WO2025212469A1

WO2025212469A1 - Use of an immunoconjugate for the treatment of gastric cancer

Info

Publication number: WO2025212469A1
Application number: PCT/US2025/022224
Authority: WO
Inventors: Pooja BHAGIA; Abby SIEGEL
Original assignee: Merck Sharp and Dohme LLC
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2024-04-03
Filing date: 2025-03-31
Publication date: 2025-10-09
Anticipated expiration: 2026-10-03

Abstract

The present disclosure relates to methods of treating gastric cancer in a patient, said methods comprising administering to the patient an Immunoconjugate of Formula (I) wherein: Ab is an antibody that binds to Trop-2; and n is an integer from 1 to 10, and wherein the amount of Immunoconjugate (I) administered is effective to treat gastric cancer.

Description

USE OF AN IMMUNOCONJUGATE FOR THE TREATMENT OF GASTRIC CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/573,921 filed April 3. 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 (25924-WO-PCT_SL.xml; Size: 10,365 bytes; and Date of Creation: May 23, 2024) are herein incorporated by reference in their entirety.

FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to use of an Immunoconjugate for the treatment of gastric cancer.

BACKGROUND OF THE DISCLOSURE

[0004] 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 growth, 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.

[0005] 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 breast cancer, colon cancer, endometrial cancer, non-small cell lung cancer (NSCLC). 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, however 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.

[0006] TROP-2 may play a role in tumor progression given the involvement in several molecular pathways traditionally associated with cancer development. High TROP-2 expression correlates with poor prognosis in various cancers, and in a meta-analysis including 2,569 patients, increased TROP-2 expression was associated with poor overall and disease-free survival outcomes across several solid tumors. [0007] Esophageal cancer is three to four times more common in men than in women. Risk factors for esophageal cancer include smoking tobacco and heavy alcohol use as well as having acid reflux, which can inflame the cells of the esophagus and GEJ. Esophageal cancer is estimated to affect approximately 500.000 people globally each year. In the U.S. alone, there will be an estimated 22,000 new cases of esophageal cancer and 16.000 deaths in 2023. The five-year relative survival rate for patients with esophageal cancer is 43% for patients with localized disease found only in the esophagus; 23% for regional disease that has spread to nearby lymph nodes and organs; and 5% for metastatic disease that has spread to distant parts of the body. [0008] In some cancers, TROP-2 expression appears to be correlated with resistance to available treatments and metastatic potential. For example, the expression of TROP2 was described in several studies as being associated with the invasion and metastasis of cancer cells, resulting in poor prognoses of gastric cancer, pancreatic cancer, oral cancer, colon cancer, and ovarian carcinoma. Studies have shown that there is a correlation between the gastric cancer patients' clinicopathologic features and the TROP2 and pTROP2 expression in their tumors. Therefore, TROP-2 presents an attractive target for development of new therapies for the treatment of gastric cancers.

[0009] There are currently no Phase 3 safety or efficacy data in gastric cancer for TROP-2 ADCs; however, preclinical studies have shown that Sacituzumab govitecan has demonstrated activity against gastric cancer. Sacituzumab govintecan is an ADC comprised of a humanized anti-TROP-2 antibody (hRS7) and a topoisomerase I inhibitor (SN-38, an irinotecan metabolite) linked through a pH-sensitive conjugation.

SUMMARY OF THE PRESENT DISCLOSURE

[0010] In a first aspect, the present disclosure provides a method of treating gastric cancer in a human patient, said method comprising administering to the patient 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 amount administered of Immunoconjugate (I) administered is effective to treat gastric cancer.

[0011] In embodiment no. 1 of this method, the gastric cancer is locally advanced.

[0012] In embodiment no. 2 of this method, the gastric cancer is metastatic.

[0013] In embodiment no. 3 of this method, the gastric cancer has been previously treated.

[0014] In embodiment no. 4 of this method, the gastric cancer has been previously treated with systemic therapy.

[0015] In embodiment no. 5 of this method, the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma. [0016] In embodiment no. 6 of this method, the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma, wherein said gastric cancer is locally advanced or metastatic.

[0017] In embodiment no. 7 of this method, the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma, wherein said gastric cancer has been previously treated with systemic therapy.

[0018] In embodiment no. 8 of this method, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0019] In embodiment no. 9 of this method, the patient is administered 4.0 mg/kg of Immunoconjugate A every 2 weeks.

[0020] In embodiment no. 10 of this method, the patient is administered 4 mg/kg of Immunoconjugate A on days 1, 15, and 29 of a 6-week cycle. DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE

DEFINITIONS AND ABBREVIATIONS

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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 w hole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0025] 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, and heteroconjugate antibodies, multi-specific (e.g, bispecific) antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFv, and tandem tri-scFv.

[0026] 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.

[0027] 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.

[0028] 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 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 two-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.

[0029] 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 well known. 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, the fragments are single-chain antibody fragments comprising a variable heavy chain region and/or a variable light chain region, such as scFvs.

[0030] 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.

[0031] “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). [0032] As used herein, the term “antibody⁷’ 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.

