0222] Embodiment 50. A pharmaceutical composition comprising ifinatamab deruxtecan for use in treating unresectable or metastatic esophageal squamous cell carcinoma (ESCC) in a subject in need thereof, wherein the pharmaceutical composition is administered in combination with pembrolizumab.

[0223] Embodiment 51. A pharmaceutical composition comprising pembrolizumab for use in treating unresectable or metastatic esophageal squamous cell carcinoma (ESCC) in a subject in need thereof, wherein the pharmaceutical composition is administered in combination with ifinatamab deruxtecan.67NAI-50070641227. Examples

[0224] The following are examples of methods and compositions of the disclosure. It is understood that various other embodiments may be practiced, given the general description provided herein. Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.7.1. Example 1: Production of Ifinatamab Deruxtecan (I-DXd)

[0225] In accordance with a production method described in WO2014 / 057687 or WO2022 / 014698, for example, ifinatamab deruxtecan (I-DXd) can be produced. The average number of units of a drug-linker that are conjugated to the anti-human-B7-H3 antibody in ifinatamab deruxtecan is, in one embodiment, 4 as determined by a HPLC method.7.2. Example 2: Clinical trial protocol for administration of Ifinatamab Deruxtecan (I-DXd) plus pembrolizumab with or without chemotherapy to patients with locally advanced unresectable / metastatic esophageal squamous cell carcinoma (ESCC) who are eligible for first-line treatment

[0226] This Example describes substudy 06E in the umbrella platform study MK-3475- U06, which is a Phase 1 / 2, multicenter, adaptive open-label adaptive study to evaluate the safety and efficacy of investigational agents plus pembrolizumab with or without chemotherapy, for the treatment of participants with locally advanced unresectable or metastatic ESCC in a first-line (1 -L) setting. Eligible participants have histologically or cytologically confirmed diagnosis of squamous cell carcinoma of the esophagus. Preliminary efficacy is evaluated by using objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST 1.1), as assessed by blinded independent central review (BICR). In this substudy, study treatment arms include one standard of care (SOC) reference arm (pembrolizumab plus mFOLFOX6) and investigational arms (investigational agents in combination with pembrolizumab with or without chemotherapy). mFOLFOX6 is oxaliplatin +5-FU + leucovorin. Collectively, study treatment is also referred to as study intervention.

[0227] Participants who meet all inclusion criteria and none of the exclusion criteria are allocated / randomized into one of the 4 study treatment arms as described below.• Arm 1 : Pembrolizumab plus chemotherapy (mFOLFOX6)• Arm 2: Ifinatamab deruxtecan (I-DXd) plus pembrolizumab68NAI-5007064122• Arm 3: Ifinatamab deruxtecan (I-DXd) plus pembrolizumab plus 5-FU (bolus and infusion) plus leucovorin or levoleucovorin• Arm 4: Ifinatamab deruxtecan (I-DXd) plus pembrolizumab plus 5-FU infusion plus oxaliplatin7.2.1. Objectives and Endpoints

[0228] Primary objectives, secondary objectives, and tertiary / expl oratory objectives are depicted in Table 1 below.Table 1. Objectives and Endpoints69NAI-5007064122RP2D= recommended Phase 2 dose; DLT=dose -limiting toxicity; RESIST= Response Evaluation Criteria In Solid Tumors; AE= adverse event; DOR= duration of response; DCR= disease control rate; PR=partial response; CR= complete response; SD= standard deviation; PFS=progression-free survival; Cmax=maximum plasma concentration; Tmax= time to maximum plasma concentration; AUC=area under the curve; PK=pharmacokinetic; ADA= antidrug antibodies.7.2.1.1. Primary Endpoints

[0229] Objective Response (OR): The OR is defined as a confirmed complete response(CR) or partial response (PR) per RECIST 1.1 as assessed by BICR.7.2.1.2. Secondary Endpoints

[0230] Duration of response (DOR): For participants who demonstrate confirmed CR or PR, duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first

[0231] Progression-free survival (PF S): PF S is defined as the time from allocation / randomization to the first documented disease progression per RECIST 1.1 byBICR or death due to any cause, whichever occurs first.

[0232] Overall survival (OS): OS is defined as the time from allocation / randomization to death due to any cause.

[0233] Disease Control: The disease control is defined as a confirmed complete response (CR) or partial response (PR), or stable disease (SD) with at least 6 months PFS per RECIST 1.1 as assessed by BICR70NAI-50070641227.2.I.3. Pharmacokinetic Endpoints

[0234] The PK profile of I-DXd (and pembrolizumab with or without chemotherapy if applicable) will be evaluated as a secondary objective. The plasma concentrations of I-DXd (intact), total anti-B7-H3 antibody (or total antibody; drug conjugated and unconjugated antibody), and Dxd (released payload) and serum concentration of pembrolizumab (if analyzed) will be used to determine PK parameters (e.g., Cmax or Ctrough).7.2.I.4. Safety Endpoints

[0235] Safety and tolerability is assessed by clinical review of all relevant parameters including AEs, laboratory test results, and vital signs.

[0236] Dose-limiting toxi cities (DLTs) are assessed for participants allocated in the Safety Lead-in (SLI) with or without dose finding (See Section 7.2.5.4.6 for definition of DLT).7.2.2. Target Population

[0237] Only patients >18 years of age with a diagnosis of locally advanced unresectable / metastatic ESCC in IL are enrolled. Patients must meet all inclusion criteria and none of the exclusion criteria.7.2.2.I. Inclusion Criteria

[0238] An individual is eligible for inclusion in the study if the individual meets all of the following criteria:

[0239] (a) Type of Participant and Disease Characteristics

[0240] 1. The participant must have a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic squamous cell carcinoma of the esophagus.

[0241] (b) Demographics

[0242] 2. Is an individual of any sex / gender, at least 18 years of age at the time of providing the informed consent.

[0243] (c) Informed Consent

[0244] 3. The participant has provided documented informed consent for the study.

[0245] (d) Additional Categories

[0246] 4. Measurable disease per RECIST 1.1 as assessed by the local site investigator / radiology assessment and verified by BICR. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.71NAI-5007064122

[0247] Note: The same image acquisition and processing parameters should be used throughout the study for a given participant.

[0248] 5. Archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated has been provided. Confirmation of evaluability of these specimens for B7-H3 expression is required by a central laboratory before allocation / randomization.

[0249] 6. Participants who have AEs due to previous anticancer therapies must have recovered to < Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement or participants who have < Grade 2 neuropathy are eligible.

[0250] 7. HIV infected participants must have well controlled HIV on antiretroviral therapy (ART), defined as: a. Participants on ART must have a CD4+ T-cell count > 350 cells / mm3at the time of screening b. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months d. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study

[0251] Note: No HIV testing is required at screening unless mandated by local health authority. Participants with newly diagnosed HIV are not eligible to participate in this study.

[0252] 8. Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to allocation / randomization.

[0253] Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

[0254] Hepatitis B screening tests are not required unless:- Known history of HBV infection72NAI-5007064122- As mandated by local health authority

[0255] 9. Participants with history of hepatitis C virus (HCV) infection are eligible ifHCV viral load is undetectable at screening.

[0256] Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to allocation / randomization.

[0257] Hepatitis C screening tests are not required unless:- Known history of HCV infection- As mandated by local health authority

[0258] 10. An Eastern Cooperative Oncology Group (ECOG) performance status within3 days before allocation / randomization.

[0259] 11. Adequate organ function as defined in the following table (Table 2).Specimens must be collected within 7 days before the start of study intervention.Table 2. Adequate Organ Function Laboratory ValuesALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase);AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); Cr=creatinine; CrCl=creatinine clearance; ULN=upper limit of normal; ULN=upper limit of normal.aCriteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.bCrCl is calculated by the Cockcroft-Gault formula = [[140 - age (year)] x weight(kg)] x F* / [72 x serum Cr (mg / dL)]. *Where F = 0.85 for female participants and F = 1 for male participants]. As an alternative, CrCl can be determined from a 24-hour urine collection.73NAI-50070641227.2.2.2. Exclusion Criteria

[0260] An individual must be excluded from the study if the individual meets any of the following criteria:

[0261] (a) Medical Conditions

[0262] 1. Has had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer. Participants may have received prior neoadjuvant or adjuvant therapy in consideration of the following:

[0263] a. Assessment of disease progression should be confirmed by CT scan. In certain situations, clinical evidence of disease progression such as any new or worsening malignant effusion (documented by ultrasound) and confirmation by pathologic criteria (histology and / or cytology) may be acceptable for assessment.

[0264] b. Treatment with curative intent, including neoadj uvant / adjuvant treatment, given as chemotherapy or chemoradiotherapy, using standard of care agents or definitive chemoradiation, will count as a line of therapy if disease progression occurs during treatment or within 6 months of cessation of treatment.

[0265] c. Dose reduction and / or switching of one or more agents due to toxicity / intolerability as deemed clinically appropriate by the investigator will not constitute a new line of therapy.

[0266] 2. Has tumor invasion into organs located adjacent to the esophageal disease site(e.g., aorta or respiratory tract) at an increased risk of fistula as assessed by investigator.

[0267] 3. Has uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage or medical intervention (clinically significant recurrence requiring an additional intervention within 2 weeks of allocation / randomization).

[0268] 4. Has clinically significant corneal disease.

[0269] 5. HIV-infected participants with a history of Kaposi’s sarcoma and / orMulticentric Castleman’s Disease.

[0270] (b) Prior / Concomitant Therapy

[0271] 6. Received prior therapy with an anti-PD-1, anti-PD-Ll, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).

[0272] 7. Prior treatment with orlotamab, enoblituzumab, or other B7-H3 -targeted agents.

[0273] 8. Has received any prior treatment with a topoisomerase-I inhibitor, includingADC.74NAI-5007064122

[0274] 9. Received prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention.

