Combination therapies for the treatment of HR+ / her2- metastatic or locally advanced breast cancer

Abstract

The present disclosure relates to methods of treating HR+ / HER2- metastatic or locally advanced breast cancer in a patient, the methods comprising administering to the patient: (a) an anti-human PD-1 antibody or antigen binding fragment thereof; and (b) an Immunoconjugate of Formula (I): wherein: Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10.

Description

COMBINATION THERAPIES FOR THE TREATMENT OF HR+ / HER2- METASTATIC ORLOCALLY ADVANCED BREAST CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 561,989 filed March 6, 2024, the entire contents of which are incorporated by reference herein.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The contents of the electronic sequence listing (25915-WO-PCT SL. xml; Size: 44,990 bytes; and Date of Creation: July 31, 2024) are herein incorporated by reference in their entirety.FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to combination therapies useful for the treatment of HR+ / HER2- metastatic or locally advanced breast cancer. Specifically, the disclosure relates to a combination therapy which comprises an antibody that binds to a Programmed Death 1 protein (PD-1) or an antigen binding fragment thereof, and an immunoconjugate.BACKGROUND OF THE DISCLOSURE

[0004] HR+ / HER2- metastatic or locally advanced breast cancer remains the most commonly diagnosed cancer among women globally, accounting for approximately 30% of all new cancer diagnoses in women annually. Predictions for 2023 estimate 297,790 new invasive HR+ / HER2- metastatic or locally advanced breast cancer cases, 55,720 new cases of ductal carcinoma in situ (DCIS), and an expected 43,700 HR+ / HER2- metastatic or locally advanced breast cancer- related deaths. These statistics underlie the ongoing efforts to evolve and refine HR+ / HER2- metastatic or locally advanced breast cancer treatment strategies.

[0005] Immune checkpoint therapies targeting the PD-1 axis have resulted in groundbreaking improvements in clinical response in multiple human cancers. Immune therapies targeting the PD-1 axis include monoclonal antibodies directed to the PD-1 receptor (KEYTRUDA™ (pembrolizumab), Merck and Co., Inc., Kenilworth, NJ. USA and OPDIVO™ (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ, USA) and also those that bind to the PD-L1 ligand (MPDL3280A; TECENTRIQ™ (atezolizumab), Genentech, San Francisco, CA, USA). Both therapeutic approaches have demonstrated anti-tumor effects in numerous cancer types.

[0006] It has been proposed that the efficacy of such antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are disregulated in tumors, and other immune enhancing agents.

[0007] Trophoblast cell surface antigen 2 (Trop-2) is a transmembrane glycoprotein involved in calcium signal transduction, and is expressed in multiple tumor types. Trop-2 is expressed in normal trophoblasts and allows for trophoblast cell grow th, migration, and proliferation. Trop-2 has been implicated in several cell signaling pathways, including intracellular calcium transduction, MAPK. signaling pathway. RAF, NF-KB, and Cyclin D / E among others.

[0008] It has been shown that Trop-2 is upregulated in cancer cells when compared to normal cell counterparts. This increased expression has been seen in many different tumor types including HR+ / HER2- metastatic or locally advanced breast cancer, colon cancer, HR+ / HER2- metastatic or locally advanced breast cancer, esophageal squamous cell cancer, thyroid cancer, and hepatobiliary cancers, raising the possibility of Trop-2 as a tumor agnostic biomarker. The reason for Trop-2 upregulation in cancer cells is unclear; how ever it is postulated that Trop-2 has critical regulatory effects on cellular proliferation and invasion, meaning that overexpression would lead to selective tumor progression. In fact, preclinical data suggests that Trop-2 overexpression stimulates tumor growth while Trop-2 knock-down inhibits tumor growth.

[0009] The success of targeting Trop-2 via antibody-drug conjugates (ADCs) in HR+ / HER2- metastatic or locally advanced breast cancer (MBC), and urothelial cancer and ongoing trials in HR+ / HER2- metastatic or locally advanced breast cancer have established Trop-2 targeting as a valid and fruitful strategy’, and several Trop-2 -targeted therapeutics have recently been developed for clinical use, such as anti-Trop-2 antibodies and Trop-2-targeted ADCs. Subsequently, multiple early-phase clinical trials have demonstrated good safety’ profiles, and clinical benefit associated with Trop-2-based ADCs across multiple tumor types. This includes clinical benefit, and tolerability in tumor types with limited treatment options, such as triple-negative HR+ / HER2- metastatic or locally advanced breast cancer, platinum-resistant urothelial cancer, and small-cell lung cancer. Examples of immunoconjugates that are currently in early phase clinical trials include those described in US Patent Publication No. 20200347075.

[0010] Given the promising results shown by both anti -human PD-1 antibodies, and immunoconjugates as monotherapy for the treatment of cancer, the combination of these therapeutic agents with their differing mechanisms of action, and non-overlapping toxicities, has the potential to provide more significant and prolonged responses in the treatment of breast cancer.SUMMARY OF THE PRESENT DISCLOSURE

[0011] In a first aspect, the present disclosure provides a method of treating HR+ / HER2- metastatic or locally advanced breast cancer in a human patient, said method comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof; and(b) an amount of an Immunoconjugate of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10, and wherein the amounts of (a) and (b) administered are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

[0012] In embodiment no. 1 of this method, the HR+ / HER2- metastatic or locally advanced breast cancer is unresectable.

[0013] In embodiment no. 2 of this method, the HR+ / HER2- metastatic or locally advanced breast cancer has been previously treated.

[0014] In embodiment no. 3 of this method, the HR+ / HER2- metastatic or locally advanced breast cancer has been previously treated with CDK4 / 6i therapy.

[0015] In embodiment no. 4 of this method, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0016] In embodiment no. 5 of this method, the patient is administered 4.0 mg / kg of Immunoconjugate A every 2 weeks.

[0017] In embodiment no. 6 of this method, the anti -human PD-1 antibody or antigen binding is pembrolizumab.

[0018] In embodiment no. 7 of this method, the patient is administered 400 mg of pembrolizumab every 6 weeks.

[0019] In embodiment no. 8 of this method, the patient is administered 400 mg of the antihuman PD-1 antibody or antigen binding fragment thereof, and 4 mg / kg of Immunoconjugate A, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is administered once every six weeks and Immunoconjugate A is administered once every 2 weeks. For instance, the human patient is administered 400 mg of the anti -human PD-1 antibody or antigen binding fragment thereof on day 1 of a 6-week cycle, and 4 mg / kg of Immunoconjugate A on days 1, 15, and 29 of a 6-week cycle.

[0020] In embodiment no. 9 of this method, a human patient is administered 400 mg of pembrolizumab on day 1 of a 6-week cycle, and 4 mg / kg of Immunoconjugate A on days 1, 15, and 29. of a 6-week cycle.

[0021] In a second aspect, the present disclosure provides a kit comprising:(a) an Immunoconjugate of Formula (I); and(b) an anti -human PD-1 antibody or antigen binding fragment thereof.

[0022] In one embodiment of this second aspect, the kit further comprises instructions for administering the Immunoconjugate of Formula (I), and the anti-human PD-1 antibody or antigen binding fragment thereof to a human patient.

[0023] In a third aspect, the present disclosure provides a therapeutic combination, comprising:(a) an Immunoconjugate of Formula (I); and(b) an anti-human PD-1 antibody or antigen binding fragment thereof for treating HR+ / HER2- metastatic or locally advanced breast cancer, in a human patient.

[0024] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof comprises three light chain CDRs of SEQ ID NO: 1, SEQ ID NO:2 and SEQ ID NO:3 and three heavy chain CDRs of SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.

[0025] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof comprises a VL region which comprises the amino acid sequence set forth in SEQ ID NO:4, and a VH region which comprises the amino acid sequence set forth in SEQ ID NO:9.

[0026] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof comprises a light chain comprising or consisting ofa sequence of amino acids as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acids as set forth in SEQ ID NO: 10.

[0027] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

[0028] In certain embodiments of the first, second, or third aspects, the anti-human PD-1 antibody or antigen binding fragment thereof is nivolumab.

[0029] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof is cemiplimab.

[0030] In certain embodiments of the first, second, or third aspects, the anti -human PD-1 antibody or antigen binding fragment thereof is dostarlimab.DETAILED DESCRIPTION OF THE PRESENT DISCLOSUREDEFINITIONS AND ABBREVIATIONS

[0031] Listed below are definitions of various terms used herein. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

[0033] As used herein, the articles “a” and “an” refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element" means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include,” “includes,” and “included,” is not limiting.

[0034] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0035] An “antibody-drug conjugate,” or “ADC,” or “immunoconjugate,” refers to an antibody molecule or an antigen-binding fragment thereof that is covalently or non-covalently bonded, with or without a linker, to one or more biologically active molecule(s). The term “antibody” is used herein in the broadest sense and includes polyclonal and monoclonal antibodies, such as intact antibodies and functional (antigen-binding) fragments thereof. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, andheteroconjugate antibodies, multi-specific (e.g. bispecific) antibodies, diabodies, tnabodies. and tetrabodies, tandem di-scFv, and tandem tri-scFv.

[0036] As used herein, the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.

[0037] The term “administration” or “administer” refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., an anti-PD-1 antibody) into a patient, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery', and / or any other methods of physical delivery described herein or known in the art.

[0038] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment” refers to a fragment of an antibody that retains the ability' to bind specifically to the antigen, e.g., fragments that retain one or more CDR regions and the ability' to bind specifically to the antigen. An antibody that “specifically binds to” PD-1 is an antibody that exhibits preferential binding to PD-1 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity. An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives. Antibodies, or binding fragments thereof, will bind to the target protein with an affinity' that is at least tw o-fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.

[0039] Antigen binding portions include, for example, Fab, Fab’, F(ab’)2, Fd, Fv, fragments including CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the antigen (e.g., PD-1). Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2. The heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three- dimensional configurations of different classes of immunoglobulins are w ell know n. An antigenbinding fragment of a full-length antibody may be used in making an immunoconjugate of the present disclosure. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; recombinant IgG (rlgG) fragments; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv or sFv); single domain antibodies (e.g., sdAb, sdFv, nanobodies); and multi-specific antibodies formed from antibody fragments. In certain embodiments, thefragments are single-chain antibody fragments comprising a variable heavy chain region and / or a variable light chain region, such as scFvs.

[0040] An "antigen" is a structure to which an antibody can selectively bind. A target antigen may be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In certain embodiments, an antigen is associated with a cell, for example, is present on or in a cell, for example, a cancer cell.

[0041] ‘‘Advanced solid tumor malignancy” and “advanced solid tumor” are used interchangeably to refer to a tumor for which curative resection is not possible. Advanced solid tumors include, but are not limited to, metastatic tumors in bone, brain, breast, liver, lungs, lymph node, pancreas, prostate, and soft tissue (sarcoma).

[0042] As used herein, the term “antibody” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to. monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic. As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.

[0043] In general, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy’ chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavychain also including a "D" region of about 10 more amino acids. See generally. Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0044] “Biotherapeutic agent” means a biological molecule, such as an antibody or fusion protein, that blocks ligand / receptor signaling in any biological pathway that supports tumor maintenance and / or growth or suppresses the anti-tumor immune response.The term “carrier,” as used herein, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in earn ing or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a patient.

[0045] As used herein, the term “comprising” may include the embodiments “consisting of’ and “consisting essentially of.” The terms “comprise(s),” “include(s),” “having,” “has,” “may,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that require the presence of the named ingredients / steps and permit the presence of other ingredients / steps. However, such description should be construed as also describing compositions or processes as “consisting of’ and “consisting essentially of’ the enumerated components, which allows the presence of only the named components or compounds, along with any acceptable carriers or fluids, and excludes other components or compounds.

[0046] As used herein, the term “Cl DI” refers to the timing of administration of: (i) an Immunoconjugate of formula (I) and / or (ii) a Programmed Death 1 protein (PD-1) or an antigen binding fragment thereof. Specifically, the term “C1D1” refers to administration on day 1 of chemotherapy cycle 1, the term “C1D15” refers to administration on day 15 of chemotherapy cycle 1, and the term “C1D57” refers to administration on day 57 of chemotherapy cycle 1.

[0047] A “CDR” refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH P-sheet framework, or one of three hypervariable regions (LI, L2, or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly. CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable domains. CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved p -sheet framework, and thus are able to adapt to different conformations. Both terminologies are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (Al-Lazikani et al.. 1997. J. Mol. Biol. 273:927-48; Morea el al., 2000, Methods 20:267-79). 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 region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is similarly well known to those skilled in the art. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art and shown below7in Table 1. In some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In yet other embodiments, the CDRs are as defined by the AbM numbering system. In still other embodiments, the CDRs are as defined by the Chothia numbering system. In yet other embodiments, the CDRs are as defined by the Contact numbering system.Table 1. Correspondence between the CDR Numbering Systems

[0048] “Chemotherapeutic agent” is a chemical compound useful in the treatment of cancer. Classes of chemotherapeutic agents include, but are not limited to: alkylating agents (including platinum-containing chemotherapeutic agents), antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytoxic / antitumor antibiotics, topoisomerase inhibitors, photosensitizers, antiestrogens and selective estrogen receptor modulators (SERMs), anti-progesterones, estrogen receptor down-regulators (ERDs), estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, and anti-sense oligonucleotides that inhibit expression of genes implicated in abnormal cell proliferation or tumor growth. Chemotherapeutic agents useful in the treatment methods of the present disclosure include cytostatic and / or cytotoxic agents.

[0049] “Chimeric antibody” refers to an antibody in which a portion of the heavy and / or light chain contains sequences derived from a particular species (e.g.. human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from anotherspecies (e.g.. mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.

[0050] As used herein, the terms “combination therapy” and “therapeutic combination” refer to treatments in which at least one anti -human PD-1 antibody (or antigen-binding fragment thereof) and Immunoconjugate of Formula (I), and optionally additional therapeutic agents, each are administered to a patient in a coordinated manner, over an overlapping period of time. The period of treatment with the at least one anti -human PD-1 antibody (or antigen-binding fragment thereof) (the “anti-PD-1 treatment”) is the period of time that a patient undergoes treatment with the anti-human PD-1 antibody (or antigen-binding fragment thereof); that is, the period of time from the initial dosing with the anti -human PD-1 antibody (or antigen-binding fragment thereof) through the final day of a treatment cycle. Similarly, the period of treatment with the Immunoconjugate of Formula (I) (the “Immunoconjugate of Formula (I) treatment”) is the period of time that a patient undergoes treatment with the Immunoconjugate of Formula (I); that is, the period of time from the initial dosing with the Immunoconjugate of Formula (I) through the final day of a treatment cycle. In the methods and therapeutic combinations described herein, the anti-PD-1 treatment overlaps by at least one day the Immunoconjugate of Formula (I) treatment. In certain embodiments, the anti-PD-1 treatment and the Immunoconjugate of Formula (I) treatment are coextensive. In embodiments, the anti-PD-1 treatment begins prior to the Immunoconjugate of Formula (I) treatment. In embodiments, the Immunoconjugate of Formula (I) treatment begins prior to the anti-PD-1 treatment. In embodiments, the anti-PD-1 treatment is terminated prior to termination of Immunoconjugate of Formula (I) treatment. In embodiments, the Immunoconjugate of Formula (I) treatment is terminated prior to termination of the anti-PD-1 treatment.

[0051] “Conservatively modified variants” or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and / or specificity. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 2 below .Table 2. Exemplary Conservative Amino Acid SubstitutionsThe term “DAR” or “Drug Antibody Ratio,” as used herein, refers to the average number of linker / drug moieties attached to an antibody in a composition comprising more than one Antibody-Drug Conjugate molecule, wherein DAR is represented as a real number from 0 to 10. Accordingly, in one embodiment, for an Antibody -Drug Conjugate of the present disclosure, the DAR is an integer from 0 to 10, 0 to 9, 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, and from 0 to 1. In additional embodiments, for an Antibody-Drug Conjugate of the present disclosure, the DAR is an integer from 1 to 8, 1 to 4, 2 to 5, 3 to 6, 4 to 7, 5 to 8, and 6 to 8. In other embodiments, for an Antibody-Drug Conjugates of the present disclosure, the DAR is an integer from 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, and 6 to 8. In further embodiments, for an Antibody -Drug Conjugate of the present disclosure, the DAR is an integer from 1 to 2, 2 to 3, 3 to 4, 4 to 5. 5 to 6, 6 to 7, and 7 to 8. Likewise, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR for the composition is an average of the DAR for all of the Antibody-Drug Conjugate molecules present in said composition. As such, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 0 to 8, from 0 to 7, from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, and from 0 to 1. In additional embodiments, for a composition comprising an Antibody-Drug Conjugate of the present disclosure, the DAR of thecomposition is a decimal from 1 to 4, 2 to 5. 3 to 6, 4 to 7, 5 to 8. and 6 to 8. In other embodiments, for a composition comprising an Antibody -Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, and 6 to 8. In further embodiments, for a composition comprising an Antibody -Drug Conjugate of the present disclosure, the DAR of the composition is a decimal from 1 to 2, 2 to 3, 3 to 4. 4 to 5, 5 to 6, 6 to 7, and 7 to 8. The term “composition” as used above, is understood to encompass pharmaceutical compositions.

[0052] As used herein, the term HR+ / HER2- metastatic or locally advanced breast cancer” meansbreast cancer which is: (a) HR+ / HER2- and metastatic, or (b) HR+ / HER2- breast cancer which is locally advanced.

[0053] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral route or parenteral route of administration. The term “enteral route” of administration refers to the administration via any part of the gastrointestinal tract. Examples of enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route. “Parenteral route” of administration refers to a route of administration other than enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal. epidural and intrastemal, subcutaneous, or topical administration. The therapeutic agents and compositions of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. A suitable route and method of administration may vary depending on a number of factors such as the specific therapeutic agent being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the patient, and can be readily selected by a person skilled in the art.

[0054] “Homology” refers to sequence similarity between two polypeptide sequences when they are optimally aligned. When a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, <?.g., if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position. The percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared * 100. For example, if 8 of 10 of the positions in two sequences are matched when the sequences are optimally aligned then the two sequences are 80% homologous. Generally, the comparison is made when two sequences are aligned to givemaximum percent homology. For example, the comparison can be performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.

[0055] The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W„ et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17: 149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., “A model of evolutionary change in proteins.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.), pp. 345-352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., “Matrices for detecting distant relationships.” in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.” M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul, S.F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S„ et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S„ et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob.22:2022-2039; and Altschul, S.F. “Evaluating the statistical significance of multiple distinct local alignments.” in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York.

[0056] “Human antibody” refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof. A human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” or “rat antibody” refer to an antibody that comprises only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.

[0057] “Humanized antibody” refers to forms of antibodies that contain sequences from nonhuman (e.g, murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The prefix “hum”, “hu” or “h”may be added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies. The humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.

[0058] An "intact" antibody is one comprising an antigen-binding site as well as a CL and at least heavy chain constant regions, CHI, CH2 and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In certain embodiments, an intact antibody has one or more effector functions.

[0059] As used herein, the term ‘'immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and nonspecific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.

[0060] As used herein, the term ‘'immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cellular proliferation, immune cell differentiation, and cytokine expression.

[0061] The term “isolated” as used in reference to an antibody or fragment thereof refers to the purification status and, in such context, means the named molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

[0062] “Kabat” as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Sendee, National Institutes of Health, Bethesda, Md.).

[0063] “Monoclonal antibody” or “mAb” or “Mab”. as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variabledomains, particularly their CDRs, which are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 1 16:731.

[0064] “PD-1 antagonist” means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1 ; PDCD1L1, PDT1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2. In any of the treatment methods, compositons. and uses of the present disclosure in which a human individual is being treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1. Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.

[0065] “Pembrolizumab” (formerly known as MK-3475, SCH 900475 and lambrolizumab) is a humanized lgG4 mAb with the structure described in WHO Drug Information. Vol. 27, No. 2. pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences and CDRs described in Table 3. 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 February 2023). The term pembrolizumab includes mAb’s having a structure as described above (Id.) but which do not include the C-terminal lysine in the heavy chain.