[0033] 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 heavy chain also including a "D" region of about 10 more amino acids. See generally. Fundamental Immunology⁷ Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0034] “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.

[0035] 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 carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a patient. [0036] 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.

[0037] A “CDR’' refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH [i-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 et 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 (ALLazikani 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 below in 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

[0038] “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.

[0039] “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 another species 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.

[0040] “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 property⁷ 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 Substitutions

[0041] The 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 the composition 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.

[0042] As used herein, the term “gastric cancer” means gastroesophageal cancer, esophageal cancer or stomach cancer. In one embodiment, the gastric cancer is stomach cancer. In a specific embodiment, the stomach cancer is gastric adenocarcinoma. In another embodiment, the gastric cancer is gastroesophageal cancer. In a specific embodiment, the gastroesophageal cancer is gastroesophageal adenocarcinoma. In other specific embodiments, the gastroesophageal adenocarcinoma is gastroesophageal junction adenocarcinoma. In some embodiments, the esophageal cancer is squamous cell cancer of the esophagus or small call cancer of the esophagus.

[0043] 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.

[0044] “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, e.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 x 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 give maximum 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.

[0045] 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.

[0046] “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.

[0047] “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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] “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 Service, National Institutes of Health, Bethesda, Md.). [0053] "Monoclonal antibody’⁷ or “mAh” 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 t pically include a multitude of different antibodies having different amino acid sequences in their variable domains, 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. 116:731.

[0054] “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 alk lating agents that crosslink DNA, resulting in ineffective DNA mismatch repair and generally leading to apoptosis. Examples of platins include cisplatin, carboplatin, and oxaliplatin.

[0055] 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.

[0056] The term “patient in need thereof’ as used herein refers to a patient diagnosed with, or suspected of having, gastric cancer, as defined herein.

[0057] 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.

[0058] 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 employed herein, 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.

[0059] Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates (“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 (Food & Drug Administration, Washington, D C. on their website). These disclosures are incorporated herein by reference thereto.

[0060] 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 alky l 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., benzy l and phenethyl bromides), and others. Compounds carrying 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.

[0061] 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.

[0062] 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.

[0063] “RECIST 1. 1 Response Criteria” as used herein means the definitions set forth in Eisenhauer, E.A. et al., Ear. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.

[0064] “Responder patient” when referring to a specific anti -tumor response to a treatment described herein, means the patient exhibited an anti-tumor response.

[0065] “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.

[0066] 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.

[0067] “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.

[0068] “Treat” or “Treating” gastric cancer as used herein means to administer an Immunoconjugate of Formula (I) to a patient having gastric cancer, or diagnosed with gastric 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 grow th, 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 therapy 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, gastric cancer.

[0069] 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. [0070] Positive therapeutic effects in cancer can be measured in a number of ways (See, W. A. Weber, J. Nucl. Med. 50: 1 S-10S (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.

[0071] 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 therapy of the present disclosure.

[0072] “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).

[0073] “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.

[0074] The term “tumor size’’ 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 know n 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.

[0075] “Variable regions” as used herein means the segment of IgG chains which is variable in sequence between 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.”

[0076] Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining 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 ammo 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.

[0077] The term “variant” when used in relation to an antibody (e.g., 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- TROP2 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-TROP2 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-TROP2 antibody variant) at least retains the antibody functional activity.

[0078] 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.

[0079] 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.

[0080] 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. [0081] 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.

The following Abbreviations are used herein, and are defined as follows:

ADC Antibody-Drug Conjugate

AE Adverse Effect

ALT Alanine transaminase

APaT All patients as treated population

ASCO American Society’ of Clinical Oncology AST Aspartate aminotransferase BICR Blinded independent central review BRCA Breast cancer gene CNS Central nervous system COVID Coronavirus disease CPS Central pain syndrome CR Complete response CRF Case report form CSR Clinical study report CT Computerized tomography CTCAE Common terminology criteria for adverse effects CYP3A4 Cytochrome P450 3A4 DOR Duration of Response ECHO Echocardiogram ECOG Eastern Cooperative Oncology Group ECG Electrocardiogram eCRF Electronic case report form eDMC Executive data monitoring committee EORTC European Organization for Research and Treatment of Cancer G-CSF Granulocyte Colony Stimulating Factor GEJ Gastroesophageal junction adenocarcinoma 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 Low er limit of quantification LVEF Left ventricular ejection fraction mAb Monoclonal antibody MASCC/ISOO Multinational association of supportive care in cancer MRI Magnetic resonance imaging MSI Microsatellite instability screening 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 OTC Over the counter PD-1 Programmed cell death protein 1 PD-L1 Programmed death ligand 1 PET Postiron Emission Tomography PFS Progression free survival PI3K Phosphoinositide 3-kinase

POCBP Persons of childbearing potential

PR Partial response

PRO Patient-reported outcome ePRO Electronic patient-reported outcome

PSA Prostate specific antigen

QoL Quality of Life

QRS QRS complex

QT QT interval

QTc QTc interval

QTcF QT interval corrected for heart rate

RECIST Response Evaluation Criteria in Solid Tumors

SAE Serious adverse effect

SAP Statistical analysis plan

SNP Special needs plan

SOC Standard of care

TPC Therapy of Physician’s choice

TROP-2 Tumor-associated calcium signal transducer 2

ULN Upper limit of normal

VH immunoglobulin heavy chain variable region

VL immunoglobulin light chain variable region

[0082] Additional abbreviations may be defined throughout this disclosure.