[0275] 10. Received prior radiotherapy within 2 weeks of start of study intervention, or has radiation-related toxicities, requiring corticosteroids.Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease is permitted. The last palliative radiotherapy treatment must have been performed at least 7 days before the first dose of study intervention.

[0276] 11. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.

[0277] (c) Prior / Concurrent Clinical Study Experience

[0278] 12. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

[0279] (d) Diagnostic Assessments

[0280] 13. Has inadequate cardiac function assessed as:- Corrected QT interval by Fredericia (QTcF) value >470 msec (mean of 3 measurements corrected for heart rate using Fridericia’s formula).

[0281] 14. Has a left ventricular ejection fraction (LVEF) below the institutional (or local laboratory) normal range, as determined by MUGA or ECHO.

[0282] 15. Has clinically significant cardiovascular disease within 6 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.

[0283] Note: Medically controlled arrhythmia is permitted.

[0284] 16. Has peripheral neuropathy > Grade 2.

[0285] 17. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.

[0286] 18. Known additional malignancy that is progressing or has required active treatment within the past 3 years.Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (Tl-T2a, Gleason score <6, and PSA <10 ng / mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.75NAI-5007064122

[0287] 19. Known active CNS metastases and / or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e., without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.

[0288] 20. Active autoimmune disease that has required systemic treatment in the past2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid) is allowed.

[0289] 21. History of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease, and / or suspected ILD / pneumonitis that cannot be ruled out by imaging at Screening.

[0290] 22. Active infection requiring systemic therapy other than those permitted inSection 7.2.2.1.

[0291] 23. Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within 3 months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc.), and potential pulmonary involvement caused by any autoimmune, connective tissue, or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis, etc.), prior pneumonectomy, or requirement for supplemental oxygen.

[0292] 24. History or current evidence of any condition (e.g., but not limited to, known deficiency of the enzyme dihydropyrimidine dehydrogenase (DPD)), therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s ability to cooperate with the requirements of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.

[0293] 25. Severe hypersensitivity (>Grade 3) to treatment with a mAb or known sensitivity or intolerance to pembrolizumab, I-DXd, study chemotherapy agents and / or to any of their excipients, murine proteins, or platinum containing products.

[0294] (e) Other Exclusions

[0295] 26. History of allogeneic tissue / solid organ transplant.

[0296] 27. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

[0297] 28. Participants who are incapacitated are not eligible for this study.76NAI-50070641227.2.3. Number of Participants

[0298] New treatment arms will be open for enrollment on a rolling basis to evaluate new investigational treatment combinations. Therefore, the total number of participants depends on the number of treatment arms open for enrollment.

[0299] Approximately 209 participants are enrolled into this study, up to 29 in the SLI (up to 6 in Arm 2, 10 in Arm 3 and 13 in Arm 4), and 180 in the randomized phase (up to 60 in Arm 1 and 40 each per arm in Arms 2, 3 and 4).7.2.3.1. Arm 1 (Reference Arm)

[0300] Up to 60 participants are enrolled in Arm 1. If more than 1 study treatment arm is open for enrollment at the same time, these treatment arms share the same reference arm. If new study treatment arms are added to the substudy, additional participants may be enrolled in the reference arm to ensure the randomization ratio at any given time is maintained at 2:1 with the reference Arm 1. The reference arm remains open for enrollment as long as an investigational arm is enrolling.7.2.3.2. Arm 2 (I-DXd Plus Pembrolizumab)

[0301] A Safety Lead-in Phase is conducted in Arm 2 and up to 6 dose-limiting toxicity (DLT) evaluable participants are planned. In the Arm 2 SLI, 6 participants will be enrolled and complete the DLT period to confirm the safety of 12 mg / kg I-DXd in combination with pembrolizumab. Based on the emergent safety profile, additional dose levels lower than 12 mg / kg may be evaluated per Bayesian Optimal Interval (BOIN) design (Section 7.2.4.2).

[0302] After I-DXd plus pembrolizumab have shown a tolerable safety profile per BOIN from the SLI Phase of this arm, randomization for both Arm 2 and Arm 1 (reference arm) is opened and approximately 40 participants are randomized in Arm 2 concurrently with the reference arm.7.2.3.3. Arm 3 (I-DXd Plus Pembrolizumab Plus 5-FU Plus LV)

[0303] A Safety Lead-in Phase for Arm 3 will be initiated SLI has been completed for Arm 2. The planned starting dose for I-DXd in Arm 3 is 12 mg / kg but if dose de-escalation is needed for Arm 2, that lower dose will be the starting dose for Arm 3. After the first 6 participants have completed the DLT period, additional participants are enrolled in accordance with the BOIN design (Section 7.2.4.2). Specifically, if out of the first 6 participants are enrolled the starting dose level, 2 or fewer participants experience a DLT, up to 10 DLT-evaluable participants will be enrolled to confirm safety of that dose level. Based77NAI-5007064122on the emergent safety profile, additional lower dose levels (e.g., 10 or 8 mg / kg) may be evaluated per BOIN.

[0304] After I-DXd plus pembrolizumab plus 5-FU (IV bolus and IV infusion) plus LV have showed a tolerable safety profile per BOIN from the SLI Phase of this arm, randomization is opened and approximately 40 participants are randomized in Arm 3.7.2.3.4. Arm 4 (I-DXd Plus Pembrolizumab Plus 5-FU Plus Oxaliplatin)

[0305] A Safety Lead-in Phase with dose escalation is conducted in Arm 4 to demonstrate a tolerable safety profile per BOIN and establish a recommended Phase 2 dose (RP2D) for the combination of I-DXd in combination with pembrolizumab plus 5-FU (IV infusion only) plus oxaliplatin. SLI with dose finding in Arm 4 will be initiated after SLI has been completed for Arm 3. Dose escalation in Arm 4 will not be higher than the established dose level in Arm 3.

[0306] During the dose finding per BOIN design, participants are treated with I-DXd in combination with pembrolizumab and 5-FU infusion with oxaliplatin. The planned starting dose for I-DXd for the dose finding is 8 mg / kg q3w. The highest anticipated dose for I-DXd during dose finding is 12 mg / kg q3w. Additional lower dose levels for I-DXd may be evaluated based on emerging safety profile, the plasma exposure and efficacy correlation analysis.

[0307] First, 3 participants are enrolled at the starting dose of 8 mg / kg. After the DLT period for the first 3 participants is complete, additional participants are enrolled in accordance with the BOIN design. If there are no DLTs observed in the first 3 participants, 3 additional participants are enrolled at 12 mg / kg. Enrollment of the first 3 participants in each new dose level is separated by at least 24 hours for additional safety monitoring; the 24-hour enrollment pause between participants begins at the time that the first dose of study intervention is administered. Intraparticipant dose escalation is not allowed. Each of these 3 participants are followed for 21 days following administration of the first dose of study intervention for the occurrence of DLTs - this is the DLT evaluation period.

[0308] Randomization is opened with the recommended dose determined from the dose finding phase and once the safety data of up to 10 DLT evaluable participants at established dose is assessed. Approximately 40 participants are randomized in Arm 4.7.2.4. Study Scheme

[0309] The study design is depicted in FIG. 1.78NAI-50070641227.2.4.L Safety Lead-In (SLI)

[0310] In SLI with or without dose finding phase, participants are closely followed for unacceptable toxicities for 21 days after the first dose of study intervention (i.e., the doselimiting toxicity (DLT) evaluation period) for the occurrence of specific AEs that are deemed to be dose-limiting (Section 7.2.5.4.6).

[0311] An AE is considered a DLT if it occurs during the DLT evaluation period and meets at least 1 of the criteria described in Section 7.2.5.4.6.

[0312] For dose modification guidelines related to individual participants, refer to Section 7.2.5.4.

[0313] Participants in SLI with or without dose finding will continue to receive study intervention at their assigned dose and be followed up in the posttreatment period as applicable. Participants at the selected dose will be included in all the analyses of safety and tolerability.7.2.4.2. Bayesian Optimal Interval in the Safety Lead-in Phase with or without Dose Finding with Target DLT Rate 30%

[0314] Participants in safety lead-in with or without dose finding will be closely followed for DLTs for the first cycle, 21 days after the first dose of study intervention (the DLT evaluation period) using the BOIN design (Yuan, Y., et al Clin Cancer Res. 2016 Sep l;22(17):4291-301) with a target DLT rate of 30%.

[0315] In Table 3 the columns indicate the numbers of participants treated at the current dose level, and the rows indicate the numbers of participants experiencing a DLT. The entries of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. For example, if 2 out of 3 participants at this dose level develop a DLT, the dose will be deescalated to the next lower dose level but may be reescalated at a later time if the lower dose is well tolerated. If 3 out of 3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose should be deescalated, if allowed per protocol, and the current dose will not be explored further.

[0316] For Arms 2 and 3, the dose will be evaluated on an ongoing basis as participants complete the DLT evaluation period. If a dose deescalation decision is made before all participants (i.e. 6 in Arm 2, 10 in Arm 3) have completed enrollment at the starting dose, the enrollment at this dose level will be halted and a new set of participants will be enrolled and treated at the next lower dose level. This process will continue until all participants (6 in Arm79NAI-50070641222, 10 in Arm 3) have been enrolled at any of the tested doses and the BOIN table indicates “S” for staying at current dose or “E” if the current dose level is the highest dose level.

[0317] For Arm 4 dose finding, a minimum of 3 participants are required at each dose. When adding participants to a dose level, the number of additional participants to be enrolled is capped to minimize the exposure to a dose that may be unacceptably toxic (denoted as DU in Table 3). To determine how many more participants can be enrolled at the dose level, one can count steps in diagonal direction (down and to the right) from the current cell to the first cell marked DU. For example, if 1 of 3 participants have experienced a DLT at a given dose level, no more than an additional 3 participants should be enrolled at this dose level until additional DLT data are available. This is because this dose level would be considered unacceptably toxic if all 3 of the additional participants experience a DLT (i.e., 4 / 6 participants with DLT in Table 3). After 10 participants have been enrolled at any of the tested doses, dose finding will stop if the BOIN table indicates “S” for staying at current dose or “E” if the current dose level is the highest dose level.

