Combinations for the treatment of cancer

Abstract

In one aspect, provided herein are methods of treating breast cancer with a combination therapy comprising an anti-human-HER3 antibody-drug conjugate and pembrolizumab, which may be administered either before or after carboplatin / paclitaxel plus pembrolizumab.

Description

Attorney Docket Number: 14463-397-228COMBINATIONS FOR THE TREATMENT OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 747,860, filed January 21, 2025, 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 content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14463-397-228_SEQ_LISTING.xmf’, was created on January 12, 2026, and is 25,719 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 is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab;and(ii) 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:1NAI-5007076236Formula Iwherein AB is an anti-human HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 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: 3; andb) 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: 4. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 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 a first therapeutically effective amount of pembrolizumab;and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti- human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II2NAI-5007076236Formula IIwherein A represents a connecting position to the anti-human-HER3 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-HER3 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: 3; andb) 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: 4;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0006] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 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 a third therapeutically effective amount of a PD-1 or PD-L1 inhibitor such as pembrolizumab or atezolizumab, and further comprises administering a fourth therapeutically effective amount of carboplatin and / or a fifth therapeutically effective amount of paclitaxel. In some embodiments, the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate. In some3NAI-5007076236embodiments, the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate.

[0008] In some embodiments of the method described herein, the subject has (i) no confirmed metastases; (ii) clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2; (iii) no previous systemic therapy; (iv) no previous excision of primary tumor; and / or (v) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. In some embodiments, the subject has no confirmed metastases. In some embodiments, the subject has clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2. In some embodiments, the subject has no previous systemic therapy. In some embodiments, the subject has no previous excision of primary tumor. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

[0009] Pharmaceutical compositions for use and uses according to the present combinational therapy are also provided herein.

[0010] In some embodiments of the methods, pharmaceutical compositions and uses provided herein, the cancer is a breast cancer. In some embodiments, the cancer is a high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a schematic diagram showing an exemplary design of a clinical study for the combination of patritumab deruxtecan and pembrolizumab (Part 1 - Safety Lead-In). As represented in FIG. 1, AUC=area under the curve; BOIN=Bayesian optimal interval; ECOG PS=Eastem Cooperative Oncology Group Performance Status; HER2=human epidermal growth factor receptor 2; HER3-DXd=patritumab deruxtecan; HR=hormone receptor; qw=once a week; q3w=once every 3 weeks; SOC=standard of care; TNBC=triple-negative breast cancer.aDLTs will be evaluated during Cycle 1 and per the BOIN design with a target DLT rate of 30%.bHER3-DXd may be evaluated at a lower dose level if dose deescalation is warranted as guided by the BOIN design. Refer to Section 7.2.4 of the Examples for dose levels.cSurgery should occur within approximately 3 to 6 weeks after last dose of neoadjuvant treatment.dFurther therapy may include radiation therapy (if clinically indicated) and systemic adjuvant therapy.4NAI-5007076236

[0012] FIG. 2 is a schematic diagram showing an exemplary design of a clinical study for the combination of patritumab deruxtecan and pembrolizumab (Part 2 - Main Study). As represented in FIG. 2, AUC=area under the curve, CPS=combined positive score; ECOG PS=Eastern Cooperative Oncology Group Performance Status; g5AC m=germline BRCA mutation; HER2=human epidermal growth factor receptor 2; HER3-DXd=patritumab deruxtecan; HR=hormone receptor; IHC=immunohistochemistry; MRI=magnetic resonance imaging; pCR=pathologic complete response; PD-L1= programmed cell death ligand 1; qw=once a week; q3w=once every 3 weeks; q6w=once every 6 weeks; SCF=Sponsor consultation form; SOC=standard of care; TNBC=triple-negative breast cancer;TPC=treatment of physician’s choice.aHER3-DXd may be evaluated at reduced dose level if dose deescalation is warranted as guided by BOIN design in Part 1. Refer to Section 7.2.4 of the Examples for dose levels.bAdministration of doxorubicin or epirubicin is physician’s choice.cSurgery should occur within approximately 3 to 6 weeks after last dose of neoadjuvant treatment. Adjuvant pembrolizumab should be initiated approximately 4 to 8 weeks after definitive surgery, as clinically appropriate, but no later than 84 days after definitive surgery. Sponsor consultation and completion of SCF is required if more than 84 days have elapsed between definitive surgery and initiation of adjuvant pembrolizumab. Surgery-related AEs must be adequately resolved before initiation of adjuvant pembrolizumab.dPostoperative radiation therapy, if clinically indicated, should be initiated when clinically appropriate after surgery but no sooner than 40 days after last dose of HER3-DXd (for participants in Arms A and B). It may be administered either concurrently with or before initiation of adjuvant pembrolizumab.eAn optional additional adjuvant TPC may be initiated either on C9D1, C10D1, or Cl 1D1 for participants with residual disease. The investigator should select the earliest of these cycles that allows adequate resolution of surgery-related toxicities and radiation-related toxicities (if administered), and after use of any steroid to treat radiation-related toxicities is discontinued. See Section 7.2.5.3 of the Examples for timing of initiation of additional adjuvant TPC relative to surgery, adjuvant pembrolizumab, and radiation therapy.fThe number of treatment cycles in the Adjuvant Treatment Phase and the duration (in weeks) of the Adjuvant Treatment Phase depends on the adjuvant study intervention administered.gAdministration of adjuvant pembrolizumab 200 mg twice every 6 weeks (DI and D22 of C9-12 and C13D1) may be considered as an alternative on a case-by case basis after Sponsor consultation and completion of a SCF.hBreast MRI will be performed only for participants in Part 2 who consent to optional MRI exams at a subset of study sites.5NAI-5007076236DETAILED DESCRIPTION1. Definitions

[0013] 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.

[0014] 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.

[0015] As used herein, the term “comprising” also specifically includes embodiments “consisting of’ and “consisting essentially of’ the recited elements, unless specifically indicated otherwise.

[0016] 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, where applicable, the term “about” or “approximately” indicates the designated value(s) ± one standard deviation of that value(s).

[0017] 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.

[0018] 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.

[0019] 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., John6NAI-5007076236Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference.

[0020] 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.

[0021] 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 chain constant 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.

[0022] “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.

[0023] “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 7NAI-5007076236binding 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.

[0024] “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 light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes 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 .

[0025] “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 8NAI-5007076236are 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 on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-396, and in International Publication 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.”

[0026] “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.

[0027] 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.

[0028] 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 9NAI-5007076236CDRs 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.

[0029] 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 a canonical 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.

[0030] 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.

[0031] More recently, a universal numbering system ImMunoGeneTics (IMGT) Information System™ has been developed and widely adopted. See Lefranc etal., Dev Comp10NAI-5007076236Immunol, 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 etal., supra). An exemplary system, shown herein, combines Kabat and Chothia CDR definitions.

[0032] 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.

[0033] 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.

[0034] The terms “constant region” or “constant domain” refer 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.

[0035] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C- 11NAI-5007076236terminal 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.

[0036] “Polynucleotide” refers to a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. Polynucleotides include, e.g., DNA and RNA (e.g., mRNA). cDNA is a typical example of a polynucleotide.

[0037] “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.

[0038] “Recombinant” refers to polynucleotides, polypeptides, vectors, viruses and other macromolecules that are prepared, expressed, created or isolated by recombinant means.

[0039] 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.

[0040] “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 12NAI-5007076236antigen 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 be represented 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®).

[0041] 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.

[0042] 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.

[0043] As used herein, the term “anti-human-HER3 antibody” refers to an antibody which binds specifically to HER3, and preferably has an activity of internalization in HER3-expressing cells by binding to HER3. In some embodiments, HER3 is human HER3.

[0044] 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 HER3 antibody-drug conjugate,” “anti-human HER3 ADC” are used interchangeably and refer to a conjugate comprising an anti-human HER3 antibody conjugated to one or more cytotoxic agents, optionally through one or more linkers.

[0045] As used herein, the term “functional fragment” of an antibody is also called “antigen binding fragment” of a human HER3 antibody, and is used to mean a partial fragment of the antibody having binding activity against human HER3, and includes, but not 13NAI-5007076236limited 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 HER3 -binding ability. These antigen-binding fragments include not only those obtained 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.

[0046] 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.

[0047] 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.

[0048] As used herein, the term “HER3-DXd” is an antibody-drug conjugate (ADC) comprising a HER3 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, HER3-DXd is patritumab deruxtecan.

[0049] As used herein, the term “patritumab deruxtecan” is an antibody-drug conjugate (ADC) comprising the anti-HER3 monoclonal antibody patritumab, which is covalently linked to deruxtecan (“DXd”). Patritumab deruxtecan is also described, e.g., in WHO Drug Information, Vol. 34, No. 1, 2020 (Recommended INN: List 83), which is incorporated by 14NAI-5007076236reference herein in its entirety. Patritumab is also described, e.g., in WHO Drug Information, Vol. 26, No. 3, 2012 (Recommended INN: List 68), which is incorporated by reference herein in its entirety. Deruxtecan is also described, e.g., in WHO Drug Information, Vol. 30, No. 4, 2016 (Proposed INN List 116), which is incorporated by reference herein in its entirety.

[0050] 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) 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).

[0051] 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.

[0052] 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 15NAI-5007076236can 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.

[0053] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that does not have notable toxicity, and can be used as a medicament.

[0054] A compound having an acidic substituent can be formed into a salt by a reaction with a base. Examples include, but are not limited to, alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt, and magnesium salt; metal salts such as aluminum salt, and iron salt; inorganic salts such as ammonium salt; amine salts including organic salts and the like such as tert-butylamine salt, tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenetylamine salt, piperazine salt, tetramethylammonium salt, and tri s(hydroxymethyl)aminom ethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt.

[0055] A compound having a basic substituent can be formed into a salt by a reaction with an acid. Examples include halide acid salts such as hydrofluoric acid salt, hydrochloric acid salt, hydrobromic acid salt, and hydroiodic acid salt; inorganic acid salts such as nitric acid salt, perchloric acid salt, sulfuric acid salt, and phosphoric acid salt; C1-C6 alkyl sulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, and ethanesulfonic acid salt; aryl sulfonic acid salts such as benzenesulfonic acid salt, and p-toluenesulfonic acid salt; organic acid salts such as acetic acid salt, malic acid salt, fumaric acid salt, succinic acid salt, citric acid salt, ascorbic acid salt, tartaric acid salt, oxalic acid salt, adipic acid salt, and maleic acid salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt.

[0056] 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)16NAI-5007076236reduction, 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 effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.

[0057] As used herein, the terms “immune oncology therapy,” “immuno-oncology therapy,” “immuno oncology therapy,” or “IO therapy” comprise administration to the subject of at least one compound capable of recognizing a tumor-cell antigen and / or a cancercell antigen. In some cases, the at least one compound capable of recognizing a tumor-cell antigen and / or a cancer-cell antigen is an engineered protein, a fusion protein, an antibody, or a cytokine. In some cases, the tumor-cell antigen and / or a cancer-cell antigen is selected from the group consisting of: 2B4, 41BB, A2AR, ALK, a B-7 family ligand, BRAF, BTK, BTLA, CCR4, CD19, CD20, CD27, CD28, CD35, CD40, CD50, CD73, CD137, CD160 / By55, CD172a / SIRPa, CD200, CD223, CD244, CEACAM, a CHK 1 kinase, a CHK2 kinase, cMET, CSF1R, CTLA-4, CXCR, DNMT, EGFr, GAL9, GITR, HD AC, HER-2, HVEM, ICOS, IDO, KIR, KRAS, LAG3, MEK, mTor, NKG2A, 0X40, PARP, PD-1, PD-L1, PD-L2, STAT3, TGF-beta, TIGIT, TIM-3, TKI, a TLR (Toll like receptors), and combinations thereof. 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 aPD-Ll 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. In some cases, the at least one compound is an antibody selected from the group consisting of: nivolumab, pembrolizumab, pidilizumab, RMP1-14, AGEN2034, cemiplimab, ipilimumab, 9D9, tremelimumab, AGEN1884, RG2077, and combinations thereof.17NAI-5007076236

[0058] 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, NJ USA; 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 Pembrolizumab18NAI-5007076236

[0059] 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.

[0060] 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 (e.g., an adult human, / .<?., greater than or equal to 18 years of age). 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.

[0061] 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.

[0062] The term “administering” refers to the act of delivering a 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, in19NAI-5007076236certain 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).

[0063] 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.

[0064] As used herein, 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). Any open 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 based on 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) and an anti-human-HER3 antibody-drug conjugate, detailed description of each of which is provided in sections below. In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody such as pembrolizumab. In one aspect, provided herein is a method for treating a cancer, e.g., a breast cancer (e.g., a triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 (or Her2) negative breast cancer) using the present combinational therapies.

[0067] In one aspect, provided is a method for treating a breast cancer in a subject in need thereof. The method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab;and20NAI-5007076236(ii) 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 Iwherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 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: 3; andb) 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: 4.In some embodiments, the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer. In some embodiments, the triple-negative breast cancer is a high-risk and / or early-stage triple negative breast cancer. In some embodiments, the triple-negative breast cancer is a high-risk early-stage triple negative breast cancer.

[0068] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab;and21NAI-5007076236(ii) 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 Iwherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises:c) 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: 3; andd) 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: 4;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer. In some embodiments, the triplenegative breast cancer is a high-risk and / or early-stage triple negative breast cancer. In some embodiments, the triple-negative breast cancer is a high-risk early-stage triple negative breast cancer.

[0069] In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0070] In another aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab;and22NAI-5007076236(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti- human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula IIwherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 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: 3; andb) 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: 4;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer. In some embodiments, the triplenegative breast cancer is a high-risk and / or early-stage triple negative breast cancer. In some embodiments, the triple-negative breast cancer is a high-risk early-stage triple negative breast cancer.

[0071] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 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.

[0072] In some embodiments of the methods described herein, the method further comprises administering to the subject a third therapeutically effective amount of pembrolizumab. In some embodiments of the methods described herein, the method further23NAI-5007076236comprises administering to the subject a fourth therapeutically effective amount of carboplatin and a fifth therapeutically effective amount of paclitaxel. In some embodiments of the methods described herein, the administering to the subject the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate. In some embodiments of the methods described herein, the administering to the subject the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate. In another aspect, provided herein is a method for treating cancer in a subject comprising administering to the subject specific combinations comprising the pembrolizumab and the anti-human-HER3 antibody drug conjugate of the present disclosure.

[0073] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula Iwherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 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: 3; and24NAI-5007076236b) 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: 4;wherein the subject has been previously administered with a therapeutically effective amount of pembrolizumab.

[0074] In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0075] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula IIwherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 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: 3; andb) 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: 4;wherein the subject has been previously administered with a therapeutically effective amount of pembrolizumab.

[0076] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of25NAI-5007076236drug-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.

[0077] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of pembrolizumab;wherein the subject has been previously administered with a therapeutically effective amount of an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula Iwherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 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: 3; andb) 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: 4.

[0078] In some embodiments herein, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0079] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of pembrolizumab;wherein the subject has been previously administered with a therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an26NAI-5007076236anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula IIwherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 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: 3; andb) 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: 4.

[0080] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 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.

[0081] In another aspect, provided is a method for treating cancer (e.g., a breast cancer) in a subject in need thereof, wherein the method comprises: (A) administering to the subject a first therapeutically effective amount of pembrolizumab as described herein; and (B) administering to the subject a second therapeutically effective amount of an anti-human-HER3 antibody-drug conjugate as described herein. In some embodiments, the drug in the anti-human-HER3 antibody-drug conjugate is a topoisomerase I inhibitor. In some embodiments, the drug represented by the following formula is released to express an antitumor activity:27NAI-5007076236Formula III

[0082] In another aspect, provided is a method wherein an antitumor compound represented by the following formula is conjugated to an anti-human-HER3 antibody through a linker with the nitrogen atom of the amino group at position 1 as the connecting position:Formula IV

[0083] In some embodiments, the antitumor compound is conjugated to the anti-human-HER3 antibody through the linker via a thioether bond which is formed at a disulfide bond moiety present in the anti-human-HER3 antibody. In some embodiments, the linker comprises a tetrapeptide residue of -Gly-Gly-Phe-Gly- (SEQ ID NO: 11).

[0084] In one aspect, the method provided herein is for treating a cancer. In one aspect, the method provided herein is for treating a breast cancer. In one aspect, the method provided herein is for treating triple-negative breast cancer. In one aspect, the method provided herein is for treating high-risk and / or early-stage triple-negative breast cancer. In some embodiments, the triple-negative breast cancer is a high-risk early-stage triple negative breast cancer. In one aspect, the method provided herein is for treating hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0085] In some embodiments, the subject has (i) no confirmed metastases; (ii) clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2; (iii) no previous systemic therapy; (iv) no previous excision of primary tumor; and / or (v) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. In some embodiments, the subject has no confirmed 28NAI-5007076236metastases. In some embodiments, the subject has clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2. In some embodiments, the subject has no previous systemic therapy. In some embodiments, the subject has no previous excision of primary tumor. In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

[0086] In one embodiment, the subject is a human subject. In one embodiment, the human subject is an adult, / .<?., greater than or equal to 18 years of age.

[0087] In certain embodiments, the combination therapy of the disclosure reduces the growth of tumor cells in vivo when administered to the subject. 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.

[0088] 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%.

[0089] In one embodiment, the subject is a human subject. In one embodiment, the human subject is an adult, i.e., greater than or equal to 18 years of age.

[0090] In one aspect, provided herein is use of pembrolizumab and an anti-human-HER3 antibody-drug conjugate (e.g., patritumab deruxtecan) for the manufacture of a medicament for treating breast cancer. In another aspect, provided herein is use of pembrolizumab for the manufacture of a medicament in combination with an anti-HER3 antibody-drug conjugate (e.g., patritumab deruxtecan) for treating breast cancer. In yet another aspect, provided herein is use of an anti-human-HER3 antibody-drug conjugate (e.g., patritumab deruxtecan) for the manufacture of a medicament in combination with pembrolizumab for treating breast cancer.29NAI-5007076236

[0091] In one aspect, provided herein is pembrolizumab for use in combination with an anti-human-HER3 antibody-drug conjugate in treating cancer in a subject in need thereof, wherein the anti-human-HER3 antibody-drug conjugate comprises an antibodydrug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula Iwherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof 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: 3; and 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: 4. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0092] In one aspect, provided herein is pembrolizumab for use in combination with an anti-human-HER3 antibody-drug conjugate in treating cancer in a subject in need thereof; and wherein the anti-human-HER3 antibody-drug conjugate comprises an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:30NAI-5007076236Formula Iwherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof 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: 3; and 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: 4. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is a high-risk and / or early-stage triple negative breast cancer. In some embodiments, cancer is a high-risk early-stage triple negative breast cancer. In some embodiments, the cancer is hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0093] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer (e.g., breast cancer), comprising a first therapeutically effective amount of pembrolizumab as defined herein, and a second therapeutically effective amount of the antibody-drug conjugate as defined herein in combination. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer (e.g., breast cancer), comprising a first therapeutically effective amount of pembrolizumab as defined herein, in combination with a second therapeutically effective amount of the antibody-drug conjugate as defined herein. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer (e.g., breast cancer), comprising a second therapeutically effective amount of the antibody-drug conjugate as defined herein, in combination with pembrolizumab as defined herein. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is a high-risk and / or early-stage triple negative 31NAI-5007076236breast cancer. In some embodiments, the cancer is a high-risk early-stage triple negative breast cancer. In some embodiments, the cancer is hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0094] In some embodiments, provided herein is a use of pembrolizumab as defined herein for the preparation of a medicament for treating cancer (e.g., breast cancer), by administration in combination with the antibody-drug conjugate as defined herein (e.g., patritumab deruxtecan). In some embodiments, provided herein is a use of the antibody-drug conjugate as defined herein (e.g., patritumab deruxtecan) for the preparation of a medicament for treating cancer (e.g., breast cancer), by administration in combination with pembrolizumab as defined herein. In some embodiments, the cancer is triple-negative breast cancer. In some embodiments, the cancer is a high-risk and / or early-stage triple negative breast cancer. In some embodiments, the cancer is a high-risk early-stage triple negative breast cancer. In some embodiments, the cancer is hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0095] Dosage and Administration of Pembrolizumab

[0096] Any suitable dose(s) of pembrolizumab may be used in the methods, compositions, and kits described herein.