[0083] The present disclosure relates to methods of treating gastric cancer, wherein the method comprises administering to a human patient in need thereof an Immunoconjugate of Formula (I).

[0084] In some embodiments of the present methods, the Immunoconjugate of Formula (I) is

Immunoconjugate A, which is described in US Patent Publication No. 20200347075 and

International Publication No. WO2019/114666. Immunoconjugate A has the structure: wherein n is an integer from 1 to 8; and Ab is sacituzumab.

The Immunoconjugate of Formula (I) [0085] 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.

[0086] In a class of this embodiment, the Ab is linked via one or more thiol group(s) to form the conjugate. In a specific embodiment, the Ab is linked via one or more thiol group(s) that are present on one or more cysteine residues of the Ab, to form the conjugate.

[0087] In certain embodiments, immunoconjugates useful in the present disclosure are those Immuoconjugates of Formula (I): wh erein n is an integer from 1 to 10; and

Ab 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: 5; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and

(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 8; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0088] In certain embodiments, immunoconjugates useful in the present disclosure are those Immuoconjugates of Formula (I): wherein n is an integer from 1 to 10; and

Ab is an antibody that binds to TROP-2 comprising:

(i) a heavy chain variable region having the amino acid sequence of SEQ ID No.: 3; and

(ii) a light chain variable region having the amino acid sequence of SEQ ID No.: 4.

[0089] In certain embodiments, immunoconj ugates useful in the present disclosure are those

Immuoconjugates of Formula (I): wherein n is integer from 1 to 10; and

Ab is an antibody that binds to TROP-2 comprising:

(i) a heavy chain having the amino acid sequence of SEQ ID No. : 1 ; and

(ii) a light chain having the amino acid sequence of SEQ ID No.: 2.

[0090] In preferred embodiments, the Immunoconjugate of Formula (I) is Immunoconjugate A, which is described in US Patent Publication No. 20200347075. Immunoconjugate A is an Immunoconjugate of Formula (I):

wherein n is an integer 1 to 8; and

Ab is sacituzumab.

[0091] In other preferred embodiments, a composition comprising the Immunoconjugates of Formula (I) is administered wherein the average “n"’ of the composition is a decimal from 0 to 8; and

Ab is sacituzumab.

[0092] In another embodiment of the present disclosure is a method of treating gastric cancer in a patient, said method comprising administering to the patient an immunoconjugate comprising an anti-Trop-2 monoclonal antibody conjugated to a linker-drug moiety of Formula (II):

(II), wherein: v/vvx 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, and wherein the amount of the Immunoconjugate of Formula (I) administered is effective to treat gastric cancer. [0093] 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: 5, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and

[0094] 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: 3, and

(ii) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 4.

[0095] 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: 1, and

(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 2.

[0096] In still another class of this embodiment, the anti-Trop-2 monoclonal antibody is sacituzumab and n is 1 to 8.

[0097] Another embodiment is a method of treating gastric cancer in a patient, said method comprising administering to the patient a composition comprising 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. wherein the amount of the Immunoconjugate of Formula (I) administered is effective to treat gastric cancer.

[0098] 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: 5, an HCDR2 comprising the ammo acid sequence of SEQ ID NO: 6; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 7, and

(ii) a light chain variable region comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 8; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 9: and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0099] In another class of this embodiment, antibody that binds to Trop-2 comprises:

[0100] 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: 1, and (li) a light chain comprising the amino acid sequence of SEQ ID NO: 2.

[0101] In still another class of this embodiment, antibody that binds to Trop-2 is sacituzumab and n is 1 to 8.

[0102] 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.

[0103] Yet another embodiment is a method of treating gastric cancer in a patient, said method comprising administering to the patient a composition comprising an 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, wherein the amount of the Immunoconjugate of Formula (I) administered is effective to treat gastric cancer.

[0104] In one class of this embodiment, the amount in the composition of the Immunoconjugate of Formula (I) is effective to treat the gastric cancer in the patient.

[0105] In yet another embodiment of the present disclosure is provided a method of treating gastric cancer in a patient in need thereof.

[0106] 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.

[0107] Table 3 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 3. List of sacituzumab (“Abl”) Amino Acid Sequences

[0108] 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.

[0109] 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). In a specific embodiment, the Immunoconjugate of Formula (I) is Immunoconjugate A, and n is from 6 to 8.

[0110] 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.

[0111] 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.

[0112] 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 Disclosure

Treatment or Prevention of Gastric Cancer

[0113] The therapies disclosed herein are potentially useful in treating gastric cancer. The terms “cancer”, “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0114] Accordingly, in one aspect, the present disclosure relates to methods of methods for treating gastric cancer in a patient, the method comprising administering to the patient an Immunoconjugate of Formula (I), wherein the amount administered is effective to treat gastric cancer.