[0318] For all safety lead-in arms with or without dose finding, a “D” or “DU” decision at the lowest dose level will stop the evaluation of the study intervention under study. An “E” decision at the highest dose level will result in staying at that level. During safety lead-in with or without dose finding, it may be acceptable to deescalate or escalate to an intermediate dose that was not predefined and not previously studied if evaluation of toxicity at such a dose is desired.

[0319] The totality of the data will be considered prior to determining the dose level in the Efficacy Evaluation.Table 3. Dose-finding Framework of BOIN Design with Target DLT Rate 30%BOIN= Bayesian Optimal Interval; D=Deescalate to the next lower dose; DLT=dose-limiting toxicity; DU=The current dose is unacceptably toxic; E=Escalate to the next higher dose; S=Stay at the current dose. [Liu, S. and Yuan, Y. J R Stat Soc Ser C Appl Statist.2015;64(3):507-23],80NAI-50070641227.2.4.3. Randomized Phase (Efficacy)

[0320] Participants are randomized to the reference arm or to the investigational arms in a 1 :2 ratio. For each new or closed investigational arm, the randomization ratio is adjusted to ensure consistent allocation among the open investigational arms and reference arm.

[0321] Randomization occurs centrally using interactive response technology (IRT).Eligible participants are randomized to receive study treatment until one of the conditions for discontinuation of study intervention is met (provided in Section 7.2.5.4.6).7.2.4.4. Allocation / Randomization

[0322] Participants are allocated by the IRT across all open study intervention arms (FIG.1) by nonrandom assignment during the dose establishment period and through random assignment during the Randomized Phase, as detailed in Section 7.2.5.1.1.7.2.4.5. Criteria and Procedures for Stopping Enrollment in an Arm

[0323] Enrollment in dose finding arms may stop early if the number of DLTs exceeds the defined threshold per BOIN.

[0324] In the event that >33% of trial participants in a given study intervention arm experience a Grade 4 drug-related AE, or if more than 1 trial participant experiences a Grade 5 drug-related AE, as determined by the investigator, enrollment into that arm is paused and all available safety data are reviewed to inform further decisions on study conduct.

[0325] Enrollment in a study treatment arm may be discontinued if the totality of the data does not support a favorable risk-benefit ratio for the treatment arm under evaluation.

[0326] If an arm is closed to enrollment based on any of the criteria above, participants already enrolled in that arm may continue on treatment. If treatment is discontinued, participants will continue in follow-up.

[0327] For arms that end enrollment due to the criteria above, further enrollment to the arm will be closed via IRT.7.2.5. Study Intervention

[0328] The study interventions are outlined in Table 4.

[0329] For reference arm (comparator), SOC chemotherapy (mF0LF0X6)=will be administered until PD or toxicity or as per local standard.

[0330] For commercially available supplies, the unit dose strength or formulation may vary, depending on market availability.81NAI-5007064122

[0331] The classification of IMP and NIMP / AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country difference^ with respect to the definition / classification of IMP and NIMP / AxMP may exist. In these circumstances, local legislation is followed.

[0332] All study interventions will be administered on an outpatient basis.

[0333] The treatment of pembrolizumab consists of 35 treatments q3w for all arms (approximately 2 years). Treatment with I-DXd will continue until a criterion for discontinuation of study intervention is met (Section 7.2.5.4.7). Note: The number of treatments is calculated starting with the first dose.

[0334] For SOC chemotherapy (mFOLFOX6), maximum cycles are as per local standard.82NAI-5007064122Table 4. Study Interventions83NAI-500706412284NAI-5007064122mFOLFOX6=oxaliplatin + 5-FU + leucovorin or levoleucovorin; NIMP / AxMP=noninvestigational / auxiliary medicinal product; PD=progressive disease; q2w=every 2 weeks; q3w=every 3 weeks; ROW=rest of world.For reference arm (comparator), SOC chemotherapy (mF0LF0X6) will be administered until PD or toxicity or as per local standard.For commercially available supplies, the unit dose strength or formulation may vary, depending on market availability.The classification of IMP and NIMP / AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the defmition / classification of IMP and NIMP / AxMP may exist. In these circumstances, local legislation is followed.85NAI-50070641227.2.5.I. Randomization and Blinding7.2.5.1.1. Intervention Assignment

[0335] Intervention is allocated by nonrandom assignment during the SLI phase and through random assignment during the Randomized Phase. Allocation / randomization across study arms occurs centrally using an IRT system. The assigned treatment arm for a participant does not change during the study; there is no crossover between treatment arms.

[0336] At the start of the study, enrollment is initially open for SLI phase of Arm 2. Randomization for Arms 1 and 2, and enrollment for Arm 3 SLI is initiated after participants enrolled in Arm 2 SLI have completed the DLT evaluation period. Enrollment for Arm 4 dose finding phase may be initiated after SLI in Arm 3 have been enrolled and completed the DLT evaluation period. Once safety evaluation has been completed for each of Arms 3 and 4, Randomized Phase enrollment begins in Arm 3 and Arm 4 accordingly. To minimize selection bias, all arms that are eligible for the Randomized Phase are randomized through a 1 :2 allocation ratio. If more than 1 treatment arm is open for enrollment, these treatment arms share the same reference arm.7.2.5.1.2. Stratification

[0337] No stratification based on age, sex, or other characteristics will be used in this study.7.2.5.1.3. Blinding

[0338] This is an open-label study.7.2.5.1.4. Concomitant Therapy

[0339] If there is a clinical indication for any medications or vaccinations prohibited, the investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. The final decision on any supportive therapy or vaccination rests with the investigator and / or the participant’s primary physician. However, the decision to continue the participant on study intervention requires the mutual agreement of the investigator and the Sponsor.

[0340] The following medications and vaccinations are prohibited during the study:• Live or live-attenuated vaccines within 30 days before the first dose of study intervention and while participating in the study, and for 30 days after the last dose of study intervention.• Systemic glucocorticoids except when used for the following purposes:86NAI-5007064122o To modulate symptoms of an AE that is suspected to have an immunologic etiology o For the prevention of emesis o To premedicate for IV contrast allergies o To treat asthma or COPD exacerbations (only short-term oral or IV use in doses >10 mg / day prednisone equivalent) o For chronic systemic replacement not to exceed 10 mg / day prednisone equivalent o To premedicate to prevent an IRR• Other glucocorticoid use except when used for the following purposes: o For topical use or ocular use o Intraarticular j oint use o For inhalation in the management of asthma or COPD• For arms with I-DXd treatment: chloroquine or hydroxychloroquine.

[0341] If the investigator determines that a participant requires any of the following prohibited medications and vaccinations for any reason during the study, study intervention must be discontinued:• Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not specified in this protocol• Investigational agents other than those specified in this protocol• Radiation therapy

[0342] Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s discretion.

[0343] Investigational vaccines (i.e., those not licensed or approved for Emergency Use) are not allowed.

[0344] Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed in the study as long as they are mRNA vaccines, replicationincompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy.

[0345] For participants receiving 5-FU:• Brivudine, Sorivudine analogs, and other inhibitors of the enzyme dihydropyrimidine dehydrogenase7.2.5.I.5. Concomitant Medications to be Used with Caution87NAI-5007064122

[0346] Caution is advised when oxaliplatin treatment is coadministered with other medicinal products known to cause QT interval prolongation. In case of combination with such medicinal products, the QT interval should be closely monitored. Cimetidine, metronidazole and interferons may increase levels of 5-FU. Reliable sources such as crediblemeds.org can be used to assist in identification of medicinal products known to cause QT interval prolongation.

[0347] Participants who are taking phenytoin in conjunction with 5-FU should be examined regularly due to a potential elevation in phenytoin plasma levels. Hepatotoxic effects (increase in alkaline phosphatase, transaminase, or bilirubin levels) are frequently observed under the treatment with 5-FU and levamisole.

[0348] Caution is advised if medicinal products associated with rhabdomyolysis are administered concomitantly with oxaliplatin.

[0349] Phenytoin should not be started with cisplatin therapy. Follow label and local guidelines for usage and dose adjustments.

[0350] For oxaliplatin, 5-FU, leucovorin / levoleucovorin, and cisplatin, refer to the product labels or local standards of care for further information regarding concomitant medications to be used with caution.

[0351] The exclusion criteria describe other medications that are prohibited in this study.

[0352] Blood transfusions are allowed at any time during the study, except to meet eligibility criteria.

[0353] All treatments that the investigator considers necessary for a participant’s welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medications will be recorded on the eCRF including all prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes occur during the study period, documentation of drug dosage, frequency, route, and date should also be included on the eCRF.

[0354] All concomitant medications received within 28 days prior to the first dose of study intervention and up to 40 days after the last dose of study intervention should be recorded. All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs and ECIs are defined in Section 7.2.5.5.3 and 7.2.5.5.4.

[0355] In addition to the medications listed here, site staff should refer to the local approved product label for permitted and prohibited medications, as well as drug-drug interactions for each chemotherapy agent used in this study.88NAI-50070641227.2.5.2. Study Intervention Administration7.2.5.2.1. Administration of Pembrolizumab

[0356] Pembrolizumab is administered using a 30-minute IV infusion every three weeks (q3w). Sites should make every effort to target infusion timing to be as close to 30 minutes as possible, documenting the start and stop time. However, given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5min / +10 min).

[0357] Pembrolizumab is dosed on Day 1 of each 3-week cycle. After Cycle 1 Day 1 (C1D1), pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each subsequent cycle for administrative reasons.7.2.5.2.2. Administration of I-DXd

[0358] I-DXd is administered after completion of the pembrolizumab infusion. The participant’s weight at baseline (defined as the last measurement on or prior to allocation / randomization) is used to calculate the initial dose. If the participant’s weight changes by ±10% or more of the baseline weight, the dose must be recalculated. After the recalculation, the updated weight of the participant is used as the new baseline weight.