[0097] In some embodiments, for example, relevant to any method as disclosed herein, the pembrolizumab is administered at a dose of about 200 mg. In some embodiments, the pembrolizumab is administered at a dose of about 400 mg. In some embodiments, for example, relevant to any method as disclosed herein, the pembrolizumab is administered every three weeks. In some embodiments, for example, relevant to any method as disclosed herein, pembrolizumab is administered intravenously.

[0098] 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.

[0099] 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 certain embodiments, the target dose is administered every 32NAI-5007076236three weeks (±2 days). In certain embodiments, the target dose is administered every three weeks (±1 days). In certain embodiments, the target dose is administered every three weeks (±0 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] 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, 200 mg Q6W, or 400 mg Q6W.

[0104] 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,33NAI-5007076236the 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.

[0105] In certain embodiments of the methods, compositions, kits and uses described herein, the human patient is administered 400 mg pembrolizumab once every six weeks.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.34NAI-5007076236

[0110] 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. In embodiments 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.

[0111] 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%.

[0112] Dosage and Administration of Antibody-Drug Conjugate

[0113] An antibody-drug conjugate (e.g., patritumab deruxtecan) as disclosed herein can be administered at any suitable dose, e.g., about 3.2 mg / kg, about 4.8 mg / kg, or about 5.6 mg / kg of the subject’s body weight.

[0114] In some embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 3.2 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg. In other embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg.

[0115] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate e.g., patritumab deruxtecan) is administered once every three weeks.35NAI-5007076236

[0116] In some embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate is administered once every three weeks.

[0117] In some embodiments relevant to any method as disclosed herein, the administration of the second therapeutically effective amount of the antibody-drug conjugate is maintained to the completion of the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0118] Any suitable dose(s) of the antibody-drug conjugate (e.g., patritumab deruxtecan) may be used in the methods, compositions, and kits described herein.

[0119] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 3.2 mg / kg, about 4.8 mg / kg, or about 5.6 mg / kg of the subject’s body weight once every three weeks.

[0120] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 3.2 mg / kg of the subject’s body weight once every three weeks.

[0121] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate e.g., patritumab deruxtecan) is administered at a dose of about 4.8 mg / kg of the subject’s body weight once every three weeks.

[0122] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 5.6 mg / kg of the subject’s body weight once every three weeks.

[0123] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of 3.2 mg / kg of the subject’s body weight once every three weeks.

[0124] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of 4.8 mg / kg of the subject’s body weight once every three weeks.

[0125] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of 5.6 mg / kg of the subject’s body weight once every three weeks.

[0126] In some embodiments of this disclosure, the antibody-drug conjugate is administered intravenously. In one embodiment, the antibody-drug conjugate is administered36NAI-5007076236via a 30 ± 5 minute IV fusion. In one embodiment, the antibody-drug conjugate is administered via a 90 ± 10 minute IV fusion.

[0127] In some embodiments, the method provided herein may include administering a premedication with one or more antiemetic agents (e.g., dexamethasone with either a 5-HT3 receptor antagonist (e.g, ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron) or an NK-1 receptor antagonist (e.g, aprepitant, casopitant, netupitant, or rolapitant)) to the subject.

[0128] Dosage and Administration of Carboplatin and Paclitaxel

[0129] A cytotoxic agent (e.g., carboplatin and / or paclitaxel) as disclosed herein can be administered at any suitable dose.

[0130] In some embodiments, carboplatin can be administered in a dose of about area under curve (AUC)l.O mg / mL / min, AUC1.5 mg / mL / min, or AUC2.0mg / mL / min.

[0131] In some embodiments, for example, relevant to any method as disclosed herein, the fourth therapeutically effective amount of carboplatin is administered at a dose of about AUC1.5 mg / mL / min.

[0132] In some embodiments, for example, relevant to any method as disclosed herein, the carboplatin is administered once every week. In some embodiments, for example, relevant to any method as disclosed herein, the fourth therapeutically effective amount of the carboplatin is administered once every week.

[0133] In some embodiments of this disclosure, the carboplatin is administered intravenously.

[0134] Any suitable dose(s) of the paclitaxel may be used in the methods, compositions, and kits described herein.

[0135] In some embodiments, paclitaxel can be administered in a dose of about 40 mg / m2, about 60 mg / m2, about 80 mg / m2, about 100 mg / m2, about 120 mg / m2, or about 140 mg / m2.

[0136] In some embodiments, for example, relevant to any method as disclosed herein, the fifth therapeutically effective amount of paclitaxel is administered at a dose of about 80 mg / m2.

[0137] In some embodiments, for example, relevant to any method as disclosed herein, the paclitaxel is administered once every week. In some embodiments, for example, relevant to any method as disclosed herein, the fifth therapeutically effective amount of the paclitaxel is administered once every week.37NAI-5007076236

[0138] Any suitable dose(s) of the paclitaxel may be used in the methods, compositions, and kits described herein.

[0139] In some embodiments, for example, relevant to any method as disclosed herein, the paclitaxel is administered at a dose of about 80 mg / m2once every week.

[0140] In some embodiments of this disclosure, the paclitaxel is administered intravenously.

[0141] In some embodiments, the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate. In some embodiments of the methods described herein, the administering to the subject the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate.

[0142] In some embodiments, the administration of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate can comprise a first neoadjuvant treatment phase and the administration of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel can comprise a second neoadjuvant treatment phase. In some embodiments, the administration of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel can comprise a first neoadjuvant treatment phase and the administration of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate can comprise a second neoadjuvant treatment phase. In some embodiments, the first neoadjuvant treatment phase occurs before the second neoadjuvant treatment phase.

[0143] In some embodiments, the methods disclosed herein comprise (1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate for 4 cycles; followed by (2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab,38NAI-5007076236the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles.

[0144] In some embodiments, each cycle length has a duration of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, or about 10 weeks. In some embodiments the first neoadjuvant treatment phase and / or the second neoadjuvant treatment phase each has a duration of about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, or about 20 weeks.

[0145] In some embodiments, each cycle length has a duration of about 3 weeks. In some embodiments, the first neoadjuvant treatment phase has a duration of about 12 weeks. In some embodiments, the second neoadjuvant treatment phase has a duration of about 12 weeks. In some embodiments, the first neoadjuvant treatment phase combined with the second neoadjuvant treatment phase has a duration of about 24 weeks.

[0146] Dosage and Administration During Adjuvant Phase

[0147] In some embodiments, following the neoadjuvant phase, (e.g., the first neoadjuvant treatment phase and the second neoadjuvant treatment phase), is an adjuvant phase. In some embodiments, the adjuvant phase comprises surgery and / or further therapy (e.g., radiation (if administered)). In some embodiments, the subject has surgery (e.g., breast cancer surgery). In some embodiment, the subject has surgery after the first neoadjuvant treatment phase and the second neoadjuvant treatment phase are completed or discontinued. In some embodiments, the surgery is breast conservation surgery (BCS) or mastectomy. In some embodiments the surgery includes axillary lymph node surgery (e.g., sentinel lymph node biopsy, axillary lymph node dissection, targeted axillary dissection). In some embodiments, the surgery is performed about 3 weeks to about 6 weeks after completion or early discontinuation of neoadjuvant treatment (e.g., the first neoadjuvant treatment and the second neoadjuvant treatment).

[0148] In some embodiments, the adjuvant treatment phase has a duration of about 30 to about 66 weeks. In some embodiments, each cycle during the adjuvant treatment phase has a duration of about 6 weeks. In some embodiments, the adjuvant phase comprises about 3 cycles or more, about 4 cycles or more, about 5 cycles or more, about 6 cycles or more, about 7 cycles or more, about 8 cycles or more, about 9 cycles or more, about 10 cycles or more, about 11 cycles or more, about 12 cycles or more, about 13 cycles or more, about 14 cycles or more, or about 15 cycles or more.39NAI-5007076236

[0149] In some embodiments, the adjuvant phase can comprise administering to the subject a sixth therapeutically effective amount of pembrolizumab, and optionally administering to the subject a seventh therapeutically effective amount of one or more additional treatments of physician’s choice (TPC). In some embodiments, the pembrolizumab is administered at a dose of about 400 mg. In some embodiments, the pembrolizumab is administered once every six weeks. In some embodiments, the pembrolizumab is administered intravenously. In some embodiments, the TPC comprises doxorubicin, epirubicin, cyclophosphamide, capecitabine, and / or olaparib. In some embodiments, the doxorubicin is administered once every two weeks or once every three weeks. In some embodiments, the doxorubicin is administered dose of about 60 mg / m2. In some embodiments, the doxorubicin is administered intravenously. In some embodiments the epirubicin is administered once every two weeks or once every three weeks. In some embodiments the epirubicin is administered at a dose of about 90 mg / m2. In some embodiments the epirubicin is administered intravenously. In some embodiments the cyclophosphamide is administered once every two weeks or once every three weeks. In some embodiments the cyclophosphamide is administered at a dose of about 600 mg / m2. In some embodiments the cyclophosphamide is administered intravenously. In some embodiments the capecitabine is administered on Days 1 to 14 and Days 22 to 35 of every 6 week cycle. In some embodiments the capecitabine is administered at a dose of about 1000 mg / m2to 1250 mg / m2. In some embodiments the capecitabine is administered intravenously. In some embodiments the olaparib is administered on Days 1 to 42 of every 6-week cycle for 8 cycles and Days 1 to 29 of the subsequent cycle. In some embodiments the olaparib is administered at a dose of about 300 mg. In some embodiments the olaparib is administered intravenously.3. Pembrolizumab and other anti-PD-1 antibodies

[0150] 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.),40NAI-5007076236atezolizumab (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).

[0151] 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.

[0152] 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.

[0153] 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.4. Anti-human-HER3 antibody-drug conjugate

[0154] Antibody-drug conjugates (ADCs) are targeted cancer therapies which comprise or consist of monoclonal antibodies (mAbs) conjugated via a linker component to cytotoxic agents (payloads). The antibody component of the ADC is directed towards a tumor-associated antigen, allowing for tumor specificity and targeted drug delivery to the tumor site. This approach is expected to result in reduced exposure of non-target tissues to the cytotoxic agent and enhanced antitumor potency. Due to the reduced toxicity of ADC-mediated drug41NAI-5007076236delivery, the therapeutic window may be broadened in comparison to traditional chemotherapy.

[0155] Human epidermal growth factor receptor 3 (also known as HER3, and ErbB3) is a transmembrane receptor belonging to an epidermal growth factor receptor subfamily of receptor protein tyrosine kinase together with HER1, HER2, and HER4. HER3 is expressed in many types of cancer such as lung cancer, breast cancer, gastrointestinal cancer, and pancreatic cancer, and is known to be phosphorylated itself by forming a heterodimer together with a tyrosine kinase receptor such as EGFR or HER2 to induce proliferation of cancer cells and an apoptosis-inhibitory signal. The RNA sequence, the cDNA sequence, and the amino acid sequence of HER3 are disclosed in public database, and are available with accession numbers such as AAA35979 (precursor containing a signal sequence consisting of 19 amino terminal amino acid residues), and M34309 (NCBI).

[0156] Anti-human-HER3 antibody-drug conjugates used in the present disclosure are known in the art. Examples of such anti-human-HER3 antibody-drug conjugates include, but are not limited to, DB-1310, IBI-133, SHR-A2009, AMT-562, and HMBD-501. Anti-HER3 antibody-drug conjugates are also described in US2021 / 0353764 (W02020063676), US2024 / 0026028 (WO2022078425), W02023017151, WO2023143365, WO2023031435, W02023041006, WO2023088382, WO2023125530, WO2023138635, WO2023143263, WO2023208216, WO2024077277, WO2024078449, WO2024083166, WO2024088388, CN118662651A, WO2024208881, and WO2024215515, all of which are incorporated herein by reference. An anti-HER3 antibody-drug conjugate is also described in International Application No. PCT / JP2024 / 20005, which is incorporated herein by reference in its entirety.

[0157] 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:42NAI-5007076236Formula Iwherein AB is an anti-human-HER3 antibody (in preferred embodiments, an antihuman HER3 antibody) or a functional fragment thereof and a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0158] In one aspect of the present disclosure, the anti-human-HER3 antibody-drug conjugate is an anti-human-HER3 antibody-drug conjugate, in which a drug-linker represented by the following formula:Formula IIwherein A represents a connecting position to an anti-human-HER3 antibody or a functional fragment thereof; is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond. In some embodiments of the method provided herein, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula II, wherein the number of druglinkers of Formula II is equal to n, and wherein n represents the drug to antibody ratio.

[0159] In one aspect of the present disclosure, n represents the Drug-to- Antibody Ratio (DAR). DAR as used herein: (i) when referring to a composition of the antibody-drug43NAI-5007076236conjugates, is the average number of drug molecules (or units of a drug-linker) that are conjugated to the anti-human-HER3 antibody or functional fragment thereof in the antibodydrug 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-HER3 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.

[0160] In some embodiments of the method provided herein, with respect to a composition of antibody-drug conjugates, n (e.g., the number of drug-linkers of Formula II) is from about 2 to about 10, from about 2 to about 8, from about 3 to about 8, from about 3 to about 9, from about 3.5 to about 8.5, from about 4 to about 8, from about 5 to about 8, from about 6 to about 8, from about 7 to about 8, from about 7.5 to about 8, or about 8. In the present disclosure, in some embodiments, the term “about 8” is from 7.8 to 8.2, from 7.9 to 8.1, or 8. In other embodiments, the number of the drug or the drug-linkers conjugated per antibody molecule in the anti-human-HER3 antibody-drug conjugate in the instant method is an integer in the range from 2 to 8, for example, 2, 3, 4, 5, 6, 7, or 8. In a specific embodiment, the number of the drug or the drug-linkers conjugated per antibody molecule in the anti-human-HER3 antibody-drug conjugate is 8. In a specific embodiment, the number of drug-linkers of Formula II conjugated per antibody molecule in the anti-human-HER3 antibody-drug conjugate is 8.

[0161] In the present disclosure, the partial structure consisting of a linker and a drug in the anti-human-HER3 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.

[0162] In particular embodiments, the drug-linker of the present disclosure includes a derivative of exatecan as a component. Exatecan, a camptothecin derivative having an antitumor effect, (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)) is a topoisomerase I inhibitor.

[0163] Exatecan is represented by the following Formula:44NAI-5007076236Formula III

[0164] After internalization into cancer cells, the anti-human-HER3 antibody-drug conjugate used in the present disclosure releases the compound represented by the following Formula V, and thereby exerts an antitumor effect.Formula IV

[0165] The aforementioned compound is inferred to be the original source of the antitumor activity of the anti-human-HER3 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).

[0166] In some embodiments, the anti-human-HER3 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-HER3 antibody-drug conjugate used in the present disclosure 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.4.1. Anti-human-HER3 antibody

[0167] In one aspect, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody (e.g., anti-human HER3 antibody) or a functional fragment thereof in the anti-human-HER3 antibody-drug conjugate used in the present disclosure 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 the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the 45NAI-5007076236present disclosure may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. Examples of anti-human-HER3 antibodies include, but are not limited to, patritumab (U3-1287), Ul-59 (International Publication No. W02007 / 077028), AV-203 (International Publication No. WO2011 / 136911), LJM-716 (International Publication No. WO2012 / 022814), duligotumab (MEHD-7945A) (International Publication No.W02010 / 108127), istiratumab (MM-141) (International Publication No. WO2011 / 047180), lumretuzumab (RG-7116) (International Publication No. WO2014 / 108484), setibantumab (MM-121) (International Publication No. W02008 / 100624), REGN-1400 (International Publication No. WO2013 / 048883; U. S. Patent No. 8,791,244 B2), ZW-9 (International Publication No. W02013 / 063702; U.S. Patent No. 9,574,010 B2), and variants, active fragments, modified products and the like thereof, all of which are incorporated herein by reference.

[0168] In the anti-human-HER3 antibody in the anti-human-HER3 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.

[0169] 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 46NAI-5007076236terminus 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-HER3 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 by amidation 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 antigen-binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure 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.

[0170] In some embodiments, an N-terminal E or Q of the anti-human-HER3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K of the anti-human-HER3 antibody provided herein is removed. In other embodiments, an N-terminal E or Q of the anti-human-HER3 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-HER3 antibody is removed. The present disclosure includes any of the above described post-translational modifications of any of the anti-human-HER3 antibody provided herein.

[0171] 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. Furthermore, variants of these can be also used as the anti-HER3 antibody of the present disclosure.

[0172] In an embodiment, the anti-human-HER3 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.,47NAI-5007076236substitutions) 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-HER3 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-HER3 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 VH-CDR2 of the anti-human-HER3 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. In some embodiments, the VH-CDR3 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 7, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 7. In some embodiments, the VL-CDR1 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 8, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 8. In other embodiments, the VL-CDR1 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 12, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 12. In some embodiments, the VL-CDR2 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 9, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 9. In some embodiments, the VL-CDR3 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 10, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 10.

[0173] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody comprises as a VH, the amino acid sequence of SEQ ID NO: 3, 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: 3. In some examples, the anti-human-HER3 antibody comprises as a VL, the amino acid sequence of SEQ ID NO: 4, 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: 4.

[0174] In one aspect, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising 48NAI-5007076236the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3, 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: 3. In one aspect, for example, relevant to any method as disclosed herein, the anti-human-HER3 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: 4, 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: 4.

[0175] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody comprises as a heavy chain (HC), the amino acid sequence of SEQ ID NO: 1, 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: 1. In some examples, the anti-human-HER3 antibody comprises as a light chain (LC), the amino acid sequence of SEQ ID NO: 2, 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: 2.4.2. Pharmaceutical Compositions Comprising the anti-human-HER3 ADC

[0176] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising an anti-human-HER3 ADC (e.g., patritumab deruxtecan) described herein. The pharmaceutical composition of the present disclosure may comprise a plurality of anti-human-HER3 ADCs as disclosed herein.

[0177] The pharmaceutical composition of the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection, a lyophilized injection, or a freeze-dried injection, and can be even more preferably used as a freeze-dried injection.

[0178] In the case that the pharmaceutical composition of the present disclosure is an aqueous injection, it can be preferably diluted with a suitable diluent and then given as an intravenous drip. Examples of the diluent include a glucose solution, and a saline solution, a49NAI-5007076236preferable example includes a glucose solution, and a more preferable example includes a 5% glucose solution.

[0179] In the case that the pharmaceutical composition of the present disclosure is a freeze-dried injection, it can be preferably administered by intravenous drip after dissolving it in water for injection, and diluting a necessary amount thereof with a proper diluent.Examples of the diluent include a glucose solution, and a saline solution, a preferable example includes a glucose solution, and a more preferable example includes a 5% glucose solution.