[0115] In a specific embodiment, the amount administered is effective to treat gastric 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. [0116] In one embodiment, the gastric cancer is relapsed. In another embodiment, the gastric cancer is refractory. In yet another embodiment, the gastric cancer is relapsed and refractory. [0117] In one embodiment, the patient has previously received treatment for the gastric cancer. In another embodiment, the patient has not previously received treatment for cancer.

[0118] In one embodiment, the patient has previously received systemic treatment for the gastric cancer. In another embodiment, the patient has not previously received systemic treatment for the gastric cancer.

[0119] In one embodiment, the patient has previously received radiation therapy for the gastric cancer. In another embodiment, the patient has not previously received radiation therapy for the gastric cancer.

[0120] In specific embodiments the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma.

[0121] The compositions, methods, kits, and uses provided herein are useful for the treatment of gastric cancer.

[0122] The term "cancerous cell" as used herein, includes a cell afflicted by any one of the above-identified conditions.

[0123] In particular embodiments, the gastric cancer is classified as stage III cancer or stage IV cancer. In some instances of these embodiments, the gastric cancer is not surgically resectable.

ADMINISTRATION AND DOSAGE

[0124] The present disclosure relates to methods of treating gastric cancer, said method comprising administering to a patient in need thereof an Immunoconjugate of Formula (I), wherein the amount administered is effective to treat or prevent the gastric cancer. In one embodiment of this method, the patient is a human patient.

[0125] The Immunoconjugates of Formula (I), will (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), 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 include oral administration, intravenous administration, and subcutaneous 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.

[0126] In embodiments of the compositions, methods, kits, and uses disclosed herein, Immunoconjugate of Formula (I) is administered by intravenous infusion or subcutaneous injection. In a specific embodiment, the Immunoconjugate of Formula (I) are each administered by intravenous infusion.

[0127] In some embodiments, the 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 therapies of the present disclosure are administered for a period until the patient is cured of the diseases or disorders. In some embodiments, the therapies of the present disclosure are administered for a period until the patient shows resistance to the therapy. In some embodiments, the therapies of the present disclosure are administered for a period until the patient shows side effects that would require discontinuation of the therapy.

[0128] 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 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 therapy is administered.

[0129] A 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.

[0130] In some embodiments, therapy of the present disclosure is administered to a patient who has not previously been treated with a biotherapeutic or chemotherapeutic agent, i.e., is treatment-naive. In other embodiments, the therapy is administered to a patient who failed to achieve a sustained response after prior therapy with the biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.

[0131] 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 (1) 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.

[0132] In one embodiment, in the 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 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.

[0133] 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-week 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 (1) 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 (1) is administered at 3.00 mg/kg every 3 weeks.

[0134] 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.

[0135] 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 and administration 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.

[0136] 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.

[0137] In one embodiment, provided is a method treating gastric cancer, said method comprising administering to a patient in need thereof an Immunoconjugate of Formula (I); wherein the Immunoconjugate of Formula (I) is administered on days 1, 15, and 29 of a six-week cycle.

[0138] In a specific embodiment, 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, 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, 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.

[0139] In a specific embodiment, the Immunoconjugate of Formula (I) is Immunconjugate A. [0140] In another embodiment, the Immunoconjugate of Formula (I) is administered in from 1 to 18 six-week cycles.

[0141] In a specific embodiment, the Immunoconjugate of Formula (I) is administered to a patient to treat gastric cancer.

[0142] In a specific embodiment, the Immunoconjugate of Formula (I) is administered to a patient to treat gastric cancer that has been previously treated.

[0143] In another specific embodiment, the Immunoconjugate of Formula (I) is administered to a patient to gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma.

[0144] In a further specific embodiment, the Immunoconjugate of Formula (I) is administered to a patient to treat metastatic or locally advanced gastric cancer that has been previously treated with systemic therapy.

Additional Therapeutic Agents

[0145] An immunoconjugate of Formula (I) 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, the Immunoconjugate of Formula (I) 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 the Immunoconjugate of Formula (I).

[0146] Accordingly, in one aspect, the present disclosure provides pharmaceutical compositions comprising: (a) an Immunoconjugate of Formula (I), (b) an additional therapeutic agent, or pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable carrier. In one embodiment, the amounts of (a) and (b) are together effective to treat gastric cancer.

[0147] In one embodiment, provided herein is a pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) 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, also known as the DAR (drug antibody ratio) for the plurality of Immunoconjugates of Formula (I) is a real number from 1 to 10.

[0148] In one class of this embodiment, the amounts of the Immunoconjugate of Formula (I) present in the composition is effective to treat gastric cancer. In specific embodiments the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma.

[0149] In one embodiment, for the pharmaceutical composition, the antibody that binds to Trop-2 is Sacituzumab, and n is an integer from 1 to 10 and the average n, also known as the DAR is a real number from 1 to 8.

[0150] Also provided herein are combination therapies comprising administering to a patient: a pharmaceutical composition comprising: (a) an Immunoconjugate of Formula (I), and (b) an additional therapeutic agent, or pharmaceutically acceptable salt thereof. In one embodiment, the amounts administered of (a) and (b) are together effective to treat gastric cancer.