[0359] Based on the totality of data from pembrolizumab and / or currently available nonclinical data from both I-DXd and pembrolizumab, the 12 mg / kg dose of I-DXd is being explored and will be confirmed as the recommended dose to be administered with pembrolizumab (doublet combination) in Arm 2 and (triplet combination with 5-FU) in Arm 3. Based on the emergent safety profile, additional dose levels other than 12 mg / kg may be evaluated if benefit-risk is not established.

[0360] The dose of 8 mg / kg I-DXd has been selected as the starting dose in combination with pembrolizumab and chemotherapy (with oxaliplatin) in Arm 4 (quadruplet therapy arm) to allow characterization of the safety profile for this combination, before exploring higher doses of I-DXd. Arm 4 will be initiated after safety lead-in for both Arms 2 and 3 has been completed. Based on safety and tolerability of 8 mg / kg, it is anticipated that 12 mg / kg (recommended dose) may be selected and further evaluated. Additional lower dose levels for I-DXd may be evaluated based on emerging safety profile, the plasma exposure and efficacy correlation analysis. Based on safety and tolerability outcomes, the highest tolerable dose will be further evaluated in the randomized portion of the study.7.2.5.2.3. Administration of Other Investigational Agents89NAI-5007064122

[0361] In some embodiments, investigational agents are administered after pembrolizumab and before chemotherapy (if applicable).7.2.5.2.4. Administration of Chemotherapy

[0362] In some embodiments, chemotherapies are administered after all procedures and assessments are completed according to the schedule of activities and after pembrolizumab and investigational agent administration, when appropriate.

[0363] Investigators are advised to counsel participants assigned to receive 5-FU about risk of photosensitivity and to take sun protection measures accordingly.

[0364] mFOLFOX6 (Arm 1)

[0365] Oxaliplatin 85 mg / m2is administered by IV infusion every 2 weeks.

[0366] Leucovorin 400 mg / m2or levoleucovorin 200 mg / m2is administered by IV infusion every 2 weeks.

[0367] 5-FU 400 mg / m2bolus IV infusion followed by 2400 mg / m2continuous IV infusion is administered every 2 weeks.

[0368] Chemotherapy administered in Arm 3

[0369] In Arm 3, leucovorin 400 mg / m2or levoleucovorin 200 mg / m2will be administered by IV infusion every 2 weeks. 5-FU 400 mg / m2bolus IV infusion followed by 2400 mg / m2continuous IV infusion will be administered every 2 weeks.

[0370] Chemotherapy administered in Arm 4

[0371] In Arm 4, oxaliplatin 60 mg / m2will be administered by IV infusion every 2 weeks. 5-FU will be administered as a continuous IV infusion of 2400 mg / m2every 2 weeks.

[0372] In some embodiments, one or more active ingredients (e.g., I-DXd, pembrolizumab, other investigational agents, and / or chemotherapies) are contained or encapsulated in different preparations and administered simultaneously. In some embodiments, “simultaneously” or “at the same time” may be or may not be at about the same time). In some embodiments, one or more active ingredients are administered separately or sequentially in any order at different times, or contained or encapsulated in the same preparation and administered.7.2.5.3. Statistical Methods7.2.5.3.I. Statistical Methods for Efficacy Analysis

[0373] The primary and secondary objectives will be evaluated within each study treatment group and by comparing each investigational treatment group to concurrently90NAI-5007064122randomized participants in Arm 1 with respect to OR (primary), DOR (secondary), PFS (secondary), OS (secondary), and DCR (secondary). Sensitivity analyses will pool all participants who are treated at the same dose level, including participants in the safety lead-in phase of investigational arms and non-concurrent participants in Arm 1.

[0374] ORR, defined as the proportion of participants with an OR, and DCR, defined as the proportion of participants with disease control, will be compared between the investigational treatment groups and Arm 1 using the Miettinen and Nurminen’s (M&N) method (Miettinen, O. and Nurminen, M. Stat Med. 1985;4:213-26). The ORR and DCR differences between the investigational arm and Arm 1 will be reported along with their 95% CI. The point estimates of ORR and DCR by study treatment group will also be reported with their 95% Cis based on the exact binomial method proposed by Clopper and Pearson (Clopper, C.J. and Pearson, E.S. Biometrika 1934;26(4):404-13).

[0375] For OS and PFS, the hazard ratio (HR) and its 95% CI will be estimated using a Cox proportional hazard model with Efron’s method of tie handling. The non-parametric Kaplan-Meier method will be used to estimate the survival curve in each treatment group.

[0376] If sample size permits, DOR will be summarized descriptively using Kaplan- Meier medians and quartiles. Otherwise, only descriptive summary statistics will be provided.

[0377] A summary of the primary analysis strategy for the key efficacy endpoints is provided in Table 5.91NAI-5007064122Table 5. Analysis Strategy for Key Efficacy Variables7.2.53.2. Statistical Methods for Safety Analysis

[0378] Safety and tolerability are assessed by clinical review of AEs and other relevant parameters, including laboratory test results, vital signs, and ECG measurements.

[0379] The overall safety evaluation includes a summary of the number and percentage of participants with at least one AE, drug-related AE, serious AE, serious drug-related AE, Grade 3-5 AE, drug-related Grade 3-5 AE, discontinuation from study intervention due to an AE, interruption of study intervention due to an AE, and an AE resulting in death. The number and percentage of participants with specific AEs will also be provided. For specific AEs that meet predefined threshold rules, point estimates and 95% Cis for the differences between treatment groups in the percentages of participants with events will be provided using the M&N method (Miettinen, O. and Nurminen, M. Stat Med. 1985;4:213-26).

[0380] The number and percentage of participants with laboratory toxicity grade increased from baseline will be summarized by the post-baseline maximum toxicity grade per CTCAE V5.0 for each gradable laboratory test.92NAI-5007064122

[0381] For continuous safety measures, such as change from baseline in laboratory, vital signs, and ECG parameters, summary statistics for baseline, on-treatment, and change from baseline values will be provided by treatment group.

[0382] During SLI with or without dose finding, the estimate of the DLT rate and the 90% Bayesian credible interval based on a prior distribution of Beta (1,1) for the estimate will be provided.7.2.5.3.3. Sample Size and Power Calculations

[0383] In this substudy, up to approximately 209 participants will be enrolled. Approximately 6 participants will be enrolled in the SLI for Arm 2 and approximately 10 participants will be enrolled in the SLI of Arm 3. During SLI with dose finding in Arm 4, a maximum of 10 DLT-evaluable participants per dose-level will be enrolled. The overall sample size for SLI with or without dose finding depends on the observed DLTs at each dose level of each arm.

[0384] During randomization, participants will be randomized 1:2 to Arm 1 and the investigational arms. If there is one investigational arm open for randomization, the randomization ratio will be 1 :2; if two investigational arms are open for randomization, the ratio will be 1 :2:2, etc.

[0385] A total of N=40 participants will be randomized to each investigational arm. Arm 1 will remain open to randomization while any investigational arms are randomizing.

[0386] Up to N=60 participants will be randomized to Arm 1. The primary efficacy analysis will be conducted in the randomized participants. Participants treated at the same dose level during SLI with or without dose finding will be pooled with participants in randomized phase for sensitivity analyses of efficacy.

[0387] Since this study does not have formal hypotheses to be tested, no power calculations are presented.7.2.5.4. Dose Modification

[0388] During treatment with study intervention, all participants should be closely monitored for treatment-related AEs and actively treated with supportive care. Dose modifications in response to treatment-related AEs / toxicities are permitted in order to keep the participant on-study intervention, when appropriate. Dose modifications must follow official current prescription information and local therapeutic guidelines. Details on the modifications for each study intervention are provided in the sections below.93NAI-5007064122

[0389] AEs will be graded using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Investigators decide the probability of the event being related to one or more drugs as to whether dose modification of one or more drugs is required. This is an open-label protocol with a novel combination of investigational agents, pembrolizumab, and chemotherapy. Because of the multiple agents included in this protocol, overlapping toxicities may occur and the determination of the contribution of agents to specific toxicities may be challenging. Dose modifications can be handled individually or collectively depending on determined relatedness.

[0390] Key toxicities with LDXd include infusion-related reaction (IRR), anemia, interstitial lung disease (ILD) and hepatoxicity. Key toxicities with chemotherapy include gastrointestinal disorders, anemia and neutropenia. Key toxicities with pembrolizumab include gastrointestinal disorders, hypothyroidism and pneumonitis. Possible overlapping toxicities include pneumonitis, IRR and anemia. Safety is monitored via clinical assessments and laboratory checks and mitigated via dose modification criteria.7.2.5.4.I. Dose Modification for Chemotherapy Agents

[0391] Dose delays and treatment restarts are made at the discretion of the site investigator according to institutional guidelines or local standard practice. If any adjustments to the chemotherapy dose modification guidelines are required per local guidelines, a Sponsor consultation is strongly recommended. If a dose reduction for toxicity occurs with any agent, the dose may not be reescalated.

[0392] Dose modifications may be needed for 5 FU (Arms 3 and 4) and oxaliplatin (Arm 4 only) in investigational arms. Dose modifications are recommended for mFOLFOX6 in the reference arm (Arm 1) as mentioned below. CTCAE Version 5.0 must be used to grade the severity of AEs. All dose modifications should be based on the AE requiring the greatest dose modification.

[0393] In participants with unrecognized dihydropyrimidine dehydrogenase (DPD) deficiency, acute, life-threatening toxicity may occur when participants are treated with 5-FU. DPD testing is recommended as appropriate per local guidelines. Participants who are characterized during screening to require dose modification are not eligible for the study.