[0180] Administration may be effected by different ways, e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, topical or intradermal administration. In some embodiments, the route of administration depends on the kind of therapy and the kind of compound contained in the pharmaceutical composition. The dosage regimen will be determined by the attending physician and other clinical factors. Dosages for any one patient depends on many factors, including the patient’s size, body surface area, age, sex, the particular compound to be administered, time and route of administration, the kind of therapy, general health and other drugs being administered concurrently.

[0181] The anti-human-HER3 ADC described herein can be administered using different dosages. In some embodiments relevant to any method as disclosed herein, the antibody-drug conjugate is administered at a dose of about 3.2 mg / kg. In some embodiments relevant to any method as disclosed herein, the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg. In some embodiments to any method as disclosed herein, the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg. In other embodiments, the antibodydrug conjugate is administered at a dose ranging from about 2 mg / kg to about 6 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the dose is about 2.5 mg / kg to about 6 mg / kg, about 3.0 mg / kg to about 5.5 mg / kg, about 4.5 mg / kg to about 6.0 mg / kg, about 5 mg / kg to about 5.5 mg / kg, about 4 mg / kg to about 4.5 mg / kg, or about 4.8 mg / kg to about 5.6 mg / kg.

[0182] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate is administered concurrently with the compound of Formula I or a pharmaceutically acceptable salt thereof of this disclosure.

[0183] In some embodiments, for example, relevant to any method as disclosed herein, the administration of the antibody-drug conjugate is maintained to the completion of the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof of this disclosure.50NAI-5007076236

[0184] In one aspect, the antibody-drug conjugate is administered once every three weeks.

[0185] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-HER3 ADC is administered intravenously (IV). In some embodiments, the anti-human-HER3 ADC via IV fusion, for example for about 20 minutes to about 120 minutes. In some embodiments, the anti-human-HER3 ADC is administered via a 30 ± 5 minute IV fusion. In some embodiments, the anti-human-HER3 ADC is administered via a 90 ± 10 minute IV fusion.5. Kits

[0186] Also provided herein is a kit comprising (i) the IO therapy agent (e.g., an anti-PD-1 antibody such as pembrolizumab), and (ii) an anti-human-HER3 ADC as disclosed herein (such as patritumab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. For example, provided herein is a kit comprising (i) pembrolizumab, (ii) an anti-human-HER3 ADC as disclosed herein (such as patritumab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, and (iii) instructions for use, e.g., in any of the methods disclosed herein.

[0187] Also provided herein are kits comprising (i) pembrolizumab or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 ADC as disclosed herein (such as patritumab deruxtecan), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, either or both of which 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.

[0188] Also provided herein are kits comprising (iii) pembrolizumab or a third pharmaceutical composition comprising the same, (iv) carboplatin, or the pharmaceutical composition comprising the same, and / or (v) paclitaxel, or the pharmaceutical composition comprising the same, any or all of which 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.

[0189] 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 vial51NAI-5007076236containing 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.

[0190] 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

[0191] Provided below is a list of non-limiting illustrative embodiments according to the present disclosure:

[0192] Embodiment 1. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab; and(ii) 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 Iwherein AB is an anti-human HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises:52NAI-5007076236(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: 3; 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: 4;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0193] Embodiment 2. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab; and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula IIwherein A represents a connecting position to the anti-human-HER3 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-HER3 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: 3; 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: 4;53NAI-5007076236wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0194] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the antihuman HER3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 5, (ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6, (iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 7, (iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8, (v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and (vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0195] Embodiment 4. The method of any one of embodiments 1-3, wherein the antihuman HER3 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: 3, and a light chain variable region (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 4.

[0196] Embodiment 5. The method of any one of embodiments 1-4, wherein the antihuman HER3 antibody is an IgGl or an IgG2.

[0197] Embodiment 6. The method of any one of embodiments 1-5, wherein the antihuman HER3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 3, and a VL comprising the amino acid sequence of SEQ ID NO: 4.

[0198] Embodiment 7. The method of any one of embodiments 1-6, wherein the antihuman HER3 antibody comprises a heavy chain (“HC”) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain (“LC”) comprising the amino acid sequence of SEQ ID NO: 2.

[0199] Embodiment 8. The method of any one of embodiments 1-7, wherein a lysine residue at the carboxyl terminus of the HC of the anti-human HER3 antibody is deleted.

[0200] Embodiment 9. The method of any one of embodiments 1 and 3-8, wherein the drug to antibody ratio is in the range of from 2 to 8, optionally wherein the drug to antibody ratio is 8.

[0201] Embodiment 10. The method of any one of embodiments 1-9, wherein the antibody-drug conjugate is patritumab deruxtecan.54NAI-5007076236

[0202] Embodiment 11. The method of any one of embodiments 1-10, wherein the first therapeutically effective amount of the pembrolizumab is administered at a dose of about 200 mg or about 400 mg.

[0203] Embodiment 12. The method of any one of embodiments 1-11, wherein the pembrolizumab is administered once every three weeks.

[0204] Embodiment 13. The method of any one of embodiments 1-12, wherein the pembrolizumab is administered intravenously.

[0205] Embodiment 14. The method of any one of embodiments 1-13, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 3.2 mg / kg.

[0206] Embodiment 15. The method of any one of embodiments 1-13, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg.

[0207] Embodiment 16. The method of any one of embodiments 1-13, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg.

[0208] Embodiment 17. The method of any one of embodiments 1-16, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered once every three weeks.

[0209] Embodiment 18. The method of any one of embodiments 1-17, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered intravenously.

[0210] Embodiment 19. The method of embodiment 18, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion.

[0211] Embodiment 20. The method of embodiment 18, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 90 ± 5 minute IV fusion.

[0212] Embodiment 21. The method of any one of embodiments 1-20, wherein the cancer is a triple-negative breast cancer.

[0213] Embodiment 22. The method of embodiment 21, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.55NAI-5007076236

[0214] Embodiment 23. The method of any one of embodiments 1-22, wherein the cancer is hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0215] Embodiment 24. The method of any one of embodiments 1-23, wherein the antihuman HER3 antibody or functional fragment thereof is an antibody.

[0216] Embodiment 25. The method of any one of embodiments 1-24, wherein the antihuman HER3 antibody or functional fragment thereof is an antibody comprised of two heavy chains and two light chains.

[0217] Embodiment 26. The method of any one of embodiments 1-25, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate.

[0218] Embodiment 27. The method of embodiment 26, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

[0219] Embodiment 28. The method of any one of embodiments 1-25, wherein the method further comprises:56NAI-5007076236(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate.

[0220] Embodiment 29. The method of embodiment 28, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

[0221] Embodiment 30. The method of any one of embodiments 26-29, wherein:(iii) the third therapeutically effective amount of pembrolizumab is administered at a dose of about 200 mg or about 400 mg;(iv) the fourth therapeutically effective amount of carboplatin is administered at a dose of about area under the curve (AUC)1.5 mg / mL / min; and(v) the fifth therapeutically effective amount of paclitaxel is administered at a dose of about 80 mg / m2.

[0222] Embodiment 31. The method of any one of embodiments 26-30, wherein the third therapeutically effective amount of pembrolizumab is administered once every three weeks, the fourth therapeutically effective amount of carboplatin is administered once every week, and the fifth therapeutically effective amount of paclitaxel is administered once every week.57NAI-5007076236

[0223] Embodiment 32. The method of any one of embodiments 26-31, wherein the third therapeutically effective amount of pembrolizumab is administered intravenously, the fourth therapeutically effective amount of carboplatin is administered intravenously, and the fifth therapeutically effective amount of paclitaxel is administered intravenously.

[0224] Embodiment 33. A method for treating a breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

[0225] Embodiment 34. A method for treating triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

[0226] Embodiment 35. The method of embodiment 34, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

[0227] Embodiment 36. The method of any one of embodiments 33-35, wherein the first therapeutically effective amount of pembrolizumab is administered at a dose of about 200 mg or about 400 mg.

[0228] Embodiment 37. The method of any one of embodiments 33-36, wherein the first therapeutically effective amount of pembrolizumab is administered once every three weeks.

[0229] Embodiment 38. The method of any one of embodiments 33-37, wherein the pembrolizumab is administered intravenously.

[0230] Embodiment 39. The method of any one of embodiments 33-38, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 3.2 mg / kg.

[0231] Embodiment 40. The method of any one of embodiments 33-38, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 4.8 mg / kg.58NAI-5007076236

[0232] Embodiment 41. The method of any one of embodiments 33-38, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 5.6 mg / kg.

[0233] Embodiment 42. The method of any one of embodiments 33-41, wherein the second therapeutically effective amount of patritumab deruxtecan is administered once every three weeks.

[0234] Embodiment 43. The method of any one of embodiments 33-42, wherein the second therapeutically effective amount of patritumab deruxtecan is administered intravenously.

[0235] Embodiment 44. The method of embodiment 43, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 30 ± 5 minute IV fusion.

[0236] Embodiment 45. The method of embodiment 43, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 90 ± 5 minute IV fusion.

[0237] Embodiment 46. The method of any one of embodiments 33-45, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

[0238] Embodiment 47. The method of embodiment 46, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective 59NAI-5007076236amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

[0239] Embodiment 48. The method of any one of embodiments 33-45, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

[0240] Embodiment 49. The method of embodiment 48, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

[0241] Embodiment 50. The method of any one of embodiments 46-49, wherein:(iii) the third therapeutically effective amount of pembrolizumab is administered at a dose of about 200 mg or about 400 mg; and(iv) the fourth therapeutically effective amount of carboplatin is administered at a dose of about area under the curve (AUC)1.5 mg / mL / min; and60NAI-5007076236(v) the fifth therapeutically effective amount of paclitaxel is administered at a dose of about 80 mg / m2.

[0242] Embodiment 51. The method of any one of embodiments 46-50, wherein the third therapeutically effective amount of pembrolizumab is administered once every three weeks and the fourth therapeutically effective amount of carboplatin is administered once every week and the fifth therapeutically effective amount of paclitaxel is administered once every week.

[0243] Embodiment 52. The method of any one of embodiments 46-51, wherein the third therapeutically effective amount of pembrolizumab is administered intravenously and the fourth therapeutically effective amount of carboplatin is administered intravenously and the fifth therapeutically effective amount of paclitaxel is administered intravenously.

[0244] Embodiment 53. A method for treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab at a dose of about 200 mg, every three weeks, intravenously; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan at a dose of about 3.2 mg / kg, once every three weeks, intravenously.

[0245] Embodiment 54. A method for treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously; and (ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan at a dose of about 4.8 mg / kg, once every three weeks, intravenously.

[0246] Embodiment 55. A method for treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously; and (ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan at a dose of about 5.6 mg / kg, once every three weeks, intravenously.

[0247] Embodiment 56. The method of any one of embodiments 53-55, wherein the method further comprises:61NAI-5007076236(iii) administering to the subject a third therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin at a dose of about AUC1.5 mg / mL / min, once every week, intravenously; and (v) administering to the subject a fifth therapeutically effective amount of paclitaxel at a dose of about 80 mg / m2, once every week, intravenously;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

[0248] Embodiment 57. The method of embodiment 56, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

[0249] Embodiment 58. The method of any one of embodiments 53-55, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin at a dose of about AUC1.5 mg / mL / min, once every week, intravenously; and (v) administering to the subject a fifth therapeutically effective amount of paclitaxel at a dose of about 80 mg / m2, once every week, intravenously;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first62NAI-5007076236therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

[0250] Embodiment 59. The method of embodiment 58, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

[0251] Embodiment 60. The method of any one of embodiments 1-59, wherein the subject is administered a premedication with one or more antiemetic agents.

[0252] Embodiment 61. The method of any one of embodiments 1-60, wherein the subject is a human subject.

[0253] Embodiment 62. The method of embodiment 61, wherein the human subject has triple-negative breast cancer.

[0254] Embodiment 63. The method of embodiment 62, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

[0255] Embodiment 64. The method of embodiment 61, wherein the human subject has hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0256] Embodiment 65. The method of any one of embodiments 1-64, wherein the human subject has(i) no confirmed metastases;(ii) clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2;(iii) no previous systemic therapy;(iv) no previous excision of primary tumor; and / or(v) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

[0257] Embodiment 66. The method of any one of embodiments 27, 29, 47, 49, 57, and 59, wherein the subject has a surgery and, optionally, a post-operative radiation therapy.63NAI-5007076236

[0258] Embodiment 67. The method of embodiment 66, wherein the surgery occurs about 3 weeks to about 6 weeks after the last cycle of the second neoadjuvant treatment.

[0259] Embodiment 68. The method of any one of embodiments 27, 29, 47, 49, 57, 59, 66, and 67, wherein the method further comprises:(3) an adjuvant treatment phase comprising:(vi) administering to the subject a sixth therapeutically effective amount of pembrolizumab; and optionally,(vii) administering to the subject a seventh therapeutically effective amount of one or more additional treatments of physician’s choice (TPC), wherein the TPC comprises doxorubicin, epirubicin, cyclophosphamide, capecitabine, and / or olaparib.

[0260] Embodiment 69. The method of embodiment 68, wherein:(vi) the pembrolizumab is administered: (a) once every six weeks; (b) at a dose of about 400 mg; and / or (c) intravenously; and optionally;(vii) when administered, wherein,(a) doxorubicin is administered (1) once every two weeks or once every three weeks, (2) at a dose of about 60 mg / m2, and / or (3) intravenously;(b) epirubicin is administered (1) once every two weeks or once every three weeks; (2) at a dose of about 90 mg / m2, and / or (3) intravenously;(c) cyclophosphamide is administered (1) once every two weeks or once every three weeks; (2) at a dose of about 600 mg / m2, and / or (3) intravenously;(d) capecitabine is administered (1) on Days 1 to 14 and Days 22 to 35 of every 6-week cycle, (2) at a dose of about 1000 mg / m2to 1250 mg / m2, and / or (3) intravenously; and / or(e) olaparib is administered (1) on Days 1 to 42 of every 6-week cycle for 8 cycles and Days 1 to 29 of the subsequent cycle; (2) at a dose of about 300 mg, and / or (3) intravenously.

[0261] Embodiment 70. The method of embodiment 68 or 69, wherein the subject has the surgery, and the adjuvant treatment phase begins about 4 weeks to about 8 weeks after surgery.

[0262] Embodiment 71. The method of any of embodiments 68-70, wherein the adjuvant treatment phase has a duration of about 30 to about 66 weeks, wherein each cycle has a duration of about 6 weeks.

[0263] Embodiment 72. A pharmaceutical composition for use in treating a breast cancer, comprising a first therapeutically effective amount of the pembrolizumab, and a second 64NAI-5007076236therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-10 in combination, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0264] Embodiment 73. A pharmaceutical composition for use in treating a breast cancer, comprising a first therapeutically effective amount of pembrolizumab, in combination with a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-10, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0265] Embodiment 74. A pharmaceutical composition for use in treating a breast cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-10, and a second therapeutically effective amount of the pembrolizumab, in combination, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0266] Embodiment 75. A pharmaceutical composition for use in treating a breast cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-10, in combination with a first therapeutically effective amount of the pembrolizumab, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0267] Embodiment 76. A pharmaceutical composition for use in treating a breast cancer, comprising a first therapeutically effective amount of pembrolizumab, in combination with a second therapeutically effective amount of patritumab deruxtecan.

[0268] Embodiment 77. A pharmaceutical composition for use in treating a breast cancer, comprising a second therapeutically effective amount of patritumab deruxtecan, in combination with a first therapeutically effective amount of pembrolizumab.

[0269] Embodiment 78. The pharmaceutical composition of any one of embodiments 72-77, wherein the pharmaceutical composition is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the pembrolizumab, carboplatin, and paclitaxel is for use after the pharmaceutical composition.65NAI-5007076236

[0270] Embodiment 79. The pharmaceutical composition of any one of embodiments 72-77, wherein the pharmaceutical composition is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the pembrolizumab, carboplatin, and paclitaxel is for use before the pharmaceutical composition.

[0271] Embodiment 80. The pharmaceutical composition for use of any one of embodiments 72-79, wherein the breast cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0272] Embodiment 81. The pharmaceutical composition for use of embodiment 80, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

[0273] Embodiment 82. The pharmaceutical composition for use of any one of embodiments 72-81, wherein first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate are formulated in two different compositions.

[0274] Embodiment 83. Use of pembrolizumab for the preparation of a medicament for treating breast cancer, by administration in combination with the antibody-drug conjugate as defined in any one of embodiments 1-10, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0275] Embodiment 84. Use of the antibody-drug conjugate as defined in any one of embodiments 1-10 for the preparation of a medicament for treating a breast cancer, by administration in combination with pembrolizumab, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0276] Embodiment 85. The use of embodiment 83 or embodiment 84, wherein the breast cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0277] Embodiment 86. The use of embodiment 85, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

[0278] Embodiment 87. The use of any one of embodiments 83-86, wherein the use is in further combination with the use of pembrolizumab, carboplatin, and paclitaxel;66NAI-5007076236wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20;wherein optionally the carboplatin and paclitaxel is administered as defined in any one of embodiments 50-52; andwherein the use of pembrolizumab and carboplatin and paclitaxel is after the use of pembrolizumab and antibody-drug conjugate.

[0279] Embodiment 88. The use of any one of embodiments 83-86, wherein the use is in further combination with the use of pembrolizumab, carboplatin, and paclitaxel;wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20;wherein optionally the carboplatin and paclitaxel is administered as defined in any one of embodiments 50-52; andwherein the use of pembrolizumab and carboplatin and paclitaxel is before the use of pembrolizumab and antibody-drug conjugate.

[0280] Embodiment 89. Pembrolizumab for use in combination with an anti-human HER3 antibody-drug conjugate as defined in any one of embodiments 1-10 in treating a breast cancer in a subject in need thereof, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0281] Embodiment 90. Pembrolizumab for use in combination with an anti-human HER3 antibody-drug conjugate as defined in any one of embodiments 1-10 in treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein optionally the pembrolizumab is administered as defined in any one of embodiments 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 14-20.

[0282] Embodiment 91. Pembrolizumab for use in combination with patritumab deruxtecan in treating triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof.

[0283] Embodiment 92. Patritumab deruxtecan for use in combination with pembrolizumab in treating triple-negative breast cancer or hormone receptor-low67NAI-5007076236positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof.

[0284] Embodiment 93. The pembrolizumab for use of embodiment 91, or the patritumab deruxtecan for use of embodiment 92, wherein triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

[0285] Embodiment 94. The pembrolizumab for use of any one of embodiments 89-91, or the patritumab deruxtecan for use of embodiment 92, wherein the use is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the use of pembrolizumab, carboplatin, and paclitaxel is after the use of pembrolizumab and patritumab deruxtecan.

[0286] Embodiment 95. The pembrolizumab for use of any one of embodiments 89-91, or the patritumab deruxtecan for use of embodiment 92, wherein the use is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the use of pembrolizumab, carboplatin and paclitaxel is before the use of pembrolizumab and patritumab deruxtecan.

[0287] Embodiment 96. The pembrolizumab for use of any one of embodiments 89-93, or the patritumab deruxtecan for use of any one of embodiments 92-93 wherein the subject is a human subject.

[0288] Embodiment 97. The pembrolizumab for use of embodiment 96, or the patritumab deruxtecan for use of embodiment 96, wherein the human subject has a confirmed diagnosis of triple-negative breast cancer.

[0289] Embodiment 98. The pembrolizumab for use of embodiment 97, or the patritumab deruxtecan for use of embodiment 97, wherein the human subject has a confirmed diagnosis of high-risk early-stage triple-negative breast cancer.