[0066] “Pembrolizumab variant” as used herein means a monoclonal antibody that comprises heavy chain and light chain sequences that are identical to those in pembrolizumab, except for having three, two or one conservative amino acid substitutions at positions that are located outside of the light chain CDRs and six, five, four, three, two or one conservative amino acidsubstitutions that are located outside of the heavy chain CDRs, e.g, the variant positions are located in the framework regions or the constant region, and optionally has a deletion of the C- terminal lysine residues of the heavy chain. In other words, pembrolizumab and a pembrolizumab variant comprise identical CDR sequences, but differ from each other due to having a conservative amino acid substitution at no more than three or six other positions in their full length light and heavy chain sequences, respectively. A pembrolizumab variant is substantially the same as pembrolizumab with respect to the following properties: binding affinity to PD-1 and ability to block the binding of each of PD-L1 and PD-L2 to PD-1.

[0067] "‘Platinum-containing chemotherapy” (also known as platins) refers to the use of chemotherapeutic agent(s) used to treat cancer that are coordination complexes of platinum. Platinum-containing chemotherapeutic agents are alkylating agents that crosslink DNA, resulting in ineffective DNA mismatch repair and generally leading to apoptosis. Examples of platins include cisplatin, carboplatin, and oxaliplatin.

[0068] The term “patient” (alternatively “subject”) as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g., pigs), ovine (e.g., sheep), capra (e.g., goats), equine (e.g., horses), canine (e.g, domestic dogs), feline (e.g, house cats). Lagomorpha (rabbits), rodents (e.g. rats or mice), Procyon lotor (e.g., raccoons). In particular embodiments, the patient is human.

[0069] The term “patient in need thereof’ as used herein refers to a patient diagnosed with, or suspected of having, HR+ / HER2- metastatic or locally advanced breast cancer, as defined herein.

[0070] The term “pharmaceutically acceptable carrier” refers to any inactive substance that is suitable for use in a formulation for the delivery of a therapeutic agent. A carrier may be an antiadherent, binder, coating, disintegrant, filler or diluent, preservative (such as antioxidant, antibacterial, or antifungal agent), sweetener, absorption delaying agent, wetting agent, emulsifying agent, buffer, and the like. Examples of suitable pharmaceutically acceptable carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), dextrose, vegetable oils (such as olive oil), saline, buffer, buffered saline, and isotonic agents such as sugars, polyalcohols, sorbitol, and sodium chloride.

[0071] The term “pharmaceutically acceptable salt” refers to a salt (including an inner salt such as a zwitterion) that possesses effectiveness similar to the parent compound and that is not biologically or otherwise undesirable (e.g., is neither toxic nor otherwise deleterious to the recipient thereof). Thus, an embodiment of the present disclosure provides pharmaceutically acceptable salts of the compounds of the present disclosure. The term “salt(s)”, as employedherein, denotes any of the following: acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. Salts of compounds of the present disclosure may be formed by methods known to those of ordinary' skill in the art, for example, by reacting a compound of the present disclosure with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0072] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates C’mesylates”), naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like. Suitable salts include acid addition salts that may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid. Additionally, acids that are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.), Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley- VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al.. The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book foo & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

[0073] Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, / -butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogencontaining groups may be quartemized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others. Compounds carry ing an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts. Also, in the case of an acid (-COOH) or alcohol group being present,pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.

[0074] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the present disclosure and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the present disclosure.

[0075] In addition, when a compound of the present disclosure contains both a basic moiety, such as, but not limited to an aliphatic primary, secondary, tertiary or cyclic amine, an aromatic or heteroaryl amine, pyridine or imidazole, and an acidic moiety, such as, but not limited to tetrazole or carboxylic acid, zwitterions ( "inner salts”) may be formed and are included within the terms “salt(s)” as used herein. It is understood that certain compounds of the present disclosure may exist in zwitterionic form, having both anionic and cationic centers within the same compound and a net neutral charge. Such zwitterions are included within the present disclosure.

[0076] "RECIST 1. 1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.

[0077] ‘‘Responder patient” when referring to a specific anti-tumor response to a treatment described herein, means the patient exhibited an anti-tumor response.

[0078] “Sustained response” means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.

[0079] The term “simultaneous administration” as used herein in relation to the administration of medicaments refers to the administration of medicaments such that the individual medicaments are present within a patient at the same time. In addition to the concomitant administration of medicaments (via the same or alternative routes), simultaneous administration may include the administration of the medicaments (via the same or an alternative route) at different times.

[0080] “Sustained response” means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.

[0081] “Treat” or “Treating” HR+ / HER2- metastatic or locally advanced breast cancer as used herein means to administer a combination therapy of an anti -human PD-1 antibody (or antigenbinding fragment thereof) and an Immunoconjugate of Formula (1) to a patient having HR+ / HER2- metastatic or locally advanced breast cancer, or diagnosed with HR+ / HER2- metastatic or locally advanced breast cancer, to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced tumor burden, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth, comprising administration by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other methods of physical delivery described herein or known in the art. Typically, the agent(s) of the treatment method are administered in an amount effective to alleviate one or more disease symptoms in the treated patient or population, whether by inducing the regression of or inhibiting the progression of such symptom(s) by any clinically measurable degree. The amount of the agent(s) of the treatment method that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapeutic combination to elicit a desired response in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. “Treatment” may include one or more of the following: inducing / increasing an antitumor immune response, decreasing the number of one or more tumor markers, halting or delaying the growth of a tumor or blood cancer or progression of disease such as cancer, stabilization of disease, inhibiting the growth or survival of tumor cells, eliminating or reducing the size of one or more cancerous lesions or tumors, decreasing the level of one or more tumor markers, ameliorating or abrogating the clinical manifestations of disease, reducing the severity or duration of the clinical symptoms, prolonging the survival of the treated patient relative to the expected survival in a similar untreated patient, and inducing complete or partial remission of a cancerous condition, wherein the disease is cancer, more specifically, HR+ / HER2- metastatic or locally advanced breast cancer.

[0082] The amount of a therapeutic agent that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired response in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity' or progression status of that symptom.

[0083] Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50: IS- IOS (2009)). For example, with respect to tumor growth inhibition, according to NCI standards, a T / C 42% is the minimum level of anti-tumor activity. A T / C <10% is considered a high anti-tumor activity- level, with T / C (%) = Median tumor volume of the treated / Median tumor volume of the control x 100. In some embodiments, the treatment achieved by a therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients. In some embodiments, response to a therapy of the disclosure is any of PR. CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria. The treatment regimen for a therapy of the disclosure that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the patient. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every patient, it should do so in a statistically significant number of patients as determined by any statistical test known in the art such as the Student’s t-test, the chi2- test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere- Terpstra-test and the Wilcoxon-test.

[0084] The terms “treatment regimen”, “dosing protocol”, and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.

[0085] “Tumor” as it applies to a patient diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

[0086] “Tumor burden” also referred to as “tumor load”, refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of tumor(s), throughout the body, including lymph nodes and bone narrow. Tumor burden can be determined by a variety of methods known in the art. such as, e.g.. by measuring the dimensions of tumor(s) upon removal from the patient, e.g., using calipers, or while in the body using imaging techniques, e.g., ultrasound, bone scan, computed tomography(CT) or magnetic resonance imaging (MRI) scans.

[0087] The term "tumor size7’ refers to the total size of the tumor which can be measured as the length and width of a tumor. Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the patient, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.

[0088] “Variable regions” as used herein means the segment of IgG chains which is variable in sequence betw een different antibodies. A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as “VH.” The variable region of the light chain may be referred to as “VL.”

[0089] Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity7determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C- terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. As referred to herein the light chain CDRs are CDRL1, CDRL2 and CDRL3, respectively, and the heavy chain CDRs are CDRH1, CDRH2 and CDRH3, respectively. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901- 917 or Chothia, et al., (1989) Nature 342:878-883.

[0090] The term “variant” when used in relation to an antibody (e.g., an anti-PD-1 antibody, or an anti-TROP2 antibody) or an amino acid region within the antibody may refer to a peptide or polypeptide comprising one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10. or about 1 to about 5) amino acid sequence substitutions, deletions, and / or additions as compared to a native or unmodified sequence. For example, a variant of an anti-PD-1 antibody may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native or previously unmodified anti-PD-1 antibody. Variants may be naturally occurring or may be artificially constructed. Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants. In specific embodiments, an antibody variant (e.g., an anti-PD-1 antibody variant) at least retainsthe antibody functional activity. In some embodiments, an anti-PD-1 antibody variant binds to PD-1 and / or is antagonistic to PD-1 activity.

[0091] Where aspects or embodiments of the disclosure are described in terms of a Markush group or other grouping of alternatives, the present disclosure encompasses not only the entire group listed as a whole, but each member of the group individually and all possible subgroups of the main group, but also the main group absent one or more of the group members. The present disclosure also envisages the explicit exclusion of one or more of any of the group members in the claims.

[0092] All ranges disclosed herein are inclusive of the recited endpoint and independently combinable (for example, the range of “from 50 mg to 500 mg’’ is inclusive of the endpoints, 50 mg and 500 mg, and all the intermediate values). The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value; they are sufficiently imprecise to include values approximating these ranges and / or values.

[0093] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word “comprise,’’ or variations such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the term “e.g.” or “for example” is not meant to be exhaustive or limiting.

[0094] Exemplary methods and materials are described herein, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0095] The following Abbreviations are used herein, and are defined as follows:ADC Antibody-Drug ConjugateAE Adverse EffectAIDS Acquired immunodeficiency syndromeALT Alanine transaminaseAPaT All patients as treated populationART Antiretroviral therapyASCO American Society of Clinical OncologyAST Aspartate aminotransferaseBID Twice dailyBICR Blinded independent central reviewBRCA Breast cancer geneCDK4 / 61 Cyclin-dependent kinases 4 and 6 inhibitor CI Confidence interval COPD Chronic obstructive pulmonary disease COVID Coronavirus disease CPS Central pain syndrome CR Complete response CRF Chronic renal failure CSR Central serous retinopathy CT Computerized tomography CTCAE Common terminology criteria for adverse effects CYP3A4 Cytochrome P450 3A4 DCR Disease control rate DOR Duration of Response ECHO Echocardiogram ECOG Eastern Cooperative Oncology Group ECG Electrocardiogram eDMC Executive data monitoring committee EGFR Epidermal growth factor receptor EORTC European Organization for Research and Treatment of Cancer EOT End of Treatment ESRI Estrogen receptor gene 1 G-CSF Granulocyte Colony Stimulating Factor HBsAg Hepatitis B surface antigen HBV Hepatitis B virus HCV Hepatitis C virus HER2 Human epidermal growth factor-2 HIV Human immunodeficiency virus HR+ Hormone receptor positive HRQoL Health-related quality -of-life scale ICH International conference on harmonization iCRO Imaging Contract Research Organization IRT Interactive response technology ITT Intention to treat LLOQ Lower limit of quantification LVEF Left ventricular ejection fraction mAb Monoclonal antibody MBC Metastatic breast cancer MPK or mpk Milligram per kilogram MRI Magnetic resonance imaging mTOR Mammalian target of rapamycin MUGA Multigated acquisition scan NCI National Cancer Institute NSAID Non-steroidal anti-inflammatory drug OR Overall response ORR Overall response rate OS Overall survival PARP Poly (ADP-ribose) polymerase PD-1 Programmed cell death protein 1PD-L1 Programmed death ligand 1 PET Postiron Emission TomographyPFS Progression free survivalPI3K Phosphoinositide 3 -kinasePOCBP Persons of childbearing potentialPR Partial responsePSA Prostate specific antigen q2w Once every' 2 weeksQoL Quality of LifeQRS QRS complexQT QT intervalQTc QTc intervalQTcF QT interval corrected for heart rateRECIST Response Evaluation Criteria in Solid TumorsSAE Serious adverse effectSAP Statistical analysis planSARS Severe acute respiratory systemSCF Stem cell factorTPC Therapy of Physician’s choiceTROP-2 Tumor-associated calcium signal transducer 2ULN Upper limit of normalVH immunoglobulin heavy chain variable regionVL immunoglobulin light chain variable region

[0096] Additional abbreviations may be defined throughout this disclosure.

[0097] The present disclosure relates to a therapeutic combinations, wherein the therapeutic combinations comprise: (a) an anti -human PD-1 antibody (or antigen-binding fragment thereof); and (b) an Immunoconjugate of Formula (I).

[0098] The present disclosure relates to methods of treating HR+ / HER2- metastatic or locally advanced breast cancer, wherein the method comprises administering to a human patient in need thereof a combination therapy that comprises (a) an anti-human PD-1 antibody (or antigenbinding fragment thereof); and (b) an Immunoconjugate of Formula (I).

[0099] In some embodiments of the methods and the therapeutic combination, the anti-human PD-1 antibody is pembrolizumab and the Immunoconjugate of Formula (I) is the compound ofFormula I. In some embodiments, the Immunoconjugate of Formula I has the structure:wherein n is an integer from 1 to 8; and Ab is sacituzumab.PD-1 antagonists or anti-human PD-1 monoclonal antibodies useful in the present disclosure

[0100] Examples of mAbs that bind to human PD-1, useful in the methods, compositions, kits, and uses of the present disclosure, are described in US 7,521.051, US 8,008,449. and US 8,354,509. Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in the methods, compositions, kits, and uses of the present disclosure include: pembrolizumab (formerly know n as MK-3475. SCH 900475 and lambrolizumab), a humanized IgG4 mAh with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161-162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Table 3, and the humanized antibodies h409Al l, h409A16 and h409A17, which are described in WO 2008 / 156712.

[0101] Additional examples of PD-1 antagonists useful in the methods, compositions, kits, and uses of the present disclosure include, but are not limited to: nivolumab (OPDIVO®. Bristol- Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO®, Regeneron Pharmaceuticals, Inc., Tarrytown, NY and Sanofi-Aventis U.S. EEC., Bridgewater, NJ) and dostarlimab (JEMPERLI®, GlaxoSmithKline LLC, Philadelphia, PA).

[0102] Provided herein are PD-1 antagonists or anti -human PD-1 monoclonal antibodies that can be used in any of the methods, compositions, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks binding of PD-L1 to PD-1 and preferably also blocks binding of PD-L2 to PD-1.

[0103] Any monoclonal antibodies that bind to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and block the interaction between PD-1 and its ligand PD-L1 or PD-L2 can be used. In some embodiments, the anti-human PD-1 monoclonalantibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1. In other embodiments, the antihuman PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L2. In yet other embodiments, the anti -human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.

[0104] In certain embodiments, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab. nivolumab, cemiplimab, dostarlimab, pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD), PDR001 (U.S. Pat. No.9,683,048), tislehzumab BGB-A317 (U.S. Pat. No. 8,735,553), and INCMGA00012 or MGA012 (MacroGenics, Rockville, MD). In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab. In one embodiment, the anti -human PD-1 monoclonal antibody is pembrolizumab. In another embodiment, the anti -human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti -human PD-1 monoclonal antibody is cemiplimab. In yet another embodiment, the anti -human PD-1 monoclonal antibody is pidilizumab. In one embodiment, the anti -human PD-1 monoclonal antibody is AMP-514. In another embodiment, the anti-human PD-1 monoclonal antibody is PDR001. In yet another embodiment, the antihuman PD-1 monoclonal antibody is BGB-A317. In still another embodiment, the anti -human PD-1 monoclonal antibody is MGA012.

[0105] In some embodiments, an anti -human PD-1 antibody or antigen binding fragment thereof for use in the methods and uses disclosed herein comprises three light chain CDRs of CDRL1, CDRL2 and CDRL3 and / or three heavy chain CDRs of CDRH1, CDRH2 and CDRH3.

[0106] In one embodiment, CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 1 or a variant of the amino acid sequence as set forth in SEQ ID NO: 1, CDRL2 has the amino acid sequence as set forth in SEQ ID NO:2 or a variant of the amino acid sequence as set forth in SEQ ID NO:2. and CDRL3 has the amino acid sequence as set forth in SEQ ID NO:3 or a variant of the amino acid sequence as set forth in SEQ ID NO: 3.

[0107] In one embodiment of the anti-human PD-1 antibody or antigen binding fragment thereof, CDRH1 has the amino acid sequence as set forth in SEQ ID NO:6 or a variant of the amino acid sequence as set forth in SEQ ID NO: 6, CDRH2 has the amino acid sequence as set forth in SEQ ID NO:7 or a variant of the amino acid sequence as set forth in SEQ ID NO:7, and CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 8 or a variant of the amino acid sequence as set forth in SEQ ID NO: 8.

[0108] In one embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 1, SEQ ID NO:2, and SEQ ID NO:3 and the three heavy’ chain CDRs have the amino acid sequences as set forth in SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.

[0109] In an alternative embodiment of the anti-human PD-1 antibody or antigen binding fragment thereof, CDRL1 has the amino acid sequence as set forth in SEQ ID NO: 11 or a variant of the amino acid sequence as set forth in SEQ ID NO: 11, CDRL2 has the amino acid sequence as set forth in SEQ ID NO: 12 or a variant of the amino acid sequence as set forth in SEQ ID NO: 12. and CDRL3 has the amino acid sequence as set forth in SEQ ID NO: 13 or a variant of the amino acid sequence as set forth in SEQ ID NO: 13.

[0110] In one embodiment of the anti -human PD- 1 antibody or antigen binding fragment thereof, CDRH1 has the amino acid sequence as set forth in SEQ ID NO: 16 or a variant of the amino acid sequence as set forth in SEQ ID NO: 16, CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 17 or a variant of the amino acid sequence as set forth in SEQ ID NO: 17. and CDRH3 has the amino acid sequence as set forth in SEQ ID NO: 18 or a variant of the amino acid sequence as set forth in SEQ ID NO: 18.[OHl] In an alternative embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18.

[0112] In a further embodiment, CDRL1 has the amino acid sequence as set forth in SEQ ID NO:21 or a variant of the amino acid sequence as set forth in SEQ ID NO:21, CDRL2 has the amino acid sequence as set forth in SEQ ID NO:22 or a variant of the amino acid sequence as set forth in SEQ ID NO:22, and CDRL3 has the amino acid sequence as set forth in SEQ ID NO:23 or a variant of the amino acid sequence as set forth in SEQ ID NO:23.

[0113] In yet another embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, CDRH1 has the amino acid sequence as set forth in SEQ ID NO:24 or a variant of the amino acid sequence as set forth in SEQ ID NO:24, CDRH2 has the amino acid sequence as set forth in SEQ ID NO: 25 or a variant of the amino acid sequence as set forth in SEQ ID NO:25, and CDRH3 has the amino acid sequence as set forth in SEQ ID NO:26 or a variant of the amino acid sequence as set forth in SEQ ID NO:26.

[0114] In another embodiment of the anti -human PD-1 antibody or antigen binding fragment thereof, the three light chain CDRs have the amino acid sequences as set forth in SEQ ID NO:21,SEQ ID NO:22, and SEQ ID NO:23 and the three heavy chain CDRs have the amino acid sequences as set forth in SEQ ID NO:24, SEQ ID NO:25 and SEQ ID NO:26.

[0115] In a sub embodiment of the anti -human PD-1 embodiments above, the anti -human PD-1 antibody or antigen binding fragment is an antibody.

[0116] Some anti-human PD-1 antibody and antigen binding fragments disclosed herein comprise a light chain variable region and a heavy chain variable region. In some embodiments, the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:4 or a variant of the amino acid sequence as set forth in SEQ ID NO: 4, and the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 9 or a variant of the amino acid sequence as set forth in SEQ ID NO:9. In further embodiments, the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 14 or a variant of the amino acid sequence as set forth in SEQ ID NO: 14, and the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 19 or a variant of the amino acid sequence as set forth in SEQ ID NO: 19. In further embodiments, the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO: 27 or a variant of the amino acid sequence as set forth in SEQ ID NO:27 and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:28 or a variant of the amino acid sequence as set forth in SEQ ID NO:28, the amino acid sequence as set forth in SEQ ID NO:29 or a variant of the amino acid sequence as set forth in SEQ ID NO:29, or the amino acid sequence as set forth in SEQ ID NO:30 or a variant of the amino acid sequence as set forth in SEQ ID NO:30. In such embodiments, a light chain variable region or heavy chain variable region sequence is identical to the reference sequence except having one, two, three, four or five amino acid substitutions. In some embodiments, the substitutions are in the framework region (i.e.. outside of the CDRs). In some embodiments, one, two, three, four or five of the amino acid substitutions are conservative substitutions.

[0117] In one embodiment of the methods, kits or uses disclosed herein, the anti-human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:4 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 9. In a further embodiment, the anti -human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 14 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO: 19. In one embodiment of the compositions, methods, kits, and uses disclosed herein, the anti-human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth inSEQ ID NO:28 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27. In a further embodiment, the anti-human PD-1 antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:29 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27. In another embodiment, the antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:30 and a heavy chain variable region comprising or consisting of the amino acid sequence as set forth in SEQ ID NO:27.