[0394] Supportive care measures as per investigators’ choice (e.g., G-CSF, erythropoietin, blood or platelet transfusion) should be used according to local standards to manage chemotherapy-induced myelosuppression, including to prevent severe infections linked to febrile neutropenia. To minimize dose reductions, interruptions, and94NAI-5007064122discontinuations of chemotherapy, it is recommended these supportive care measures be used before implementing dose modifications, when clinically appropriate. Prophylactic use is acceptable.7.2.5.4.I.I. 5-Fluorouracil (5-FU)

[0395] Refer to Table 6 and Table 7 for dose modification criteria for 5-FU containing investigational arms.Table 6. Recommended Dose Modifications 5-FU Containing Investigational ArmsTable 7. Dose Modification Guidelines for 5-FU Drug-related Adverse Events95NAI-50070641225 -FU=5 -fluorouracil; AE=adverse event; DL=dose level; G-CSF= granulocyte colony-stimulating factor; NA=not applicable.aParticipants with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion.bPermanent discontinuation should be considered for any severe or life-threatening event. Consult Sponsor before restarting treatment after Grade 4 drug-related AE.cParticipants with intolerable or persistent Grade 2 drug-related AE may hold at physician discretion. Permanently discontinue from agent for persistent Grade 2 adverse reactions for which treatment has been held and did not recover to Grade 0 or 1 within 12 weeks of the last dose.7.2.5.4.I.2. FOLFOX6

[0396] Refer to Table 8 for dose modification criteria for mFOLFOX6.Table 8. Recommended Dose Modification Guidelines for mFOLFOX6 Drug-relatedAdverse Events (Mandatory for 5 FU only arm)96NAI-5007064122aminotransferase; GI=gastrointestinal; PRES=posterior reversible encephalopathy syndrome;RPLS=reversible posterior leukoencephalopathy syndrome; ULN=upper limit of normalFurther dose reduction may be considered on Sponsor’s approvalDo not retreat until the ANC >1.5 x 109 / L and the platelets >75-100 x 109 / L, GI and neurotoxicities have resolved and other nonhematologic toxicities < Grade 1.aMay consider restarting when neutrophil count resolves to >1000 / mm3per local guidance.bDiscontinue if sepsis / septic shock.cTransient >7days-<l cycle; persistent >1 cycle.dFor skin toxicity, reduce 5-FU dose only.7.2.5.4.2. Dose Modification for Investigational Agent Intervention

[0397] All dose modifications (interruption, delay, reduction, and / or discontinuation) are applicable only to AEs that are considered related to I-DXd by the investigator(s) and should be based on the worst preceding toxicity (NCI CTCAE v5.0). An exception is that dose modification criteria should be applied to AEs which are confirmed to be ILD / pneumonitis97NAI-5007064122regardless of the investigator’s causality assessment. Dose modification decisions may be based on local laboratory results. Dose reduction levels for I-DXd is listed in Table 9. Recommended dose modification guidelines for I-DXd are provided in Table 10.Table 9. Dose Reduction Levels for I-DXdTable 10. Dose Modifications for Nonhematologic and Hematologic Toxicity Related to I-DXd98NAI-500706412299NAI-5007064122100NAI-5007064122101NAI-5007064122102NAI-5007064122

[0398] The dose for I-DXd can be delayed for up to 28 days from the planned date of administration, for a total of up to 49 days from the last dose administered. If a participant is assessed as requiring a dose delay longer than 4 weeks (28 days) from the planned date of103NAI-5007064122administration (or longer than 49 days from the last dose administered), the investigator should contact the Sponsor medical monitor to discuss on a case-by-case basis.

[0399] Once the dose of I-DXd has been reduced because of toxicity, all subsequent cycles should be administered at that lower dose level unless further dose reduction is required. More than 2 dose reductions are not allowed, and the participant will be discontinued from the study intervention if further toxicity meeting the requirement for dose reduction occurs. Once the dose of I-DXd is reduced, no dose re-escalation is permitted.

[0400] Dose increases are not permitted for I-DXd. No dose modification is required for Grade 1 or 2 events unless specified. For Grade 3 or 4 events, monitoring (including local laboratory tests when appropriate) should be performed frequently and at an interval of no more than 7 days until the AE is determined to be resolving or back to baseline. Prophylactic or supportive treatment for expected toxicities, including management of study-drug-related AEs, will be as per the treating investigator’s discretion and institutional guidelines unless otherwise specified.

[0401] Dose reductions for I-DXd are described in Section 7.2.5.4.2.7.2.5.4.2.I. Toxicity Management of Infusion Reactions Associated with I-DXd

[0402] Recommended guidelines for toxicity management of I-DXd-related infusion reactions are provided in Table 11. The management actions should be based on the worst preceding toxicity (NCI CTCAE v5.0).104NAI-5007064122Table 11. 1-DXd Infusion Reaction Dose Modification and Treatment Guidelines105NAI-50070641227.2.5.4.2.2. Dose Modification for Overlapping Toxicity

[0403] When overlapping toxicities are not clearly attributed to one single drug in the combination, in general, I-DXd should be modified first, and initiate management as outlined in Section 7.2.5.4.2.2 (for the investigational agent). If toxicity does not improve, the investigator should consider discontinuing the participant. If applicable, management of ILD / pneumonitis should follow I-DXd dose modification guideline (Table 10), irrespective of attribution to study drugs for the I-DXd treatment arms. Details on the dose modifications guidelines for overlapping toxicity related to I-DXd and pembrolizumab are provided in Table 12.

[0404] If a specific AE can be attributed to only one of the study interventions, then the management guidelines for that specific intervention should be followed (see Section 7.2.5.4.2 for I-DXd, Section 7.2.5.4.3 for pembrolizumab, or Section 7.2.5.4.1 for chemotherapy). If attribution of specific AE to an individual study intervention is difficult or causality is suspected to more than one study intervention, then dose modification instructions (i.e., dose reduction, withholding, or discontinuation) and the toxicity management guidelines for each study intervention should be consulted. The investigator should follow specific dose modification instructions for each individual study intervention and the most conservative guidelines for the management of AE itself, as described in Sections 7.2.5.4.2, 7.2.5.4.1, and 7.2.5.4.3. For any irAEs, other than ILD / pneumonitis, listed in Table 13, the guidelines for pembrolizumab must be followed. If toxicity does not improve, the investigator should consider discontinuing each study intervention.

[0405] Study intervention discontinuation guidelines for overlapping toxicity related to I- DXd and / or pembrolizumab (applicable to Arm 2, 3 and 4) are provided in Table 12.

[0406] IRRs can often be attributed to a specific study intervention. Therefore, although IRRs / hypersensitivity can occur with both I-DXd and pembrolizumab, these toxicities are not considered overlapping and can be managed according to individual dose modification guidelines. In cases in which there is uncertainty as to which intervention caused an infusion reaction (e.g., in case of delayed infusion reaction in participants receiving I-DXd and pembrolizumab on the same day or receiving chemotherapy / pembrolizumab on the same day), guidelines for management of IRRs for each of the study interventions administered should be consulted and the most conservative guidelines followed. For participants receiving I-DXd and pembrolizumab who have IRR > Grade 3, both I DXd and pembrolizumab should be permanently discontinued if the intervention that caused the infusion reaction is uncertain.106NAI-5007064122If a participant experiences an infusion reaction during administration of one of the study interventions, administration of the remainder of the study interventions due that day may be withheld if investigator deems is in the best interest of the participant.Table 12. Dose Modification Guidelines for Overlapping Toxicity Related to I-DXd andPembrolizumabAST=aspartate aminotransferase; ALT=alanine aminotransferase; DILI=drug -induced liver injury; HBV=hepatitis B virus; HCV=hepatitis C virus; ILD=interstitial lung disease; NCI-CTCAE=National Cancer Institute - Common Terminology Criteria for Adverse Events; ULN=upper limit of normal; ULN=upper limit of normal.aFor suspected ILD / pneumonitis events, weekly monitoring of symptoms is recommended. Continued monitoring for pulmonary symptoms after the restart of study intervention(s) is also recommended, as there may be a risk for development of subsequent ILD events.bGrade 0 refers to full resolution of ILD / pneumonitis including the disappearance of radiological findings associated with active ILD / pneumonitis. Residual scarring or fibrosis following recovery of ILD / pneumonitis is not considered to be active disease.cConfirmation of reactivation of HBV / HCV in the presence of AST or ALT >3 X ULN requires discontinuation of I-DXd. Although reactivation of HBV / HCV is not also a pembrolizumab- associated toxicity, participants with active HBV / HCV are not candidates for pembrolizumab, thus pembrolizumab would need to be discontinued in this situation in addition to discontinuing I-DXd.107NAI-5007064122

[0407] If I-DXd is either interrupted or discontinued, dosing with pembrolizumab and chemotherapy may continue if the criteria outlined in Sections 7.2.5.4.1 and 7.2.5.4.3 are not met. If pembrolizumab is either interrupted or discontinued, dosing with I-DXd and chemotherapy may continue if the criteria outlined in Sections 7.2.5.4.2 and 7.2.5.4.1 are not met.7.2.5.4.3. Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)7.2.5.4.3.I. Dose Modification and Toxicity Management for Immune-related AEs Associated With Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0408] (a) Dose Modification and Toxicity Management for Immune-related AEsAssociated With Pembrolizumab Monotherapy, Coformulations, or IO Combinations:

[0409] AEs associated with pembrolizumab monotherapy, coformulation, or IO combination exposure may represent an immune-related response. These irAEs may occur shortly after the first dose or several months after the last dose of pembrolizumab monotherapy, coformulation, or IO combination treatment and may affect more than one body system simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce complications. Based on existing clinical study data, most irAEs were reversible and could be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO combination administration of corticosteroids and / or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation.

[0410] (b) Attribution of Toxicity:

[0411] When study interventions are administered in combination, attribution of an adverse event to a single component is likely to be difficult. Therefore, while the investigator may attribute a toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, pembrolizumab monotherapy, coformulations, or IO combinations must be held according to the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events.

[0412] In these cases where the toxicity is attributed to pembrolizumab coformulations, or IO combinations, reinitiation of pembrolizumab as a monotherapy may be considered after communication with and agreement by the Sponsor.