[0290] Embodiment 99. The pembrolizumab for use of embodiment 96, or the patritumab deruxtecan for use of embodiment 96, wherein the human subject has a confirmed diagnosis of hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

[0291] Embodiment 100. The pembrolizumab for use of any one of embodiments 89-99, or the patritumab deruxtecan for use of any one of embodiments 89-99, wherein the human subject has:(i) no confirmed metastases;(ii) clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2;(iii) no previous systemic therapy;68NAI-5007076236(iv) no previous excision of primary tumor; and / or(v) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

[0292] Embodiment 101. A kit comprising (i) pembrolizumab, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 antibody-drug conjugate as defined in any one of embodiments 1-10, or a second pharmaceutical composition comprising the same, optionally further comprising instructions for treating a breast cancer in a subject in need thereof according to the method of any one of embodiments 1-71.

[0293] Embodiment 102. The method of any one of embodiments 1-13, 17-38, and 44-71, 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 5.6 mg / kg of the subject’s body weight and the second dose is about 4.8 mg / kg of the subject’s body weight;(b) the first dose is about 4.8 mg / kg of the subject’s body weight and the second dose is about 3.2 mg / kg of the subject’s body weight;(c) the first dose is about 3.2 mg / kg of the subject’s body weight and the second dose is discontinued.

[0294] Embodiment 103. The method of embodiment 102, wherein the adverse event is:(i) an infusion-related reaction;(ii) fatigue, asthenia, and / or malaise;(iii) a blood and lymphatic system disorder, optionally selected from decreased neutrophil count, febrile neutropenia, decreased lymphocyte count, anemia, or decreased platelet count;(iv) a cardiac disorder, optionally selected from hear failure, decreased ejection fraction, or electrocardiogram QT interval prolongation;(v) a respiratory, thoracic and / or mediastinal disorder, optionally pulmonary toxicity;(vi) an eye disorder;(vii) a renal and / or urinary disorder, optionally increased creatinine;(viii) a hepatobiliary disorder, optionally selected from an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) without increased total bilirubin 69NAI-5007076236(TBL), an increase in TBL, an increase in AST or ALT with TBL increased, AST or ALT > 3.0 x upper limit of normal (ULN) with known Hepatitis B and / or Hepatitis C infection at baseline, or increase alkaline phosphatase (ALP); or(ix) a gastrointestinal disorder, optionally selected from nausea, vomiting, diarrhea, colitis, or mucositis oral.

[0295] Embodiment 104. The method of any one of embodiments 1-71, wherein the method comprises:(i) administering to the subject the pembrolizumab;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present reducing the dose, delaying the dose, or permanently discontinuing the dose of pembrolizumab to the subject.

[0296] Embodiment 105. The method of embodiment 104, wherein the adverse event is:(i) an immune-related adverse event as shown in Table 12; or(ii) an infusion-related adverse event as shown in Table 13.

[0297] Embodiment 106. The method of any one of embodiments 26-29, 31, 32, 46-49, 51, and 52, wherein the method comprises:(i) administering to the subject the paclitaxel and carboplatin;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present,(a) administering to the subject the paclitaxel at a second dose; wherein:(1) the first dose is about 80 mg / m2and the second dose is reduced by about 20%;(2) the first dose is about 80 mg / m2reduced by about 20% and the second dose is discontinued; and / or(b) administering to the subject the carboplatin at a second dose; wherein:(1) the first dose is about AUC1.5 mg / mL / min and the second dose is about AUC 1.1 mg / mL / min; and(2) the first dose is about AUC 1.5 mg / mL / min and the second dose is discontinued.

[0298] Embodiment 107. The method of embodiment 68 or 69, wherein the method comprises:(i) administering to the subject the TPC;(ii) determining the presence of one or more adverse events; and70NAI-5007076236(iii) if the adverse event is present reducing the dose, delaying the dose, or permanently discontinuing the dose of the TPC to the subject, wherein optionally the dose is reduced as shown in Table 14.7. EXAMPLES

[0299] 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, efc.), but some experimental error and deviation should, of course, be allowed for.7.1. Example 1: Production of Patritumab Deruxtecan (HER3-DXd)

[0300] In accordance with a production method described in International Publication No. WO2015 / 155998, for example, patritumab deruxtecan (HER3-DXd) can be produced. The average number of units of a drug-linker that are conjugated to the anti-human-HER3 antibody in patritumab deruxtecan is, in one embodiment, about 8 as determined by a HPLC method.7.2. Example 2: Clinical trial protocol for administration of Pembrolizumab and Patritumab Deruxtecan (HER3-DXd) to patients with high-risk early-stage triple-negative breast cancer (TNBC) or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer (HR-low+ / Her2- BC)7.2.1. Objectives and Endpoints

[0301] Primary objectives, secondary objectives, and tertiary / expl oratory objectives are depicted in Table 1 below.Table 1 Objectives and Endpoints71NAI-500707623672NAI-500707623673NAI-500707623674NAI-50070762367.2.1.1. Rationale for Endpoints7.2.1.1.1. Efficacy Endpoints

[0302] Part 1 participants will not be included in Part 2 efficacy analyses and therefore will not contribute to analyses of primary / secondary efficacy objectives for Part 2.

[0303] In Part 2, the primary endpoint of pCR (ypTO / Tis ypNO) and the secondary endpoints of pCR-no DCIS (ypTO ypNO) and EFS follow the FDA guidance on ‘Pathological Complete Response in Neoadjuvant Treatment of High-risk Early-stage Breast Cancer’ [Food and Drug Administration 2020] and EMA’s ‘Guideline on Evaluation of Anticancer Medicinal Products in Man.’ Patients who achieved pCR have demonstrated sustained clinical benefit regardless of breast cancer subtypes. A large, pooled analysis showed strong association of pCR, when defined as no tumor in both breast and lymph nodes (ypTO ypNO or ypTO / Tis yp NO) following neoadjuvant therapy for breast cancer, with improved long-term benefit as measured by EFS and OS [Carey LA, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007;13(8):2329-34.; Liedtke C, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008 Mar 10;26(8): 1275-81.] .

[0304] OS has been recognized as the gold standard for the demonstration of superiority of a new antineoplastic therapy in randomized clinical studies.

[0305] The secondary endpoint of RCB provides a standardized pathologic approach to evaluate and quantify the extent of residual invasive cancer in the breast or regional lymph nodes after neoadjuvant therapy. RCB has been shown to be associated with efficacy outcomes, with lower EFS and DRFS among individuals with higher RCB [Symmans WF, et al. Assessment of residual cancer burden and event-free survival in neoadjuvant treatment for high-risk breast cancer: an analysis of data from the LSPY2 randomized clinical trial. JAMA Oncol. 2021 Nov;7(ll): 1654-63; Symmans WF, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25(28):4414-22], Therefore, RCB is considered as an acceptable surrogate for clinical time-to-event endpoints in signal finding studies.

[0306] DPDRFS, which measures distant progression before surgery and distance recurrence or death after surgery, is an additional secondary endpoint for evaluation of treatment efficacy across neoadjuvant- and adjuvant settings.75NAI-50070762367.2.1.1.1.1. Primary

[0307] Pathologic Complete Response (pCR) (ypTO / Tis ypNO)

[0308] pCR (ypTO / Tis ypNO) is defined the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy per current American Joint Committee of Cancer (AJCC) staging criteria assessed by the local pathologist at the time of definitive surgery.7.2.1.1.1.2. Secondary

[0309] Pathologic Complete Response (pCR) -no DCIS (ypTO ypNO)

[0310] pCR-no DCIS (ypTO ypNO) is defined as the absence of residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes after completion of neoadjuvant systemic therapy per current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery.

[0311] Event-Free Survival (EFS)

[0312] EFS is defined as the time from randomization to disease progression that precludes surgery, local or distant recurrence, or death due to any cause, whichever occurs first. Progression of disease and local or distant recurrence are based on investigator assessment. Local or distant recurrence events considered to be EFS events include invasive ipsilateral local / regional recurrence (i.e. invasive ipsilateral recurrence in breast and / or regional lymph nodes), invasive contralateral breast cancer considered to be a distant recurrence or distant recurrence elsewhere. New second primary non-breast malignancies and new breast cancer considered to be new second primaries are not considered to be EFS events.

[0313] Overall Survival (OS)

[0314] OS is defined as the time from randomization to death due to any cause.Participants without documented death at the time of the analysis will be censored at the date of last known to be alive.

[0315] Distant Progression or Distant Recurrence-Free Survival (DPDRFS)

[0316] The DPDRFS is defined as the time from randomization to first distant progression or distant recurrence, or death due to any cause, whichever occurs first.76NAI-5007076236

[0317] Residual Cancer Burden (RCB)

[0318] The RCB is residual disease in either the breast or lymph node at the time of definitive surgery as assessed by the local pathologist. RCB score provides a continuous measurement of the extent of residual cancer. The following cut points are applied to define four RCB classes: RCB-0 (RCB score 0), RCB-1 (0< RCB score <1.36), RCB-2 (1.36 <RCB score <3.28), and RCB-3 (RCB score >3.28).7.2.1.1.1.3. Exploratory

[0319] Invasive Disease-Free Survival (IDFS)

[0320] The IDFS is time from definitive surgery to local or distant recurrence, or death due to any cause, whichever occurs first. Local or distant recurrence events considered to be IDFS events include invasive ipsilateral local / regional recurrence (i.e. invasive ipsilateral recurrence in breast and / or regional lymph nodes), invasive contralateral breast cancer considered to a distant recurrence or distant recurrence elsewhere.

[0321] Distant Recurrence-Free Survival (DRFS)

[0322] The DRFS is defined as the time from definitive surgery to first distant recurrence, or death due to any cause, whichever occurs first.

[0323] Objective Response (OR) Based on RECIST 1.1

[0324] The OR is defined as complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by central radiology review after the first four cycles of the neoadjuvant phase and prior to definitive surgery. Participants with missing outcome for objective response will be considered non-responders and included in the total number of participants. This will be applied to the subset of individuals who consent to optional breast MR. I exam.

[0325] Objective Response (OR) Based on Breast MRI FTV

[0326] The OR Based on breast MRI FTV is defined as complete response (CR) or partial response (PR) according to change in Breast MRI Functional Tumor volume (FTV) from baseline to after the first four cycles of neoadjuvant therapy and from baseline to prior to definitive surgery as assessed by central radiology review. The cut points to define CR / PR based on breast MRI FTV is the same as those in RECISIT 1.1. Participants with missing outcome for objective response will be considered non-responders and included in the total number of participants. This will be applied to the subset of individuals who consent to optional breast MRI exam.77NAI-50070762367.2.1.1.2. Safety Endpoints

[0327] Safety is a primary endpoint for Part 1 and Part 2.

[0328] Safety endpoints in Part 1 and Part 2 will be analyzed separately and by dose received.

[0329] Safety parameters frequently used for evaluating investigational-systemic anticancer treatments are included as safety endpoints including, but not limited to, the incidence of, causality, and outcome of AEs / SAEs, and changes in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 5.0.

[0330] The primary safety endpoints are DLTs (for Part 1 of the study only), AEs, and discontinuation of study intervention due to AEs. Safety and tolerability will be assessed by clinical review of all relevant parameters including adverse events, laboratory values and vital signs.

[0331] Definition of DLTs is described in Section 7.2.7.6.4 of the protocol. Safety measurements are provided in Section 7.2.1.1.2 and Section 7.2.7.6 of the protocol.7.2.2. Target Population

[0332] Males and females with high-risk, early-stage TNBC and HR-low+ / HER2- breast cancer.7.2.2.I. Inclusion Criteria

[0333] An individual is eligible for inclusion in the study if the individual meets all of the following criteria:

[0334] (a) Type of Participant and Disease Characteristics

[0335] 1. The participant must have locally advanced, non-metastatic (M0) breast cancer, defined as any of the following combined primary tumor (T) and regional lymph node (N) staging per current AJCC criteria as assessed by the investigator based on radiological and / or clinical assessment:• cTlc, N1-N2• cT2, N0-N2• cT3, N0-N2• cT4a-d, N0-N2

[0336] Note: Bilateral tumors (i.e., synchronous cancers in both breasts) and / or multifocal (i.e., 2, separate lesions in the same quadrant) / multicentric (i.e., 2 separate lesions78NAI-5007076236in different quadrants) tumors are allowed, as well as inflammatory breast cancer, and the tumor with the most advanced T stage should be used to assess the eligibility.

[0337] 2. Date of biopsy for tissue diagnosis of the current breast cancer must be either:• Less than 29 days prior to the date of signing the informed consent or• Between 29 to 56 days prior to the date of signing the informed consent with Sponsor consultation and completion of Sponsor consultation form (SCF)

[0338] Note: For participants who undergo >1 biopsy for tissue diagnosis (e.g. those with bilateral / multifocal or multicentric disease), the date of the earliest biopsy must be used to determine if Sponsor consultation and completion of SCF is required.

[0339] 3. A core needle biopsy from the primary breast tumor (or from each breast / focus in the case of bilateral or multifocal / multicentric disease) must be sent for central confirmation of histology, estrogen receptor (ER), progesterone receptor (PgR), HER2, HER3, and PD-L1 status at Screening.

[0340] Note: Central confirmation of breast cancer diagnosis and of ER, PgR, HER2, HER3 and PD-L1 are required for eligibility / stratification. Adequacy of the biopsy specimen(s) for the above analyses will be assessed by the central laboratory. If adequate tumor tissue was not provided and / or if specimen(s) is not evaluable for ER, PgR, HER2, HER3 and PD-L1, the participant will be considered ineligible. Additional tissue may be submitted once, if the investigator thinks it is acceptable to delay initiation of therapy.

[0341] Note: A new core needle biopsy can be obtained after signing informed consent if needed.

[0342] 4. The participant must have a centrally confirmed diagnosis of breast cancer that is triple-negative or HR-low+ / HER2- breast cancer that will be treated according to the TNBC paradigm, in accordance with local SOC / guidelines. The tumor must be either:• Triple-negative, defined as ER expression in <1% of cells, PgR expression in <1% of cells and HER2- as per *ASCO / CAP guidelines.

[0343] OR• HR-low+ / HER2-, defined as ER-low+ expression in 1 to 10% cells and HER2-, as per the *ASCO / CAP guidelines. Participants with HR low+ / HER2- breast cancer may have any level of PgR expression.

[0344] Note: If the participant has either bilateral or multifocal / multicentric disease, all foci must be triple-negative or HR-low+ / HER2- as centrally confirmed.79NAI-5007076236

[0345] * ASCO / C AP 2018 guidelines for HER2 testing [Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology / College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018 Jul 10;36(20):2105-22] and 2020 guidelines for ER / PgR [Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL, et al. Estrogen and progesterone receptor testing in breast cancer: ASCO / CAP guideline update. J Clin Oncol. 2020;38(12): 1346-66. Supplemental material; 2 p.].

[0346] (b) Demographics

[0347] 5. Is an individual of any sex / gender, from 18 years of age inclusive, at the time of providing the informed consent. Follow local regulatory requirements if the legal age of consent for participation is >18 years of age.

[0348] (c) Informed Consent

[0349] 6. The participant has provided documented informed consent for the study.

[0350] Note: References to “legally acceptable representative” for consenting purposes are not applicable in the EEA. Individuals in EEA countries who require a legally designated representative for informed consent, as defined by the European Regulation, are not eligible to participate.

[0351] Individuals in EEA countries who are legally able to consent for themselves but require an Impartial Witness to the consenting process (e.g., individuals who are blind, unable to read or write, or unable to sign due to a physical disability) may be enrolled.Investigators must follow local regulations and processes for using an Impartial Witness.

[0352] (d) Additional Categories

[0353] 7. HIV infected participants must have well controlled HIV on ART, defined as:

[0354] a. Participants on ART must have a CD4+ T-cell count ^350 cells / mm3 at the time of screening

[0355] 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

[0356] c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months80NAI-5007076236

[0357] 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

[0358] 8. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.

[0359] Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

[0360] Hepatitis B screening tests are not required unless:• Known history of HBV infection• As mandated by local health authority

[0361] 9. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.

[0362] Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to randomization.

[0363] Hepatitis C screening tests are not required unless:• Known history of HCV infection• As mandated by local health authority

[0364] 10. An ECOG performance status of 0 to 1 assessed within 28 days before all ocati on / randomizati on .

[0365] 11. Adequate organ function as defined in the following table (Table 2).Specimens must be collected within 14 days before start of study intervention.81NAI-5007076236Table 2 Adequate Organ Function Laboratory Values>>> >>< <><<><

[0366] 12. Has left ventricular ejection fraction (LVEF) of > 50% orlower limit of normal (LLN) as assessed by echocardiogram (ECHO) or multigate acquisition scan (MUGA) scan performed at screening.

[0367] 13. Participants with history of exposure to anthracy cline at any time are eligible after Sponsor consultation and completion of SCF if cumulative lifetime doses are as follows: doxorubicin <100 mg / m2; epirubicin <180 mg / m2; mitoxantrone <40 mg / m2; idarubicin <22.5 mg / m2. If another anthracy cline or more than one anthracy cline has been used, the cumulative dose must not exceed the equivalent of 100 mg / m2of doxorubicin.7.2.2.2. Exclusion Criteria

[0368] An individual must be excluded from the study if the individual meets any of the following criteria:82NAI-5007076236

[0369] (a) Medical Conditions

[0370] 1. Has documented Grade >2 peripheral neuropathy.

[0371] 2. Has uncontrolled or significant cardiovascular disease before randomization, such as:Corrected QT interval by Fredericia (QTcF) prolongation interval >470 ms.• Resting systolic blood pressure of >180 mm Hg or diastolic blood pressure of >110 mm Hg.• History of acute coronary syndromes (including myocardial infarction, unstable angina, or coronary angioplasty / stenting / bypass grafting) within the last 6 months prior to screening.• congestive heart failure (CHF) New York Heart Association (NYHA) Class 2-4 or history of CHF NYHA class 3 or 4.• Cardiac arrhythmia requiring anti arrhythmic treatment.• Diagnosed or suspected long QT syndrome or known family history of long QT syndrome.• History of clinically relevant ventricular arrythmias such as ventricular tachycardia, ventricular fibrillation or Torsade de Pointes.• Bradycardia of less than 50 bpm unless the participant has a pacemaker.• History of second- or third degree heart block.

[0372] Note: Individuals with history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemaker.• Complete left bundle branch block.

[0373] 3. Has clinically significant corneal disease.

[0374] 4. HIV-infected participants with a history of Kaposi’s sarcoma and / or Multicentric Castleman’s Disease.

[0375] (b) Prior / Concomitant Therapy

[0376] 5. 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).

[0377] 6. Received prior systemic anticancer therapy including investigational agents within 4 weeks or 5-half-lives (whichever is shorter) before randomization.

[0378] 7. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines is allowed.83NAI-5007076236

[0379] 8. Received any prior treatment, including radiation, systemic therapy, and / or definitive surgery for currently diagnosed breast cancer.

[0380] Note: Letrozole or other drugs used during ovarian stimulation for fertility preservation are permitted. LHRH analogs initiated for ovarian protection in anticipation of chemotherapy for this breast cancer are permitted.

[0381] 9. Has received prior treatment with an anti-HER3 antibody and / or ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., trastuzumab deruxtecan).

[0382] 10. Has received chloroquine / hydroxychloroquine <14 days prior to randomization.

[0383] 11. For individuals with centrally confirmed HR-low+ / HER2- breast cancer: Intention to receive adjuvant endocrine therapy with or without CDK4 / 6 inhibitor therapy.

[0384] (c) Prior / Concurrent Clinical Study Experience

[0385] 12. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.

[0386] (d) Diagnostic Assessments

[0387] 13. Has metastatic (Stage IV) breast cancer or cN3 nodal involvement.