[0151] When an Immunoconjugate of Formula (I) is 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.

[0152] 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 therepeutic 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. [0153] When an Immunoconjugate of Formula (I) is used contemporaneously with one or more additional therapeutic agents, the Immunoconjugate of Formula (I) may be administered either simultaneously with, or before or after, one or more additional therapeutic agent(s). 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).

[0154] The weight ratio of the additional therapeutic agent(s) 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 an Immunoconjugate of Formula (I), and one or more additional therapeutic agents will generally include a therapeutically effective dose of each therapeutic agent. In such combinations, the Immunoconjugate of Formula (I), and the 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 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.

[0155] In one embodiment, this disclosure provides an Immunoconjugate of Formula (I), and at least one additional therapeutic agent as a combined preparation for simultaneous, separate or sequential use in the treatment of gastric cancer. In specific embodiments the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma.

[0156] Anti-viral compounds that may be used in combination with an Immunoconjugate of Formula (1) 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.

[0157] Antigens and adjuvants that may be used in combination with an Immunoconjugate of Formula (I) include B7 costimulatory molecule, interleukin-2, interferon-y. 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, a toll-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.

[0158] Chemotherapeutic agents that may be used in combination with an Immunoconjugate of Formula (I) 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, 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, taxanes. 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.

[0159] 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.

[0160] Examples of topoisomerase II inhibitors, include but are not limited to, etoposide, and teniposide.

[0161] 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/m² to 150 mg/m², administered intravenously. In a specific embodiment, when co-administered with cisplatin, the dose of cisplatin is 75 mg/m², administered intravenously.

[0162] Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin, bleomycin, daunorubicin liposomal (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0163] Examples of anti -metabolites include, but are not limited to, claribine, 5-fluorouracil, 6- thioguanine, pemetrexed (sold under the tradename ALIMTA®), cytarabine (also know n 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.

[0164] Examples of retinoids include, but are not limited to, alitretinoin, tretinoin, isotretinoin, and bexarotene.

ADDITIONAL EMBODIMENTS

[0165] 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 the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.

Kits

[0166] 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, and optionally an additional therapeutic agent, and instructions for use according to a treatment regimen described herein. The Immunoconjugate of Formula (I), 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.

[0167] 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.

[0168] In one embodiment, the present disclosure provides a kit comprising 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 amount of the Immunoconjugate of Formula (I) in the kit is effective to treat gastric cancer.

[0169] In another embodiment, for a kit of the present disclosure, the Immunoconjugate of Formula (I) contained in the kit is Immunoconjugate A.

GENERAL METHODS

[0170] Standard methods in molecular biology’ are described Sambrook, Fritsch and Maniatis

(1982 & 1989 2^nd Edition, 2001 3^rd Edition) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Laboratory Press. Cold Spring Harbor. NY; Sambrook and Russell (2001) Molecular Cloning, 3^rd ed., 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).

[0171] 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).

[0172] 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.) (2001) 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).

[0173] 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).

[0174] 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).

[0175] 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, 2^nd ed. 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).

[0176] 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).

[0177] Software packages and databases for determining, e.g., antigenic fragments, leader sequences, protein folding, functional domains, glycosylation sites, and sequence alignments, are available (see, e.g.. GenBank. Vector NT1® 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

[0178] 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 [0179] Immunoconjugate A can be made using the methodology described in US Patent Publication No. US Patent Publication No. 20200347075, and International Publication No. WO2019/114666 wherein Immunoconjugate A is referred to as “BT001021.”

EXAMPLE 2

Study of Immunoconjugate A and Pembrolizumab as Combination Therapy in Subjects with Gastric cancer

STUDY POPULATION

[0180] This is a global, randomized, open-label Phase 3 study to evaluate the efficacy, safety, and tolerability of Immunoconjugate A monotherapy compared to TPC (SOC chemotherapy) in participants with 3L+, advanced or metastatic gastric, GEJ, or esophageal adenocarcinoma.

[0181] Approximately 450 participants will be randomized in a 1 : 1 ratio to either:

Arm 1 - Immunoconjugate A at a dose of 4 mg/kg IV on Days 1, 15, and 29 of every 42-day cycle

Arm 2 - TPC including either trifluridine-tipiracil (35 mg/m² po bid on Days 1 to 5 and 8 to 12 of every' 28-day cycle), irinotecan (150 mg/m² IV on Days 1 and 15 of every 28-day cycle), paclitaxel (80 mg/m² IV on Days 1, 8, and 15 of every 28-day cycle), or docetaxel (75 mg/m² IV on Day 1 of every’ 21-day cycle).

[0182] Both treatment arms will also receive best supportive care.

[0183] Before randomization, investigators will choose and document TPC selection and rationale in the event that the participant is randomly assigned to Arm 2. Participants in Arm 2 should continue on the same chemotherapy regimen chosen before randomization throughout the study.

[0184] The study will include participants with and without (naive) prior exposure to immunooncology therapy. It will include participants with HER2- tumors and HER2+ tumors that progressed beyond trastuzumab where approved/available. Participants who received prior topoisomerase 1 inhibitor-based therapy (ADC or chemotherapy) in any line will be excluded.