[0118] In another embodiment, the methods, kits or uses disclosed herein comprise an antihuman PD-1 antibody or antigen binding protein that has a VL domain and / or a VH domain with at least 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VL domains or VH domains described above, and exhibits specific binding to PD-1. In another embodiment, the anti-human PD-1 antibody or antigen binding protein of the present method comprises VL and VH domains having up to 1, 2, 3, 4, or 5 or more amino acid substitutions, and exhibits specific binding to PD-1.

[0119] In any of the embodiments above, the PD-1 antagonist may be a full-length anti-PD-1 antibody or an antigen binding fragment thereof that specifically binds human PD-1. In certain embodiments, the PD-1 antagonist is a full-length anti-PD-1 antibody selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE. Preferably, the antibody is an IgG antibody. Any isotype of IgG can be used, including IgGi, IgG , IgG?. and IgG-i. Different constant domains may be appended to the VL and VH regions provided herein. For example, if a particular intended use of an antibody (or fragment) disclosed herein were to call for altered effector functions, a heavy chain constant domain other than IgGl may be used. Although IgGl antibodies provide for long half-life and for effector functions, such as complement activation and antibody -dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody. In such instances an IgG4 constant domain, for example, may be used.

[0120] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 10. In alternative embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain compnsing or consisting of a sequence of amino acid residues as set forth in SEQ ID NO: 15 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:20. In further embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of ammo acid residues as set forth in SEQ ID NO:32 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In additional embodiments, the PD-1 antagonist is an anti -PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:33 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In yet additional embodiments, the PD-1 antagonist is an anti-PD-1 antibody comprising a light chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:34 and a heavy chain comprising or consisting of a sequence of amino acid residues as set forth in SEQ ID NO:31. In some compositions, methods, kits, and uses disclosed herein, the PD-1 antagonist is pembrolizumab or a pembrolizumab biosimilar. In some compositions, methods, kits, and uses disclosed herein, the PD-1 antagonist is nivolumab or a nivolumab biosimilar. In one such embodiment, the agent is pembrolizumab. In another such embodiment, the agent is nivolumab. In another such embodiment, the agent is cemiplimab. In another such embodiment, the agent is dostarlimab.

[0121] Ordinarily, amino acid sequence variants of the anti-PD-1 antibodies and antigen binding fragments disclosed herein will have an amino acid sequence having at least 75% amino acid sequence identity with the amino acid sequence of a reference antibody or antigen binding fragment (e.g., heavy chain, light chain, VH, VL, or humanized sequence), more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95, 98, or 99%. Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the anti-PD-1 residues, 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. None of N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence shall be construed as affecting sequence identity or homology.

[0122] Sequence identity refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences. The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al., (1990) J. Mol. Biol. 215:403-410; Gish, W., et al., (1993) Nature Genet. 3:266-272; Madden, T.L., et al., (1996)Meth. Enzymol. 266: 131-141; Altschul. S.F., et al.. (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., "A model of evolutionary' change in proteins." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.). pp. 345- 352, Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., "Matrices for detecting distant relationships." in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3." M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S„ et al.. (1992) Proc. Natl. Acad. Sci. USA 89: 10915-10919; Altschul, S.F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S„ et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S„ et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S.F. "Evaluating the statistical significance of multiple distinct local alignments." in Theoretical and Computational Methods in Genome Research (S. Suhai, ed ), (1997) pp. 1-14, Plenum, New York.

[0123] Likewise, either class of light chain can be used in the compositions and methods herein. Specifically, kappa, lambda, or variants thereof are useful in the present compositions and compositions, methods, kits, and uses disclosed herein.Table 3. Exemplary PD-1 Antibody SequencesTable 4. Additional PD-1 Antibodies and Antigen Binding Fragments Useful in theMethods and Uses disclosed herein.

[0124] In embodiments of the compositions, methods, kits, and uses disclosed herein, the antihuman PD-1 antibody (or antigen-binding fragment thereof) is an anti-PD-1 monoclonal antibody. In particular aspects of these embodiments, the anti-human PD-1 antibody (or antigenbinding fragment thereof) is selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, and AMP -224. In specific aspects of these embodiments, the anti -human PD-1 antibody (or antigen-binding fragment thereof) is selected from nivolumab and pembrolizumab. In a more specific aspect, the anti -human PD-1 antibody (or antigen-binding fragment thereof) is nivolumab. In a further specific aspect, the anti -human PD-1 antibody (or antigen-binding fragment thereof) is pembrolizumab.

[0125] In embodiments of the compositions, methods, kits, and uses disclosed herein, the antihuman PD-1 antibody is pembrolizumab. In other such embodiments, the anti -human PD-1 antibody is nivolumab. In other such embodiments, the anti-human PD-1 antibody ispidilizumab. In other such embodiments, the anti -human PD-1 antibody is tislelizumab. In other such embodiments, the anti-human PD-1 antibody is AMP-514. In other such embodiments, the antihuman PD-1 antibody is cemiplimab. In other such embodiments, the anti-human PD-1 antibody is dostarlimab.The Immunoconjugate of Formula (I)

[0126] Immunoconjugates useful in the present disclosure are those immuoconjugates of Formula (I):wherein Ab is an antibody that binds to TROP-2; and and n is an integer from 1 to 10.

[0127] In a class of this embodiment, the Ab is linked via one or more thiol group(s) to form the conjugate.

[0128] In certain embodiments, immunoconjugates useful in the present disclosure are thoseImmuoconjugates of Formula (I):wherein n is an integer from 1 to 10; andAb is an antibody that binds to TROP-2 comprising:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the ammo acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0129] In certain embodiments, immunoconjugates useful in the present disclosure are those Immuoconjugates of Formula (I):wherein n is an integer from 1 to 10; andAb is an antibody that binds to TROP-2 comprising:(i) a heavy chain variable region having the amino acid sequence of SEQ ID No.: 37; and(ii) a light chain variable region having the amino acid sequence of SEQ ID No.:38.

[0130] In certain embodiments, immunoconjugates useful in the present disclosure are thoseImmuoconjugates of Formula (1):wherein n is integer from 1 to 10; andAb is an antibody that binds to TROP-2 comprising:(i) a heavy chain having the amino acid sequence of SEQ ID No. : 35; and(ii) a light chain having the amino acid sequence of SEQ ID No. :36.

[0131] In some preferred embodiment, the Immunoconjugate of Formula (I) is :wherein n is an integer 1 to 8; andAb is sacituzumab.

[0132] In other preferred embodiments, a composition comprising the Immunoconjugates of Formula (I) is administered wherein the Immunoconjugate of Formula (I) is:the average “n"’ of the composition is a decimal from 0 to 8; andAb is sacituzumab.

[0133] In additional preferred embodiments, the Immunoconjugate of Formula (I) is “BT001021,” which is described in US Patent No. 11,970,506, and referred to herein as “Immunoconjugate A.'’ US Patent No. 11,970,506 is incorporated by reference herein in its entirety.

[0134] In another embodiment of the present disclosure is a method of treating HR+ / HER2- metastatic or locally advanced breast cancer in a patient, said method comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof; and(b) an amount of an immunoconjugate comprising an anti-Trop-2 monoclonal antibody conjugated to a linker-drug moiety of Formula (II):,(II), wherein:' / v' represents the site of attachment of the drug-linker moiety to a cysteine of the antibody; and wherein the number of linker-drug moieties per antibody is from 1 to 8.

[0135] In one class of this embodiment, the anti-Trop-2 monoclonal antibody comprises:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0136] In another class of this embodiment, the anti-Trop-2 monoclonal antibody comprises:(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38.

[0137] In yet another class of this embodiment, the anti-Trop-2 monoclonal antibody comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35. and(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0138] In still another class of this embodiment, the anti-Trop-2 monoclonal antibody is sacituzumab and n is 1 to 8.

[0139] Another embodiment is a method of treating HR+ / HER2- metastatic or locally advanced breast cancer in a patient, said method comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof; and(b) a composition comprising Immunoconjugates of Formula (I) having a DAR:(I), wherein:Ab is an antibody that binds to Trop-2; n is an integer from 1 to 10, representing the number of drug linkers bound to a particular Ab. and the DAR is the drug-antibody ratio and is a real number from 1 to 10, representing the average of n of the composition.In a class of this embodiment, the amounts of (a) and (b) administered are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

[0140] In one class of this embodiment, the antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

[0141] In another class of this embodiment, antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38.

[0142] In yet another class of this embodiment, antibody that binds to Trop-2 comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35. and(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36.

[0143] In still another class of this embodiment, antibody that binds to Trop-2 is sacituzumab and n is 1 to 8.

[0144] In one class of this embodiment, the DAR is a real number from 1 to 8. In a subclass, the DAR is a real number from 5 to 8. In another subclass, the DAR is a real number from 6 to 8. In yet another subclass, the DAR is a real number from 7 to 8. In still another subclass, the DAR is a real number from 6 to 7.

[0145] Y et another embodiment is a method of treating HR+ / HER2- metastatic or locally advanced breast cancer in a patient, said method comprising administering to the patient: an amount of a composition comprising an Immunoconjugates of Formula (I) having a DAR:wherein:Ab is an antibody that binds to Trop-2; n is an integer from 1 to 10, representing the number of drug linkers bound to a particular Ab, and the DAR is the drug-antibody ratio and is a real number from 1 to 10, representing the average of n of the composition; separately, sequentially or simultaneously with an amount of anti -human PD-1 antibody or antigen fragment thereof.

[0146] In one class of this embodiment, the amounts of the composition of the Immunoconjugate of Formula (I) and the anti-human PD-1 antibody or antigen fragment thereof are together effective to treat the HR+ / HER2- metastatic or locally advanced breast cancer in the patient.

[0147] In yet another embodiment of the present disclosure is provided a method of treating a cancer selected from: HR+ / HER2- metastatic breast cancer and HR+ / HER2-] locally advanced or locally advanced breast cancer in a patient in need thereof.

[0148] In some embodiments of the present disclosure, the anti-TROP-2 antibody of the Immunoconjugates of Formula (I) is sacituzumab (or hRS7), which is described in US Patent Publication No. 2012 / 0237518. This antibody can also be obtained by screening through carrier design, construction of an antibody library displaying antibodies as disclosed in CN103476941A, or can be obtained by screening a G-MAB® library of Sorrento Therapeutics, Inc.

[0149] Table C shows the SEQ ID NOs for the amino acid sequences of the heavy and light chain complementarity-determining regions (HCDRs and LCDRs), heavy and light chain variable domains (VH and VL), and heavy and light chains (HC and LC) of sacituzumab.Table 5. List of sacituzumab (“Abl”) Amino Acid Sequences

[0150] In certain embodiments, the Immunoconjugate of Formula (I) comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linker / drug moieties per antibody (z.e., n is from 1 to 10). In certain embodiments, the Immunoconjugate of Formula (I) comprises one or more (e.g., 1 to 10. 1 to 9, 1 to 8, 1 to 7. 1 to 6, 1 to 5, 1 to 4. 1 to 3, or 1 to 2) linker / drug moieties.

[0151] In a particular embodiment, the Immunoconjugate of Formula (I) comprises from about 6 to about 8 linker / drug moieties per antibody (i.e., n is from about 6 to about 8).

[0152] The Immunoconjugates of Formula (I) comprise antibodies or fragments thereof that are specific for human Trop-2 and thus can serve as excellent targeting moieties for delivering the conjugated payloads to cells (e.g., Trop-2-positive cells). In certain embodiments, an immunoconjugate used in a treatment regimen of the present disclosure is any anti-Trop-2 immunoconjugate that is described in US Patent Publication No. 20200347075.

[0153] Compositions comprising a plurality of Immunoconjugates of Formula (I) having a DAR wherein the DAR is the drug-antibody ratio and is a real number from 1 to 10, representing the average number of drug linkers bound to Ab may be administered as a component of the present method or may comprise part of the present pharmaceutical composition, or a component of the present kit.

[0154] In one class are compositions wherein the DAR is a decimal from 0 to 8, from 0 to 7. from 0 to 6, from 0 to 5, from 0 to 4, from 0 to 3, from 0 to 2, and from 0 to 1 . In additional embodiments, are compositions wherein the DAR is a decimal from 1 to 4, 2 to 5, 3 to 6, 4 to 7, 5 to 8, 6 to 8. and 7-8. In other embodiments, are compositions wherein the DAR is a 6.1, 6.2. 6.3. 6.4. 6.5. 6.6. 6.7. 6.8, 6.9, 7.0, 7.1. 7.2, 7.3, 7.4, 7.5. 7.6, 7.7, 7.8, 7.9. or 8.0.Uses of the Combination Therapies of the Present DisclosureTreatment or Prevention of Breast Cancer

[0155] The combination therapies disclosed herein are potentially useful in treating HR+ / HER2- metastatic or locally advanced breast cancer. The terms “cancer”, “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0156] Accordingly, in one aspect, the present disclosure relates to methods of methods for treating HR+ / HER2- metastatic or locally advanced breast cancer in a patient, the method comprising administering to the patient a combination therapy that comprises: (a) an anti -human PD-1 antibody (or antigen-binding fragment thereof); and (b) an Immunoconjugate of Formula (I), wherein the amounts administered are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

[0157] In a specific embodiment, the amount administered is effective to treat HR+ / HER2- metastatic or locally advanced breast cancer in a human patient. In another specific embodiment, the amount administered is effective to inhibit cancer cell replication or cancer cell metastasis in the patient.

[0158] In one embodiment, the HR+ / HER2- metastatic or locally advanced breast cancer is relapsed. In another embodiment, the HR+ / HER2- metastatic or locally advanced breast cancer is refractory. In yet another embodiment, the HR+ / HER2- metastatic or locally advanced breast cancer is relapsed and refractory.

[0159] In one embodiment, the patient has previously received treatment for the HR+ / HER2- metastatic or locally advanced breast cancer. In another embodiment, the patient has not previously received treatment for cancer.

[0160] In one embodiment, the patient has previously received systemic treatment for the HR+ / HER2- metastatic or locally advanced breast cancer. In another embodiment, the patient has not previously received systemic treatment for the HR+ / HER2- metastatic or locally advanced breast cancer.

[0161] In one embodiment, the patient has previously received radiation therapy for the HR+ / HER2- metastatic or locally advanced breast cancer. In another embodiment, the patient has not previously received radiation therapy for the HR+ / HER2- metastatic or locally advanced breast cancer.

[0162] The compositions, methods, kits, and uses provided herein are useful for the treatment of HR+ / HER2- metastatic or locally advanced breast cancer.

[0163] The term "cancerous cell" as used herein, includes a cell afflicted by any one of the above-identified conditions.

[0164] In a specific embodiment, the cancer is HR+ / HER2- metastatic or locally advanced breast cancer, with PD-L1 TPS greater than or equal to 50%.

[0165] In a specific embodiment, the cancer is treatment-naive HR+ / HER2- metastatic or locally advanced breast cancer, with PD-L1 TPS greater than or equal to 50%.

[0166] In one embodiment, provided herein is a method of treating HR+ / HER2- metastatic or locally advanced breast cancer in a human patient. In one embodiment, the HR+ / HER2- metastatic or locally advanced breast cancer patient’s tumor expresses PD-L1 TPS greater than or equal to 50%.

[0167] In certain embodiments the PD-L1 TPS is determined by an FDA-approved test.

[0168] In particular embodiments, the cancer is classified as stage III cancer or stage IV cancer. In some instances of these embodiments, the cancer is not surgically resectable.ADMINISTRATION AND DOSAGE

[0169] The present disclosure relates to methods of treating HR+ / HER2- metastatic or locally advanced breast cancer, said method comprising administering to a patient in need thereof a combination therapy that comprises: (a) an anti -human PD-1 antibody (or antigen-binding fragment thereof); and (b) an Immunoconjugate of Formula (I), wherein the amounts administered are together effective to treat or prevent the HR+ / HER2- metastatic or locally advanced breast cancer. In one embodiment of this method, the patient is a human patient.

[0170] The Immunoconjugates of Formula (I), and the anti-human PD-1 antibody (or antigenbinding fragment thereof), will each (with a pharmaceutically acceptable carrier or excipient(s)). typically be formulated into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include those adapted for (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; and (2) parenteral administration, such as sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically acceptable carriers or excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients may be chosen for a particular function that they may serve in the composition. In embodiments, the Immunoconjugate of Formula (I), and / or the anti -human PD-1 antibody (or antigen-binding fragment thereof) may be formulated into a dosage form that allows for systemic use, i.e., distribution throughout the body of the patient; examples of such systemic administration includeoral administration, intravenous administration, and subcutaneous administration. In additional embodiments, the Immunoconjugate of Formula (I), and / or the anti-human PD-1 antibody (or antigen-binding fragment thereof) may be formulated into a dosage form that allows for targeted or isolated use, i.e., administration of the Immunoconjugate of Formula (I), and / or the antihuman PD-1 antibody (or antigen-binding fragment thereof) only to the portion of the patient’s body to be treated; examples of such targeted administration include intratumoral injection.

[0171] In some embodiments, at least one of the therapeutic agents (the anti-PD-1 antibody, or binding fragment thereof, and the Immunoconjugate of Formula (I)) in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and / or shorter treatment duration.

[0172] In embodiments of the compositions, methods, kits, and uses disclosed herein, the antihuman PD-1 antibody (or antigen binding fragment thereof) is administered by intravenous infusion or subcutaneous injection, and the Immunoconjugate of Formula (I) is administered by intravenous infusion or subcutaneous injection. In specific embodiments, the human PD-1 antibody (or antigen binding fragment thereof) the Immunoconjugate of Formula (I) are each administered by intravenous infusion.

[0173] When administering a combination therapy of the present disclosure to a patient, the agents comprising the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various agents in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for non-limiting illustration purposes, an Immunoconjugate of Formula (I), and an anti-human PD-1 antibody (or antigen-binding fragment thereof) may be present in fixed amounts (dosage amounts) in a single dosage unit.

[0174] In one embodiment, the Immunoconjugate of Formula (I) is administered during a time when the anti-human PD-1 antibody (or antigen-binding fragment thereof) exerts its prophylactic or therapeutic effect, or vice versa.

[0175] In another embodiment, the Immunoconjugate of Formula (I), and the anti-human PD-1 antibody (or antigen-binding fragment thereof) are administered in doses commonly employed when such agents are used as monotherapy for treating cancer.

[0176] In another embodiment, the Immunoconjugate of Formula (1). and the anti-human PD-1 antibody (or antigen-binding fragment thereof) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating cancer.

[0177] In still another embodiment, the Immunoconjugate of Formula (I), and the anti-human PD-1 antibody (or antigen- binding fragment thereof) act synergistically and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating cancer.

[0178] The Immunoconjugate of Formula (I), and the anti-human PD-1 antibody (or antigenbinding fragment thereof) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or both of these agents, and / or less frequent administration of one or both of these agents. A lower dosage or less frequent administration of these agents may lower the toxicity of therapy without reducing the efficacy of therapy.

[0179] In one embodiment, the administration of Immunoconjugate of Formula (I), and the anti-human PD-1 antibody (or antigen-binding fragment thereof) may inhibit the resistance of cancer to either or both of these agents.

[0180] In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient shows no symptoms of the diseases or disorders. In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient is cured of the diseases or disorders. In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient shows resistance to the therapy. In some embodiments, the combination therapies of the present disclosure are administered for a period until the patient shows side effects that would require discontinuation of the therapy.

[0181] In some embodiments, the patient is fasting for at least 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours before one or more components of a combination therapy is administered. In some embodiments, the patient needs to fast for at least 1 hour, 2 hours, 3 hours, 4 hours, 6 hours. 8 hours, 12 hours after one or more components of a combination therapy is administered.

[0182] A combination therapy of the present disclosure may be used prior to or following surgery to remove a tumor and may be used prior to, during, or after radiation treatment.

[0183] In some embodiments, a combination therapy of the present disclosure is administered to a patient who has not previously been treated with a biotherapeutic or chemotherapeutic agent, z.e., is treatment-naive. In other embodiments, the combination therapy is administered to apatient who failed to achieve a sustained response after prior therapy with the biotherapeutic or chemotherapeutic agent, z.e., is treatment-experienced.

[0184] Products provided as therapeutic combinations may include a composition comprising an anti -human PD-1 antibody (or antigen-binding fragment thereof), and a composition comprising an Immunoconjugate of Formula (I) in separate form, e.g, in the form of a kit or in any form designed to enable separate administration either concurrently or on separate dosing schedules.