[0388] 14. Has undergone excisional biopsy of the primary tumor, and / or axillary lymph node dissection prior to study treatment.

[0389] 15. 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.

[0390] 16. Known additional malignancy that is progressing or has required active treatment within the past 5 years.

[0391] 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.

[0392] 17. Known active CNS metastases and / or carcinomatous meningitis.

[0393] 18. Severe hypersensitivity (>Grade 3) to any of the study interventions and / or any of their excipients.

[0394] 19. Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid) is allowed.84NAI-5007076236

[0395] 20. History of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease, or where suspected ILD / pneumonitis cannot be ruled out by standard diagnostic assessments at screening

[0396] 21. Active infection requiring systemic therapy.

[0397] 22. Concurrent active Hepatitis B (defined as HBsAg positive and / or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.

[0398] Note: Hepatitis B and C screening tests are not required unless:• Known history of HBV and HCV infection• As mandated by local health authority

[0399] 23. History or current evidence of any condition, 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.

[0400] 24. Has clinically severe respiratory compromise (based on the investigator’s assessment) resulting from intercurrent pulmonary illness including, but not limited to,• Severe underlying pulmonary disorder (e.g., pulmonary emboli within 3 months prior to Cycle 1 Day 1, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, or pleural effusion).• Any autoimmune, connective tissue, or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren’s syndrome, and sarcoidosis) where there is documented or a suspicion of pulmonary involvement at the time of screening. For participants with such disorders without evidence of pulmonary involvement, details of the disorder should be recorded for participants who are included in the study.• Prior complete pneumonectomy.

[0401] (e) Other Exclusions

[0402] 25. History of stem cell / solid organ transplant.

[0403] 26. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.7.2.3. Number of Participants

[0404] Up to 30 participants (up to 10 per dose level) may be enrolled in Part 1 (Safety Lead-in) and approximately 342 participants will be randomized in Part 2 (Main Study) as described in the SAP.85NAI-50070762367.2.4. Study Scheme

[0405] This is an open-label, randomized, active-controlled, parallel-group, multisite, study to evaluate safety and efficacy of patritumab deruxtecan (referred to throughout this example as HER3-DXd) plus pembrolizumab administered either before or after carboplatin / paclitaxel plus pembrolizumab compared with carboplatin / paclitaxel plus pembrolizumab and anthracycline / cyclophosphamide plus pembrolizumab, followed by surgery and adjuvant pembrolizumab for previously untreated high-risk, early-stage TNBC or HR-low+ / HER2- breast cancer. This study will have 2 parts: Part 1 (Safety Lead-in) to establish the tolerability of HER3-DXd in combination with pembrolizumab followed by Part 2 (Main study).7.2.4.I. Part 1 - Safety Lead-In

[0406] There is a Safety Lead-in to demonstrate a tolerable safety profile of HER3-DXd and pembrolizumab (FIG. 1). Objective of Part 1 (Safety Lead-in) is safety and tolerability only. Therefore, no efficacy evaluations are planned.

[0407] Up to 30 participants (up to 10 per dose level) may be enrolled in Arm A during the Safety Lead-in:• Neoadjuvant pembrolizumab+HER3-DXd x 4 cycles (12 weeks) [Treatment 1], followed by pembrolizumab+paclitaxel+carboplatin x 4 (12 weeks) [Treatment 2]

[0408] The BOIN design [Yuan Y, Hess KR, Hilsenbeck SG, Gilbert MR. Bayesian optimal interval design: a simple and well-performing design for phase I oncology trials. Clin Cancer Res. 2016 Sep 1 ;22(17):4291 -30] with a target DLT rate of 30% will be used to determine an acceptable dose level of HER3-DXd for Part 2, as outlined in Table 4 in Section 7.2.4.1. Dose decision entries, E, S, D, and DU, in Table 4 represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. DLTs will be evaluated during Cycle 1 (21 days) of neoadjuvant pembrolizumab+HER3-DXd in Part 1.

[0409] Initially, 3 to 6 participants will be enrolled, with at least a 24-hour pause between dosing each of the first 3 participants during the DLT evaluation period. After the first 3 to 6 participants complete the DLT evaluation period, the initial decision about the dose level to continue enrollment will be made according to the BOIN design. With “D” or “DU” decision, the initial enrollment will be repeated at the new dose level. Part 1 (Safety Lead-in) will conclude after approximately 10 participants have been enrolled at a dose, leading to a “S” or86NAI-5007076236“E” decision. With up to 3 dose levels and the target of enrolling approximately 10 participants at the selected dose, the total sample size for Part 1 is expected to be up to 30 participants (up to 10 participants per dose level).

[0410] For the definition of DLTs, see Section 7.2.7.6.4. The planned dose levels for HER3-DXd are shown in Table 3. The dose of pembrolizumab is fixed at 200 mg q3w. If HER3-DXd at 5.6 mg / kg q3w is not acceptable (i.e., a D or DU decision is reached at any point during the DLT evaluation period (Table 4), additional participants will be enrolled at 4.8 mg / kg q3w dose level and the DLT evaluation will be repeated. If HER3-DXd at 4.8 mg / kg q3w is not acceptable, additional participants may be enrolled at 3.2 mg / kg q3w dose level and the DLT evaluation will be repeated. The 3.2 mg / kg dose level will be evaluated only after a review of the totality of the data to determine the benefit-risk ratio of this dose level.Table 3 Dose Levels of Patritumab Deruxtecan for Part 1 Arm A

[0411] Refer to Sections 7.2.4.1.1 and 7.2.7.6.4 for additional details.7.2.4.L1. Bayesian Optimal Interval in the Safety Lead-in with Target DLT Rate 30%

[0412] Participants will be closely followed for dose-limiting toxicity (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. Bayesian optimal interval design: a simple and well-performing design for phase I oncology trials. Clin Cancer Res. 2016 Sep l;22(17):4291-30] with a target DLT rate of 30%. The dose will be evaluated on an ongoing basis as participants complete the DLT evaluation period. 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 re-escalated 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 dose87NAI-5007076236should be deescalated, if allowed per protocol, and the current dose will not be explored further. If, at any point, the dosing decision is “E” after evaluation of all enrolled patients at a dose, the dose may be escalated to a higher predetermined dose provided that the higher dose has not previously been discontinued due to a “DU” decision. If the DLT rate of 33% is observed repeatedly, dose de-escalation would be considered.

[0413] 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 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.

[0414] The totality of the data will be considered prior to determining the dose level of HER3-DXd for the Efficacy Evaluation in Part 2.Table 4 Dose-finding Framework of BOIN Design with Target DLT Rate 30%

[0415] Diagonal rule is used to determine the number of additional participants to be enrolled 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 4).7.2.4.2. Part 2 - Main Study

[0416] Part 2 of the study will open once the required number of participants in Part 1 have completed the DLT evaluation period and the decision by BOIN is either “E” or “S” at the selected HER3-DXd dose. The primary objectives of Part 2 are pCR (ypTO / Tis ypNO), as assessed by local pathologist, and safety and tolerability. The secondary efficacy objectives are pathological complete response - no ductal carcinoma in situ (pCR-no DCIS) (ypTO88NAI-5007076236ypNO) as assessed by local pathologist, event-free survival (EFS) as assessed by the investigator, overall survival (OS), residual cancer burden (RCB) as assessed by local pathologist, and distant progression / distant recurrence-free survival (DPDRFS) as assessed by the investigator.

[0417] Following Part 1, approximately 342 participants will be randomly assigned in a 1:1:1 ratio to following 3 arms in Part 2:• Arm A: neoadjuvant pembrolizumab+HER3 DXd X 4 cycles (12 weeks) [Treatment 1], followed by pembrolizumab+paclitaxel+carboplatin x 4 (12 weeks) [Treatment 2] • Arm B: neoadjuvant pembrolizumab+paclitaxel+carboplatin x 4 cycles (12 weeks) [Treatment 1], followed by pembrolizumab+HER3 DXd X 4 cycles (12 weeks) [Treatment 2]• Arm C: neoadjuvant pembrolizumab+paclitaxel+carboplatin x 4 cycles (12 weeks) [Treatment 1], followed by pembrolizumab+doxorubicin (or epirubicin)+cyclophosphamide X 4 cycles (12 weeks) [Treatment 2],

[0418] Enrollment will be paused once approximately 30 participants (at least 10 participants per arm) have been randomized into Part 2 to allow evaluation of safety. An internal DMC will perform all interim safety evaluations before the first efficacy IA. After the second interim safety evaluation, enrollment in Part 2 may resume and approximately an additional 312 participants will be randomly assigned in a 1:1:1 ratio to Arms A, B, and C.

[0419] See FIG. 2 for details.

[0420] Crossover from one arm to another is not permitted.

[0421] In Part 2, MRI of the breast will be performed at a subset of study sites during the Neoadjuvant Treatment Phase. MRIs will be limited to those participants who consent to optional breast MRI examinations for a more accurate clinical staging of the primary tumor and axillary lymph nodes. Change from baseline using objective response per RECIST 1.1 will be assessed by the local radiologist and by BICR. Change from baseline using objective response per RECIST 1.1 and using objective response based on MRI FTV will be assessed by BICR [Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.] [Hylton NM, et al. Neoadjuvant chemotherapy for breast cancer: functional tumor volume by MR imaging predicts recurrence-free survival-results from the ACRIN 6657 / CALGB 150007 I-SPY 1 TRIAL. Radiology. 2016 Apr;279(l):44-55.]. Breast MRIs will be sent to designated central imaging vendor for collection, quality review, and independent imaging review.89NAI-5007076236

[0422] Enrollment will be paused once approximately 30 participants (at least10 participants per arm) have been randomized into Part 2 to allow evaluation of safety. An internal DMC will perform all interim safety evaluations before the first efficacy IA. After the second interim safety evaluation, enrollment in Part 2 may resume and approximately an additional 312 participants will be randomly assigned in a 1:1:1 ratio to Arms A, B, and C.

[0423] See FIG. 2 for details.

[0424] Crossover from one arm to another is not permitted.

[0425] In Part 2, MRI of the breast will be performed at a subset of study sites during the Neoadjuvant Treatment Phase. MRIs will be limited to those participants who consent to optional breast MRI examinations for a more accurate clinical staging of the primary tumor and axillary lymph nodes. Change from baseline using objective response per RECIST 1.1 will be assessed by the local radiologist and by BICR. Change from baseline using objective response per RECIST 1.1 and using objective response based on magnetic resonance imaging functional tumor volume (MRI FTV) will be assessed by BICR [Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.] [Hylton NM, et al. Neoadjuvant chemotherapy for breast cancer: functional tumor volume by MR imaging predicts recurrence-free survival-results from the ACRIN 6657 / CALGB 150007 I-SPY 1 TRIAL. Radiology. 2016 Apr;279(l):44-55.]. Breast MRIs will be sent to designated central imaging vendor for collection, quality review, and independent imaging review.

[0426] In Part 2, participants who either complete adjuvant pembrolizumab ± additional adjuvant treatment of physician’s choice (TPC), or discontinue the study intervention for any reasons other than distant progression / recurrence will enter the Efficacy Follow-up Phase for assessment of disease recurrence / progression (including for pathological complete response (pCR) status if definitive surgery is performed off-study after discontinuation in the Neoadjuvant Treatment Phase) and assessment of survival, for approximately 8 years from the date of randomization, or until distant progression / recurrence, death, or until end of study. Participants with local / regional progression / recurrence without distant recurrence during the Efficacy Follow-up Phase will continue in the Efficacy Follow-up Phase for assessment of distant recurrence. Participants with distant progression / recurrence at any time during the study will be followed every 12 weeks for survival in the Survival Follow-up Phase until death or end of the study. Participants may be contacted for disease and survival status at any time during the study upon Sponsor’s request to ensure availability of current and complete90NAI-5007076236survival data at the time of database lock (DBLs) for Data Monitoring Committee (DMC) review, interim analysis(ses) (IA), and / or final analysis (FA).7.2.4.3. Measures to Minimize Bias: Randomization and Blinding7.2.4.3.I. Intervention Assignment

[0427] Part 1 - Safety Lead-In: Participants in Part 1 will be allocated by nonrandom assignment to Arm A as shown in FIG. 1.

[0428] Part 2 - Main Study: Intervention randomization will occur centrally using an IRT system. There are 3 study intervention arms. Participants will be assigned randomly in a 1:1:1 ratio to Arms A, B, and C as shown in FIG. 2.7.2.4.4. Stratification

[0429] Part 1 - Safety Lead-In: Treatment assignment will not be stratified in Part 1.

[0430] Part 2 - Main Study: Intervention randomization will be first stratified by breast cancer subtype (TNBC vs HR-low+ / HER2- breast cancer). No further stratification is planned within the HR-low+ / HER2- breast cancer subgroup. Participants within the TNBC subgroup will be further stratified by following 3 factors,• PD-L1 status (combined positive score (CPS) >10 vs CPS <10)• Overall clinical stage (Stage II vs Stage III)• HER3 expression (low vs high)

[0431] For stratification purpose, if PD-L1 and / or HER3 is not centrally evaluable the participant will be considered ineligible.7.2.4.5. Blinding

[0432] This is an open-label study; therefore, the Sponsor, investigator, and participant will know the intervention administered.

[0433] As the local pathologist is the outcomes assessor for the primary endpoint of pathological complete response (pCR), the local pathologist will be blinded to the treatment assignment.

[0434] Central radiologist reviewing study-specific MRIs, the assessor for exploratory endpoint of ORR, will also be blinded to the treatment assignment.91NAI-50070762367.2.5. Treatment Phases7.2.5.1. Neoadjuvant Treatment Phase

[0435] A participant is not required to receive a minimum number of neoadjuvant treatment cycles before undergoing surgery. Sponsor consultation and completion of sponsor consultation form (SCF) is required if participant completes fewer than 12 weeks of neoadjuvant treatment before undergoing definitive surgery.7.2.5.2. Surgery Phase

[0436] The Pre-surgery Safety Visit should occur 30 (±3) days after the last dose of the neoadjuvant treatment and before the definitive surgery on-study. If surgery is scheduled to occur less than 30 days after the last dose of the neoadjuvant treatment, then the Pre-surgery Safety Visit should occur before surgery.

[0437] The Post-surgery Safety Visit should occur 30 (±3) days after the definitive surgery. For participants who require >1 surgical procedure to complete definitive surgery, the Post-surgery Safety Visit is to be completed 30 (±3) days after the last surgery.

[0438] For participants in Part 1, Post-surgery Safety Visit will serve as both EOT and Safety Follow-up Visit. All activities for the Post-surgery Safety Visit, the EOT / Discontinuation Visit, and the Safety Follow-up Visit are to be completed on that visit. Participants in Part 1 may receive further therapy, including radiation therapy (if clinically indicated) and systemic adjuvant therapy, off-study per local SOC / guidelines.

[0439] For participants in Part 2, Post-surgery Safety Visit can be combined with the Adjuvant C9D1 if C9 begins at 30 (±3) days after the definitive surgery.7.2.5.2.I. Definitive Surgery

[0440] Definitive surgery is defined as breast conservation surgery (BCS) or mastectomy with axillary lymph node surgery, if indicated, (e.g. sentinel lymph node biopsy, axillary lymph node dissection, targeted axillary dissection) that is performed with curative intent. Definitive surgery will be performed approximately 3 to 6 weeks after completion or early discontinuation of neoadjuvant treatment, as clinically appropriate, and per the local SOC / guidelines.

[0441] Additional surgical procedures, (e.g., re-excision(s) to address positive surgical margin(s), additional axillary lymph node surgery) will follow local SOC / guidelines and will be considered a component of definitive surgery. Surgical reconstruction may be performed92NAI-5007076236at the time of and / or after definitive surgery as per local / institutional standards. Reconstruction is not considered a component of definitive surgery.

[0442] More than 1 procedure may be performed to complete definitive surgery. For participants with >1 procedure to complete definitive surgery, date of the last procedure is considered the date of the definitive surgery. Details regarding the date(s) of surgery(s), surgical findings, type(s) of surgery, tumor resectability, etc. will be recorded. All tumor tissue will be reviewed by the local pathologist for staging following surgery.7.2.5.2.2. Management of the Axilla

[0443] Performing axillary sentinel lymph node biopsy, if indicated, after neoadjuvant therapy is preferred, however participants who have had axillary sentinel lymph node biopsy performed prior to study enrolment are eligible. The recommended management of the axilla after neoadjuvant therapy for participants who do not undergo sentinel lymph node biopsy prior to neoadjuvant treatment is summarized in Table 5; however, if institutional / local SOC deviates from these recommendations or if the clinical scenario is not included in Table 5, institutional / local SOC should be followed [National Comprehensive Cancer Network.NCCN clinical practice guidelines in oncology: breast cancer; version 4.2024. Plymouth Meeting (PA): National Comprehensive Cancer Network (NCCN); 2024. p. 257; Loibl S, et al. Early breast cancer: ESMO clinical practice guideline for diagnosis, treatment and followup. Ann Oncol. 2024;35(2): 159-82.]93NAI-5007076236Table 5 Recommended Management of the Axilla After Neoadjuvant Therapy>7.2.5.2.3. Radiation Therapy

[0444] In Part 2, postoperative radiation therapy on-study should be administered if clinically indicated and will be according to the applicable local / institutional SOC (e.g., cases of BCS, large primary tumor, some positive lymph node disease, positive margins that cannot be addressed surgically). Details regarding the radiation therapy will be recorded in the eCRF.

[0445] Postoperative radiation therapy, if clinically indicated, should not be initiated until adequate resolution of surgery -related AEs, but must not be started sooner than 40 days after the last dose of HER3-DXd (Arms A and B only). Radiation therapy may be administered concurrently with adjuvant pembrolizumab or may be completed prior to initiation of adjuvant pembrolizumab. Radiation may not be administered concurrently with additional adjuvant TPC.94NAI-5007076236

[0446] If pembrolizumab is administered concurrently with adjuvant radiotherapy and radiation-induced dermatitis occurs, hold pembrolizumab for > Grade 3 AEs and resume when desquamation is no longer moist. Adjust radiation delivery as necessary following institutional guidelines when treatment is resumed.7.2.5.3. Adjuvant Treatment Phase (Part 2 Only)

[0447] Start of the Adjuvant Treatment Phase is defined as the first day of radiation (if administered), C9D1 of pembrolizumab or DI of the first cycle of additional adjuvant TPC (if administered), whichever is first. The end of the Adjuvant Treatment Phase is defined as the end of the radiation, the last dose of adjuvant pembrolizumab or the last dose of additional adjuvant TPC (if administered), whichever is later.

[0448] Assessments / procedures are to be performed before administration of adjuvant study intervention.

[0449] Adjuvant pembrolizumab ± additional adjuvant TPC should not be initiated until adequate resolution of surgery-related AEs. Adjuvant pembrolizumab should be initiated approximately 4 to 8 weeks after the last surgery, as clinically appropriate but no greater than 84 days later. Sponsor consultation and completion of SCF is required if more than 84 days have elapsed between the last surgery and initiation of adjuvant pembrolizumab. For participants who require >1 procedure to complete definitive surgery, timing of initiation of adjuvant pembrolizumab should be based on the date of last surgery.7.2.6. Study Interventions Administered

[0450] The study interventions to be used in this study are outlined in Table 6.95NAI-5007076236Table 6 Study Interventions96NAI-500707623697NAI-500707623698NAI-5007076236response; pCR=pathological complete response; DCIS=ductal carcinoma in situ; EFS=event-free survival; OS=overall survival; DPDRFS=distant progression / distant recurrence-free survival; RCB=residual cancer burden; iDFS=invasive disease-free survival; DRFS=distant recurrence-free survival; BICR=blinded independent central review; MRI=magnetic resonance imaging; FTV=functional tumor volume; ORR=objective response rate;PK=pharmacokinetic; Cmax=maximum plasma concentration; AUC=area under the curve; Ctrough=trough plasma concentration; ADA=antidrug antibodies; HRQoL=health-related quality of life; EORTC QLQ-C30=European Organisation for Research and Treatment of Cancer core quality of life questionnaire; QLQ-BR42=European Organisation for Research and Treatment of Cancer breast cancer questionnaire; AUC=area under the curve; bid=twice daily;EEA=European Economic Area; HER3 DXd=patritumab deruxtecan; IMP=investigational medicinal product; NIMP / AxMP=noninvestigational / auxiliary medicinal product; qXw=every X weeks.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 definition / classification of IMP and NIMP / AxMP may exist. In these circumstances, local legislation is followed.99NAI-5007076236

[0451] Study intervention should begin within 3 days of allocation / randomization.