[0413] (c) Holding Study Interventions:108NAI-5007064122

[0414] When study interventions are administered in combination and if the AE is considered immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should be held according to recommended Dose Modification criteria.

[0415] If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO combinations.

[0416] (d) Restarting Study Interventions:

[0417] Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as described below:

[0418] If the toxicities do resolve and conditions are aligned with what is defined in the Dose Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, coformulations, or IO combinations may be restarted at the discretion of the investigator.

[0419] Dose Modification and Toxicity Management Guidelines for irAEs associated with pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 13.Table 13. Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With Pembrolizumab Monotherapy, Coformulations, or IOCombinations109NAI-5007064122110NAI-5007064122111NAI-50070641227.2.5.4.4. Dose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0420] Pembrolizumab monotherapy, coformulations, or IO combinations may cause severe or life-threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab monotherapy, coformulations or IO combinations associated infusion reactions are provided in Table 14.Table 14. Pembrolizumab Monotherapy, Coformulations or IO Combinations InfusionReaction Dose Modification and Treatment Guidelines112NAI-50070641227.2.5.4.5. Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0421] Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for situations other than treatment-related AEs such as medical or surgical events and / or unforeseen circumstances not related to study intervention. However, study intervention is to be restarted within 3 weeks for q3w (21 days) of the originally scheduled113NAI-5007064122dose and within 42 days (for q3w) of the previously administered dose, unless otherwise discussed with the Sponsor. The reason for study intervention interruption is to be documented in the participant’s study record.7.2.5.4.6. Definition of Dose-limiting Toxicity

[0422] The DLT window of observation will be during Cycle 1.

[0423] The occurrence of any of the following toxicities will be considered a DLT if assessed by the investigator to be possibly, probably, or definitely related to study intervention administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.:• Grade 4 nonhematologic toxicity (not laboratory)• Grade 4 hematologic toxicity lasting >7 days, except thrombocytopenia: o Grade 4 thrombocytopenia of any duration o Grade 3 thrombocytopenia associated with clinically significant bleeding• Any nonhematologic AE >Grade 3 in severity should be considered a DLT, with the following exceptions: o Grade 3 fatigue lasting <3 days; o Grade 3 diarrhea, nausea, or vomiting without use of antiemetics or antidiarrheals per standard of care; o Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care• Any Grade 3 or Grade 4 nonhematologic laboratory value if: o Clinically significant medical intervention is required to treat the participant, or o The abnormality leads to hospitalization, or o The abnormality persists for >1 week o The abnormality results in a DILI (see Section 7.2.5.5.4 for criteria) o Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities including liver function tests, uric acid, etc.• Febrile neutropenia Grade 3 or Grade 4: o Grade 3 is defined as ANC <1000 / mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >38 degrees C (100.4 degrees F) for more than 1 hour114NAI-5007064122o Grade 4 is defined as ANC <1000 / mm3 with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated• Prolonged delay (>2 weeks) in initiating Cycle 2 due to study intervention-related toxicity• Any study intervention-related toxicity that causes the participant to discontinue intervention during Cycle 1• Missing >25% of study intervention doses as a result of drug-related AEs during the first cycle• Grade 5 toxicity7.2.5.4.7. Discontinuation of Study Interventions

[0424] Discontinuation of study intervention does not represent withdrawal from the study.

[0425] As certain data on clinical events beyond study intervention discontinuation may be important to the study, they must be collected through the participant’s last scheduled follow-up, even if the participant has discontinued study intervention. Therefore, all participants who discontinue study intervention before completion of the protocol-specified treatment period will still continue to be monitored in this study and participate in the study visits and procedures unless the participant has withdrawn from the study.

[0426] Participants may discontinue study intervention at any time for any reason or be discontinued from the study intervention at the discretion of the investigator should any untoward effect occur. In addition, a participant may be discontinued from study intervention by the investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or for administrative and / or other safety reasons.

[0427] A participant must be discontinued from study intervention, but continue to be monitored in the study for any of the following reasons:

[0428] The participant or participant’s legally acceptable representative requests to discontinue study intervention.

[0429] Any prolonged interruption of study intervention beyond the permitted periods, for irAE management or other allowed dose interruptions, as noted in Section 7.2.5.4, requires Sponsor consultation prior to restarting treatment. If treatment will not be restarted,115NAI-5007064122the participant will continue to be monitored in the study and the reason for discontinuation of study intervention will be recorded in the medical record.

[0430] The participant has a medical condition or personal circumstance which, in the opinion of the investigator and / or Sponsor, placed the participant at unnecessary risk from continued administration of study intervention.

[0431] The participant has a confirmed positive serum pregnancy test.

[0432] Radiographic disease progression outlined in Section 7.2.5.5.1 (after obtaining informed consent addendum and Sponsor communication, the investigator may elect to continue treatment beyond disease progression).

[0433] Any progression or recurrence of malignancy or any occurrence of another malignancy that requires active treatment.

[0434] Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection do not have to discontinue study intervention.

[0435] Any study intervention-related toxicity specified as a reason for permanent discontinuation as defined in the guidelines for dose modification due to AEs in Section 7.2.5.4. For participants who are discontinued from study intervention, but continue to be monitored in the study, all visits and procedures should be completed.

[0436] Discontinuation from study intervention is “permanent.” Once a participant is discontinued from study intervention, they shall not be allowed to restart study intervention.7.2.5.5. Study Assessments and Procedures7.2.5.5.I. Tumor Imaging and Assessment of Disease

[0437] Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess tumor burden and may include cross-sectional imaging (such as CT or MRI), medical photography, or other methods as specified in this protocol.

[0438] In addition to survival, efficacy will be assessed based on evaluation of scan changes in tumor burden over time, until the participant is discontinued from the study or goes into survival follow-up. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by local practice. The same scan technique should be used in a participant throughout the study to optimize the reproducibility of the assessment of116NAI-5007064122existing and new tumor burden and improve the accuracy of the response assessment based on scans.

[0439] Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local investigator at the site and / or the radiological reviewer at the site or at an offsite facility.

[0440] If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is medically contraindicated.

[0441] Bone scans may be performed to evaluate bone metastases. Any supplemental scans performed to support a positive or negative bone scan, such as plain x-rays acquired for correlation, should also be submitted.

[0442] Other imaging modalities that may be collected, submitted, and included in the response assessment include FDG-PET. Other types of medical imaging (such as ultrasound) should not be submitted and will not be included in response assessment. Refer to the SIM for acceptable modalities and further details.

[0443] The scans required for this protocol may expose the participant to ionizing radiation, which increases long-term risk of developing additional malignancies. The SIM allows for alternative scanning options, where possible, which may be selected by the investigator if believed to be in the best interest of the participant and / or required by local regulations.

[0444] The required scans and scan schedule are designed to evaluate the endpoints of the clinical study. The scan schedule may differ from the local SOC for the indication. These estimates are based on commonly used equipment specifications, image acquisition parameters, and expected anatomical coverage. However, the actual radiation dose per scan can only be determined by the medical physicist at each site, based on the specific equipment and settings used.

[0445] At screening, participant eligibility will require radiographic documentation of at least one lesion that meets the requirements for selection as a target lesion, as defined by RECIST 1.1 verified by BICR, prior to participant allocation / randomization.

[0446] All scheduled scans for participants will be submitted. In addition, a scan that is obtained at an unscheduled time point, for any reason (including suspicion of progression or other clinical reason), should also be submitted if it shows disease progression, or if it is used to support a response assessment. All scans acquired within the protocol-specified window of time around a scheduled scan visit are to be classified as pertaining to that visit.

[0447] (a) Initial Tumor Scans117NAI-5007064122

[0448] The screening scans must be submitted to verify eligibility criteria have been met before allocation / randomization.

[0449] Bone scans are required at screening for participants with a history of bone metastases and / or for those participants with indicative clinical signs / symptoms such as bone pain or elevated alkaline phosphatase levels. Bone scan refers to imaging methods used to assess bone metastasis. If brain scans are required to document the stability of existing metastases, the brain scan should be acquired during screening.

[0450] (b) Tumor Scans During the Study

[0451] The first on-study scan should be performed at 6 weeks (42 days +7 days) from the date of allocation / randomization. Subsequent tumor scans should be performed every 6 weeks (42 days ±7 days) or more frequently if clinically indicated. After Year 1, participants who remain on treatment will have scans performed every 9 weeks (63 days ±10 days). Scan timing should follow calendar days and should not be adjusted for delays in cycle starts. Scans are to be performed until disease progression is identified by the investigator, or until any of these conditions are met:• the start of a new anticancer treatment• pregnancy• death• withdrawal of consent• the end of the study

[0452] Objective response should be confirmed by a repeat scan performed at least 4 weeks after the first indication of a response is observed. Participants will then return to the regular scan schedule, starting with the next scheduled time point. Participants who receive additional scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 weeks later; scans may resume at the subsequent scheduled time point.

[0453] On-study brain and / or bone scans should be performed if clinically indicated or to confirm CR (if other lesions indicate CR and brain and / or bone lesions existed at baseline).

[0454] (c) End-of-treatment and Follow-up Tumor Scans

[0455] If participants discontinue study intervention, tumor scans should be performed at the time of discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of discontinuation. If participants discontinue study intervention due to documented disease progression, this is the final required tumor scan. The scan type and anatomical118NAI-5007064122coverage performed at end-of-treatment should adhere to the requirements of the scheduled imaging visits. Additional imaging may be acquired as clinically indicated, or to confirm CR.

[0456] If participants discontinue study intervention without documented disease progression, every effort is to be made to monitor disease status by acquiring tumor scans using the same schedule calculated from the date of allocation / randomization.