[0185] In some embodiments, the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof 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 / patient.

[0186] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof 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.

[0187] In some specific methods, the dose of the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof 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 300 mg to about 400 mg, from about 350 mg to about 450 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 the anti-PD-1 antibody (e.g., anti-PD-1 monoclonal antibody) or antigen binding fragment thereof 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. In a specific embodiment, the dose of the anti-PD-1 antibody (e.g, anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is about 400 mg.

[0188] In another embodiment, the PD-1 antagonist in the therapy is the anti-PD-1 antibody pembrolizumab, or a pembrolizumab variant, which 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, the PD-1 antagonist in the therapy is pembrolizumab, or a pembrolizumab variant, which is administered in a liquid medicament at a flat dose such as 200 mg Q3W, or 400 mg Q6W.

[0189] In some embodiments of the methods, compositions, kits and uses described herein, the anti-human PD-1 antibody (e.g.. anti-PD-1 monoclonal antibody) or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg, about 240 mg, about 400 mg, about 480 mg, or about 2 mg / kg pembrolizumab once every three or six weeks. In one embodiment, the human patient is administered about 200 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered about 240 mg pembrolizumab once even- three weeks. In a specific embodiment, the human patient is administered 2 mg / kg pembrolizumab once every three weeks. In another specific embodiment, the human patient is administered 400 mg pembrolizumab once every' six weeks.

[0190] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab and the human patient is administered 200 mg pembrolizumab once every three weeks.

[0191] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab and the human patient is administered 400 mg pembrolizumab once every six weeks.

[0192] In some embodiments of the methods, compositions, kits and uses described herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and 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 200 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered about 240 mg 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 480 mg pembrolizumab once every six weeks. In one embodiment, the human patient is administered 2 mg / kg pembrolizumab once every six weeks.

[0193] 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 mMhistidine 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.

[0194] In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 200 mg pembrolizumab once even,' three weeks. In certain embodiments of the methods, compositions, kits and uses described herein, the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab, and the human patient is administered about 400 mg pembrolizumab once every six weeks.

[0195] 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.

[0196] In some embodiments, the selected dose of pembrolizumab is administered subcutaneously. In certain embodiments, 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, pembrolizumab is administered by subcutaneous injection at a dose of about 300 mg to about 450 mg. In yet a further embodiment, pembrolizumab is administered subcutaneously at a dose of about 320 mg to about 450 mg.

[0197] In certain embodiments, 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 certain embodiments, 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 certain embodiments, pembrolizumab is administered subcutaneously to the patient in two injections. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in one pre-filled syringe. In certain embodiments, the amount of pembrolizumab administered subcutaneously to the patient is 380 mg in two pre-filled syringes.

[0198] 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%.

[0199] In other embodiments of the methods, compositions, kits, and uses described herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab, the human patient is administered about 240 mg or about 3 mg / kg nivolumab, and nivolumab is administered once every two weeks. In one specific embodiment, the human patient is administered about 240 mg nivolumab once every two weeks. In one specific embodiment, the human patient is administered about 3 mg / kg nivolumab once every’ two weeks. In other embodiments of the methods, compositions, kits and uses described herein, the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab, the human patient is administered about 480 mg nivolumab once every' four weeks.

[0200] The immunoconjugates of Formula (I), and a pharmaceutically acceptable carrier or excipient(s) will typically be formulated into a dosage form adapted for administration to a patient by a desired route of administration. For example, dosage forms include sterile solutions, suspensions, and powders for reconstitution. Suitable pharmaceutically' acceptable carriers or excipients will vary' depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable carriers or excipients may be chosen for a particular function. In embodiments, the Immunoconjugate of Formula (I) may be formulated into a dosage form that allows for systemic use, i.e., distribution of Immunoconjugate of Formula (I) throughout the body of the patient; examples of such systemic administration include subcutaneous administration and intravenous administration. In additional embodiments, the Immunoconjugate of Formula (I) may be formulated into a dosage form that allows for targeted or isolated use. i.e., administration of the Immunoconjugate of Formula (I) only to the portion of the patient’s body to be treated; examples of such targeted administration include intratumoral injection. In certain embodiments, the doses are provided intravenously or subcutaneously. A total dose for a treatment interval is generally at least 0.25 mg / kg body weight, more generally at least 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1.0 mg / kg, 1.25 mg / kg, 1.50 mg / kg, 1.75 mg / kg, 2.00 mg / kg, 2.25 mg / kg, 2.50 mg / kg, 2.75 mg / kg, 3.00 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg,6.00 mg / kg, 6.25 mg / kg. 6.50 mg / kg, 6.75 mg / kg. and 7.00 mg / kg. In other embodiments. Immunoconjugates of Formula (I) are administered subcutaneously or intravenously, on a weekly, biweekly, “every 3 weeks,” “every 4 weeks,” monthly, “every 6 weeks,” bimonthly, or quarterly basis at 2.00 mg / kg, 2.25 mg / kg. 2.50 mg / kg, 2.75 mg / kg, 3.00 mg / kg, 3.25 mg / kg, 3.50 mg / kg, 3.75 mg / kg. 4.00 mg / kg, 4.25 mg / kg. 4.50 mg / kg, 4.75 mg / kg. 5.00 mg / kg, 5.25 mg / kg, 5.50 mg / kg, 5.75 mg / kg, or 6.00 mg / kg. In a specific embodiments, the Immunoconjugate of Formula (I) is administered at 3.50 mg / kg, 3.75 mg / kg, 4.00 mg / kg, 4.25 mg / kg, 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg, every 2 weeks. In specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.50 mg / kg, 4.75 mg / kg, 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg, every 2 weeks, every 3 weeks, every 4 weeks or every 6 weeks. In another specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 2 weeks, every 3 weeks, every 4 weeks, or every' 6 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 2 weeks.

[0201] In one embodiment, in the combination therapies of the present disclosure, an Immunoconjugate of Formula (I) is administered at a dose of 0.25 mg / kg to 10 mg / kg. In some embodiments, the Immunoconjugate of Formula (I) may be administered at a dose of 0.25 0.5, 0.75, 1. 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25. 4.5, 4.75, 5, 5.5, 6. 6.5, 7, 8, 9, or 10 mg / kg as a single dose, or in any combination thereof for multiple doses. In certain embodiments, the Immunoconjugate of Formula (I) is administered at a dose of 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, or 6 mg / kg. In other embodiments, the Immunoconjugate of Formula (I) is administered at a dose of 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5, 5.25, or 5.5 mg / kg. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of about 3.0 mg / kg. In another specific embodiment, the Immunoconjugate of Formula (1) is administered at a dose of about 4.0 mg / kg. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of about 5.0 mg / kg.

[0202] In some embodiments, the Immunoconjugate of Formula (I) is administered in repeated cycles of 1, 2, 3, 4. 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15. or 16 weeks. In one specific embodiment, the Immunoconjugate of Formula (I) is administered in two-week cycles. In another specific embodiment, the Immunoconjugate of Formula (I) is administered in three-week cycles. In another specific embodiment, the Immunoconjugate of Formula (I) is administered in four-w eek cycles. In still another specific embodiment, the Immunoconjugate of Formula (I) is administered in six-week cycles. The treatment regimen may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more cycles of administration (e.g., 3 or more cycles, or 4 or more cycles). In certain embodiments, the Immunoconjugate of Formula (I) is administered on one,two, three, four, five, six, or seven days of the cycle. The days of administration may be consecutive or may have one, two, three, four, five, or six days, one week, two weeks, three weeks, or four weeks, or any combination thereof, between them. In particular embodiments, the Immunoconjugate of Formula (I) is administered on Day 1 only of each cycle (e.g., a two-week cycle). In particular embodiments, the Immunoconjugate of Formula (I) is administered on Days 1 and 8 of each cycle (e.g., a three-week cycle). In particular embodiments, the Immunoconjugate of Formula (I) is administered on Days 1, 8, and 15 of each cycle (e.g., a four- week cycle or a six-week cycle). In a specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 2-week cycle. In another specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 3-week cycle. In another specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 4- week cycle. In another embodiment, the Immunoconjugate of Formula (I) is administered on days 1, 15, and 29 of a six-week cycle. In other embodiments, the Immunoconjugate of Formula (I) is administered at 3.50 mg / kg, 3.75 mg / kg. 4.00 mg / kg, 4.25 mg / kg. 4.50 mg / kg, 4.75 mg / kg. 5.00 mg / kg, 5.25 mg / kg, or 5.50 mg / kg, every 2 weeks, every 3 weeks, every 4 weeks, or every 6 weeks. In a specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 2 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 3 weeks. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 2 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 3 weeks. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 2 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 3 weeks.

[0203] The Immunoconjugate of Formula (I) may be administered initially according to a dosage regimen described herein and subsequently according to a different dosage regimen described herein (e.g., to increase or decrease the frequency of administration). In some embodiments, the Immunoconjugate of Formula (I) is administered weekly during the first 1, 2, 3, 4, 5, or 6, 7, 8, 9, 10, 11, or 12 weeks, then every 3 weeks thereafter. In certain embodiments, the Immunoconjugate of Formula (I) is administered weekly during the first 2, 3, 4, 5, or 6 weeks, and then every 3 weeks. In certain embodiments, the Immunoconjugate of Formula (I) is administered weekly during the first 1, 2, 3, 4. 5, or 6 weeks, and then every 4 weeks.

[0204] The Immunoconjugate of Formula (I) may be administered via parenteral administration. As used herein, ‘'parenteral administration” of an immunoconjugate includes any route of administration characterized by physical breaching of a tissue of a patient andadministration of the immunoconjugate through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, but is not limited to, administration of an immunoconjugate by injection of the immunoconjugate, by application of the immunoconjugate through a surgical incision, by application of the immunoconjugate through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrastemal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, and intrasynovial injection or infusions; and kidney dialytic infusion techniques. In a specific embodiment, the Immunoconjugate of Formula (I) is administered intravenously. In another specific embodiment the Immunoconjugate of Formula (I) is administered subcutaneously. Regional perfusion is also contemplated. In some embodiments, the infusion may be administered by one route (e.g, intravenously) for initial doses and then be administered by another route for subsequent doses.

[0205] In certain embodiments, the Immunoconjugate of Formula (I) is administered by intravenous (IV) infusion. The infusion may take place over a period of about 0. 1 to about 4 hours (e.g, about 5, 10, 15, 20, 25, 30, 35, 40. 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 120, or 180 minutes). In particular embodiments, the infusion time is 30 minutes. Infusion times may be extended as necessary to accommodate individual patient tolerance of treatment. Where the immunoconjugate is administered in more than one dose, in some embodiments, the infusion time for the first dose is longer than the infusion time for subsequent doses, or alternatively, the infusion time for the first dose is shorter than the infusion time for subsequent doses.

[0206] In one embodiment, provided is a method treating HR+ / HER2- metastatic or locally advanced breast cancer, said method comprising administering to a patient in need thereof a combination therapy that comprises: (a) an anti -human PD-1 antibody (or antigen-binding fragment thereof); and (b) an Immunoconjugate of Formula (I); wherein the anti-human PD-1 antibody (or antigen- binding fragment thereof) is administered on day 1, and the Immunoconjugate of Formula (I) is administered on days 1, 15, and 29 of a six-week cycle (‘'Combination Regimen 1”)

[0207] In a specific embodiment, for Combination Regimen 1, the anti -human PD-1 antibody (or antigen-binding fragment thereof) is administered at a single dose of 400 mg on day 1 of each 6-week cycle, and the Immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg on each of days 1, 15, and 29 of each 6-week cycle. In another specific embodiment, forCombination Regimen 2, the anti -human PD-1 antibody (or antigen-binding fragment thereof) isadministered at a single dose of 400 mg on day 1 of each 6-week cycle, and the Immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg on each of days 1, 15, and 29 of each 6-week cycle. In another specific embodiment, for Combination Regimen 2, the antihuman PD-1 antibody (or antigen-binding fragment thereof) is administered at a single dose of 400 mg on day 1 of each 6-week cycle, and the Immunoconjugate of Formula (I) is administered at a dose of 3 mg / kg on each of days 1, 15, and 29 of each 6-week cycle.

[0208] In a specific embodiment, for Combination Regimen 1, the anti-human PD-1 antibody is pembrolizumab.

[0209] In a specific embodiment, for Combination Regimen 1 , the Immunoconj ugate of Formula (I) is Immunconj ugate A.

[0210] In another specific embodiment, for Combination Regimen 1, the anti -human PD-1 antibody is pembrolizumab, and the Immunoconjugate of Formula (I) is Immunconj ugate A.

[0211] In another embodiment, Combination Regimen 1 is administered in from 1 to 18 six- week cycles.

[0212] In a specific embodiment. Combination Regimen 1 is administered to a patient to treat metastatic or locally advanced HR+ / HER2- metastatic or locally advanced breast cancer.

[0213] In a specific embodiment, Combination Regimen 1 is administered to a patient to treat metastatic or locally advanced HR+ / HER2- metastatic or locally advanced breast cancer that has been previously treated.

[0214] In a further specific embodiment, Combination Regimen 1 is administered to a patient to treat metastatic or locally advanced HR+ / HER2- metastatic or locally advanced breast cancer that has been previously treated with CDK4 / 6i therapy.

[0215] In a specific embodiment, for Combination Regimen 2, the anti -human PD-1 antibody is pembrolizumab.

[0216] In a specific embodiment, for Combination Regimen 2, the Immunoconjugate of Formula (I) is Immunconj ugate A.

[0217] In another specific embodiment, for Combination Regimen 2, the anti -human PD-1 antibody is pembrolizumab, and the Immunoconjugate of Formula (I) is Immunconj ugate A.

[0218] In another embodiment, Combination Regimen 1 is administered in from 1 to 18 six- week cycles.

[0219] In a specific embodiment, Combination Regimen 2 is administered to a patient to treat metastatic or locally advanced HR+ / HER2- metastatic or locally advanced breast cancer.

[0220] In a specific embodiment, Combination Regimen 2 is administered to a patient to treat metastatic or locally advanced HR+ / HER2- metastatic or locally advanced breast cancer that has been previously treated.

[0221] In a further specific embodiment. Combination Regimen 2 is administered to a patient to treat metastatic or locally advanced HR+ / HER2- metastatic or locally advanced breast cancer that has been previously treated with CDK4 / 6i therapy.

[0222] In some embodiments, at least one of the therapeutic agents (the anti-PD-1 antibody, or binding fragment thereof, and the Immunoconjugate of Formula (I)) in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and / or shorter treatment duration.Additional Therapeutic Agents

[0223] The therapeutic combinations, and combination therapies disclosed herein may be used in combination with one or more other additional therapeutic agents, including but not limited to, additional anti-cancer agents, wherein said additional anti-cancer agents are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cellular proliferative disorders). In one embodiment, a therapeutic combination disclosed herein is combined with one or more additional anti-cancer agents for use in the prevention, treatment, control amelioration, or reduction of risk of cancer. Such additional therapeutic agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a combination therapy of the present disclosure.

[0224] Accordingly, in one aspect, the present disclosure provides pharmaceutical compositions comprising: (a) the Immunoconjugate of Formula (I); (b) an anti -human PD-1 antibody (or antigen-binding fragment thereof); and (c) an additional therapeutic agent, or pharmaceutically acceptable salt thereof, and (d) a pharmaceutically acceptable carrier. In one embodiment, the amounts of (a), (b), and (c) present in the pharmaceutical composition are together effective to treat cancer.

[0225] In one embodiment, provided herein is a pharmaceutical composition comprising:(a) an anti -human PD-1 antibody or antigen binding fragment thereof;(b) a pharmaceutically acceptable carrier; and(c) a plurality of Immunoconjugates of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and n represents the average number of linker / payload moieties joined to each antibody for the plurality of Immunoconjugates of Formula (I).

[0226] In one class of this embodiment, the amounts of (a) and (c) present in the composition are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

[0227] In one embodiment, for the pharmaceutical composition, the antibody that binds to Trop-2 is sacituzumab.

[0228] In another embodiment, for the pharmaceutical composition, the anti -human PD-1 antibody or antigen binding fragment thereof is pembrohzumab.

[0229] Also provided herein are combination therapies comprising administering to a patient: a pharmaceutical composition comprising: (a) the Immunoconjugate of Formula (I); (b) an antihuman PD-1 antibody (or antigen-binding fragment thereof); and (c) an additional therapeutic agent, or pharmaceutically acceptable salt thereof. In one embodiment, the amounts administered of (a), (b), and (c) are together effective to treat cancer.

[0230] When co-administered with an additional therapeutic agent, the additional therapeutic agent can be administered in repeated cycles of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11. 12, 13, 14, 15, or 16 weeks. In one specific embodiment, the additional therapeutic agent is administered in three- week cycles. In another specific embodiment, the additional therapeutic agent is administered in four-week cycles. In still another specific embodiment, the additional therapeutic agent is administered in six-week cycles. In certain embodiments, the additional therapeutic agent is administered on one. two, three, four, five, six, or seven days of the cycle. The days of administration may be consecutive or may have one, two. three, four, five, or six days, one week,two weeks, three weeks, or four weeks, or any combination thereof, between them. In particular embodiments, the additional therapeutic agent is administered on Day 1 only of each cycle (e.g., a two-week cycle, a three-week cycle, or a 4-week cycle). In particular embodiments, the additional therapeutic agent is administered on Day 1 of a three-week cycle. In another specific embodiment, the additional therapeutic agent is administered on the first day of a 4-week cycle. In particular embodiments, the additional therapeutic agent is administered on Days 1, 8, and 15 of a three-week cycle, a four-week cycle or a six-week cycle.

[0231] The additional therapeutic agent(s) may be one or more agents selected from the group consisting of STING agonists, poly ADP ribose polymerase (PARP) inhibitors, mitogen- activated protein kinase (MEK) inhibitors, cyclin-dependent kinase (CDK) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, tryptophan 2,3-dioxygenase (TDO) selective inhibitors, anti-viral compounds, antigens, adjuvants, anti-cancer agents, CTLA-4, LAG-3 and PD-1 pathway antagonists, lipids, liposomes, peptides, cytotoxic agents, chemotherapeutic agents, immunomodulatory cell lines, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, topoisomerase II inhibitors, smoothen inhibitors, alkylating agents, anti-tumor antibiotics, anti-metabolites, retinoids, and immunomodulatory agents including but not limited to anti-cancer vaccines. It will be understood the descriptions of the above additional therapeutic agents may be overlapping. It will also be understood that the treatment combinations are subject to optimization, and it is understood that the best combination to use of the antihuman PD-1 antibody (or antigen-binding fragment thereof), the Immunoconjugate of Formula (I), and one or more additional therapeutic agents will be determined based on the individual patient needs.

[0232] When the therapeutic combination disclosed herein is used contemporaneously with one or more additional therapeutic agents, the anti -human PD-1 antibody (or antigen-binding fragment thereof) and / or the Immunoconjugate of Formula (I) may be administered either simultaneously with, or before or after, one or more additional therapeutic agent(s). Either of the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or the Immunoconjugate of Formula (I) may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition as the other agent(s).

[0233] The weight ratio of the anti -human PD-1 antibody (or antigen-binding fragment thereof) to the Immunoconjugate of Formula (I) may be varied and will depend upon the therapeutically effective dose of each agent. Generally, a therapeutically effective dose of each will be used. Combinations including at least one anti-human PD-1 antibody (or antigen-binding fragment thereof), an Immunoconjugate of Formula (I), and one or more additional therapeutic agents willgenerally include a therapeutically effective dose of each therapeutic agent. In such combinations, the anti-human PD-1 antibody (or antigen-binding fragment thereof) and / or the Immunoconjugate of Formula (I) disclosed herein, and additional therapeutic agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent with, or subsequent to the administration of additional therapeutic agent(s). In one embodiment, the Combinations including at least one anti -human PD-1 antibody (or antigen-binding fragment thereof), an Immunoconjugate of Formula (I), and one or more additional therapeutic agents will comprise a dose of each component, such the amounts administered are together effective to treat cancer.

[0234] In one embodiment, this disclosure provides an anti -human PD-1 antibody (or antigenbinding fragment thereof) and / or an Immunoconjugate of Formula (I), and at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of HR+ / HER2- metastatic or locally advanced breast cancer.