[0452] For all study interventions that are administered based on weight, the participant’s weight at screening or at CID 1 should be used to calculate the initial dose. The participant’s weight will be determined before each dose of study intervention. If, at any time throughout the course of treatment, the participant’s weight changes by >10% from baseline, the dose will be recalculated using this new weight and will be considered the new baseline for all subsequent dosing calculations. The dose(s) of study intervention(s) should be recalculated as needed throughout the study. Dose adjustments for changes in body weight <10% are permitted per institutional standards.

[0453] Pembrolizumab and HER3-DXd will be administered by the investigator and / or an appropriately qualified designee. Carboplatin, paclitaxel, doxorubicin (or epirubicin), and cyclophosphamide will be administered by the investigator and / or an appropriately qualified designee according to the approved product labels and local SOC / guidelines.

[0454] Participants will self-administer capecitabine or olaparib (Part 2 only), as clinically indicated, according to the approved product label or instructions provided by the investigator and / or an appropriately qualified designee.7.2.6.I. Timing of Dose Administration

[0455] Study intervention should be administered in the following order in the Neoadjuvant Treatment Phase:• Arm A: pembrolizumab then HER3-DXd; pembrolizumab then paclitaxel then carboplatin• Arm B: pembrolizumab then paclitaxel then carboplatin; pembrolizumab then HER3-DXd• Arm C: pembrolizumab then paclitaxel then carboplatin; pembrolizumab then doxorubicin (or epirubicin) then cyclophosphamide

[0456] In Part 2, study interventions should be administered in the following order in the Adjuvant Treatment Phase to participants who concurrently receive pembrolizumab and an additional adjuvant TPC on the same day:• Pembrolizumab then doxorubicin (or epirubicin) then cyclophosphamide• Pembrolizumab and then capecitabine• Olaparib then pembrolizumab

[0457] Note: the sequence of IV chemotherapy administration can follow local / institutional standard practice but should always be administered after pembrolizumab.100NAI-5007076236

[0458] Prophylactic medications should be administered before chemotherapy according to the approved product label and / or local / institutional standard practice.7.2.6.2. Neoadjuvant Treatment Phase7.2.6.2.1. Pembrolizumab

[0459] Pembrolizumab, at a dose of 200 mg, will be administered as an IV infusion on Day 1 of each 3-week cycle of the Neoadjuvant Treatment Phase (x8 cycles). Pembrolizumab will be administered prior to HER3-DXd and chemotherapy.7.2.6.2.2. HER3-DXd

[0460] HER3-DXd, at a starting dose of 5.6 mg / kg, will be administered as an IV infusion on Day 1 of each 3-week cycle of the Neoadjuvant Treatment Phase (x4 cycles). HER3-DXd should be administered at least 30 minutes after the end of pembrolizumab infusion.7.2.6.2.3. Paclitaxel

[0461] Paclitaxel, at a dose level of 80 mg / m2, will be administered as an IV infusion on Days 1, 8, and 15 of each cycle of the paclitaxel / carboplatin regimen during the Neoadjuvant Treatment Phase (x4 cycles) as per the approved label or local / institutional standard practice.

[0462] Paclitaxel should be administered after pembrolizumab. All participants should be premedicated with oral or IV steroid and antihistamines according to the approved product label or local / institutional standard practice. Additional premedication should be administered as per standard practice.7.2.6.2.4. Carboplatin

[0463] Carboplatin, at AUC 1.5 mg / mL / min (maximum dose of 225 mg), will be administered as an IV infusion on Days 1, 8, 15 of each cycle of the paclitaxel / carboplatin regimen during the Neoadjuvant period (x4 cycles) as per the approved product label or local / institutional standard practice immediately following the administration of paclitaxel. Additional premedication should be administered as per local / institutional standard practice.7.2.6.2.5. Doxorubicin

[0464] Doxorubicin, at a dose level of 60 mg / m2, should be administered as an IV push on Day 1 of each cycle of the AC regimen (Arm C only) during the Neoadjuvant Treatment Phase (x4 cycles) as per the approved label or local / institutional standard practice.101NAI-5007076236Doxorubicin should be administered after pembrolizumab. Additional premedication should be administered as per local / institutional standard practice.7.2.6.2.6. Epirubicin

[0465] Epirubicin (if administered), at a dose level of 90 mg / m2, should be administered as an IV push on Day 1 of each cycle of the EC regimen (Arm C only) during the Neoadjuvant Treatment Phase (x4 cycles) as per the approved label or local / institutional standard practice. Epirubicin should be administered after pembrolizumab. Additional premedication should be administered as per local / institutional standard practice.7.2.6.2.7. Cyclophosphamide

[0466] Cyclophosphamide, at a dose level of 600 mg / m2, will be administered as an IV infusion on Day 1 of each cycle of the AC / EC regimen (Arm C only) during the Neoadjuvant Treatment Phase (x4 cycles) as per the approved product label or local / institutional standard practice. Cyclophosphamide should be administered after doxorubicin (or epirubicin).Additional premedication should be administered as per local / institutional standard practice.7.2.6.3. Adjuvant Treatment Phase (Part 2 only)7.2.6.3.1. Pembrolizumab

[0467] Pembrolizumab, at a dose of 400 mg, will be administered as an IV infusion on Day 1 of each 6-week cycle of the Adjuvant Treatment Phase (x5 cycles). Alternatively, pembrolizumab may be administered, at a dose of 200 mg, as an IV infusion on Day 1 and Day 22 of Cycles 9 to 12 and Day 1 of Cycle 13 after Sponsor consultation and completion of SCF. Pembrolizumab will be administered prior to chemotherapy.7.2.6.3.2. Optional Additional TPC

[0468] Adjuvant therapy On-study: in Part 2, one optional additional adjuvant TPC may be administered to participants with residual disease as shown in Table 7. If a participant initiates an additional adjuvant TPC and then permanently discontinues it prior to its completion for any reason, then they may not receive another additional adjuvant TPC.102NAI-5007076236Table 7 Options for One Adjuvant Treatment of Physician’s Choice for Participants in Part 2 With Residual Disease

[0469] Refer to Table 7 for optional additional adjuvant TPC options for participants with residual disease.

[0470] Additional adjuvant TPC, if elected, should be administered until completion based on the approved label or local / institutional standard practice. Premedication should be administered as per local / institutional standard practice. When administered on the same day, IV chemotherapy should be administered after pembrolizumab. Capecitabine, after pembrolizumab, or olaparib, before pembrolizumab, can be self-administered at home.Doses / schedules for adjuvant TPC are as follows:• Doxorubicin 60 mg / m2IV q2w or q3w x 4 administrations OR epirubicin 90 mg / m2IV q2w or q3w x4 cycles; G-CSF support required for q2w dosing schedule.• Cyclophosphamide 600 mg / m2IV q2w or q3w x4 cycles.• Capecitabine 1000 mg / m2to 1250 mg / m2po bid on Days 1 to 14 and Days 22 to 35 of every 6-week cycle x4 cycles.• Olaparib 300 mg po bid for 1 year (Days 1 to 42 of every 6-week cycle x8 cycles and Days 1 to 29 of the subsequent cycle).103NAI-5007076236

[0471] Note: olaparib is limited to participants with known deleterious or suspected deleterious gBRCAm and where locally approved.

[0472] For participants with residual disease who receive an additional adjuvant TPC, the adjuvant TPC will start on either C9D1, C10D1 or Cl ID 1. The investigator should select the earliest date the participant is clinically ready and according to the criteria listed below. Administration of adjuvant TPC relative to local therapy and adjuvant pembrolizumab should be as follows:• If no radiation is given,o adjuvant TPC should ideally be initiated on either C9D1, C10D1 or Cl ID 1, as soon as clinically appropriate, defined as:■ Adequate resolution of any surgery-related toxicities• If radiation is given before adjuvant pembrolizumab,o adjuvant TPC should be initiated on either C9D1, C10D1 or Cl ID 1 as soon as clinically appropriate, defined as:■ radiation-related toxicities resolved to Grade <1■ use of any steroids to treat radiation-related toxicities is discontinued ■ at least 14 days have elapsed since last dose of radiation• If radiation is given concurrent with adjuvant pembrolizumab,o adjuvant TPC should be initiated on Day 1 of the next pembrolizumab cycle (but no later than Cl ID 1 ) that meets the following 3 criteria:■ is at least 14 days after last dose of radiation■ radiation-related toxicities resolved to Grade <1■ use of any steroids to treat radiation-related toxicities is discontinued 7.2.6.4. Maximum Dose Exposure

[0473] The maximum dose exposures for study interventions are provided in Table 8.104NAI-5007076236Table 8 Maximum Dose Exposure in the Study7.2.6.5. Statistical Methods7.2.6.5.I. Estimands

[0474] The estimands of primary efficacy objectives in this study are constructed in accordance with ICH E9 (Rl)fEuropean Medicines Agency 2020],7.2.6.5.I.I. Estimands for Pathologic Complete Response (pCR)(ypTO / Tis ypNO)7.2.6.5.I.I.I. Estimand for neoadjuvant treatment comparison of HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus pembrolizumab to carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab

[0475] In the language of ICH E9(Rl)[European Medicines Agency 2020], there are six ‘intercurrent events’ of interest: IE1) discontinuation of neoadjuvant treatments with HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus pembrolizumab or with105NAI-5007076236carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab, IE2) neoadjuvant treatment with any other systemic anti-cancer therapy not specified by the study, IE3) distant progression of disease, IE4) local progression of disease that precludes surgery, IE5) local progression of disease that does not preclude surgery, and IE6) death.

[0476] Primary Objectives

[0477] To compare neoadjuvant HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus pembrolizumab versus carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab, with respect to pCR (ypTO / Tis ypNO), as assessed by local pathologist, at the time of definitive surgery.

[0478] Primary Estimands

[0479] The primary estimand is intended to contrast the effect of neoadjuvant treatment comparison of HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus pembrolizumab, relative to carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab, regardless of discontinuation of neoadjuvant treatments with HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus pembrolizumab or with carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab.

[0480] The primary estimand consists of the following attributes:• Target population: males and females with high-risk, early-stage TNBC and HR- low+ / HER2- breast cancer• Endpoint: binary variable indicating a pathological complete response (pCR) using the definition of ypTO / Tis ypNO at the time of surgery, if the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes is obtained. Participants who receive neoadjuvant treatment with any other systemic anti-cancer therapy not specified by the study, or develop distant progression of disease or local progression disease that precludes surgery, or die prior to surgery are considered as “non-responders”. The occurrence of local progression of disease that does not preclude surgery is considered irrelevant to the endpoint.• Treatment regimen: neoadjuvant HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus pembrolizumab versus carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab, regardless of discontinuation of neoadjuvant HER3-DXd plus pembrolizumab before carboplatin / paclitaxel plus106NAI-5007076236pembrolizumab versus carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab.• Population level-summary: differences in proportions between treatment regimens.

[0481] More details for intercurrent events and handling strategy will be provided in SAP.7.2.6.5.I.2. Estimand for neoadjuvant treatment comparison of HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab to carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab

[0482] In the language of ICH E9(R1) [European Medicines Agency 2020], there are six ‘intercurrent events’ of interest: IE1) discontinuation of neoadjuvant treatments with HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab or with carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab, IE2) neoadjuvant treatment with any other systemic anti-cancer therapy not specified by the study, IE3) distant progression of disease, IE4) local progression of disease that precludes surgery, IE5) local progression of disease that does not preclude surgery, and IE6) death.

[0483] Primary Objectives

[0484] To compare neoadjuvant HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab versus carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab with respect to pCR (ypTO / Tis ypNO), as assessed by local pathologist, at the time of definitive surgery.

[0485] Primary Estimands

[0486] The primary estimand is intended to contrast the effect of neoadjuvant treatment comparison of HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab, relative to carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab, regardless of discontinuation of neoadjuvant treatments with HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab or with carboplatin / paclitaxel plus pembrolizumab followed by AC / EC plus pembrolizumab.

[0487] The primary estimand consists of the following attributes:• Target population: males and females with high-risk, early-stage TNBC and HR- low+ / HER2- breast cancer• Endpoint: binary variable indicating a pathological complete response (pCR) using the definition of ypTO / Tis ypNO at the time of surgery, if the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast 107NAI-5007076236specimen and all sampled regional lymph nodes is obtained. Participants who receive neoadjuvant treatment with any other systemic anti-cancer therapy not specified by the study, or develop distant progression of disease or local progression disease that precludes surgery, or die prior to surgery are considered as “non-responders”. The occurrence of local progression of disease that does not preclude surgery is considered irrelevant to the endpoint.• Treatment regimen: neoadjuvant HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab versus carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab, regardless of discontinuation of neoadjuvant treatments with HER3-DXd plus pembrolizumab after carboplatin / paclitaxel plus pembrolizumab or with carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab.• Population level-summary: differences in proportions between treatment regimens.

[0488] More details for intercurrent events and handling strategy will be provided in SAP.7.2.6.5.2. Statistical Methods for Efficacy Analyses

[0489] The primary hypotheses will be evaluated by comparing HER3-DXd plus pembrolizumab before (Arm A) or after (Arm B) carboplatin / paclitaxel plus pembrolizumab versus carboplatin / paclitaxel plus pembrolizumab followed by ACZEC plus pembrolizumab (Arm C) with respect to pCR (ypTO / Tis ypNO) at the time of definitive surgery. Refer to Protocol Section 7.2.4.1 for details regarding study interventions administered in Arm A-C.

[0490] Point estimates for pCR (ypTO / Tis ypNO) rates and the corresponding exact 95% confidence intervals based on the Clopper-Pearson method will be provided for each arm. The stratified Miettinen and Nurminen’s method will be used for the comparison of pCR (ypTO / Tis ypNO) rates between Arm A and Arm C and between Arm B and Arm C, separately. The difference in pCR (ypTO / Tis ypNO) rates and its 95% CI from the stratified Miettinen and Nurminen’s method with strata weighting by sample size will be reported. The stratification factors used for randomization (see Protocol Section 7.2.4.4 - Stratification) will be applied to the analysis. The secondary efficacy endpoints of pCR-no DCIS (ypTO ypNO) will be analyzed similarly.

[0491] For EFS, OS and DPDRFS, the non-parametric Kaplan-Meier method will be used to estimate the survival curve for each arm. Kaplan-Meier estimates and the corresponding 95% Cis at 1-year, 3-year and 5-year will be provided for EFS, OS and108NAI-5007076236DPDRFS. An unstratified Cox proportional hazard model with Efron’s method of tie handling will be used to assess the magnitude of the treatment difference (i.e., HR) between Arm A and Arm C and between Arm B and Arm C, separately. The HR and its 95% CI from the unstratified Cox model with Efron's method of tie handling and with a single treatment covariate will be reported.

[0492] The descriptive summary table of RCB classes will be provided.

[0493] The primary endpoint pCR (ypTO / Tis ypNO) will be tested and all other endpoints will be estimated only. A summary of the analysis strategy for key efficacy endpoints is provided in Table 9.Table 9 Analysis Strategy for Key Efficacy Variables&&7.2.6.5.3. Statistical Methods for Safety Analyses

[0494] Safety and tolerability will be assessed by clinical review of AEs and other relevant parameters, including laboratory tests, vital signs, and ECG measurements.109NAI-5007076236Participants enrolled in Part 1 and Part 2 will be analyzed separately, and by the dose received.

[0495] The overall safety evaluation will include 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, an AE resulting in dose reduction, 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. Comparative Analysis of Two Rates. Stat Med 1985;4:213-26],

[0496] 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.

[0497] 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.

[0498] For Part 1 only, DLTs will be listed and summarized by dose level during the DLT evaluation period Cycle 1 Days 1-21.7.2.6.5.4. Statistical Methods for PRO Analyses

[0499] This section describes the planned analyses for the applicable PRO endpoints.

[0500] To assess the treatment effects on the PRO score changes from baseline, a constrained longitudinal data analysis (cLDA) model proposed by Liang and Zeger [Liang K-Y and Zeger SL. Longitudinal data analysis of continuous and discrete responses for pre-post designs. Sankhya: The Indian Journal of Statistics 2000;62(Series B, Pt. 1): 134-48] will be applied with the PRO score as the response variable, and treatment, time, the treatment by time interaction as covariates. The treatment difference in terms of least square (LS) mean change from baseline will be estimated from this model together with 95% CI.

[0501] Overall improvement rate, defined as the proportion of participants who have achieved an overall improvement, will be compared between the 2 treatment groups using the unstratified M&N method. The difference in overall improvement rate and its 95% CI will be provided. The point estimate of overall improvement rate and its 95% CI will be provided by treatment group using exact binomial method by Clopper and Pearson (1934) [Clopper CJ110NAI-5007076236and Pearson ES. The use of confidence or fiducial limits illustrated in the case of the binomial. Biometrika 1934;26(4):404-13], The same method will be used to analyze the overall improvement + stability rate, defined as the proportion of participants who have achieved overall improvement + stability.7.2.7. Dose Modification7.2.7.I. Dose Modification for Patritumab Deruxtecan

[0502] All dose modifications (interruption of infusion, dose delay, dose reduction, and / or discontinuation) should be based on the worst preceding toxicity (NCI CTCAE v5.0). Dose modification decisions may be based on local laboratory results.

[0503] Dose modifications are applicable only to AEs that are assessed as related to use of HER3-DXd by the investigator(s), except for confirmed ILD, for which dose modification should be followed regardless of causality. For nondrug-related AEs, follow standard clinical practice. Appropriate clinical experts should be consulted as deemed necessary. All dose modifications must be recorded on the AE and drug administration eCRF pages. Missed dose(s) due to interruptions can be administered late if within the allowed time interval for dose delay. See Section 7.2.7.5 for details.7.2.7.I.I. Dose Delay Guidelines for Patritumab Deruxtecan

[0504] In circumstances of AE management, medical intervention or any other reason, HER3-DXd can be delayed for up to 28 days (4 weeks) from the planned date of administration. HER3-DXd may be resumed within 28 days of the planned date of administration if the investigator deems the participant is deriving benefit clinically and / or radiologically unless discontinuation of HER3-DXd is mandated as per the HER3-DXd dose modification guidelines [Table 11],

[0505] If a participant resumes HER3-DXd after a delay <28 days from the planned date of administration and then experiences another delay in HER3-DXd >7 days from the planned date of administration, then HER3-DXd should be either permanently discontinued or can be continued after Sponsor consultation and completion of SCF if the investigator deems the participant is deriving benefit clinically and / or radiologically and permanent discontinuation of HER3-DXd is not mandated as per the HER3-DXd dose modification guideline (Table 11).111NAI-5007076236

[0506] If a participant is assessed as requiring a HER3-DXd dose delay of longer than 28 days (4 weeks) from the planned date of administration, then the participant should permanently discontinue HER3-DXd. See Section 7.2.7.5 for details.7.2.7.I.2. Dose Reduction Guidelines for Patritumab Deruxtecan

[0507] If dose reduction is required, HER3-DXd dosing should be reduced by 1 dose level at a time (Table 10). Once the dose of HER3-DXd has been reduced due to an AE, all subsequent cycles should be administered at that lower dose level unless further dose reduction is required. In absence of dose level lower than (-2), HER3-DXd will be discontinued if participant experiences toxicity at dose level (2) that requires further dose reduction.Table 10 Dose Reduction Levels for 5.6 mg / kg Fixed-dose Regimen of Patritumab Deruxtecan7.2.7.I.3. Dose Modification Guidelines for Patritumab Deruxtecan

[0508] Dose modification guidelines for management of nonhematologic and hematologic toxicity related to HER3-DXd are provided in Table 11.