[0457] Scans are to be continued until one of the following conditions are met:• disease progression as defined by RECIST 1.1• the start of a new anticancer treatment• pregnancy• death• withdrawal of consent• the end of the study7.2.5.5.2. RECIST 1.1 Assessment of Disease

[0458] RECIST 1.1 is used as the primary measure for assessment of tumor response, date of disease progression

[0459] RECIST 1.1 is used as the primary measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g., discontinuation of study intervention). If disease progression is established by the investigator, the process continues as follows:• investigator judgment will determine action• if the participant is clinically stable and study intervention is to continue, communication with the Sponsor is required and a reconsent addendum must be signed. In addition, the following are to occur: o continue scans per protocol schedule (the next scheduled scan should be ^4 weeks from most recent scan acquired) o send scans until any of these conditions are met: the start of a new anticancer treatment, pregnancy, death, withdrawal of consent, or the end of the study.

[0460] For the purpose of this decision process, lack of clinical stability is defined as:• unacceptable toxicity• clinical signs or symptoms indicating clinically significant disease progression decline in performance status119NAI-5007064122• rapid disease progression or threat to vital organs or critical anatomical sites (e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative medical intervention7.2.5.5.3. Adverse Events, Serious Adverse Events, and Other Reportable Safety Events

[0461] The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing causality of AE and SAE and the procedures for completing and transmitting AE, SAE, and other reportable safety event reports can be found below.

[0462] Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative).

[0463] The investigator and any designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE as well as other reportable safety events. Investigators need to document if an SAE was associated with a medication error, misuse, or abuse.

[0464] Investigators remain responsible for following up AEs, SAEs, and other reportable safety events. The investigator, who is a qualified physician, will assess events that meet the definition of an AE or SAE as well as other reportable safety events with respect to seriousness, intensity / toxicity, and causality.

[0465] Selected serious and nonserious AEs are also known as ECIs and must be reported to the Sponsor.7.2.5.5.3.I. Definitions of AE or SAE

[0466] (a) Definition of AE

[0467] An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.

[0468] Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.

[0469] Note: For purposes of AE definition, study intervention includes any pharmaceutical product, biological product, vaccine, diagnostic agent, medical device, combination product, or protocol-specified procedure whether investigational or marketed120NAI-5007064122(including placebo, active comparator product, or run-in intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor for human use in this study.

[0470] (b) Events meeting the AE definition

[0471] Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen from baseline, considered clinically significant in the medical and scientific judgment of the investigator.

[0472] Exacerbation of a chronic or intermittent preexisting condition including either an increase in frequency and / or intensity of the condition.

[0473] New conditions detected or diagnosed after study intervention administration even though it may have been present before the start of the study.

[0474] Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

[0475] Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication.

[0476] For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term should reflect the clinical symptoms or abnormal test result. An overdose without any associated clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or intentional overdose without adverse effect.”

[0477] Any new cancer (that is not a condition of the study). Progression of the cancer under study is not a reportable event.

[0478] (c) Events NOT meeting the AE definition

[0479] Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE.

[0480] Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital).

[0481] Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or detected at the start of the study that do not worsen.

[0482] Surgical procedure(s) planned prior to informed consent to treat a preexisting condition that has not worsened.

[0483] (d) Definition of SAE

[0484] If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met.

[0485] An SAE is defined as any untoward medical occurrence that, at any dose:

[0486] a. Results in death121NAI-5007064122

[0487] b. Is life-threatening• The term “life-threatening” in the definition of “serious” refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe.

[0488] c. Requires inpatient hospitalization or prolongation of existing hospitalization• Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a preexisting condition that has not worsened is not an SAE.) A preexisting condition is a clinical condition that is diagnosed prior to the use of an MSD product and is documented in the participant’s medical history.

[0489] d. Results in persistent or significant disability / incapacity• The term disability means a substantial disruption of a person’s ability to conduct normal life functions.• This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a substantial disruption.

[0490] e. Is a congenital anomaly / birth defect• In offspring of participant taking the product regardless of time to diagnosis.

[0491] f. Other important medical events• Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate in other situations such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. These events should usually be considered serious.• Examples of such events include invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.7.2.5.5.4. Events of Clinical Interest

[0492] Events of clinical interest (ECI) for this study include:122NAI-5007064122

[0493] Potential drug-induced liver injury (DILI) events defined as an elevated AST or ALT laboratory value that is greater than or equal to 3* the ULN and an elevated total bilirubin laboratory value that is greater than or equal to 2* the ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 2* the ULN, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.*

[0494] *Note: These criteria are based on available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology.

[0495] Any hypersensitivity or infusion-related reaction should be reported whether it is considered a nonseri ous AE or an SAE and regardless of investigator’ s assessment of causality.

[0496] Any event of ILD / pneumonitis should be reported within 24 hours regardless of investigator’s assessment of causality.Summary

[0497] The present disclosure relates to the combination of an anti-B7-H3 ADC such as ifinatamab deruxtecan with an anti-PD-1 antibody such as pembrolizumab, as well as related dosing regimens and patient populations. Without being bound by theory, the present disclosure believes that the combination and combined dosing regimens of pembrolizumab with an anti-B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan (I-DXd)) may be more efficacious than either treatment alone, for instance, for ESCC treatment, e.g., by overcoming the occurrence of resistance and improving patient outcomes. In addition, it is thought that the combination and combined dosing regimens of pembrolizumab and an anti- B7-H3 antibody-drug conjugate (e.g., ifinatamab deruxtecan (I-DXd)) may allow for a treatment that requires fewer chemotherapy agent(s) and / or a lower dose of the chemotherapy agent(s) compared to current standard of care therapies for ESCC. For example, in some examples, the payload of I-DXd may replace oxaliplatin in combination with 5-FU to provide a platinum-free therapy. Additionally, the present disclosure believes that the combination or combined dosing regimens may not result in cumulative toxicities such that it will be better tolerated than existing therapies.

[0498] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes123NAI-5007064122may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.

[0499] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.124NAI-5007064122SEQUENCES125NAI-5007064122126NAI-5007064122

Claims

What is claimed is:

1. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II127NAI-5007064122Formula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8; and(ii) administering to the subject pembrolizumab; wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

3. The method of claim 1 or 2, wherein the unresectable or metastatic ESCC is locally advanced unresectable or metastatic ESCC.

4. The method of claim 3, wherein the unresectable or metastatic ESCC is locally advanced unresectable ESCC.

5. The method of claim 3, wherein the unresectable or metastatic ESCC is metastatic ESCC.

6. The method of any one of claims 1-5, wherein the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC.128NAI-50070641227. The method of any one of claims 1-6, wherein the subject has not had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.

8. The method of any one of claims 1-7, wherein the subject has received prior neoadjuvant or adjuvant therapy.

9. The method of any one of claims 1-8, wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 1,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 2,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 3,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 4,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 6.

10. The method of any one of claims 1-9, wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises a heavy chain variable region (“VH”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 7, and a light chain variable region (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 8.

11. The method of any one of claims 1-10, wherein the anti-human B7-H3 antibody is an IgGl.

12. The method of any one of claims 1-11, wherein the anti-human B7-H3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 7, and a VL comprising the amino acid sequence of SEQ ID NO: 8.

13. The method of any one of claims 1-12, wherein the anti-human B7-H3 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 11, and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

14. The method of any one of claims 1-13, wherein the antibody-drug conjugate is ifinatamab deruxtecan.129NAI-500706412215. The method of any one of claims 1-14, further comprising:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject leucovorin or levoleucovorin.

16. The method of any one of claims 1-14, further comprising:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject oxaliplatin.

17. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I wherein AB is an anti-human B7-H3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin.130NAI-500706412218. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject an antibody-drug conjugate, wherein the antibodydrug conjugate comprises an anti-human-B7-H3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula II wherein A represents a connecting position to the anti-human-B7-H3 antibody or a functional fragment thereof, wherein the number of drug-linkers of Formula II is equal to n wherein n represents the drug to antibody ratio, and wherein the anti-human-B7-H3 antibody or the functional fragment thereof comprises:(a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 7; and(b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 8;(ii) administering to the subject pembrolizumab;(iii) administering to the subject 5 -fluorouracil; and(iv) administering to the subject leucovorin, levoleucovorin or oxaliplatin.

19. The method of claim 17 or 18, wherein the cancer is unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

20. The method of claim 19, wherein the unresectable or metastatic ESCC is locally advanced unresectable or metastatic ESCC.131NAI-500706412221. The method of claim 20, wherein the unresectable or metastatic ESCC is locally advanced unresectable ESCC.

22. The method of claim 20, wherein the unresectable or metastatic ESCC is metastatic ESCC.

23. The method of any one of claims 17-22, wherein the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC.

24. The method of any one of claims 17-23, wherein the subject has not had systemic anticancer therapy for locally advanced unresectable or metastatic esophageal cancer.

25. The method of any one of claims 17-24, wherein the subject has received prior neoadjuvant or adjuvant therapy.

26. The method of any one of claims 17-25, wherein the method comprises:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject leucovorin or levoleucovorin.

27. The method of any one of claims 17-25, wherein the method comprises:(iii) administering to the subject 5-fluorouracil, and(iv) administering to the subject oxaliplatin.

28. The method of any one of claims 1-27, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a dose of about 12 mg / kg or about 8 mg / kg of the subject’s body weight; and(ii) administering to the subject pembrolizumab at a dose of about 200 mg or about 400 mg.

29. The method of claim 28, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days; and(ii) administering to the subject pembrolizumab by intravenous administration every three weeks + / - 3 days or every six weeks + / - 3 days.132NAI-500706412230. The method of claim 15 or 26, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a dose of about 12 mg / kg of the subject’s body weight;(ii) administering to the subject pembrolizumab at a dose of about 200 mg;(iii) administering to the subject 5 -fluorouracil at a dose of about 400 mg / m2followed by about 2400 mg / m2;(iv) administering to the subject leucovorin at a dose of about 400 mg / m2or levoleucovorin at a dose of about 200 mg / m2.