[0235] The disclosure also provides the use of an Immunoconjugate of Formula (I) for treating HR+ / HER2- metastatic or locally advanced breast cancer, where the patient has previously (e.g., within 24 hours) been treated with an anti -human PD-1 antibody (or antigen-binding fragment thereof). In one embodiment, the Immunoconjugate of Formula (I) is administered within 30 minutes after the administration of the anti -human PD-1 antibody (or antigen-binding fragment thereof) is complete. The disclosure also provides the use of an anti-human PD-1 antibody (or antigen-binding fragment thereof) for treating, where the patient has previously (e.g., within 24 hours) been treated with an Immunoconjugate of Formula (I). In one embodiment, the antihuman PD-1 antibody (or antigen-binding fragment thereof) is administered within 30 minutes after the administration of the Immunoconjugate of Formula (I) is complete.

[0236] Anti-viral compounds that may be used in combination with the therapeutic combinations disclosed herein include hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors. HCV polymerase inhibitors. HCV NS4A inhibitors, HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.

[0237] Antigens and adjuvants that may be used in combination with the therapeutic combinations disclosed herein include B7 costimulatory molecule, interleukin-2, interferon- / , GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim, levamisol, vaccinia virus, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surface active substances such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants,such as aluminum hydroxide or aluminum phosphate, can be added to increase the ability of the vaccine to trigger, enhance, or prolong an immune response. Additional materials, such as cytokines, chemokines, and bacterial nucleic acid sequences, like CpG, atoll-like receptor (TLR) 9 agonist as well as additional agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR7 / 8, TLR9, and TLR 8 / 9 including lipoprotein, lipopolysaccharide (LPS). monophosphoryllipid A. lipoteichoic acid, imiquimod, resiquimod, and in addition retinoic acid-inducible gene I (RIG-I) agonists such as poly I:C, used separately or in combination are also potential adjuvants.

[0238] Chemotherapeutic agents that may be used in combination with the therapeutic combinations disclosed herein include abiraterone acetate, altretamine, anhydrovinblastine, aroplatin, asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase), auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4- methoxyphenyl)benzene sulfonamide, bleomycin, N,N-dimethyl-L-valyl-L-valyl-N-methyl-L- valyl-L-prolyl- 1 -Lproline-t-butylamide (SEQ ID NO: 45), cachectin, cemadotin, chlorambucil, cyclophosphamide, 3',4'-didehydro-4'deoxy-8'-norvin-caleukoblastine, dinaciclib, docetaxol. doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea andtaxanes, ifosfamide, liarozole, lonidamine, lomustine, MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, olaparib, onapristone, oxaliplatin, paclitaxel, prednimustine, procarbazine, RPR109881, selumetinib, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine. and pharmaceutically acceptable salts thereof.

[0239] Examples of vascular endothelial growth factor (VEGF) receptor inhibitors include, but are not limited to, bevacizumab (sold under the trademark AVASTIN by Genentech / Roche), axitinib (described in PCT International Patent Publication No. W001 / 002369), Brivanib Alaninate ((S)-((R)-l-(4-(4-Fluoro-2-methyl-lH-indol-5-yloxy)-5-methylpyrrolo[2,l- f|[l,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-lH-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3- pyridinecarboxamide. and described in International Patent Publication No. W002 / 068470). pasireotide (also known as SO 230, and described in International Patent Publication No. W002 / 010192), and sorafenib.

[0240] Examples of topoisomerase II inhibitors, include but are not limited to, etoposide, and teniposide.

[0241] Examples of alkylating agents, include but are not limited to, 5-azacytidine, decitabine, temozolomide, dactinomycin (also known as actinomycin-D, melphalan, altretamine, carmustine, bendamustine, busulfan. platinum-based chemotherapeutic agents (e.g., aroplatin, cisplatin, carboplatin, and oxaliplatin), lomustine, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, streptozocin, thiotepa, and pharmaceutically acceptable salts thereof. In one embodiment, the additional thereapeutic agent is a platinum-based chemotherapeutic agent. In a specific embodiment, the additional therapeutic agent is cisplatin. In another specific embodiment, the additional therapeutic agent is carboplatin. In specific embodiments, when co-administered with carboplatin, the dose of carboplatin is from about AUC 1 mg / mL / min to AUC 10 mg / mL / min, administered intravenously. In a specific embodiment, when co-administered with carboplatin, the dose of carboplatin is AUC 5 mg / mL / min, administered intravenously. In other embodiments, when co-administered with cisplatin, the dose of cisplatin is from about 10 mg / m2to 150 mg / m2, administered intravenously. In a specific embodiment, when co-administered with cisplatin, the dose of cisplatin is 75 mg / m2, administered intravenously.

[0242] Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin, bleomycin, daunorubicin liposomal (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0243] Examples of anti-metabolites include, but are not limited to, claribine, 5-fluorouracil, 6- thioguanine, pemetrexed (sold under the tradename ALIMTA®), cytarabine (also known as arabinosylcytosine (Ara-C)). cytarabine liposomal (also known as Liposomal Ara-C. sold under the tradename DEPOCYT™), decitabine (sold under the tradename DACOGEN®), hydroxyurea and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin.

[0244] Examples of retinoids include, but are not limited to, alitretinoin, tretinoin, isotretinoin, and bexarotene.ADDITIONAL EMBODIMENTS

[0245] Additional embodiments of the disclosure include the compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that theembodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.Kits

[0246] The present disclosure also provides articles of manufacture, e.g., kits, comprising one or more containers (e.g.. single-use or multi-use containers) containing a pharmaceutical composition of an Immunoconjugate of Formula (I) described herein at a dose described herein, a pharmaceutical composition of an anti -human PD-1 antibody (or antigen-binding fragment thereof) described herein at a dose described herein, optionally an additional therapeutic agent, and instructions for use according to a treatment regimen described herein. The Immunoconjugate of Formula (I), anti-human PD-1 antibody (or antigen-binding fragment thereol), and additional therapeutic agent can be packaged together or separately in suitable packing such as a vial or ampule made from non-reactive glass or plastic.

[0247] In one embodiment, the kit comprises means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet. A kit of this disclosure may be used for administration of different dosage forms, for example, oral and parenteral, for administration of the separate compositions at different dosage intervals, or for titration of the separate compositions against one another. To assist with compliance, a kit of the disclosure typically comprises directions for administration.

[0248] In one embodiment, the present disclosure provides a kit comprising:(a) an anti -human PD-1 antibody or antigen binding fragment thereof; and(b) an Immunoconjugate of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and each n is an integer from 1 to 10.wherein the amounts of (a) and (b) present in the kit are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

[0249] In one embodiment, for a kit of the present disclosure, the anti -human PD-1 antibody or antigen binding fragment contained in the kit is pembrolizumab.

[0250] In another embodiment, for a kit of the present disclosure, the Immunoconjugate of Formula (I) contained in the kit is Immunoconjugate A.GENERAL METHODS

[0251] Standard methods in molecular biolog}' are described Sambrook, Fritsch and Maniatis (1982 & 1989 2ndEdition, 2001 3rdEdition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory' Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA. Vol. 217, Academic Press. San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology, Vols.1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0252] Methods for protein purification including immunoprecipitation, chromatography, electrophoresis, centrifugation, and crystallization are described (Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 7, John Wiley and Sons, Inc., New York). Chemical analysis, chemical modification, post-translational modification, production of fusion proteins, glycosylation of proteins are described (see. e.g., Coligan, et al. (2000) Current Protocols in Protein Science, Vol. 2, John Wiley and Sons, Inc., New York; Ausubel, et al. (2001) Current Protocols in Molecular Biology, Vol. 3, John Wiley and Sons, Inc., NY, NY, pp. 16.0.5-16.22.17; Sigma-Aldrich, Co. (2001) Products for Life Science Research, St. Louis, MO; pp. 45-89;Amersham Pharmacia Biotech (2001) BioDirectory, Piscataway, N.J., pp. 384-391). Production, purification, and fragmentation of polyclonal and monoclonal antibodies are described (Coligan, et al. (2001) Current Protocols in Immunology, Vol. 1, John Wiley and Sons, Inc., New York; Harlow and Lane (1999) Using Antibodies , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Harlow and Lane, supra). Standard techniques for characterizing ligand / receptor interactions are available (see, e.g., Coligan, et al. (2001) Current Protocols in Immunology. Vol. 4, John Wiley, Inc., New York).

[0253] Monoclonal, polyclonal, and humanized antibodies can be prepared (see, e.g.. Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New York, NY;Kontermann and Dubel (eds.) (20G ) Antibody Engineering, Springer-Verlag, New York; Harlow and Lane (1988) Antibodies A Laboratory Manual, Cold Spring Harbor Laboratory' Press, Cold Spring Harbor. NY, pp. 139-243; Carpenter, et al. (2000) J. Immunol. 165:6205; He. et al. (1998) J. Immunol. 160: 1029; Tang et al. (1999) J. Biol. Chem. 274:27371-27378; Baca et al. (1997) J. Biol. Chem. 272:10678-10684; Chothia et al. (1989) Nature 342:877-883; Foote and Winter (1992) J. Mol. Biol. 224:487-499; U.S. Pat. No. 6.329,511).

[0254] An alternative to humanization is to use human antibody libraries displayed on phage or human antibody libraries in transgenic mice (Vaughan et al. (1996) Nature Biotechnol. 14:309- 314; Barbas (1995) Nature Medicine 1:837-839; Mendez et al. (1997) Nature Genetics 15:146- 156; Hoogenboom and Chames (2000) Immunol. Today 21:371-377; Barbas et al. (2001) Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory’ Press, Cold Spring Harbor, New York; Kay et al. (1996) Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, San Diego, CA; de Bruin et al. (1999) Nature Biotechnol. 17:397-399).

[0255] Purification of antigen is not necessary' for the generation of antibodies. Animals can be immunized with cells bearing the antigen of interest. Splenocytes can then be isolated from the immunized animals, and the splenocytes can fused with a myeloma cell line to produce a hybridoma (see, e.g., Meyaard et al. (1997) Immunity 7:283-290; Wright et al. (2000) Immunity 13:233-242; Preston et al., supra,' Kaithamana et al. (1999) J Immunol. 163:5157-5164).

[0256] Methods for flow cytometry', including fluorescence activated cell sorting (FACS), are available (see, e.g.. Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice. John Wiley and Sons, Hoboken. NJ; Givan (2001) Flow Cytometry. 2nded.', Wiley-Liss. Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g.. as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes. Inc., Eugene, OR; Sigma- Aldrich (2003) Catalogue, St. Louis, MO).

[0257] Standard methods of histology of the immune system are described (see, e.g., Muller- Harmelink (ed.) (1986) Human Thymus: Histopathology and Pathology, Springer Verlag, New York, NY; Hiatt, et al. (2000) Color Atlas of Histology. Lippincott. Williams, and Wilkins, Phila, PA; Louis, et al. (2002) Basic Histology: Text and Atlas, McGraw-Hill, New York, NY).

[0258] Software packages and databases for determining, e.g., antigenic fragments, leadersequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g., GenBank, Vector NTI® Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys, Inc., San Diego, CA); DeCypher® (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods Programs Biomed. 68: 177-181 ; von Heijne (1983) Eur. J. Biochem. 133: 17-21; von Heijne (1986) Nucleic Acids Res. 14:4683-4690).EXAMPLES

[0259] The following examples illustrate representative embodiments of the present disclosure and are not meant to be limiting in any way.EXAMPLE 1 Preparation of Immunoconjugate A

[0260] Immunoconjugate A can be made using the methodology7described in US Patent Publication No. US Patent Publication No. 20200347075, wherein Immunoconjugate A is referred to as “BT001021.”EXAMPLE 2Study of Immunoconjugate A and Pembrolizumab as Combination Therapy in Subjects with HR+ / HER2- metastatic or locally advanced breast cancer

[0261] This is a Phase 3, randomized, active-controlled, open-label, multi site study of Immunoconjugate A in combination with pembrolizumab versus treatment of physician’s choice in the treatment of participants at least 18 years of age, with hormone receptor positive (HR+) / human epidermal growth factor receptor-2 negative (HER2-) unresectable locally advanced or metastatic breast cancer (MBC), who have not been previously treated with chemotherapy in the metastatic setting.

[0262] Approximately 1200 participants will be randomly assigned in a 3:3:2 ratio to one of the following treatment arms, respectively:1. Arm A: Immunoconjugate A alone2. Arm B: Immunoconjugate A plus Pembrolizumab3. Arm C: TPC consisting of either of the following:• Paclitaxel (80 mg / m2) on Day 1 q I wORPaclitaxel (90 mg / m2) on Days 1, 8, and 15, q4wOR• Nab-paclitaxel (100 mg / m2) on Days 1, 8, and 15, q4wOR• Capecitabine (1000 mg / m2) BID on Days 1 to 14, q3wOR• Liposomal Doxorubicin (50 mg / m2) on Day 1, q4w

[0263] Immunoconjugate A will be administered q2w and pembrolizumab will be administered q6w. Before randomization, investigators must select and record the TPC option and the rationale for selecting that option if the participant is assigned to Arm C. Once randomization has been performed, and a participant is assigned to Arm C, the choice of chemotherapy cannot be changed. Crossover between treatment arms will not be permitted.

[0264] Participants will be stratified by a) PD-L1 status (CPS <1 vs CPS 1-9 vs CPS >10), b) TROP2 expression (low+medium vs high), and c) region (Western Europe vs North America vs Rest of World).

[0265] Participants will be evaluated with tumor scans to assess response to study interventions every 9 weeks (±7 days) from randomization through 54 weeks, and every 12 weeks (±7 days) after 54 weeks. All scans obtained during the study will be submitted to an iCRO for efficacy evaluation.

[0266] Tumor scans showing initial investigator assessment of disease progression will be submitted for expedited verification of disease progression by BICR. Treatment beyond centrally-verified disease progression per RECIST 1.1 may be permitted at the discretion of the investigator after consultation with the Sponsor with documented SCF and receiving signed reconsent addendum.

[0267] Treatment with pembrolizumab will continue for up to 18 treatments (approximately 2 years) or until any of the discontinuation criteria are met. Treatment with Immunoconjugate A and TPC will continue until any of discontinuation criteria are met.

[0268] Survival follow-up will begin after centrally-verified disease progression (or upon completion of all efficacy assessments if the participant is receiving study intervention beyond centrally-verified disease progression) or EOT, Safety Follow-Up, or end of Efficacy Follow-up, whichever occurs last. Upon Sponsor request, participants may be contacted for survival information at any time during the study.

[0269] The AE monitoring will be ongoing throughout the study and graded in severity according to the guidelines outlined in the NCI CTCAE version 5.0. Each participant will be monitored for AEs and SAEs.

[0270] Details and timing of the IA and final analysis for the study are described in the SAP. Results of the IAS will be reviewed by an eDMC, which will make recommendations to the Sponsor to continue, modify, or end the study.Efficacy Endpoints

[0271] This study will use PFS based on RECIST 1.1 criteria as assessed by BICR as the primary endpoint and OS as the key secondary endpoint.

[0272] PFS is an acceptable measure of clinical benefit for a late-stage study that shows superiority of a new7antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has an acceptable risk / benefit profile. The use of BICR and RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities. Images will be read by an independent central review blinded to treatment assignment to minimize bias in the response assessments. In addition, the final determination of radiologic progression w ill be based on the central assessment of progression, rather than a local site investigator / radiology assessment. Expedited verification of radiologic progression as determined by central review will be communicated to the site.

[0273] OS is a key secondary endpoint in this study' with string Type-I control: OS will be tested hierarchically after successful PFS outcomes in both comparisons of the experimental arms to chemotherapy.

[0274] OS has been recognized as the gold standard for the demonstration of superiority of a new antineoplastic therapy7in randomized clinical studies.

[0275] Other secondary' and exploratory7efficacy endpoints include ORR, DCR, DOR based on RECIST 1.1 as assessed by BICR, and PFS2 as assessed by investigator.RECIST 1.1

[0276] RECIST 1.1 will be used when assessing scans for efficacy measures. Although original RECIST 1.1 publication recommends a maximum of 5 target lesions in total and 2 per organ, this protocol has implemented an adjustment to RECIST 1. 1 to allow a maximum of 10 target lesions in total and 5 per organ, if a larger number of target lesions is needed to adequately represent the tumor burden.Safety Endpoints

[0277] 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.Patient-reported Outcomes

[0278] Symptomatic improvement is considered a clinical benefit and accepted by health authorities as additional evidence of the risk-benefit profile of any new study intervention. In this study, HRQoL and disease-related symptoms will be investigated via the following assessment tools: EORTC QLQ-C30, EORTC QLQ-BR45, and EQ-5D-5L questionnaires. Health utilities will be evaluated using the EQ-5D-5L PRO instrument. These measures are not pure efficacy or safety endpoints because they are affected by both disease progression and treatment tolerability. EORTC QLQ-C30

[0279] EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for assessing HRQoL in oncology studies [Aaronson, N. K., et al. 1993] The EORTC QLQ-C30 is the most widely used cancer-specific HRQoL instrument, which contains 30 items and measures 5 functional dimensions (physical, role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea / vomiting, and pain), 6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial impact), and a global health and QoL scale [Aaronson, N. K., et al. 1993] For the global health status or QoL and function scales, a higher value indicates a better level of function; for symptom scales and items, a higher value indicates increased severity of symptoms. TTD and mean change from baseline in global health status or QoL scale of the EORTC QLQ-C30, will be evaluated as secondary objectives.EORTC QLQ-BR45

[0280] The EORTC QLQ-BR45 is a HRQoL questionnaire developed to assess the extent of symptoms or problems in participants receiving treatment for breast cancer. The validated tool is used in conjunction with the EORTC QLQ-C30 and follows the same 4-point scale described above. Tumor location, treatment, and QoL dimensions are disease-specific aspects incorporated into question design. The tool consists of 45 questions and is divided into 5 sections; 3 sections with a recall period of 1 week and 2 section with a recall period of 4 weeks. Administer EORTC QLQ-BR45 to female participants only.EQ-5D-5L

[0281] The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will provide data to develop health utilities for use in health economic analyses [Rabin, R. and deCharro, F. 2001], The 5 health state dimensions in the EQ-5D-5L include the following: Mobility, Self-Care, Usual Activities, Pain / Discomfort, and Anxiety / Depression. Each dimension is rated on a 5-point scale from 1 (no problem) to 5 (unable to / extreme problems). The EQ-5D- 5L also includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or her general state of health at the time of the assessment. This instrument has been used extensively in cancer studies and published results from these studies support its validity and reliability [Pickard, A. S., et al. 2007]Pharmacokinetic Endpoints

[0282] Serum concentrations of Immunoconjugate A will sen e as the primary readout for the PK, and these data will be used to derive PK parameters (e.g..Ctrough and Cmax) of Immunoconjugate A monotherapy and in combination.Planned Exploratory Biomarker Research

[0283] The mechanism of action of many antitumor agents is not completely understood and much remains to be learned regarding how best to leverage new drugs in treating patients. Thus, to aid future patients, it is important to investigate the determinants of response or resistance to cancer treatments. These efforts may identify novel predictive / pharmacodynamic biomarkers and generate information that may better guide single-agent and combination therapy with antineoplastic drugs. To identify novel biomarkers, biospecimens (e.g., blood components, tumor material, etc) will be collected to support analyses of cellular components (e.g., protein, DNA, RNA, metabolites) and other circulating molecules. Investigations may include, but are not limited to the following:Germline genetic analyses (e.g.,SM’ analyses, whole exome sequencing, whole genome sequencing)

[0284] This research may evaluate whether genetic variation within a clinical study population correlates with response to the treatment(s) under evaluation. If genetic variation is found to predict efficacy, the data might inform optimal use of therapies in the patient population. Furthermore, it is important to evaluate germline DNA variation across the genome to interpret tumor-specific DNA mutations.Genetic (DNA) tumor analyses

[0285] The application of new technologies, such as next generation sequencing, has provided scientists the opportunity to identify important tumor-specific DNA changes (e.g., mutations, methylation status, microsatellite instability, etc). Key molecular changes of interest to oncology drug development may also include the mutational burden of tumors and the clonality of T-cells in the tumor microenvironment. Microsatellite instability may also be evaluated as this is animportant biomarker for some cancers (e.g. colorectal cancer). Genome-wide approaches may be used for this effort. Note that to understand tumor-specific mutations, it is necessary to compare the tumor genome with the germline genome. Circulating tumor DNA may also be evaluated from biospecimens (e.g., blood, urine, etc).Tumor and / or blood RNA analyses

[0286] Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue and / or in blood may be performed to define gene signatures that might correlate to clinical response to treatment with antitumor therapies. Specific gene sets (e.g., those capturing interferon-gamma transcriptional pathways) may be evaluated and new signatures may be identified. Expression of individual genes may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal profiling. Circulating tumor RNA may also be evaluated from biospecimens (e.g., blood, urine, etc).Immunohistochemical (IHC) and / or proteomic analyses using tumor

[0287] Tumor samples from this study may undergo histopathological (e.g.,PD-Ll IHC). proteomic, and / or immunological analyses. These approaches could identify novel protein biomarkers that could aid in patient selection for antitumor therapy.Other biomarkers

[0288] In addition to expression on the tumor tissue, tumor-derived proteins can be shed from tumor and released into the blood. Assays such as ELISA may be used to measure such proteins in serum and / or plasma. Correlation of expression with response to therapy may identify new approaches for predictive biomarkers in blood, representing a major advance from today’s reliance on assessing tumor biomarkers.