[0185] Participants will be stratified by TROP2 expression (low vs. medium+high), geographic region (East Asia vs. North America+Westem Europe vs. Rest of World), and ECOG performance status (0 vs. 1).

[0186] Each participant will take part in the study from the time the participant provides documented informed consent through the final contact. Administration of study intervention should begin on the day of randomization or as close as possible to the date on which the participant is randomized, within a 3-day window.

[0187] Participants will receive study intervention until disease progression is radiographically- documented by the investigator and verified by BICR per RECIST 1. 1, an AE leads to permanent discontinuation of study intervention, or any of the other protocol-specified conditions for discontinuation of study intervention are met.

[0188] Participants may be permitted to continue study intervention beyond BICR-verified disease progression per RECIST 1.1 after consultation with the Sponsor as long as the treating investigator considers that the participant may experience clinical benefit with continued treatment and the participant is tolerating study intervention with no adverse effect. Reconsent is required at first indication of radiographic progression. Participants who continue study intervention beyond BICR-verified disease progression per RECIST 1. 1 will continue with all protocol-specified assessments and procedures.

[0189] Participants who discontinue study intervention for reasons other than BICR-verified disease progression will have posttreatment follow-up imaging to assess disease status until any of the conditions for discontinuation of imaging are met.

[0190] After verification of progression per RECIST 1. 1 by BICR and/or initiation of a subsequent anticancer therapy, all participants will be followed for survival (by phone contact or clinic visit) until death, withdrawal of consent, or the end of the study, whichever occurs first. [0191] The primary endpoint of the study is OS. Secondary efficacy endpoints are PFS, OR, and DOR per RECIST 1.1 as assessed by BICR. Participants will undergo imaging at the timepoints described in the SoA.

[0192] AEs will be monitored 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.

[0193] An independent, external DMC will monitor the safety and efficacy of this study. An initial interim safety analysis will be performed and reviewed by the eDMC approximately 6 months after the first participant is randomized or after the first 50 participants are randomized, whichever occurs later.

Efficacy Endpoints

[0194] OS is the primary endpoint. OS has been recognized as the gold standard for the demonstration of superiority of a new antineoplastic therapy in randomized clinical studies. [0195] Secondary efficacy endpoints include PFS. OR, and DOR per RECIST 1.1 as assessed by BICR. PFS and OR are acceptable measures of clinical benefit for a late-stage study that demonstrates superiority of a new antineoplastic 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 and response to treatment is typically considered acceptable by regulatory authorities. Images will be submitted to an iCRO and read by an independent central reviewer blinded to treatment assignment to minimize bias in response assessments. Expedited verification of radiologic progression as determined by central review will be communicated to sites.

[0196] DOR will serve as an additional measure of efficacy and is frequently accepted as an endpoint by both regulatory authorities and the oncology community.

Safety Endpoints

[0197] 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

[0198] 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-STO22, 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

[0199] EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for assessing HRQoL in oncology studies. 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. 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. EORTC QLQ-STO22

[0200] The EORTC QLQ-STO22 is a disease-specific questionnaire developed and validated to address measurements specific to gastric cancer. It is one of multiple disease-specific modules developed by the EORTC Quality-of-Life Group designed for use in clinical studies, to be administered in addition to the EORTC QLQ-C30, to assess disease-specific treatment measurements. It contains 22 items with symptoms of dysphagia (3 items), pain or discomfort (4 items), reflux symptoms (3 items), eating restrictions (4 items), anxiety (3 items), dry mouth, hair loss, taste, and body image.

EQ-5D-5L

[0201] 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 de Charro, 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.

Pharmacokinetic Endpoints

[0202] To characterize the PK profile of Immunoconjugate A and support the proposed dosing regimen, an integrated analysis of Immunoconjugate A PK data obtained in this study and from other studies, may be performed to estimate PK parameters.

Planned Exploratory Biomarker Research

[0203] 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 administered, as well as determinants of AEs in the course of our clinical studies. 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 (i.e.. blood components, tumor material) 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: Germline (blood) genetic analyses (e.g., SNP analyses, whole exome sequencing, whole genome sequencing)

[0204] 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 or AEs, 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. Finally, MSI may be evaluated as this is an important biomarker for some cancers.

Genetic (DNA) analyses from tumor

[0205] The application of new technologies, such as next generation sequencing, has provided scientists the opportunity to identify tumor-specific DNA changes (i.e., mutations, methylation status, microsatellite instability). Key molecular changes of interest to oncology drug development include the mutational burden of tumors and the clonality of T-cells in the tumor microenvironment. Increased mutational burden (sometimes called a ’hyper-mutated’ state) may generate neoantigen presentation in the tumor microenvironment. To conduct this type of research, it is important to identify tumor-specific mutations that occur across all genes in the tumor genome. Thus, 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. Microsatellite instability may also be evaluated as this is an important biomarker for some cancers. Circulating tumor DNA and/or RNA may also be evaluated from blood samples.