31. The method of claim 30, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days; and(ii) administering to the subject pembrolizumab by intravenous administration every three weeks + / - 3 days;(iii) administering to the subject 5 -fluorouracil at a dose of about 400 mg / m2by bolus intravenous administration followed by about 2400 mg / m2by continuous intravenous administration every two weeks + / - 3 days; and(iv) administering to the subject leucovorin or levoleucovorin by intravenous administration every two weeks + / - 3 days.

32. The method of claim 16 or 27, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a dose of about 8 mg / kg or about 12 mg / kg of the subject’s body weight;(ii) administering to the subject pembrolizumab at a dose of about 200 mg;(iii) administering to the subject 5 -fluorouracil at a dose of about 2400 mg / m2; and(iv) administering to the subject oxaliplatin at a dose of about 60 mg / m2of the subject’s body weight.

33. The method of claim 32, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days;(ii) administering to the subject pembrolizumab by intravenous administration every three weeks + / - 3 days;(iii) administering to the subject 5 -fluorouracil at a dose of about 2400 mg / m2by133NAI-5007064122continuous intravenous administration every two weeks + / - 3 days; and(iv) administering to the subject oxaliplatin by intravenous administration every two weeks + / - 3 days.

34. The method of any one of claims 1-27, wherein the method comprises administering to the subject the antibody-drug conjugate at a dose of about 4 mg / kg, about 6 mg / kg, about 8 mg / kg, or about 12 mg / kg of the subject’s body weight.

35. The method of claim 34, wherein the dose of the antibody-drug conjugate is a dose of about 4 mg / kg, about 4.5 mg / kg, about 5 mg / kg, about 5.5 mg / kg, about 6 mg / kg, about 6.5 mg / kg, about 7 mg / kg, about 7.5 mg / kg, 8 mg / kg, about 8.5 mg / kg, about 9 mg / kg, about 9.5 mg / kg, about 10 mg / kg, about 10.5 mg / kg, about 11.0 mg / kg, about 11.5 mg / kg, or about 12.0 mg / kg.

36. The method of claim 34 or 35, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate by intravenous administration every three weeks + / - 3 days.

37. The method of any one of claims 1-27, wherein if the method comprises administering to the subject 5-fluorouracil, the dose of the 5 -fluorouracil is a dose of about 2800 mg / m2, about 2400 mg / m2, or about 2000 mg / m2.

38. The method of any one of claims 1-37, wherein the subject is greater than or equal to 18 years of age.

39. A pharmaceutical composition for use in treating unresectable or metastatic ESCC in a subject in need thereof, comprising:(A)(i) an antibody-drug conjugate, as defined in any one of claims 1-14, and(ii) pembrolizumab in combination, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 28, 29, and 34-36 and pembrolizumab is administered as defined in any one of claims 28 or 29;134NAI-5007064122(B)(i) the antibody-drug conjugate, as defined in any one of claims 1-14,(ii) pembrolizumab,(iii) 5-fluorouracil, and(iv) leucovorin or levoleucovorin in combination, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 30, 31, and 34-36, pembrolizumab is administered as defined in claim 30 or 31, 5-fluorouracil is administered as defined in claim 30 or 31, and leucovorin or levoleucovorin is administered as defined in claim 30 or 31; or(C)(i) the antibody-drug conjugate, as defined in any one of claims 1-14,(ii) pembrolizumab,(iii) 5-fluorouracil, and(iv) oxaliplatin in combination, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 32-36, pembrolizumab is administered as defined in claim 32 or 33, 5- fluorouracil is administered as defined in claim 32 or 33, and oxaliplatin is administered as defined in claim 32 or 33.

40. A pharmaceutical composition for use in treating unresectable or metastatic ESCC in a subject in need thereof, comprising:(A)(i) an antibody-drug conjugate, as defined in any one of claims 1-14, in combination with (ii) pembrolizumab, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 28, 29, and 34-36 and pembrolizumab is administered as defined in any one of claims 28 or 29;(B)(i) the antibody-drug conjugate, as defined in any one of claims 1-14, in combination with (ii) pembrolizumab, (iii) 5-fluorouracil, and (iv) leucovorin or levoleucovorin, wherein optionally, the antibody-drug conjugate is administered as defined in any one135NAI-5007064122of claims 30, 31, and 34-36, pembrolizumab is administered as defined in claim 30 or 31, 5 -fluorouracil is administered as defined in claim 30 or 31, and leucovorin or levoleucovorin is administered as defined in claim 30 or 31; or(C)(i) the antibody-drug conjugate, as defined in any one of claims 1-14, in combination with (ii) pembrolizumab, (iii) 5-fluorouracil, and (iv) oxaliplatin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 32-36, pembrolizumab is administered as defined in claim 32 or 33, 5- fluorouracil is administered as defined in claim 32 or 33, and oxaliplatin is administered as defined in claim 32 or 33.

41. A pharmaceutical composition for use in treating unresectable or metastatic ESCC in a subject in need thereof, comprising:(A)(ii) pembrolizumab, in combination with (i) an antibody-drug conjugate, as defined in any one of claims 1-14, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 28, 29, and 34-36 and pembrolizumab is administered as defined in any one of claims 28 or 29;(B)(ii) pembrolizumab, in combination with (i) the antibody-drug conjugate, as defined in any one of claims 1-14, (iii) 5-fluorouracil, and (iv) leucovorin or levoleucovorin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 30, 31, and 34-36, pembrolizumab is administered as defined in claim 30 or 31, 5-fluorouracil is administered as defined in claim 30 or 31, and leucovorin or levoleucovorin is administered as defined in claim 30 or 31; or(C)(ii) pembrolizumab, in combination with (i) the antibody-drug conjugate, as defined in any one of claims 1-14, (iii) 5-fluorouracil, and (iv) oxaliplatin, wherein optionally, the antibody-drug conjugate is administered as defined in any one of claims 32-36, pembrolizumab is administered as defined in claim 32 or 33, 5- fluorouracil is administered as defined in claim 32 or 33, and oxaliplatin is administered136NAI-5007064122as defined in claim 32 or 33.

42. The pharmaceutical composition of any one of claims 39-41, wherein the subject has a histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic ESCC.

43. Use of the antibody-drug conjugate as defined in any one of claims 1-14 for the preparation of a medicament for treating unresectable or metastatic ESCC, by administration in combination with pembrolizumab, optionally wherein the use further comprises administration of:(i) 5 -fluorouracil, and leucovorin or levoleucovorin; or(ii) 5 -fluorouracil and oxaliplatin.

44. The antibody-drug conjugate as defined in any one of claims 1-14 for use in combination with pembrolizumab in treating unresectable or metastatic ESCC in a subject, optionally wherein the antibody-drug conjugate is for use with(i) 5 -fluorouracil, and leucovorin or levoleucovorin; or(ii) 5 -fluorouracil and oxaliplatin.

45. A kit for treating unresectable or metastatic ESCC comprising:(i) antibody-drug conjugate as defined in any one of claims 1-14 , or a pharmaceutical composition comprising the same; and(ii) pembrolizumab, or a pharmaceutical composition comprising the same; optionally wherein the kit further comprises:(iii) 5 -fluorouracil, and leucovorin or levoleucovorin; or(iv) 5 -fluorouracil and oxaliplatin.

46. The method of any one of claims 1-38, wherein the method comprises:(i) administering to the subject the antibody-drug conjugate at a first dose;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present, administering to the subject the antibody-drug conjugate at a second dose; wherein:(a) the first dose is about 12 mg / kg of the subject’s body weight and the137NAI-5007064122second dose is about 10 mg / kg of the subject’s body weight;(b) the first dose is about 10 mg / kg of the subject’s body weight and the second dose is about 8 mg / kg of the subject’s body weight;(c) the first dose is about 8 mg / kg of the subject’s body weight and the second dose is about 6.4 mg / kg of the subject’s body weight; or(d) the first dose is about 6.4 mg / kg of the subject’s body weight and the second dose is about 4.8 mg / kg of the subject’s body weight.

47. The method of claim 46, wherein:(i) the adverse event is a hematologic toxicity selected from decreased neutrophil count, decreased white blood cell count, decreased lymphocyte count, anemia, or decreased platelet count;(ii) the adverse event is a non-hematologic toxicity selected from cardiac toxicity or electrocardiogram QT interval prolongation;(iii) the adverse event is an interstitial lung disease or pneumonitis;(iv) the adverse event is an ocular toxicity;(v) the adverse event is increased blood creatinine;(vi) the adverse event is a hepatotoxicity; or(vii) the adverse event is a gastrointestinal event selected from nausea, vomiting, diarrhea, or colitis.

48. The method of any one of claims 1-38 wherein, if the method comprises administering to the subject 5-fluorouracil, the method further comprises:(i) administering to the subject 5-fluorouracil at a first dose;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present, administering to the subject 5-fluorouracil at a second dose; wherein:(a) the first dose is about 400 mg / m2by bolus intravenous administration followed by about 2400 mg / m2by continuous intravenous administration and the second dose is about 2400 mg / m2by continuous intravenous administration;(b) the first dose is about 2400 mg / m2by continuous intravenous administration and the second dose is about 2000 mg / m2by continuous138NAI-5007064122intravenous administration; or(c) the first dose is about 2000 mg / m2by continuous intravenous administration and the second dose is discontinued.

49. The method of claim 48, wherein:(i) the adverse event is a hematologic toxicity selected from neutropenia, febrile neutropenia, and thrombocytopenia; or(ii) the adverse event is a non-hematologic toxicity selected from diarrhea, mucositis, and hand-foot syndrome.

50. A pharmaceutical composition comprising ifinatamab deruxtecan for use in treating unresectable or metastatic esophageal squamous cell carcinoma (ESCC) in a subject in need thereof, wherein the pharmaceutical composition is administered in combination with pembrolizumab.

51. A pharmaceutical composition comprising pembrolizumab for use in treating unresectable or metastatic esophageal squamous cell carcinoma (ESCC) in a subject in need thereof, wherein the pharmaceutical composition is administered in combination with ifinatamab deruxtecan.139NAI-5007064122

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