[0289] Other molecular changes of interest may include the subtype of T-cells in the tumor microenvironment. The T-cell repertoire from tumor tissue and blood components may be evaluated. Furthermore, when applicable, cell populations may be also separated by either flow cytometry or mass cytometry-based sorting. These approaches may be used to quantify cell- and / or tissue-based analytes to further elucidate mechanism of action and / or assess disease- related parameters.Maximum Dose Exposure for This Study

[0290] The maximum duration of exposure to pembrolizumab 400 mg is 18 administrations (~2 years).

[0291] There is no maximum dose / exposure for Immunoconjugate A. Treatment with Immunoconjugate A will continue until any of the criteria for discontinuation are met.

[0292] The maximum dose and duration of exposure to chemotherapy will follow the approved label and / or institutional standards.Beginning and End-of-Studv Definition

[0293] The overall study begins when the first participant (or their legally acceptable representative) provides documented informed consent. The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up. For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last.STUDY POPULATION

[0294] As stated in the Code of Conduct for Clinical Trials, this study includes participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The collection and use of these demographic data will follow all local laws and participant confidentiality guidelines while supporting the study of the disease, its related factors, and the IMP under investigation.

[0295] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.Inclusion Criteria

[0296] An individual is eligible for inclusion in the study if the individual meets all of the following criteria:Type of Participant and Disease Characteristics1. Has unresectable locally advanced or metastatic centrally-confirmed HR+ / HER2- breast cancer, defined as:ER+ and / or PgR+ as determined by central testing on a tumor biopsy obtained preferably from a distant metastasis site or a local recurrence before study entry based on ASCO / CAP guidelines. Tumor will be considered HR+ if the tumor shows >1% expression of ER or PgR.HER2- as determined by central testing on a tumor biopsy obtained preferably from a distant metastasis site or a local recurrence before study entry based on ASCO / CAP guidelines. Tumor will be considered HER2- if the tumor shows HER2 zero or low, defined as IHC 0, 1+ or IHC 2+ / ISH-.

[0297] Note 1: ER / HER2 / PD-L1 / TROP2 reported as unknown or unevaluable will not be considered as valid result for eligibility / stratifi cation. No TROP2 expression will be considered as “Low”.

[0298] Note 2: Participants initially diagnosed with HER2+ breast cancer and TNBC are allowed but must have central confirmation of HR+ / HER2- breast cancer in the most recent tumor biopsy obtained (last archival or newly obtained from a distant metastasis site or a local recurrence).

[0299] Note 3: If an archival sample from a locally recurrent or distant (metastatic) site is not available and biopsy of a new metastatic lesion is not feasible due to anatomic site inaccessibility and / or participant safety concerns, an archival tumor tissue sample from the primary site may be accepted after consultation with the Sponsor with documented SCF.

[0300] Note 4: For participants who have metastatic disease with coexisting locally advanced lesions, if a newly obtained biopsy from a distant (metastatic) lesion is not feasible due to anatomic site inaccessibility and / or participant safety concerns, a new biopsy from the local disease (breast, chest wall, and / or regional lymph nodes) is permitted.

[0301] Note 5: Tumor tissue from bone metastasis (without soft tissue component) is not evaluable for biomarker status and therefore, this is not acceptable. Soft tissue from bone metastasis is acceptable.

[0302] Note 6: Adequacy of biopsy specimen for the above analyses must be confirmed by the central laboratory. Submission of another tumor specimen may be required if adequate tumor tissue was not provided the first time.2. Participants must have either:• Radiographic disease progression, as assessed by the investigator, on one or more lines of endocrine therapy for unresectable locally advanced / metastatic HR+ / HER2- breast cancer, with one in combination with a CDK4 / 6 inhibitor.OR• Radiographic disease progression as assessed by the investigator within 6 months (i.e., <6 months) of starting IL endocrine therapy in combination with a CDK4 / 6 inhibitor that was prematurely discontinued (before experiencing radiologic disease progression due to intolerance) for unresectable locally advanced or metastatic disease.OR• Radiographic disease progression as assessed by the investigator after 6 months (i.e., >6 months) of starting IL endocrine therapy in combination with a CDK 4 / 6 inhibitor that was prematurely discontinued (before experiencing radiologic disease progression due to intolerance) AND have also experienced radiologic disease progression on an additional endocrine therapy, either as monotherapy or as combination therapy (with a PI3K inhibitor or an mTOR inhibitor), for unresectable locally advanced or metastatic disease.OR• A relapse during, or within 12 months of completing adjuvant CDK.4 / 6 inhibitors in combination with adjuvant endocrine therapy.

[0303] Note 1 : Prior treatment with mTOR and / or PI3K inhibitors is allowed.

[0304] Note 2: Single-agent CDK4 / 6 inhibitors are considered a line of endocrine therapy.

[0305] Note 3: Changes in dosing schedules, or discontinuation and retreatment with the same combinations of drugs, or same class of drugs, i.e., changing from one aromatase inhibitor to another and / or from one CDK4 / 6 inhibitor to another in the absence of radiographic disease progression will not be considered separate lines of previous endocrine therapy.

[0306] Note 4: For participants with ER-low positive tumor (defined as ER expression between 1% and 10%) previous therapy with CDK4 / 6 inhibitors and / or endocrine therapy is permitted but not required.3. Is a chemotherapy candidate that meets the following criteria:• Participants who received taxane and / or anthracy clines (or capecitabine per local or institutional guidelines) in the neoadjuvant / adjuvant setting can be treated with same class of chemotherapy (taxane or anthracycline or capecitabine) if >12 months have elapsed between the completion of treatment with curative intent (e.g., date of primary breast tumor surgery or date of last adjuvant chemotherapy administration, whichever occurred last) and first documented local or distant disease recurrence.• Participants who will be selected to receive liposomal doxorubicin must have a LVEF of at least 50% or above the institution limit of normal, as assessed by ECHO or MUGA scan performed before the first dose administration.Demographics4. Is an individual of any sex / gender, from at least 18 years of age at the time of providing the informed consent.Male Participants5. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:• Immunoconjugate A: 100 days after the final dose• Paclitaxel: 95 days after the final dose• Nab-paclitaxel: 95 days after the final dose• Capecitabine: 95 days after the final dose• Liposomal doxorubicin: 95 days after the final dose• Pembrolizumab: no requirementsRefrains from donating spermPLUS either:Abstains from penile-vaginal intercourse as their preferred and usual 1 i fes tyl e (abstinent on a long-term and persistent basis) and agrees to remain abstinent ORUses contraception as detailed below unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) as detailed below:• Uses a penile / extemal condom when having penile-vaginal intercourse with a nonparticipant of childbearing potential who is not currently pregnant PLUS partner use of an additional contraceptive method, as a condom may break or leak.Note: Participants capable of producing ejaculate whose partner is pregnant or breastfeeding must agree to use a penile / extemal condom during each episode of sexual activity in which the partner is at risk of drug exposure via ejaculate.• Contraceptive use by participants capable of producing sperm should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be follow ed.Female Participants6. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the follow ing conditions applies: Is not a POCBPORIs a POCBP and:• Uses a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or is abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The participant agrees not to donate eggs (ova, oocytes) to others or freeze / store eggs during this period for the purpose of reproduction. The length of time required to continue contraception for each study intervention is: Immunoconjugate A: 190 days after the final dosePaclitaxel: 185 days after the final dose Nab-paclitaxel: 185 days after the final dose Capecitabine: 185 days after the final dose Liposomal doxorubicin: 185 days after the final dose Pembrolizumab: 120 days after the final dose• The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by POCBPs should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions are more stringent than the requirements above, the local label requirements are to be followed.• Has a negative highly sensitive pregnancy test (urine or serum) as required by local regulations within 24 hours (for a urine test) or 72 hours (for a serum test) before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g.,an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.• Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention.Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a POCBP with an early undetected pregnancy.Informed Consent7. The participant (or legally acceptable representative) has provided documented informed consent for the study.Additional Categories8. Measurable disease per RECIST 1.1 as assessed by the local site investigator / radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.

[0307] Note 1: Participants with bone-only disease can be included only if they have lytic or mixed lytic bone lesions with an identifiable soft tissue component which can be measured by RECIST 1. 1 as evaluated by CT or MRI, and they are able to provide a biopsy either from the bone associated soft tissue (last archival or newly obtained), or from the locally advanced tissue (locally recurrent breast, chest wall, and / or regional lymph node and / or primary’) if it coexists, as noted in Inclusion Criteria #!.

[0308] Note 2: Chest wall recurrence can be used as a target lesion, only if measurable by diagnostic quality CT or MRI (digital photography alone is not adequate).9. Participants who have AEs due to previous anticancer therapies must have recovered to <Grade 1 or baseline (except alopecia or vitiligo). Participants with endocrine-related AEs who are adequately treated with hormone replacement are eligible.10. If receiving bisphosphonates or RANK ligand inhibitors, with stable doses for >4 weeks before the date of randomization, the participant may continue receiving this therapy during the study treatment. If participant needs to initiate these agents during the screening period, a bone scan to evaluate bone disease should be performed before randomization.1 1. Adequate organ function as defined in the following table (Table 1). Specimens must be collected within 7 days before randomization.Table 1 Adequate Organ Function Laboratory Values12. HIV-infected participants must have well controlled HIV on ART, defined as: a. Participants on ART must have a CD4+ T-cell count >350 cells / mm3at the time of screening b. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening c. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months d. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study e. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors / inducers / substrates(https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers)

[0309] HIV screening test is not required unless mandated by local health authority.13. 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.

[0310] Note: Participants should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy post completion of study intervention.

[0311] Hepatitis B screening tests are not required unless:• Known history of HBV infection• As mandated by local health authority14. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.

[0312] Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to randomization.

[0313] Hepatitis C screening tests are not required unless:• Known history of HCV infection• As mandated by local health authority15. An ECOG performance status of 0 to 1 assessed within 7 days before randomization. a. Exclusion Criteria

[0314] An individual must be excluded from the study if the individual meets any of the following criteria:Medical Conditions1. Has breast cancer amenable to treatment with curative intent.2. Has experienced an early recurrence (<6 months after completing adjuvant / neoadjuvant chemotherapy) and therefore is eligible to receive 2L treatment.3. Has a known ESRI mutation and has not received previous treatment ith elacestrant (where available and not medically contraindicated).4. Has a known germline BRCA mutation (deleterious or suspected deleterious) and has not received previous treatment with PARP inhibition either in the adjuvant or metastatic setting (where available and not medically contraindicated).

[0315] ote: Single-agent PARP inhibitor wall not be counted as a line of chemotherapy or endocrine therapy.5. Has a history or current evidence of any condition (e.g. transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that is specifically contraindicated per the current locally approved labeling, that might confound the results of the study, interfere with the participant's involvement for the full duration of the study, or is not in the best interest of the participant to be involved, in the opinion of the treating investigator.6. Has advanced / metastatic, symptomatic visceral spread at risk of rapidly evolving into life-threatening complications, such as lymphangitic lung metastases, bone marrow replacement, carcinomatous meningitis, significant symptomatic liver metastases, shortness of breath requiring supplemental oxygen, symptomatic pleural effusion requiring supplemental oxygen, symptomatic pericardial effusion, symptomatic peritoneal carcinomatosis, or the need to achieve rapid symptom control.

[0316] Note:• Participants with symptomatic pleural effusion who have dyspnea at rest requiring supplemental oxygen, but which is alleviated by drainage of the fluid can be enrolled.• Participants with symptomatic ascitic effusion caused by peritoneal carcinomatosis which is alleviated after drainage of the ascitic fluid can be enrolled.• Participants with symptomatic liver metastases include participants with rapidly increasing bilirubin >1.5 x ULN in the absence of biliary obstruction with involvement of over than 50% of liver parenchyma by the disease.7. Has skin only disease. Participants who have metastatic disease fulfilling the previous criteria in addition to skin disease can be enrolled.8. Has active inflammatory bowel disease requiring immunosuppressive medication or previous history of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis, or chronic diarrhea).9. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >480 ms, and / or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention.10. Has Grade >2 peripheral neuropathy.11. Has history of documented severe dry eye syndrome, severe Meibomian gland disease and / or blepharitis, or comeal disease that prevents / delays comeal healing.Prior / Concomitant Therapy12. Has received prior chemotherapy for unresectable locally advanced or MBC.13. Has received prior treatment with a TROP2-targeted ADC at any time for early-stage or metastatic disease.14. Requires treatment with a strong inhibitor or inducer of CYP3A4 at least 14 days before the first dose of study intervention and throughout the study.

[0317] Note: A list of strong inhibitors or induces of CYP3A4 can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug- interactions-table-substrates-inhibitors-and-inducers15. Received prior systemic anti cancer therapy including investigational agents within4 weeks before randomization.

[0318] Note: Participants previously treated with endocrine therapy plus a targeted agent (e.g.,mT0R or PI3K or CDK4 / 6 inhibitors) may participate as long as at least 2 weeks have elapsed since the last dose of therapy was administered.16. Received prior radiotherapy for non-CNS disease, or required corticosteroids for radiation-related toxicities. within 14 days of the first dose of study intervention.17. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.Prior / Concurrent Clinical Study Experience18. Has received an investigational agent or has used an investigational device within4 weeks before randomization.Diagnostic Assessments19. 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 the first dose of study medication.20. Known additional malignancy that is progressing or has required active treatment within the past 5 years.

[0319] 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 prostatecancer (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.21. Participants with previously treated brain metastasis(es) may be eligible for study participation provided metastatic disease to the brain is radiographically stable, i.e., without site / investigator-assessed radiologic evidence of progression for at least 4 weeks prior to the screening brain scan. A brain scan must be obtained during screening (i.e., within 28 days of Cycle 1, Day 1) and must be >4 weeks after the previous post-treatment brain scan. Any neurologic symptoms must have returned to baseline and steroids must not have been used for management of symptoms related to brain metastases for at least 14 days prior to the first dose of study intervention. Participants with carcinomatous meningitis are excluded regardless of clinical stability.22. Severe hypersensitivity (>Grade 3) to pembrolizumab and / or any of its excipients.23. Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (e.g.. thyroxine, insulin, or physiologic corticosteroid) is allowed.24. History of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.25. Active infection requiring systemic therapy.26. HIV-infected participants with a history of Kaposi's sarcoma and / or Multicentric Castleman’s Disease.27. Has an ongoing symptomatic SARS-CoV-2 infection except for participants who have recovered clinically but continue to have a detectable presence of SAR-CoV-2 antigen. No COVID- 19 testing is required unless mandated by local authorities.28. 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. Note: Hepatitis B and C screening tests are not required unless:• Known history of HBV and HCV infection• As mandated by local health authority29. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the individual’s abi 1 i ty to cooperate with the requirements of the study, or interfere with the individual’s participation for the full duration of the study, such that it is not in the best interest of the individual to participate, in the opinion of the treating investigator.Other Exclusions30. Severe hypersensitivity (Grade >3) to Immunoconjugate A, any of its excipients and / or to another biologic therapy.31. History of allogeneic tissue / solid organ transplant.32. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.Measures to Minimize Bias: Randomization and BlindingIntervention Assignment

[0320] Intervention randomization will occur centrally using an IRT system. There are 3 study intervention arms. Participants will be assigned randomly in a 3:3:2 ratio to Immunoconjugate A, Immunoconjugate A plus pembrolizumab, or TPC, respectively .Concomitant Therapy

[0321] If there is a clinical indication for any medications or vaccinations prohibited, the investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. The final decision on any supportive therapy or vaccination rests with the investigator and / or the participant’s primary physician. However, the decision to continue the participant on study intervention requires the mutual agreement of the investigator and the Sponsor.

[0322] The following medications and vaccinations are prohibited during the study:• Live or live-attenuated vaccines within 30 days before the first dose of study intervention and while participating in the study, and for 30 days after the last dose of study intervention.• Systemic glucocorticoids except when used for the following purposes:• To modulate symptoms of an AE that is suspected to have an immunologic etiology• For the prevention of emesis• To premedicate for IV contrast allergies• To premedicate for IV chemotherapy• To premedicate for Immunoconjugate A• To treat asthma or COPD exacerbations (only short-term oral or IV use in doses >10 mg / day prednisone equivalent)• For chronic systemic replacement not to exceed 10 mg / day prednisone equivalent• Other glucocorticoid use except when used for the following purposes:• For topical use or ocular use• Intraarticular joint use• For inhalation in the management of asthma or COPD• Strong inhibitors or inducers of CYP3A4

[0323] Note: A list of strong inhibitors or induces of CYP3A4 can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-drug-interactions- table-substrates-inhibitors-and-inducers• Any medication prohibited in combination with chemotherapy as described in the respective product labels for paclitaxel, nab-paclitaxel, capecitabine, and liposomal doxorubicin.• Antineoplastic endocrine therapy, or combinations of endocrine therapy with other targeted agents or biological therapy not specified in this protocol, are not allowed.

[0324] Note: Bisphosphonates or RANK ligand inhibitors for bone metastases as standard of care (the participant must have been receiving stable doses for >4 weeks before randomization) are permitted per investigator’s discretion.

[0325] Note: If the participant will need to initiate bisphosphonates or RANK ligand inhibitors during the screening period, they should perform a bone scan before randomization.

[0326] Note: A participant with previously diagnosed bone metastatic disease can initiate bisphosphonates or RANK ligand inhibitors during the study treatment period, provided the bone progression is ruled out by imaging.

[0327] If the investigator determines that a participant requires any of the following prohibited medications and vaccinations for any reason during the study, study intervention must be discontinued:• Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not specified in this protocol• Investigational agents other than those specified in this protocol• Radiation therapyNote: It is highly recommended to institute palliative radiotherapy before study initiation in clinically indicated lesions if possible.Note: On-study palliative radiotherapy of non-target lesions only may be permitted after consultation with the Sponsor with documented SCF. During radiotherapy, the study intervention should be interrupted and resumed at least 1 week after the termination of radiotherapy. Radiotherapy of target lesions is not permitted.Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s discretion .• Investigational vaccines (i.e., those not licensed or approved for Emergency Use) are not allowed.Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country7is allowed in the study as long as they are mRNA vaccines, replication-incompetentadenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy.Rescue Medications and Supportive Care

[0328] Participants should receive appropriate supportive care measures as deemed necessary' by the treating investigator.Immunocon jugate A

[0329] The use of antiemetic therapy should follow Multinational Association of Supportive Care in Cancer and European Society for Medical Oncology7guidelines [Roila, F., et. Al. 2016] however, strong inhibitors or inducers of CYP3A4 are not permitted.

[0330] Before treatment with Immunoconjugate A, participants should receive prophylactic treatment to mitigate the onset and severity of stomatitis / oral mucositis in accordance with published ASCO and MASCC / ISOO guidelines [Broyvn, T. J. and Gupta, A. 2020] [Elad, S., et al. 2020],

[0331] It is highly recommended that participants use daily prophylactic steroid-containing mouthwash (e.g.. dexamethasone oral solution 0. 1 mg / mL 10 mL or equivalent [per institutional guidelines]) 4 times per day.• In the absence of a steroid-containing mouthwash, rinsing with bland solutions (e.g., normal saline, sodium bicarbonate, or tap water) at least 4 times per day or Mucoadhesive hydrogel (e.g.,MuGard) or calcium phosphate rinses (e.g.,Caphosol) are recommended.• Oral nystatin suspension or other topical antifungal agent can be used folloyving the steroid- containing mouthwash per investigator discretion and folloyving institutional guidelines.

[0332] Participants should also follow additional preventative measures:• Brushing with a soft toothbrush 2 times per day and flossing daily.• If a participant is considered high-risk for developing stomatitis, consider early dental assessment for aggressive prophylactic care (e.g., treatment of caries and extraction of compromised teeth).• Cryotherapy or ice chip therapy, where patients hold ice chips in their mouth for 30 minutes before and during the infusion.Pembrolizumab

[0333] Suggested supportive care measures for the management of AEs associated with study intervention are outlined along yvith the dose modification guidelines.