Tumor and/or blood RNA analyses

[0206] 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 correlate to clinical response to treatment with antitumor therapies. Specific gene sets (i.e., those capturing interferon-gamma transcriptional pathways) may be evaluated and new signatures may be identified. Individual genes may also be evaluated (e.g.. IL-10). MicroRNA profiling may also be pursued as well as exosomal profiling.

Proteomics and IHC using blood and/or tumor

[0207] Tumor and/or blood samples from this study may undergo proteomic analyses (e.g., PD- L1 IHC). Therefore, tumor tissue may be subjected to proteomic analyses using a variety of platforms that could include, but are not limited to, immunoassays and liquid chromatography /mass spectrometry. This approach could identify' novel protein biomarkers that could aid in patient selection for antitumor therapy. Maximum Dose Exposure for This Study

[0208] There is no maximum duration of exposure for Immunoconjugate A. The maximum dose exposure for TPC will be determined by local standard clinical practice.

[0209] Dosing with study intervention in Arms 1 and 2 will continue until disease progression is radiographically-documented by the investigator and verified by BICR per RECIST 1. 1. an AE leads to permanent discontinuation of study intervention, or any of the other protocol-specified conditions for discontinuation of study intervention are met.

Beginning and End-of-Study Definition

[0210] 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. [0211] If the study includes countries in the European Economic Area (EEA), the local start of the study in the EEA is defined as First Site Ready (FSR) in any Member State.

The Sponsor estimates that the maximum duration of the study from first participant entered through long-term follow-up will be 4 years.

STUDY POPULATION

[0212] 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.

[0213] Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.

Inclusion Criteria

[0214] An individual is eligible for inclusion in the study if the individual meets all of the following criteria:

Type of Participant and Disease Characteristics

1. Has a histologically- or cytologically-confirmed diagnosis of advanced, unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma. 2. Has 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 show n in such lesions.

3. Has received, and progressed on, at least 2 prior chemotherapy and/or immunotherapy regimens.

[0215] Note: For the purpose of this study, perioperative, neoadjuvant, and adjuvant chemotherapy regimens will not count as a prior regimen, unless the patient progressed while receiving adjuvant therapy or within 6 months of receiving adjuvant treatment. The date of progression and how progression was determined must be known with documentation available confirming progression on or after treatment.

[0216] Note: Previous treatment regimens must have included a fluoropyrimidine and platinum doublet (as part of either a line of therapy or adjuvant treatment).

[0217] Note: Prior immunotherapy may have been received alone or in combination with fluoropyrimidine and platinum-based chemotherapy.

4. Participants are eligible regardless of HER2 status. If HER2 status is unknown, sites should follow local standards to determine if HER2 testing is required as SOC. Participants who are HER2+ must have previously received trastuzumab where available/appropriate.

[0218] Note: Participants who received prior trastuzumab-deruxtecan/T-DXd (topoisomerase 1 inhibitor-based ADC) in any line are not eligible.

Demographics

5. Is an individual of any sex/gender and is at least 18 years of age at the time of providing the informed consent.

Male Participants

6. If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate the study interv ention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:

Immunoconjugate A: 100 days

Trifluridine-tipiracil: 100 days

Irinotecan: 100 days

Paclitaxel: 100 days

Docetaxel: 100 days

Refrains from donating sperm PLUS either:

Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent

OR

Uses 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 PL S partner use of an additional contraceptive method, as a condom may break or leak.

[0219] 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 followed.

Female Participants

7. A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and at least one of the following conditions applies:

Is not a POCBP

OR

Is a POCBP and: i) 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 lifesty le (abstinent on a long-term and persistent basis), as described in Appendix 5 during the intervention period and for at least the time needed to eliminate the 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 • Trifhiridine-tipiracil: 190 days

• Irinotecan: 190 days

• Paclitaxel: 190 days

• Docetaxel: 190 days

[0220] 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. ii) 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. iii) Abstains from breastfeeding during the study intervention period and for at least 10 days after study intervention. iv) 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 Consent

8. The participant (or legally acceptable representative) has provided documented informed consent/assent for the study.

Additional Categories

9. Has provided an archival tumor tissue sample or most recently obtained core, incisional, or excisional biopsy of a tumor lesion from any site not previously irradiated. Details pertaining to tumor tissue submission can be found in the Laboratory Manual. Tissue is required for determination of TROP2 status by the central laboratory. TROP2 status is required for stratification and must be determined by the central laboratory before randomization.

10. Participants who have AEs due to previous anticancer therapies must have recovered to Grade <1 or baseline (except for alopecia and vitiligo). Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy are eligible.

11. Adequate organ function as defined in the following table (Table 4). Specimens must be collected within 10 days before the start of study intervention. Table 4. Adequate Organ Function Laboratory Values

12. Has ECOG performance status of 0 or 1 within 3 days before randomization.

13. Be willing and able to comply with study procedures, laboratory' tests, and other requirements of the study.

14. Has a life expectancy of at least 3 months.

15. Individuals who may receive trifluridine-tipiracil must have the ability to swallow oral medication.

Exclusion Criteria

[0221] An individual must be excluded from the study if the individual meets any of the following criteria:

Medical Conditions

1. Has experienced weight loss >20% over 3 months before the first dose of study intervention.

2. Has a history of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, or comeal disease that prevents/delays comeal healing.