[0509] In addition, investigator may consider dose reductions or discontinuations of the study drug according to the participant’s condition and after discussion with the study Medical Monitor or designee.Table 11 Dose Modification Guideline for Nonhematologic and Hematologic Toxicity Related to Patritumab Deruxtecan112NAI-5007076236<113NAI-5007076236<< << >< << < << <>><<<114NAI-5007076236<<< <>< << < <>><><<<>< >< >< > <>115NAI-5007076236116NAI-5007076236<>117NAI-5007076236<<><> >>> >> ><<>> >118NAI-5007076236> ><<>> ><<><<>>>119NAI-5007076236> >>>> >120NAI-5007076236> >> ><< << ><< << >>121NAI-5007076236<< << ><< << ><<>>7.2.7.2. Dose Modification for Pembrolizumab7.2.7.2.I. Dose Modification and Toxicity Management for Immune- related AEs Associated With Pembrolizumab

[0510] AEs associated with pembrolizumab 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 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 122NAI-5007076236interruptions of pembrolizumab, 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.

[0511] Dose Modification and Toxicity Management Guidelines for irAEs Associated With Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 12.Table 12 Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With Pembrolizumab Monotherapy, Coformulations, or IO CombinationsGeneral instructions:1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.2. Pembrolizumab monotherapy, coformulations, or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not10 mg / day within 12 weeks of the last treatment.3. The corticosteroid taper should begin when the irAE isGrade 1 and continue at least 4 weeks.4. If pembrolizumab monotherapy, coformulations, or IO combinations have been withheld, treatment may resume after the irAE decreased toGrade 1 after corticosteroid taper.123NAI-5007076236>124NAI-5007076236125NAI-5007076236> >> >> > > >> >> ><126NAI-50070762367.2.7.2.2. Dose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0512] 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 13.Table 13 Pembrolizumab Monotherapy, Coformulations, or IO Combinations Infusion Reaction Dose Modification and Treatment Guidelines<127NAI-50070762367.2.7.2.3. Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0513] 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 dosing) and 6 weeks (for q6w dosing regimens) of the originally scheduled dose and within 42 days (for q3w dosing) and 84 days (for q6w dosing regimens) 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.7.2.7.3. Dose Modification for Other Study-related Neoadjuvant and Adjuvant Therapies On-study

[0514] Toxi cities related to paclitaxel, carboplatin, doxorubicin, epirubicin, cyclophosphamide, capecitabine, and olaparib should be managed per the locally approved label and / or treatment guidelines / institutional standards.

[0515] Dose reductions, decision to delay dosing or decision to permanently discontinue paclitaxel, carboplatin, doxorubicin, epirubicin, cyclophosphamide, capecitabine, and olaparib due to toxicity should be as per local treatment guidelines / institutional standards. Once the dose of chemotherapy(ies) or olaparib has been reduced due to an AE, all subsequent cycles / doses should be administered at that lower dose level unless further dose reduction is required.

[0516] In circumstances of AE management, medical intervention or any other reason, neoadjuvant paclitaxel, carboplatin, and AC / EC can be delayed for up to 28 days (4 weeks)128NAI-5007076236from the planned date of administration. These neoadjuvant chemotherapies may be resumed within 28 days of the planned date of administration if the investigator deems the participant is deriving benefit clinically and / or radiologically. If a participant who resumes neoadjuvant paclitaxel, carboplatin, or ACZEC after a delay ^28 days from the planned date of administration experiences another delay >7 days from the planned date of administration, they should permanently discontinue the delayed neoadjuvant chemotherapy(s) unless Sponsor approval is obtained via completion of SCF to continue.

[0517] If a participant is assessed as requiring a delay in neoadjuvant paclitaxel, carboplatin, or AC / EC of longer than 28 days (4 weeks) from the planned date of administration, then the participant should discontinue the delayed neoadjuvant chemotherapy(s).

[0518] In circumstances of AE management, medical intervention or any other reason, adjuvant ACZEC (Part 2 only) can be delayed for up to 28 days (4 weeks) from the planned date of administration. These adjuvant chemotherapies may be resumed within 28 days of the planned date of administration if the investigator deems the participant is deriving benefit clinically. If a participant who resumes adjuvant ACZEC after a delay of ^28 days from the planned date of administration experiences another delay in these study interventions >7 days from the planned date of administration, they should permanently discontinue adjuvant ACZEC unless Sponsor approval is obtained via completion of SCF to continue.

[0519] If a participant is assessed as requiring a delay in adjuvant ACZEC of >28 days (4 weeks) from the planned date of administration, then the participant should permanently discontinue adjuvant ACZEC.

[0520] In circumstances of AE management, medical intervention or any other reason, adjuvant capecitabine or olaparib (Part 2 only) can be interrupted for up to 28 days (4 weeks). Capecitabine or olaparib may be resumed within 28 days of the last dose if the investigator deems the participant is deriving benefit clinically. If a participant who resumes adjuvant capecitabine or olaparib after an interruption of <28 days from the last dose experiences another interruption in adjuvant capecitabine or olaparib by >7 days from the last dose, they should permanently discontinue adjuvant capecitabine or olaparib unless Sponsor approval is obtained via completion of SCF to continue.

[0521] If a participant is assessed as requiring an interruption in adjuvant capecitabine or olaparib of >28 days (4 weeks) from the last dose, then the participant should permanently discontinue adjuvant capecitabine or olaparib.129NAI-5007076236

[0522] See Table 14 for recommended dose modifications for other study-related neoadjuvant and adjuvant therapies. Local SOC / guidelines and practices should be followed, if different than these recommendations.Table 14 Suggested Dose Modifications for Other Study-related Neoadjuvant and Adjuvant Therapies7.2.7.4. Management of Overlapping Toxicides

[0523] 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 7.2.7.1 forHER3 DXd, Section 7.2.7.2 for pembrolizumab, or Section 7.2.7.3 for SOC. chemotherapy / olaparib). 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) for each study intervention should be consulted, and the most conservative toxicity management guidelines should be followed for the management of AE itself.

[0524] IRRs can often be attributed to a specific study intervention. 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 HER3-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 HER-DXd and130NAI-5007076236pembrolizumab who have IRR >Grade 3, both HER3-DXd and pembrolizumab should be permanently discontinued if the intervention that caused the infusion reaction is uncertain. If a participant experiences an infusion reaction during administration of one of the study interventions on a given day, no other study interventions should be administered until resolution of the infusion reaction, and rest of the study interventions due that day may be withheld entirely at investigator’s discretion. See Section 7.2.7.5 for management of such situations.7.2.7.5. Instructions on Delaying or Withholding of a Component or Entire Study Intervention Regimen

[0525] Neoadjuvant Treatment Phase

[0526] If an investigator determines that a participant must interrupt therapy with any specific study intervention(s) for any reason, the investigator may either withhold the specific study intervention(s) thought to require interruption or may delay the entire regimen. Of note, in situations in which doxorubicin / epirubicin or cyclophosphamide must be interrupted, it is recommended that both be interrupted.• For example, if an investigator determines that a participant in Arm A cannot receive pembrolizumab on C2D1 for any reason, it is up to the investigator, according to clinical judgment, to decide if administration of both pembrolizumab and HER3-DXd should be interrupted and initiation of C2 be delayed, or if C2 should be initiated as planned and HER3-DXd be administered alone on C2D1 while pembrolizumab is withheld.

[0527] If the investigator opts to withhold only the specific study intervention(s) thought to require interruption and to proceed with administering other study intervention(s) according to the study calendar:• The missed dose(s) of the interrupted study intervention(s) may not be made up. • If the investigator determines that the interrupted study intervention(s) may be resumed within the allowed time interval (see Sections 7.2.7.1, 7.2.7.2 and 7.2.7.3 for allowed durations of delay for each study intervention), the next dose of the interrupted therapy(s) should be administered according to the study calendar.o For example, if a participant in Arm A receives only HER3-DXd on C2D1 because pembrolizumab is withheld that day, both HER3-DXd and pembrolizumab will next be administered on C3D1 (if it is determined that the131NAI-5007076236participant may resume pembrolizumab prior to the scheduled date for C3D1), and the missed C2 dose of pembrolizumab will not be made up.• If it is determined, in the investigator’s opinion, that the interrupted study intervention(s) cannot be resumed during the allowed time interval and must be permanently discontinued, see Section 7.2.7.2 for instructions on discontinuation of a component or the entire study intervention regimen.

[0528] If the investigator opts to delay the entire regimen because any specific study intervention(s) must be interrupted:• The entire regimen may be resumed if it is determined the participant is able to do so within the allowed time intervals (see Sections 7.2.7.1, 7.2.7.2 and 7.2.7.3 for allowed durations of delay for each study intervention).• In this case, missed doses can be made up.o For example, a participant in Arm A who requires interruption of pembrolizumab at the scheduled date for C2D1 in whom the investigator opts to administer neither pembrolizumab nor HER3-DXd but rather to delay the entire cycle, may subsequently receive C2D1 with both drugs if it is determined that pembrolizumab may be resumed within the allowed duration of delay and HER3-DXd has also not been delayed beyond the allowed duration.• Alternatively, in cases in which the entire regimen is delayed because any specific study intervention(s) must be interrupted, the investigator may opt, as clinically indicated, to subsequently permanently discontinue a component of the study regimen but to resume another component of the study intervention, provided that resumption of the component that is not permanently discontinued occurs within the allowed time intervals for delays (see Sections 7.2.7.1, 7.2.7.2 and 7.2.7.3 for allowed durations of delay for each study intervention and Section 7.2.7.2 for instructions on discontinuation of a component of the study regimen).o For example, a participant in Arm A who requires interruption of pembrolizumab at the scheduled date for C2D1 in whom the investigator opts to administer neither pembrolizumab nor HER3-DXd but rather to delay the entire cycle, may subsequently receive a delayed C2D1 with HER3-DXd alone if it is determined that pembrolizumab will be permanently discontinued and the allowed duration of delay in HER3-DXd has not been surpassed.132NAI-5007076236

[0529] In any situation in which there is interruption of study intervention(s), if the investigator determines that either a component or the entire study regimen must be permanently discontinued, see Section 7.2.7.2 for instructions.

[0530] In any situation in which there is a delay between Neoadjuvant Treatment 1 and Neoadjuvant Treatment 2 for any reason, Sponsor consultation and completion of SCF is required if the interval between the last dose of Neoadjuvant Treatment 1 and C5D1 is >28 days for participants in Arms B and C, or >42 days for participants in Arm A.

[0531] Adjuvant Treatment Phase (Part 2 only)

[0532] For participants receiving only adjuvant pembrolizumab or only additional TPC, follow dose modification guidelines in Section 7.2.7.2 or Section 7.2.7.3 if an investigator determines that a participant must interrupt therapy for any reason.

[0533] For participants receiving adjuvant pembrolizumab and additional adjuvant TPC concurrently:• If an investigator determines that a participant must interrupt the additional adjuvant TPC, the investigator should:o Continue adjuvant pembrolizumab as scheduled while withholding the additional adjuvant TPC. Note that for participants receiving adjuvant AC / EC, if doxorubicin / epirubicin or cyclophosphamide require interruption, it is recommended that both be interrupted. The investigator may subsequently choose to resume the additional adjuvant TPC when clinically appropriate provided the allowed duration of delay has not been surpassed and the investigator does not think permanent cessation of the additional adjuvant TPC is required. The missed doses of the adjuvant additional TPC can be made up in this situation. Resumption of the additional adjuvant TPC relative to the ongoing pembrolizumab cycles should be timed as follows, if possible:■ For participants receiving adjuvant AC / EC q2w, it should be resumed on DI, DI 5, or D29, and continued q2w until a total of 4 cycles have been administered.■ For participants receiving adjuvant AC / EC q3w, it should be resumed on DI or D22, and continued q3w until a total of 4 cycles have been administered.■ For participants receiving olaparib, it may be resumed at any time during the ongoing pembrolizumab cycles and continued until a total133NAI-5007076236of 730 doses (365 days) have been administered. In this case, it will end after C17D29.■ For participants resuming capecitabine, the investigator may choose to either omit the remaining doses of the 14-day dosing period that was interrupted and resume with initiation of the next 14-day dosing period or administer remaining doses of the 14-day dosing period that was interrupted. Resumption of capecitabine should be timed such that dosing coincides with DI to D 14 and D22 to D35 of pembrolizumab cycles. A total of 4 cycles, each comprised of two 14-day dosing periods, followed by 7 days off of capecitabine should be administered.• If an investigator determines that a participant must interrupt adjuvant pembrolizumab, the investigator should:o Continue the additional adjuvant TPC as scheduled while withholding the adjuvant pembrolizumab. The investigator may subsequently choose to resume the adjuvant pembrolizumab when clinically appropriate provided the allowed duration of delay has not been surpassed and the investigator does not think permanent cessation of adjuvant pembrolizumab is required. The missed doses of adjuvant pembrolizumab can be made up. In this case, pembrolizumab would continue beyond C13 until a total of up to 5 adjuvant cycles of q6w dosing (or 9 adjuvant cycles of q3w dosing) have been administered. Resumption of adjuvant pembrolizumab should be timed to DI of a given cycle, if possible (or to DI or D22 for participants receiving q3w dosing).• If an investigator determines that a participant must interrupt both adjuvant pembrolizumab and additional adjuvant TPC:o Both adjuvant pembrolizumab and additional adjuvant TPC should be withheld. If clinically appropriate, one or other or both can be resumed subsequently provided the allowed duration of delay(s) has not been surpassed and criteria for permanent discontinuation have not been met.

[0534] Note: The investigator may choose to resume additional adjuvant TPC and adjuvant pembrolizumab at the same time or at different times. The above guidelines with regard to timing of resumption of therapies in relation to timing within the cycles should be followed.134NAI-5007076236

[0535] In any situation in which there is interruption of study intervention(s), if the investigator determines that either a component or the entire study regimen must be permanently discontinued, see Section 7.2.7.2 for instructions.7.2.7.6. Adverse Events, Serious Adverse Events, and Other Reportable Safety Events7.2.7.6.I. Definition of AE

[0536] AE definition• 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.• 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.• 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 marketed (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.

[0537] Events meeting the AE definition• 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.• Exacerbation of a chronic or intermittent preexisting condition including either an increase in frequency and / or intensity of the condition.• New conditions detected or diagnosed after study intervention administration even though it may have been present before the start of the study.• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a concomitant medication.• 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 135NAI-5007076236without any associated clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or intentional overdose without adverse effect.” • Any new cancer (that is not a condition of the study). Recurrence of the cancer under study is not a reportable event.

[0538] Note: progression of cancer under study is also not a reportable event.

[0539] Events NOT meeting the AE definition• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the procedure is the AE.• Situations in which an untoward medical occurrence did not occur (social and / or convenience admission to a hospital).• 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.• Surgical procedure(s) planned prior to informed consent to treat a preexisting condition that has not worsened.7.2.7.6.2. Definition of SAE

[0540] If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met.

[0541] An SAE is defined as any untoward medical occurrence that, at any dose:

[0542] a. Results in death

[0543] 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.

[0544] 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.

[0545] d. Results in persistent or significant disability / incapacityThe term disability means a substantial disruption of a person’s ability to conduct normal life functions.136NAI-5007076236• 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.

[0546] e. Is a congenital anomaly / birth defect• In offspring of participant taking the product regardless of time to diagnosis.

[0547] 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.7.2.7.6.3. Additional Events Reported

[0548] Additional events that require reporting

[0549] In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH definition, are reportable to the Sponsor.• Is a new cancer (that is not the cancer under study).• Is associated with an overdose.7.2.7.6.4. Definition of Dose-limiting Toxicity

[0550] All toxicities will be graded using NCI CTCAE Version 5.0 based on the investigator assessment.

[0551] The DLT window of observation will be during Cycle 1 of neoadjuvant treatment 1 for Arm A in Part 1 (Safety Lead-in).

[0552] The occurrence of any of the following toxicities during the DLT observation window will be considered a DLT, if assessed by the investigator to be possibly, probably, or definitely related to study intervention administration.• Any Grade 3 or 4 nonhematologic toxicity should be considered a DLT, with the following exceptions:137NAI-5007076236o Grade 3 fatigue lasting <3 days;o Grade 3 diarrhea, nausea, or vomiting lasting <3 days. Any Grade 3 diarrhea, nausea, or vomiting lasting >3 days would be considered a DLT; o Grade 3 rash lasting <7 days. Any Grade 3 rash lasting >7 days or requiring treatment with systemic corticosteroids would be considered a DLT.• Any Grade 3 or Grade 4 laboratory value (hematologic or nonhematologic), except for the following:o Grade 3+ electrolyte imbalances that last <72 hours, are not clinically complicated, and resolve spontaneously or with conventional medical interventions.o Grade 3+ amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis;o Grade 3 or 4 anemia or Grade 3 neutropenia or Grade 3 thrombocytopenia (in the absence of clinically significant bleeding) responsive to medical management and that resolves to Grade <1 within 7 days;o AST or ALT >5 x ULN that resolves to Grade <1 or baseline within 7 days.• Febrile neutropenia Grade 3 or Grade 4:o Grade 3 is defined as ANC <1000 / mm3with 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.o Grade 4 is defined as ANC <1000 / mm3with 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 intervention-related toxicity.• Any intervention-related toxicity that causes the participant to discontinue intervention during Cycle 1.• ILD as per the investigator• Any other Grade >3 pulmonary toxicityGrade 5 toxicity.

[0553] The present disclosure relates to the combination of an anti-HER3 ADC such as patritumab 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 combination138NAI-5007076236and combined dosing regimens of pembrolizumab with an anti-HER3 ADC (e.g., patritumab deruxtecan (HER3-DXd)) may be more efficacious than either treatment alone, for instance, for breast cancer treatment (e.g., triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer). In some embodiments, the combination and combined dosing regimens of pembrolizumab with an anti-HER3 ADC disclosed herein may be more efficacious than current treatments (e.g., neoadj uvant / adjuvant pembrolizumab in addition to neoadjuvant chemotherapy). In some embodiments, the combination and combined dosing regimens of pembrolizumab with an anti-HER3 ADC disclosed herein may be more efficacious than the current standard of care (e.g., neoadjuvant carboplatin / paclitaxel plus pembrolizumab followed by ACZEC (AC=doxorubicin and cyclophosphamide; EC=epirubicin and cyclophosphamide) plus pembrolizumab).