[0334] Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, the investigator does not need to follow the treatment guidance.

[0335] It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of evaluation of the event.Chemotherapy

[0336] Paclitaxel-related, nab-paclitaxel-related, capecitabine-related, and liposomal- doxorubicin-related AEs should be managed according to local approved labels.

[0337] Supportive care measures (e.g.,G-CSF, erythropoietin, blood transfusion) should be used according to local standards to manage chemotherapy-induced myelosuppression, including to prevent severe infections linked to febrile neutropenia. To minimize dose reductions, intermptions, and discontinuations of chemotherapy or ADC, these supportive care measures should be used before implementing dose modifications, when clinically appropriate.Dose Modification (Escalation / Titration / Other)

[0338] During treatment with study intervention, all participants should be closely monitored for treatment-related AEs and actively treated with supportive care. Dose modifications in response to treatment-related AEs are permitted to keep the participant on study intervention, when appropriate. Details on the modifications for each study intervention are provided in the sections below.

[0339] If a participant experiences a >10% weight change, the doses of Immunoconjugate A or TPC should be recalculated.Dose Modification for Immunoconjugate A

[0340] Recommended dose modification guidelines for Immunoconjugate A are provided in Table 2. Dosing delays for Immunoconjugate A due to an AE should not exceed 28 days of the last administered dose, unless otherwise discussed with the Sponsor.

[0341] If a dose reduction for an AE associated with Immunoconjugate A is needed, the dose can be reduced in 1 mg / kg increments [Table 2], One dose reduction is allowed (i.e., from 4 mg / kg to 3 mg / kg). If the participant experiences an AE that requires a second dose reduction but the participant is deriving clinical benefit, the decision to reduce and continue the participant on study intervention requires the mutual agreement of the investigator and the Sponsor.

[0342] Once the Immunoconjugate A dose has been reduced because of toxicity, all subsequent cycles are to be administered at that lower dose level unless further dose reduction is required. Reescalation is not permitted. If toxicity continues after all permitted dose reductions, then Immunoconjugate A should be permanently discontinued.

[0343] Participants should receive appropriate supportive care measures as deemed necessary by the treating investigator. If the proposed dose modification plan is inconsistent with theguidelines provided in Table 2, the investigator should discuss the management details with the Sponsor.Dose Modification and Toxicity Management of Infusion Reactions Related to Immunoconjugate A

[0344] Immunoconjugate A may cause severe or fatal infusion-related 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.

[0345] Premedication to prevent hypersensitivity and / or infusion reactions is required before each dose of Immunoconjugate A. Participants should be premedicated 1.5 hours (±30 minutes) before an infusion of Immunoconjugate A. For the first 4 administrations, participants should be premedicated with diphenhydramine (or equivalent [per approved product label]), H2 receptor antagonist (if available, per approved product label), acetaminophen (or equivalent [per approved product label]), and a corticosteroid (dexamethasone 10 mg IV [or equivalent]). After the fourth infusion, in the absence of prior infusion-related or hypersensitivity AEs. participants should be premedicated with diphenhydramine (or equivalent [per approved product label]) and acetaminophen (or equivalent [per approved product label]) with the addition of a corticosteroid and an H2 receptor antagonist at the discretion of the investigator. Dose modification and toxicity management of infusion reactions after Immunoconjugate A administration are provided in Table 3.

[0346] For participants in Arm B, pembrolizumab will be administered before Immunoconjugate A. Premedication for Immunoconjugate A should be administered after completion of the pembrolizumab infusion. In the event of an infusion reaction that occurs after pembrolizumab administration, Immunoconjugate A should be held until the infusion reaction has resolved.Other Allowed Dose Interruption for Immunoconjugate A

[0347] Immunoconjugate A 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. Study intervention is to be restarted within 14 days of the originally scheduled dose and within 28 days of the last administered dose, unless otherwise discussed with the Sponsor. The reason for study interv ention interruptions is to be documented in the participant’s studyrecord.Table 2 Dose Modification and Toxicity Management Guidelines for Adverse Events Associated With Immunoconjugate ATable 3 Infusion Reaction Dose Modification and Treatment Guidelines for Immunoconjugate ADose Modification for PembrolizumabImmune-Related Events and Dose Modification (Withhold, Treat, Discontinue)Dose Modification and Toxicity Management for Immune-related AEs Associated With Pembrolizumab

[0348] 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 interruptions 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.

[0349] Dose Modification and Toxicity Management Guidelines for irAEs Associated With Pembrolizumab Monotherapy, Coformulations, or IO Combinations are provided in Table 4.Table 4 Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With Pembrolizumab Monotherapy. Coformulations, or IO CombinationsDose Modification and Toxicity Management of Infusion Reactions Related to Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0350] 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 5.Table 5 Pembrolizumab Monotherapy, Coformulations, or IO Combinations Infusion Reaction Dose Modification and Treatment GuidelinesOther Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, or IO Combinations

[0351] 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 6 weeks of the originally scheduled dose and within 84 days 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.Dose Modification for TPC

[0352] Chemotherapy in the control arm can be reduced, interrupted, or discontinued as per the local label and / or local standard of care. Standard or reduced dose for any of the chemotherapy may be used after the first cycle as per standard clinical practice in case of toxicity. If a dose reduction for toxicity occurs with chemotherapy, the dose(s) may not be re-escalated. Participants may have a maximum of 2 dose modifications per chemotherapy (if applicable) for toxicities throughout the course of the study. If a participant experiences several toxicities and there are conflicting recommendations, the most conservative dose adjustment recommended should be followed (dose reduction appropriate to the most severe toxicity).

[0353] Should an investigator discontinue chemotherapy treatment in the absence of centrally-verified progression, the start of any type of subsequent therapy, including endocrine therapy, is not allowed. If this is absolutely necessary7, a discussion with the Sponsor’s Clinical Director is required.

[0354] Suggested dose modifications for chemotherapy are detailed in Table 6 (local guidelines and practices should be followed, if different than below recommendations).Table 6 Suggested Dose Modification for ChemotherapyManagement of Overlapping Toxicities

[0355] The IBs for Immunoconjugate A and pembrolizumab individually describe AEs commonly observed relative to each study intervention, as well as less common serious findings.

[0356] Attribution of such AEs to an individual study intervention may be difficult. The management actions (i.e., dose reduction, withholding or discontinuation) for toxicities with uncertain attribution should apply to both Immunoconjugate A and pembrolizumab, and the investigator should follow the most conservative dose modification guidelines and the approved labeling for pembrolizumab. If toxicity does not improve, the investigator should consider discontinuing each study intervention.DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANTWITHDRAWALDiscontinuation of Study Intervention

[0357] Discontinuation of study intervention does not represent withdrawal from the study.

[0358] As certain data on clinical events beyond study intervention discontinuation may be important to the study, they must be collected through the participant's last scheduled follow-up, even if the participant has discontinued study intervention. Therefore, all participants who discontinue study intervention before completion of the expected treatment period will still continue to be monitored in this study and participate in the study visits and procedures as specified unless the participant has withdrawn from the study.

[0359] Participants may discontinue study intervention at any time for any reason or be discontinued from the study intervention at the discretion of the investigator should any untoward effect occur. In addition, a participant may be discontinued from study intervention by the investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or for administrative and / or other safety reasons.

[0360] A participant must be discontinued from study intervention, but continue to be monitored in the study for any of the following reasons:• The participant or participant’s legally acceptable representative requests to discontinue study intervention.• Any prolonged interruption of study intervention beyond the permitted periods, for AE management or other allowed dose interruptions, require Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the participant will continue to be monitored in the study and the reason for discontinuation of study intervention will be recorded in the medical record.• The participant has a medical condition or personal circumstance which, in the opinion of the investigator and / or Sponsor, placed the participant at unnecessary risk from continued administration of study intervention.• The participant has a confirmed positive serum pregnancy test.• Radiographic disease progression (after obtaining informed consent addendum and Sponsor communication, the investigator may elect to continue treatment beyond BICR- verified disease progression).• Any progression or recurrence of malignancy, or any occurrence of another malignancy that requires active treatment.Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (excluding carcinoma in situ of the bladder) who have undergone potentially curative resection do not have to discontinue study intervention.• Any study intervention-related toxicity specified as a reason for permanent discontinuation as defined in the guidelines for dose modification due to AEs.• The participant requires prohibited medications. Note: Initiation of strong inhibitors or inducers of CYP3A4 by participants in either treatment arm will require discontinuation of study intervention.

[0361] For participants who are discontinued from study intervention, but continue to be monitored in the study, all visits and procedures, should be completed.

[0362] In Arm B, if a participant completes 18 administrations of pembrolizumab, the participant must be discontinued from pembrolizumab study intervention but may continue Immunoconjugate A treatment at the investigator’s discretion. The participant should continue to be monitored in the study.

[0363] Discontinuation from study interv ention is “permanent.” Once a participant is discontinued from study intervention, they shall not be allowed to restart study intervention. Timing of Dose Administration

[0364] Study intervention is to be administered at the study visits. After Cycle 1, study intervention may be administered up to 3 days before or after the scheduled day of administration. Participants will continue receiving study intervention until one of the criteria for treatment discontinuation are met. For participants in Arm B, pembrolizumab will be administered before Immunoconjugate A.Pembrolizumab

[0365] Pembrolizumab will be administered as a 30-minute IV infusion q6w. Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. A window of —5 minutes / +10 minutes is permitted.Immunocon jugate A

[0366] Immunoconjugate A will be administered by IV infusion on Days 1, 15, 29, 43, 57, and 71 of each 12-week cycle. The duration of the Immunoconjugate A infusions should be 90 minutes (±15) minutes and infusion-related AEs will be monitored. The infusion duration may be adjusted to be longer than 105 minutes at the discretion of investigator, but the infusion of Immunoconjugate A needs to be completed within the time frame specified in the Pharmacy Manual. After at least 4 administrations and in the absence of either infusion-related AEs or anaphylactic reactions, the infusion of Immunoconjugate A may be shortened at the discretion of investigator but cannot be shorter than 60 minutes (±15) minutes.

[0367] All participants are to be premedicated. Participants are to be closely monitored during infusions for the development of hypersensitivity reactions and / or infusion reactions. Emergency rescue medications (including epinephrine) and appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.TPC

[0368] TPC consists of one of the treatment options below. Management of toxicities should be performed in accordance with local guideline and practices.• Paclitaxel (80 mg / m2) will be administered as IV infusion on Day 1, qlw.• Paclitaxel (90 mg / m2) will be administered as IV infusion on Days 1, 8, and 15, q4w.• Nab-paclitaxel (100 mg / m2) will be administered as IV infusion on Days 1, 8, and 15, q4w.• Capecitabine will be administered orally BID on Days 1 to 14, q3w. On-site administrations will be on Days 1, 22, 43, and 64 of each cycle.• Liposomal doxorubicin (50 mg / m2) will be administered as IV infusion on Day 1 , q4w.Discontinuation and Withdrawal

[0369] Participants who discontinue study intervention before completion of the treatment period should be encouraged to continue to be followed for all remaining study visits.

[0370] Participants who withdraw from the study should be encouraged to complete all applicable activities scheduled for the final study visit at the time of withdrawal. Any AEs that are present at the time of withdrawal should be followed in accordance with the safety requirements.

[0371] Survival data should be collected from public sources (where permissible per local requirements) if a participant cannot be contacted directly.Participant Blinding / Unblinding

[0372] This is an open-label study; there is no blinding for this study. The emergency unblinding call center will be available so that a health care provider can obtain information about study intervention in emergency situations where the investigator is not available.Calibration of Equipment

[0373] The investigator or qualified designee has the responsibility to ensure that any device or instrument used for a clinical evaluation / test during a clinical study that provides information about inclusion / exclusion criteria and / or safety or efficacy parameters shall be suitably calibrated and / or maintained to ensure that the data obtained are reliable and / or reproducible.Documentation of equipment calibration must be retained as source documentation at the study site.Tumor Tissue for Biomarker Status

[0374] During the screening period, a tumor sample for each participant is required and is to be:A newly obtained core, incisional, or excisional biopsy of a metastatic tumor lesion, which was not previously irradiated.ORAn archival tumor tissue sample from a metastatic site if a new biopsy is unavailable (preferably the last one obtained before randomization).ORAn archival tumor tissue sample from the primary site may be accepted after consultation with the Sponsor with documented SCF, if an archival sample from a locally recurrent or distant (metastatic) site is not available and biopsy of a new metastatic lesion is not feasible due to anatomic site inaccessibility and / or participant safety concerns.

[0375] FFPE tissue blocks are preferred to slides. Newly obtained biopsies need to be performed before baseline (screening) tumor scan assessment.

[0376] Details pertaining to tumor tissue submission can be found in the Laboratory Manual.

[0377] The central laboratory will use the tissue sample to ascertain PD-L1 status using the PD- L1 IHC 22C3 pharmDx assay. This assay has been analytically validated to determine PD-L1 expression in breast cancer patients screening for the clinical study.

[0378] The central laboratory will use the tissue sample to ascertain TROP2 expression via immunohistochemistry. This assay has been analytically validated to determine TROP2 expression in breast cancer patients screening for the clinical study.

[0379] In case of samples obtained at the same time but the assessment yielded different biomarker expression results, the highest marker result will be used for determining eligibility and stratification.

[0380] The PD-L1 and TROP2 results will be masked to the site.Elevated Transaminases With Treated HBV or HCV

[0381] Participants who were treated for HBV or HCV, enrolled in the study, and present with elevated transaminases according to the criteria below should be evaluated for viral hepatitis exacerbation / reactivation.

[0382] If baseline AST / ALT <2 x ULN and an increase of AST / ALT >5 x ULN

[0383] If baseline AST / ALT >2 x ULN and an increase of AST / ALT >3 x baseline level

[0384] AST / ALT >500 U / L regardless of baseline

[0385] Viral load testing and additional hepatitis serologies should be included as required.Participants With Treated HIV

[0386] Participants with HIV should continue ongoing management by their health care provider(s), including monitoring of HIV viral load, CD4+ T-cell count, and additional supportive care measures.Efficacy AssessmentsTumor Imaging and Assessment of Disease

[0387] Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess tumor burden and may include cross-sectional imaging (such as CT or MRI), medical photography, or other methods as specified in this protocol.Initial Tumor Scans

[0388] Baseline tumor scans must be performed during the 28-day screening window to confirm measurable disease based on RECIST 1.1, as assessed by the site / local radiology review. Baseline tumor scans should be submitted for retrospective BICR.

[0389] If brain scans are required to document the stability of existing metastases, the brain scan should be acquired during screening. The specific methods permitted for this study are described in the SIM.

[0390] Bone scans are required at screening for participants with a history' of bone metastases and / or for those participants with indicative clinical signs / symptoms such as bone pain or elevated alkaline phosphatase levels.

[0391] Bone scan refers to imaging methods used to assess bone metastasis.Tumor Scans During the Study

[0392] The first on-study scan should be performed at 9 weeks (63 days ±7 days) from the date of randomization. Subsequent tumor scans should be performed every 9 weeks (63 days ±7 days) or more frequently if clinically indicated. After 54 weeks (378 days ±7 days), participants who remain on treatment will have scans performed every 12 weeks (84 days ±7 days). Scan timing should follow calendar days and should not be adjusted for delays in cycle starts.

[0393] Scans are to be performed until disease progression is identified by the investigator and verified by the BICR, or until any of these conditions are met:• the start of a new anti cancer treatment• pregnancy• death withdrawal of consent the end of the study

[0394] Note: New anticancer treatment refers to systemic therapy.

[0395] Objective response should be confirmed by a repeat scan performed at least 4 weeks after the first indication of a response is observed. Participants will then return to the regular scan schedule, starting with the next scheduled time point. Participants who receive additional scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 weeks later; scans may resume at the subsequent scheduled time point.

[0396] On-study brain scans should be performed at every study -related tumor assessment for participants with known stable brain metastases. Additional on-study brain scans should be performed if clinically indicated to all participants participating in the study.

[0397] On-study bone scans should be performed if clinically indicated or to confirm CR (if other lesions indicate CR and bone lesions existed at baseline).End-of- treatment and Follow-up Tumor Scans

[0398] If participants discontinue study intervention, tumor scans should be performed at the time of discontinuation (±4-week window) unless previous scans were obtained within 4 weeks of discontinuation. If participants discontinue study intervention due to documented disease progression, this is the final required tumor scan.

[0399] If participants discontinue study intervention without documented disease progression, every effort is to be made to monitor disease status by acquiring tumor scans using the same schedule calculated from the date of randomization.

[0400] Scans are to be continued until one of the following conditions are met:• disease progression as defined by RECIST 1.1 and verified by BICR• the start of a new anti cancer treatment

[0401] Note: An exception applies to participants who discontinue study intervention in the absence of a verified by BICR disease progression according to RECIST 1.1 to receive any type of endocrine therapy as new treatment. These participants will continue to submit images until their disease progresses by RECIST 1.1 according to investigator assessment, or until they start subsequent chemotherapy or ADC, whichever happens first.• pregnancy• death• withdrawal of consent• the end of the studv

[0402] Note: New anticancer treatment refers to systemic therapy.RECIST 1.1 Assessment of Disease

[0403] RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease progression, and as a basis for all protocol guidelines related to disease status (e.g, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.

[0404] Upon investigator-assessed disease progression, the indicative scan(s) are to be submitted immediately to iCRO for BICR verification of progression. After submission of scan(s), the iCRO will email the assessment to the site and Sponsor.

[0405] If disease progression is not verified, the process continues as follows:• If participant is clinically stable, continue study intervention per protocol• continue scans per protocol schedule (the next scheduled scan should be >4 weeks from most recent scan acquired)• send scans to iCRO• continue local assessment• do not change investigator assessment of progression• if subsequent scan(s) indicate progression, request verification from iCRO• If the participant is not clinically stable, best medical practice is to be applied.

[0406] If disease progression is verified, the process continues as follows:• investigator judgment will determine action• if the participant is clinically stable and study intervention is to continue, communication with the Sponsor is required and a reconsent addendum must be signed• obtain scans locally per original protocol schedule• do not send scans to iCRO

[0407] For the purpose of the study intervention decision process, lack of clinical stability is defined as: unacceptable toxicity clinical signs or symptoms indicating clinically significant disease progression decline in performance status- rapid disease progression or threat to vital organs or critical anatomical sites (e.g., CNS metastasis, respiratory failure due to tumor compression, spinal cord compression) requiring urgent alternative medical intervention.Patient-reported Outcomes

[0408] The EORTC QLQ-C30, EORTC QLQ-BR45, and EQ-5D-5L questionnaires will be administered by trained site personnel and completed electronically by participants in the following order: EORTC QLQ-C30 first, then EORTC QLQ-BR45 (administered to female participants only), and lastly EQ-5D-5L.

[0409] The questionnaires should be administered at the timepoints briefly summarized below:• Before dosing during the treatment period• At the EOT visit• At the 30-day safety follow-up visit (If the EOT visit occurs >30 days after the last dose of study intervention (i.e., no 3-day Safety Follow-up Visit occurs). PRO assessments only need to be performed at that visit.

[0410] It is best practice and strongly recommended that ePROs are administered to randomized participants before drug administration. AE evaluation, and disease status notification.Physical Examinations

[0411] Physical examination (full and directed) will be conducted by an investigator or medically qualified designee (consistent with local requirements) per institutional standard. Height and weight will also be measured and recorded. If >10% change in body weight occurs, the doses of Immunoconjugate A or TPC should be recalculated.Full Physical Examination

[0412] The investigator or qualified designee will perform a complete physical examination during the Screening period. Clinically significant abnormal findings should be recorded as medical history. After the first dose of study intervention, new clinically significant abnormal findings should be recorded as AEs.

[0413] Investigators should pay special attention to clinical signs related to previous serious illnesses.Directed Physical Examination

[0414] For cycles that do not require a full physical examination, the investigator or qualified designee will perform a directed physical examination as clinically indicated prior to study intervention administration. New clinically significant abnormal findings should be recorded as AEs.

[0415] Investigators should pay special attention to clinical signs related to previous serious illnesses.Vital Signs

[0416] Vital signs will be collected by the investigator or a medically qualified designee during screening, at each on-site dosing visit before any blood collection and administration of study intervention, treatment discontinuation, and safety follow-up.

[0417] Vital signs will include temperature, pulse rate, respiratory' rate, and BP (systolic and diastolic).

[0418] BP and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.Electrocardiograms

[0419] A 12-lead ECG will be obtained and reviewed by an investigator or medically qualified designee (consistent with local requirements) using an ECG machine that automatically calculates the heart rate and measures pulse rate, QRS, QT, and QTc intervals.

[0420] At screening, a single 12-lead ECG with QTcF measurement will be obtained for all participants.

[0421] For participants receiving Immunoconjugate A (Arm A), ECGs will be performed as follows during the treatment period:• On C1D1, before the first dose of Immunoconjugate A, a 12-lead ECG with QTcF measurement will be performed in triplicate in a supine position with the participant having rested for at least 5 minutes. The ECG tracings should be obtained as closely as possible in succession and no more than 5 minutes apart.• A single 12-lead ECG with QTcF measurement will be obtained before each subsequent dose. The predose ECG may be obtained within the 3 days preceding the scheduled dose.• A single 12-lead ECG with QTcF measurement will be obtained within 30 minutes after the end of the first, second, and fifth Immunoconjugate A infusions (i.e., C1D1, C1D15, and C!D57).

[0422] For participants receiving Immunoconjugate A in combination with pembrolizumab (Arm B), ECGs will be performed as follows during the treatment period:• On C1D1, before the first dose of Immunoconjugate A, a 12-lead ECG with QTcF measurement will be performed in triplicate in a supine position with the participant having rested for at least 5 minutes. The ECG tracings should be obtained as closely as possible in succession and no more than 5 minutes apart.• A single 12-lead ECG with QTcF measurement will be obtained before every third infusion of Immunoconjugate A. The predose ECG may be obtained within the 3 days preceding the scheduled dose.

[0423] Note: Clinically significant abnormal findings are to be evaluated including repeated ECGs if necessary. Additional time points may be performed as clinically indicated.

[0424] For participants assigned to TPC (Arm C), ECGs should be performed as clinically indicated during the treatment period.

[0425] For participants assigned to Arm B, if Immunoconjugate A is held but pembrolizumab is administered, ECG will not be collected.Echocardiogram or Multigated Acquisition Scan

[0426] A MUGA scan (using a technetium-based tracer) or an ECHO will be performed to assess LVEF. MUGA or ECHO scans should be performed locally in accordance with the institution's standard practice. Whichever modality is used for an individual participant at baseline should be repeated for all subsequent LVEF assessments for that participant. Investigator assessment will be based on institutional reports.

[0427] Participants who are selected to receive liposomal doxorubicin must meet prespecified LVEF requirements (at least 50% or above the institution limit of normal). The results should be available before administration on CID 1 dose of study intervention. LVEF should be measured by MUGA or ECHO. Additional LVEF assessments to be performed during the treatment according to institutional guidelines even in the absence of symptoms and as clinically indicated using always the same method (MUGA or ECHO) throughout the study.Clinical Safety Laboratory Assessments

[0428] The investigator or medically qualified designee (consistent with local requirements) must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study in the AE section of the CRF. The laboratory' reports must befiled with the source documents. Clinically significant abnormal laboratory findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant’s condition.

[0429] If laboratory' values from nonprotocol-specified laboratory assessments performed at the institution’s local laboratory require a change in study participant management or are considered clinically significant by the investigator (e.g.,SAE or AE or dose modification), then the results must be recorded in the appropriate CRF (e g , SLAB).

[0430] For any laboratory' tests with values considered clinically significantly abnormal during participation in the study or within 30 days after the last dose of study intervention, every attempt should be made to perform repeat assessments until the values return to normal or baseline or if a new baseline is established as determined by the investigator.Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)

[0431] Details regarding specific laboratory procedures / assessments to be performed in this study are provided below. The total amount of blood / tissue to be drawn / collected over the course of the study (from prestudy to poststudy visits), including approximate blood / tissue volumes drawn / collected by visit and by sample type per participant can be found in the Laboratory Manual.Pregnancy Testing

[0432] Pregnancy testing (urine or serum) should be conducted at every protocol treatment cycle.

[0433] Home pregnancy testing is acceptable if a clinic visit is not possible, however, the site must make monthly contact with the participant to determine the results of the pregnancy test.

[0434] Pregnancy testing (urine or serum) should be conducted for the time required to eliminate systemic exposure after the last dose of each study intervention and should correspond with the time frame for the participant’s contraception. The length of time required to continue pregnancy testing for each study intervention is:° Immunoconjugate A: 190 days after the final dose° Pembrolizumab: 120 days after the final dose° Paclitaxel: 185 days after the final dose° Nab-paclitaxel: 185 days after the final dose° Capecitabine: 185 days after the final dose° Liposomal doxorubicin: 185 days after the final dose

[0435] Additional serum or urine pregnancy tests may be performed, as determined necessary by the investigator or required by local regulation, to establish the absence of pregnancy at any time during the participant’s participation in the study.Performance AssessmentsEastern Cooperative Oncology Group Performance Status

[0436] The ECOG Performance Status is standardized criteria to measure how cancer impacts level of functioning (performance status) in terms of ability to care for oneself, daily activity, and physical ability (walking, working, etc.) with Grades 0 to 5.

[0437] The investigator or qualified designee will assess ECOG status at screening, before the administration of each dose of study intervention and during the follow-up period.Adverse Events, Serious Adverse Events, and Other Reportable Safety Events

[0438] Adverse events, SAEs, and other reportable safety events will be reported by the participant (or. when appropnate, by a caregiver, surrogate, or the participant’s legally authorized representative).

[0439] The investigator and any designees are responsible for detecting, documenting, and reporting events that meet the definition of an AE or SAE as well as other reportable safety events. Investigators need to document if an SAE was associated with a medication error, misuse, or abuse.

[0440] Investigators remain responsible for following up AEs, SAEs, and other reportable safety events for outcome. The investigator, who is a qualified physician, will assess events that meet the definition of an AE or SAE as well as other reportable safety events with respect to seriousness, intensity / toxicity. and causality.

[0441] AEs will not be collected for participants who consent to the limited screening visit for archival tissue collection if the participant has not undergone any other protocol-specified procedure or intervention.

[0442] AEs will be collected according to guidelines for standard AE reporting if the participant has consented and had any protocol-specified procedure or intervention during the limited screening (e.g., a blood draw).KEY STATISTICAL CONSIDERATIONS

[0443] This section outlines the principal statistical analysis strategy and procedures for the study. If, after the study has begun, but prior to any unblinding, changes are made to primary and / or key secondary hypotheses, then the protocol will be amended (consistent with ICHGuideline E9). Changes to ex loratory or other nonconfirmatory analyses made after the protocol has been finalized, but prior to final database lock, will be documented in an amendment of the SAP and referenced in the CSR for the study. Post hoc exploratory analyses will be clearly identified in the CSR. Other planned analyses (i.e., those specific to the analysis of PK data and biomarker data) will be documented in separate analysis / operational plans.Responsibility for Analyses / In-house Blinding

[0444] The statistical analysis of the data obtained from this study will be the responsibility of the Clinical Biostatistics department of the Sponsor.

[0445] This study is being conducted as a randomized, open-label study, i.e., participants, investigators, and Sponsor personnel will be aware of participant treatment assignments after each participant is enrolled and treatment is assigned. Although the study is open-label, analyses or summaries, generated by randomized study intervention assignment or by actual study intervention received, will be limited and documented. In addition, the independent radiologist(s) will perform the central imaging review without knowledge of treatment group assignment.

[0446] The investigator, study team of the Sponsor consisting of clinical, statistical, statistical programming and data management personnel, will be blinded to participant-level PD-L1 and TROP2 biomarker results. An unblinded Sponsor clinical scientist, unblinded data management personnel, unblinded Sponsor statistician and unblinded Sponsor statistical programmer will have access to the participant-level PD-L1 and TROP2 results for the purpose of data review and will have no other responsibilities associated with the study. A summary of PD-L1 and TROP2 biomarker prevalence may be provided to the study team of the Sponsor by the IRT vendor or the unblinded Sponsor statistician.

[0447] The Clinical Biostatistics department of the Sponsor will generate the randomized allocation schedule(s) for study treatment assignment, the randomization will be implemented in an IRT by a study vendor. is Endpoints

[0448] Efficacy and safety endpoints that will be evaluated are listed below.Efficacy EndpointsPrimaryProgression-free Survival (PFS)

[0449] PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review (BICR) or death due to any cause, whichever occurs first.• Overall Survival (OS)

[0450] OS is defined as the time from randomization to death due to any cause.Secondary• Objective Response (OR)The OR is defined as a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by BICR.• Duration of Overall Response (DOR)

[0451] For participants who demonstrate confirmed CR or PR per RECIST 1.1 as assessed by BICR, DOR is defined as the time from the first documented evidence of CR or PR until disease progression per RECIST 1. 1 based on BICR or death due to any cause, whichever occurs first.Exploratory• Disease Control (DC)

[0452] The DC is defined as a confirmed CR or PR or demonstrated SD for at least 24 weeks, per RECIST 1. 1 as assessed by BICR.• Progression-free Survival 2 (PFS2) as assessed by investigator

[0453] PFS2 is defined as the time from randomization to the documented second objective disease progression as assessed by the investigator or death due to any cause, whichever occurs first.Safety Endpoints

[0454] Safety7and tolerability7will be assessed by clinical review of all relevant parameters including adverse events, laboratory values and vital signs.PRO EndpointsSecondary• Change from baseline in EORTC QLQ-C30 global health status / QoL, physical functioning, emotional functioning, fatigue, and diarrhea scores.• Time to first deterioration (TTD) as measured by EORTC QLQ-C30 global health slalus / quality of life, physical functioning, emotional functioning, fatigue, and diarrhea scores is defined as the time from baseline to the first onset of a 10-points deterioration from baseline with confirmation at the subsequent visit of a 10-points deterioration from baseline.Analysis PopulationsEfficacy Analysis Populations

[0455] The ITT population will serve as the primary' population for analysis of efficacy data in this study, which consists of all randomized participants. Participants will be included in the treatment group to which they are randomized for the analysis of efficacy data using the ITT population.

[0456] The analysis population for DOR consists of participants in the analysis population of OR who demonstrate confirmed CR or PR.Safety Analysis Populations

[0457] Safety7Analyses will be conducted in the APaT population, which consists of all randomized participants who received at least one dose of study intervention. Participants will be included in the treatment group corresponding to the study intervention they actually received for the analysis of safety data using the APaT population. This will be the treatment group to which they are randomized except for participants who take incorrect study intervention for the entire treatment period; such participants will be included in the treatment group corresponding to the study intervention actually received.

[0458] Analyses of laboratory and vital sign will include only participants with at least one measurement obtained after at least one dose of study intervention. If the analysis will assess change from baseline, a baseline measurement is also required.PRO Analysis Populations

[0459] The PRO analy ses are based on the PRO Full Analysis Set (PRO FAS) population, defined as all randomized participants who have at least one PRO assessment available for the specific endpoint and have received at least one dose of the study intervention. Participants will be analyzed in the treatment group to which they are randomized.Statistical MethodsStatistical Methods for Efficacy Analyses

[0460] The primary hypotheses will be evaluated by comparing Immunoconjugate A as a single agent or in combination with pembrolizumab to the treatment of physician’s choice with respect to PFS in all participants. The key secondary hypotheses will be evaluated by comparing Immunoconjugate A as a single agent or in combination with pembrolizumab to the treatment of physician’s choice with respect to OS in all participants and comparing Immunoconjugate A in combination with pembrolizumab to Immunoconjugate A as a single agent with respect to PFS in all participants.- I ll -

[0461] For PFS and OS, the treatment difference in survival will be assessed by the stratified log-rank test. The hazard ratio (HR) and its 95% CI will be estimated using a stratified Cox proportional hazard model with Efron’s method of tie handling. The non-parametric Kaplan- Meier method will be used to estimate the survival curve in each treatment group.

[0462] ORR. defined as the proportion of participants with an OR, will be compared between the 2 treatment groups using the stratified Miettinen and Nurminen’s (M&N) method [Miettinen, O. and Nurminen, M. 1985] with strata weighting by sample size. The ORR difference and its 95% CI will be reported. The point estimate of ORR and its 95% CI will be provided by treatment group using the exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, E. S. 1934],

[0463] If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians and quartiles. Otherwise, only descriptive summary7statistics will be provided.Table 8 Analysis Strategy for Key Efficacy VariablesStatistical Methods for Safety Analyses

[0464] Safety and tolerability will be assessed by clinical review of AEs and other relevant parameters, including laboratory' test results and vital signs measurements.

[0465] The overall safety evaluation will include a summary' by treatment group 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. 1985] [.

[0466] 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.

[0467] For continuous safety measures, such as change from baseline in laboratory values, vital signs, summary statistics for baseline, on-treatment, and change from baseline values will be provided by treatment group.Statistical Methods for PRO Analyses

[0468] This section describes the planned analyses for the applicable PRO endpoints.

[0469] 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, S. L. 2000] will be applied with the PRO score as the response variable, and treatment, time, the treatment by time interaction, and stratification factors used for randomization as covariates. The treatment difference in terms of least square (LS) mean change from baseline will be estimated from this model together with 95% CL

[0470] The Kaplan-Meier method will be used to estimate the TTD curve in each treatment group. The treatment difference in TTD will be assessed by the stratified log-rank test. HR and its 95% CI will be estimated using a stratified Cox proportional hazard model with Efron’s method of tie handling.

[0471] 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 stratified M&N method with strata weighting by sample size. 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, C. J. and Pearson, E. S. 1934], 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.Interim Analyses

[0472] There are 2 planned IAS. Inferential analyses for PFS and OS will be provided to evaluate efficacy / futility. Interim results will be reviewed by an eDMC. Details will be provided in the SAP.

[0473] Access to the allocation schedule and the participant-level PD-L1 and TROP2 results will be restricted to an internal unblinded statistician and scientific programmer performing the IA, who will have no other responsibilities associated with the study.

[0474] The DMC will perform periodic interim safety reviews as specified in the DMC charter.Multiplicity

[0475] The overall type I error rate over the primary and key secondary hypotheses is strongly controlled at 2.5% (1 -sided) level, with initial alpha allocation of 1.5% to PFS for treatment comparison of Immunoconjugate A to TPC (Hl) and 1% to PFS for treatment comparison of Immunoconjugate A plus pembrolizumab to TPC (H2). The study uses the graphical method of Maurer and Bretz [Maurer, W., et al. 2011] to provide strong multiplicity control for multiple hypotheses as well as interim analyses. According to this approach, study hypotheses may be tested more than once, and when a particular null hypothesis is rejected, the a allocated to that hypothesis can be reallocated to other hypothesis tests. Details will be provided in the SAP.Sample Size and Power Calculations

[0476] The study will randomize -1200 participants in a 3:3:2 ratio into the Immunoconjugate A, Immunoconjugate A plus pembrolizumab and TPC arms. PFS is primary endpoint for the study, with OS as the key secondary endpoint.

[0477] For the PFS endpoint for treatment comparison of Immunoconjugate A to TPC. based on a target number of 518 events in all participants at the final PFS analysis, the study has approximately 88.6% power to detect a hazard ratio of 0.74 at the initially allocated a=0.015 (1- sided).

[0478] For the PFS endpoint for treatment comparison of Immunoconjugate A plus pembrolizumab to TPC, based on a target number of 486 events in all participants at the final PFS analysis, the study has approximately 99.9% power to detect a hazard ratio of 0.58 at the initially allocated a=0.01 (1-sided).

[0479] For the OS endpoint for treatment comparison of Immunoconjugate A to TPC, based on a target number of 488 events in all participants at the final OS analysis, the study has approximately 80. 1% power to detect a hazard ratio of 0.75 at a=0.012 (1-sided) when PFS hypothesis for treatment comparison of Immunoconjugate A to TPC is rejected.

[0480] For the OS endpoint for treatment comparison of Immunoconjugate A plus pembrolizumab to TPC, based on a target number of 479 events in all participants at the final OS analysis, the study has approximately 89.7% power to detect a hazard ratio of 0.71 at a=0.008 (1- sided) when PFS hypothesis for treatment comparison of Immunoconjugate A to TPC is rejected.

[0481] For the PFS endpoint for treatment comparison of Immunoconjugate A plus pembrolizumab to Immunoconjugate A, based on a target number of 635 events in all participants at the final PFS analysis, the study has approximately 64.6% power to detect a hazard ratio of 0.79 at a=0.005 (1-sided) when both PFS hypotheses for treatment comparisons to TPC are rejected.

Claims

WHAT IS CLAIMED IS:

1. A method of treating HR+ / HER2- metastatic or locally advanced breast cancer in a human patient, said method comprising administering to the patient:(a) an amount of an anti -human PD-1 antibody or antigen binding fragment thereof; and(b) an amount of an Immunoconjugate of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10, and wherein the amounts of (a) and (b) administered are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

2. The method of claim 1, wherein n is from 6 to 8.

3. The method of claim 1 or 2, wherein the antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 39, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 40; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 41, and(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 44.

4. The method of any of claims 1-3, wherein the antibody that binds to Trop-2 comprises:(i) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 37, and(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 38.

5. The method of any of claims 1-4, wherein the antibody that binds to Trop-2 comprises:(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 35, and(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 36.

6. The method of any of claims 1-5, wherein the antibody that binds to Trop-2 is sacituzumab, and n is 1 to 8.

7. The method of any of claims 1-6, wherein the Immunoconjugate of Formula (I) is administered to the patient at a dose from 1.0 mg / kg to 6.0 mg / kg.

8. The method of any of claims 1-7, wherein the PD-1 antagonist thereof is selected from nivolumab. cemiplimab, dostarlimab, pidilizumab, tislelizumab and pembrolizumab.

9. The method of claim 8, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

10. The method of any of claims 1-9, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is administered to the patient at a dose of 50 mg to 500 mg.1 1. The method of any of claims 1-10, wherein the Immunoconjugate of Formula (I) is administered in two week cycles, and administered on day 1 of each two-week cycle.

12. The method of any of claims 1-1 1. wherein the Immunoconjugate of Formula (I) and the anti -human PD-1 antibody or antigen binding fragment are administered in six-week cycles, wherein the Immunoconjugate of Formula (I) is administered on days 1, 15, and 29 of each six -week cycle, and the anti -human PD-1 antibody or antigen binding fragment thereof is administered on day 1 of each six-week cycle.

13. The method of any of claims 1-12, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400 mg, and the Immunoconjugate of Formula (I) is administered at a dose of about 4 mg / kg.

14. The method of any of claims 1-12, wherein the anti-human PD-1 antibody or antigen binding fragment thereof is administered at a dose of about 400 mg, and the Immunoconjugate of Formula (I) is administered at a dose of about 5 mg / kg.

15. The method of any of claims 11-14, wherein the number of cycles is from 1-18.

16. The method of any of claims 1-15. wherein the HR+ / HER2- metastatic or locally advanced breast cancer is unresectable.

17. The method of any of claims 1-16, wherein the HR+ / HER2- metastatic or locally advanced breast cancer has been previously treated.

18. The method of claim 17, wherein the HR+ / HER2- metastatic or locally advanced breast cancer was previously treated with CDK4 / 6i therapy.

19. The method of any of claims 1-18. further comprising administering to the patient an additional anticancer agent.

20. A pharmaceutical composition comprising:(a) an anti -human PD-1 antibody or antigen binding fragment thereof;(b) a pharmaceutically acceptable carrier; and(c) a plurality of Immunoconjugates of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and wherein n is an integer from 1 to 10 and the average of n for the plurality of Immunoconjugates of Formula (I) is a real number from X to Y; and wherein the amounts of (a) and (c) present in the composition are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

21. The pharmaceutical composition of claim 20, wherein the antibody that binds to Trop-2 is sacituzumab.

22. The pharmaceutical composition of claim 20 or 21, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

23. A kit comprising:(a) an anti -human PD-1 antibody or antigen binding fragment thereof; and(b) an Immunoconjugate of Formula (I):(I), wherein:Ab is an antibody that binds to Trop-2; and each n is an integer from 1 to 10, wherein the amounts of (a) and (b) present in the kit are together effective to treat HR+ / HER2- metastatic or locally advanced breast cancer.

24. The kit of claim 23, further comprising instructions for administering the Immunoconjugate of Formula (I), and the anti-human PD-1 antibody or antigen binding fragment thereof to a human patient.

25. The kit of claim 23 or 24, wherein the anti -human PD-1 antibody or antigen binding fragment thereof is pembrolizumab.

26. The kit of any of claims 23-25, wherein the Immunoconjugate of Formula (I) is Immunoconjugate A.

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