[0554] As a non-limiting example, in some embodiments, a subject with triple-negative breast cancer (e.g., high-risk and / or early-stage triple-negative breast cancer) or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer may not achieve a desired result (e.g., improved pCR, EFS, and / or OS rates) with current approaches. Without being bound by theory, an anthracycline-based component (ACZEC) of the neoadjuvant portion of certain current regimens for the treatment of breast cancer may be replaced with the HER3 -targeting ADC (e.g., patritumab deruxtecan (HER3-DXd). In some embodiments, replacing the anthracycline-containing component with an anti-HER3 ADC may improve outcomes. Additionally, the combination or combined dosing regimens may not result in cumulative toxicities such that they will be better tolerated than existing therapies.

[0555] 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 changes may 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.

[0556] 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.139NAI-5007076236SEQUENCE TABLE140NAI-5007076236141NAI-5007076236142NAI-5007076236

Claims

CLAIMS1. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab;and(ii) 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 Iwherein AB is an anti-human HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 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: 3; andb) 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: 4;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

2. A method for treating cancer in a subject in need thereof, wherein the method comprises:143NAI-5007076236(i) administering to the subject a first therapeutically effective amount of pembrolizumab;and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti- human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula IIFormula IIwherein A represents a connecting position to the anti-human-HER3 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-HER3 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: 3; andb) 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: 4;wherein the cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

3. The method of claim 1 or claim 2, wherein the anti-human HER3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 5,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 7,144NAI-5007076236(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and (vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

4. The method of any one of claims 1-3, wherein the anti-human HER3 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: 3, and a light chain variable region (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 4.

5. The method of any one of claims 1-4, wherein the anti-human HER3 antibody is an IgGl or an IgG2.

6. The method of any one of claims 1-5, wherein the anti-human HER3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 3, and a VL comprising the amino acid sequence of SEQ ID NO: 4.

7. The method of any one of claims 1-6, wherein the anti-human HER3 antibody comprises a heavy chain (“HC”) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain (“LC”) comprising the amino acid sequence of SEQ ID NO: 2.

8. The method of any one of claims 1-7, wherein a lysine residue at the carboxyl terminus of the HC of the anti-human HER3 antibody is deleted.

9. The method of any one of claims 1 and 3-8, wherein the drug to antibody ratio is in the range of from 2 to 8, optionally wherein the drug to antibody ratio is 8.

10. The method of any one of claims 1-9, wherein the antibody-drug conjugate is patritumab deruxtecan.

11. The method of any one of claims 1-10, wherein the first therapeutically effective amount of the pembrolizumab is administered at a dose of about 200 mg or about 400 mg.145NAI-500707623612. The method of any one of claims 1-11, wherein the pembrolizumab is administered once every three weeks.

13. The method of any one of claims 1-12, wherein the pembrolizumab is administered intravenously.

14. The method of any one of claims 1-13, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 3.2 mg / kg.

15. The method of any one of claims 1-13, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg.

16. The method of any one of claims 1-13, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg.

17. The method of any one of claims 1-16, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered once every three weeks.

18. The method of any one of claims 1-17, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered intravenously.

19. The method of claim 18, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion.

20. The method of claim 18, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 90 ± 5 minute IV fusion.

21. The method of any one of claims 1-20, wherein the cancer is a triple-negative breast cancer.

22. The method of claim 21, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.146NAI-500707623623. The method of any one of claims 1-22, wherein the cancer is hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

24. The method of any one of claims 1-23, wherein the anti-human HER3 antibody or functional fragment thereof is an antibody.

25. The method of any one of claims 1-24, wherein the anti-human HER3 antibody or functional fragment thereof is an antibody comprised of two heavy chains and two light chains.

26. The method of any one of claims 1-25, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate.

27. The method of claim 26, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.147NAI-500707623628. The method of any one of claims 1-25, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate.

29. The method of claim 28, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

30. The method of any one of claims 26-29, wherein:(iii) the third therapeutically effective amount of pembrolizumab is administered at a dose of about 200 mg or about 400 mg;(iv) the fourth therapeutically effective amount of carboplatin is administered at a dose of about area under the curve (AUC)1.5 mg / mL / min; and(v) the fifth therapeutically effective amount of paclitaxel is administered at a dose of about 80 mg / m2.148NAI-500707623631. The method of any one of claims 26-30, wherein the third therapeutically effective amount of pembrolizumab is administered once every three weeks, the fourth therapeutically effective amount of carboplatin is administered once every week, and the fifth therapeutically effective amount of paclitaxel is administered once every week.

32. The method of any one of claims 26-31, wherein the third therapeutically effective amount of pembrolizumab is administered intravenously, the fourth therapeutically effective amount of carboplatin is administered intravenously, and the fifth therapeutically effective amount of paclitaxel is administered intravenously.

33. A method for treating a breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

34. A method for treating triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

35. The method of claim 34, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

36. The method of any one of claims 33-35, wherein the first therapeutically effective amount of pembrolizumab is administered at a dose of about 200 mg or about 400 mg.

37. The method of any one of claims 33-36, wherein the first therapeutically effective amount of pembrolizumab is administered once every three weeks.149NAI-500707623638. The method of any one of claims 33-37, wherein the pembrolizumab is administered intravenously.

39. The method of any one of claims 33-38, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 3.2 mg / kg.

40. The method of any one of claims 33-38, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 4.8 mg / kg.

41. The method of any one of claims 33-38, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 5.6 mg / kg.

42. The method of any one of claims 33-41, wherein the second therapeutically effective amount of patritumab deruxtecan is administered once every three weeks.

43. The method of any one of claims 33-42, wherein the second therapeutically effective amount of patritumab deruxtecan is administered intravenously.

44. The method of claim 43, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 30 ± 5 minute IV fusion.

45. The method of claim 43, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 90 ± 5 minute IV fusion.

46. The method of any one of claims 33-45, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first 150NAI-5007076236therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

47. The method of claim 46, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

48. The method of any one of claims 33-45, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab;(iv) administering to the subject a fourth therapeutically effective amount of carboplatin; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel;wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

49. The method of claim 48, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles; followed by151NAI-5007076236(2) a second neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

50. The method of any one of claims 46-49, wherein:(iii) the third therapeutically effective amount of pembrolizumab is administered at a dose of about 200 mg or about 400 mg; and(iv) the fourth therapeutically effective amount of carboplatin is administered at a dose of about area under the curve (AUC)1.5 mg / mL / min; and(v) the fifth therapeutically effective amount of paclitaxel is administered at a dose of about 80 mg / m2.

51. The method of any one of claims 46-50, wherein the third therapeutically effective amount of pembrolizumab is administered once every three weeks and the fourth therapeutically effective amount of carboplatin is administered once every week and the fifth therapeutically effective amount of paclitaxel is administered once every week.

52. The method of any one of claims 46-51, wherein the third therapeutically effective amount of pembrolizumab is administered intravenously and the fourth therapeutically effective amount of carboplatin is administered intravenously and the fifth therapeutically effective amount of paclitaxel is administered intravenously.

53. A method for treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab at a dose of about 200 mg, every three weeks, intravenously; and (ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan at a dose of about 3.2 mg / kg, once every three weeks, intravenously.152NAI-500707623654. A method for treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan at a dose of about 4.8 mg / kg, once every three weeks, intravenously.

55. A method for treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan at a dose of about 5.6 mg / kg, once every three weeks, intravenously.

56. The method of any one of claims 53-55, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously; (iv) administering to the subject a fourth therapeutically effective amount of carboplatin at a dose of about AUC1.5 mg / mL / min, once every week, intravenously; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel at a dose of about 80 mg / m2, once every week, intravenously; wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs after the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.153NAI-500707623657. The method of claim 56, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles;wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

58. The method of any one of claims 53-55, wherein the method further comprises:(iii) administering to the subject a third therapeutically effective amount of pembrolizumab at a dose of about 200 mg, once every three weeks, intravenously; (iv) administering to the subject a fourth therapeutically effective amount of carboplatin at a dose of about AUC1.5 mg / mL / min, once every week, intravenously; and(v) administering to the subject a fifth therapeutically effective amount of paclitaxel at a dose of about 80 mg / m2, once every week, intravenously; wherein the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel occurs before the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan.

59. The method of claim 58, wherein the method comprises:(1) a first neoadjuvant treatment comprising the administering of the third therapeutically effective amount of pembrolizumab, the fourth therapeutically effective amount of carboplatin, and the fifth therapeutically effective amount of paclitaxel for 4 cycles; followed by(2) a second neoadjuvant treatment comprising the administering of the first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the patritumab deruxtecan for 4 cycles;154NAI-5007076236wherein the combined administering of (1) and (2) has a duration of about 24 weeks; andwherein each cycle length has a duration of about 3 weeks.

60. The method of any one of claims 1-59, wherein the subject is administered a premedication with one or more antiemetic agents.

61. The method of any one of claims 1-60, wherein the subject is a human subject.

62. The method of claim 61, wherein the human subject has triple-negative breast cancer.

63. The method of claim 62, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

64. The method of claim 61, wherein the human subject has hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

65. The method of any one of claims 1-64, wherein the human subject has(i) no confirmed metastases;(ii) clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2;(iii) no previous systemic therapy;(iv) no previous excision of primary tumor; and / or(v) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

66. The method of any one of claims 27, 29, 47, 49, 57, and 59, wherein the subject has a surgery and, optionally, a post-operative radiation therapy.

67. The method of claim 66, wherein the surgery occurs about 3 weeks to about 6 weeks after the last cycle of the second neoadjuvant treatment.

68. The method of any one of claims 27, 29, 47, 49, 57, 59, 66, and 67, wherein the method further comprises:(3) an adjuvant treatment phase comprising:155NAI-5007076236(vi) administering to the subject a sixth therapeutically effective amount of pembrolizumab; and optionally,(vii) administering to the subject a seventh therapeutically effective amount of one or more additional treatments of physician’s choice (TPC), wherein the TPC comprises doxorubicin, epirubicin, cyclophosphamide, capecitabine, and / or olaparib.

69. The method of claim 68, wherein:(vi) the pembrolizumab is administered: (a) once every six weeks; (b) at a dose of about 400 mg; and / or (c) intravenously; and optionally;(vii) when administered, wherein,(a) doxorubicin is administered (1) once every two weeks or once every three weeks, (2) at a dose of about 60 mg / m2, and / or (3) intravenously;(b) epirubicin is administered (1) once every two weeks or once every three weeks; (2) at a dose of about 90 mg / m2, and / or (3) intravenously;(c) cyclophosphamide is administered (1) once every two weeks or once every three weeks; (2) at a dose of about 600 mg / m2, and / or (3) intravenously;(d) capecitabine is administered (1) on Days 1 to 14 and Days 22 to 35 of every 6-week cycle, (2) at a dose of about 1000 mg / m2to 1250 mg / m2, and / or (3) intravenously; and / or(e) olaparib is administered (1) on Days 1 to 42 of every 6-week cycle for 8 cycles and Days 1 to 29 of the subsequent cycle; (2) at a dose of about 300 mg, and / or (3) intravenously.

70. The method of claim 68 or 69, wherein the subject has the surgery, and the adjuvant treatment phase begins about 4 weeks to about 8 weeks after surgery.

71. The method of any of claims 68-70, wherein the adjuvant treatment phase has a duration of about 30 to about 66 weeks, wherein each cycle has a duration of about 6 weeks.

72. A pharmaceutical composition for use in treating a breast cancer, comprising a first therapeutically effective amount of the pembrolizumab, and a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-10 in combination, wherein optionally the pembrolizumab is administered as defined in any one of156NAI-5007076236claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

73. A pharmaceutical composition for use in treating a breast cancer, comprising a first therapeutically effective amount of pembrolizumab, in combination with a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-10, wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

74. A pharmaceutical composition for use in treating a breast cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-10, and a second therapeutically effective amount of the pembrolizumab, in combination, wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

75. A pharmaceutical composition for use in treating a breast cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-10, in combination with a first therapeutically effective amount of the pembrolizumab, wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

76. A pharmaceutical composition for use in treating a breast cancer, comprising a first therapeutically effective amount of pembrolizumab, in combination with a second therapeutically effective amount of patritumab deruxtecan.

77. A pharmaceutical composition for use in treating a breast cancer, comprising a second therapeutically effective amount of patritumab deruxtecan, in combination with a first therapeutically effective amount of pembrolizumab.157NAI-500707623678. The pharmaceutical composition of any one of claims 72-77, wherein the pharmaceutical composition is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the pembrolizumab, carboplatin, and paclitaxel is for use after the pharmaceutical composition.

79. The pharmaceutical composition of any one of claims 72-77, wherein the pharmaceutical composition is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the pembrolizumab, carboplatin, and paclitaxel is for use before the pharmaceutical composition.

80. The pharmaceutical composition for use of any one of claims 72-79, wherein the breast cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

81. The pharmaceutical composition for use of claim 80, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

82. The pharmaceutical composition for use of any one of claims 72-81, wherein first therapeutically effective amount of the pembrolizumab and the second therapeutically effective amount of the antibody-drug conjugate are formulated in two different compositions.

83. Use of pembrolizumab for the preparation of a medicament for treating a breast cancer, by administration in combination with the antibody-drug conjugate as defined in any one of claims 1-10, wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

84. Use of the antibody-drug conjugate as defined in any one of claims 1-10 for the preparation of a medicament for treating a breast cancer, by administration in combination with pembrolizumab, wherein optionally the pembrolizumab is administered as defined in158NAI-5007076236any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

85. The use of claim 83 or claim 84, wherein the breast cancer is triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

86. The use of claim 85, wherein the triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

87. The use of any one of claims 83-86, wherein the use is in further combination with the use of pembrolizumab, carboplatin, and paclitaxel;wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20;wherein optionally the carboplatin and paclitaxel is administered as defined in any one of claims 50-52; andwherein the use of pembrolizumab, carboplatin, and paclitaxel is after the use of pembrolizumab and antibody-drug conjugate.

88. The use of any one of claims 83-86, wherein the use is in further combination with the use of pembrolizumab, carboplatin, and paclitaxel;wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20;wherein optionally the carboplatin and paclitaxel is administered as defined in any one of claims 50-52; andwherein the use of pembrolizumab, carboplatin, and paclitaxel is before the use of pembrolizumab and antibody-drug conjugate.

89. Pembrolizumab for use in combination with an anti-human HER3 antibody-drug conjugate as defined in any one of claims 1-10 in treating a breast cancer in a subject in need thereof, wherein optionally the pembrolizumab is administered as defined in any one of159NAI-5007076236claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

90. Pembrolizumab for use in combination with an anti-human HER3 antibody-drug conjugate as defined in any one of claims 1-10 in treating high-risk early-stage triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof, wherein optionally the pembrolizumab is administered as defined in any one of claims 11-13, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 14-20.

91. Pembrolizumab for use in combination with patritumab deruxtecan in treating triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof.

92. Patritumab deruxtecan for use in combination with pembrolizumab in treating triple-negative breast cancer or hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer in a subject in need thereof.

93. The pembrolizumab for use of claim 91, or the patritumab deruxtecan for use of claim 92, wherein triple-negative breast cancer is a high-risk and / or early-stage triple-negative breast cancer.

94. The pembrolizumab for use of any one of claims 89-91, or the patritumab deruxtecan for use of claim 92, wherein the use is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the use of pembrolizumab, carboplatin, and paclitaxel is after the use of pembrolizumab and patritumab deruxtecan.

95. The pembrolizumab for use of any one of claims 89-91, or the patritumab deruxtecan for use of claim 92, wherein the use is in further combination with pembrolizumab, carboplatin, and paclitaxel;wherein the use of pembrolizumab, carboplatin and paclitaxel is before the use of pembrolizumab and patritumab deruxtecan.160NAI-500707623696. The pembrolizumab for use of any one of claims 89-93, or the patritumab deruxtecan for use of any one of claims 92-93 wherein the subject is a human subject.

97. The pembrolizumab for use of claim 96, or the patritumab deruxtecan for use of claim 96, wherein the human subject has a confirmed diagnosis of triple-negative breast cancer.

98. The pembrolizumab for use of claim 97, or the patritumab deruxtecan for use of claim 97, wherein the human subject has a confirmed diagnosis of high-risk early-stage triple-negative breast cancer.

99. The pembrolizumab for use of claim 96, or the patritumab deruxtecan for use of claim 96, wherein the human subject has a confirmed diagnosis of hormone receptor-low positive / human epidermal growth factor receptor-2 negative breast cancer.

100. The pembrolizumab for use of any one of claims 89-99, or the patritumab deruxtecan for use of any one of claims 89-99, wherein the human subject has:(i) no confirmed metastases;(ii) clinical stage cTlc Nl-2 or clinical stage cT2-4 NO-2;(iii) no previous systemic therapy;(iv) no previous excision of primary tumor; and / or(v) an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

101. A kit comprising (i) pembrolizumab, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 antibody-drug conjugate as defined in any one of claims 1-10, or a second pharmaceutical composition comprising the same, optionally further comprising instructions for treating a breast cancer in a subject in need thereof according to the method of any one of claims 1-71.

102. The method of any one of claims 1-13, 17-38, and 44-71, 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; and161NAI-5007076236(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 5.6 mg / kg of the subject’s body weight and the second dose is about 4.8 mg / kg of the subject’s body weight;(b) the first dose is about 4.8 mg / kg of the subject’s body weight and the second dose is about 3.2 mg / kg of the subject’s body weight;(c) the first dose is about 3.2 mg / kg of the subject’s body weight and the second dose is discontinued.

103. The method of claim 102, wherein the adverse event is:(i) an infusion-related reaction;(ii) fatigue, asthenia, and / or malaise;(iii) a blood and lymphatic system disorder, optionally selected from decreased neutrophil count, febrile neutropenia, decreased lymphocyte count, anemia, or decreased platelet count;(iv) a cardiac disorder, optionally selected from hear failure, decreased ejection fraction, or electrocardiogram QT interval prolongation;(v) a respiratory, thoracic and / or mediastinal disorder, optionally pulmonary toxicity; (vi) an eye disorder;(vii) a renal and / or urinary disorder, optionally increased creatinine;(viii) a hepatobiliary disorder, optionally selected from an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) without increased total bilirubin (TBL), an increase in TBL, an increase in AST or ALT with TBL increased, AST or ALT > 3.0 x upper limit of normal (ULN) with known Hepatitis B and / or Hepatitis C infection at baseline, or increase alkaline phosphatase (ALP); or(ix) a gastrointestinal disorder, optionally selected from nausea, vomiting, diarrhea, colitis, or mucositis oral.

104. The method of any one of claims 1-71, wherein the method comprises:(i) administering to the subject the pembrolizumab;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present reducing the dose, delaying the dose, or permanently discontinuing the dose of pembrolizumab to the subject.162NAI-5007076236105. The method of claim 104, wherein the adverse event is:(i) an immune-related adverse event as shown in Table 12; or(ii) an infusion-related adverse event as shown in Table 13.

106. The method of any one of claims 26-29, 31, 32, 46-49, 51, and 52, wherein the method comprises:(i) administering to the subject the paclitaxel and carboplatin;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present,(a) administering to the subject the paclitaxel at a second dose; wherein:(1) the first dose is about 80 mg / m2and the second dose is reduced by about 20%;(2) the first dose is about 80 mg / m2reduced by about 20% and the second dose is discontinued; and / or(b) administering to the subject the carboplatin at a second dose; wherein:(1) the first dose is about AUC1.5 mg / mL / min and the second dose is about AUC 1.1 mg / mL / min; and(2) the first dose is about AUC1.5 mg / mL / min and the second dose is discontinued.

107. The method of claim 68 or 69, wherein the method comprises:(i) administering to the subject the TPC;(ii) determining the presence of one or more adverse events; and(iii) if the adverse event is present reducing the dose, delaying the dose, or permanently discontinuing the dose of the TPC to the subject, wherein optionally the dose is reduced as shown in Table 14.163NAI-5007076236

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