3. Has Grade >2 peripheral neuropathy. 4. 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).

5. 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 6 months before the first dose of study intervention.

6. Has accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks before the first dose of study intervention. Participants who are receiving diuretic drugs for other reasons are eligible. Consult with the Sponsor if the participant has more than trivial/trace fluid accumulation.

Prior/Concomitant Therapy

7. Received prior treatment with a TROP2-targeted ADC, a topoisomerase 1 inhibitor-based ADC, and/or a topoisomerase 1 inhibitor-based chemotherapy.

8. Received prior systemic anticancer therapy within 2 weeks before the first dose of study intervention.

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

10. Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.

11. Is currently receiving a strong and/or moderate inducer/inhibitor of CYP3 A4 that cannot be discontinued for the duration of the study. The required washout period before starting Immunoconjugate A is 2 weeks.

[0222] 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.

Prior/Concurrent Clinical Study Experience

12. Has received an investigational agent or has used an investigational device within 4 weeks before the first dose of studv intervention. Diagnostic Assessments

13. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

[0223] 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 are not excluded.

[0224] Note: Participants with low-risk early-stage prostate cancer (Tl-T2a, Gleason score <6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surv eillance with stable disease are not excluded.

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

15. Has an active infection requiring systemic therapy.

16. Has a history⁷ of HIV infection. HIV testing is not required unless mandated by local health authority⁷.

17. Has concurrent active hepatitis B (defined as HBsAg reactive and/or detectable HBV DNA) and/or hepatitis C (defined as anti-HCV Ab positive and detectable HCV RNA) infection or a known history of hepatitis B and/or C infection. Testing for hepatitis B and C is not required unless mandated by local health authority.

18. Has a 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 ability 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 Exclusions

19. Severe hypersensitivity⁷ (Grades >3) to Immunoconjugate A, any of its excipients, and/or to another biologic therapy.

20. Has had major surgery or significant traumatic injury within 4 weeks before the first dose of study intervention. Anticipation of the need for major surgery during the course of treatment with study intervention is also exclusionary.

[0225] Note: Participants who underw ent major surgery^ must have adequately recovered from toxicity and/or complications from the surgery⁷ before starting study intervention. Measures to Minimize Bias: Randomization and Blinding

Intervention Assignment

[0226] Intervention randomization will occur centrally using an IRT system. There are 2 study intervention arms. Participants will be assigned randomly in a 1 : 1 ratio to receive Immunoconjugate A (Arm 1) or TPC (Arm 2; trifluridine-tipiracil, irinotecan, paclitaxel, or docetaxel).

Concomitant Therapy

[0227] 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 studyintervention requires the mutual agreement of the investigator and the Sponsor.

[0228] 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.

[0229] Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular country is allowed in the study as long as they are mRNA vaccines, replication-incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy.

• Investigational vaccines (i.e.. those not licensed or approved for Emergency Use) are not allowed.

• Strong inhibitors or inducers of CYP3A4 within 14 days before the first dose of study intervention and for the duration of treatment with study intervention.

[0230] 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.

[0231] Investigators should review the locally approved label for all concomitant therapy to ensure it is not a strong inhibitor or inducer of CYP3A4.

[0232] If the investigator determines that a participant requires any of the following prohibited medications and vaccinations for any reason during the study, study intervention must be discontinued: • Systemic antineoplastic chemotherapy, immunotherapy, or biological therapy not specified in this protocol

• Investigational agents other than those specified in this protocol

• Radiation therapy

[0233] Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator’s discretion.

[0234] The exclusion criteria describe other medications that are prohibited in this study.

[0235] Blood transfusions are allowed at any time during the study, except to meet eligibilitycriteria.

[0236] For further information on the prohibited concomitant therapies for trifluridine-tipiracil, irinotecan, paclitaxel, or docetaxel please refer to the respective prescribing information.

[0237] All treatments that the investigator considers necessary- for a participant’s welfare may be administered at the discretion of the investigator in keeping with the community- standards of medical care. All concomitant medications will be recorded on the eCRF including all prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes occur during the study period, documentation of drug dosage, frequency, route, and date should also be included on the eCRF.

[0238] All concomitant medications received within 28 days prior to the first dose of study intervention and up to 30 days after the last dose of study intervention should be recorded. All concomitant medications administered during S AEs or ECIs are to be recorded.

Rescue Medications and Supportive Care

[0239] Participants should receive appropriate supportive care measures as deemed necessary by the treating investigator.

[0240] Suggested supportive care measures for the management of AEs associated with study intervention are outlined along with the dose modification guidelines.

[0241] The use of antiemetic therapy should follow Multinational Association of Supportive Care in Cancer and European Society for Medical Oncology- guidelines; hoyvever, strong inhibitors or inducers of CYP3A4 are not permitted.

[0242] Premedication is required before each dose of Immunoconjugate A.

[0243] Before treatment with Immunoconjugate A, participants should also receive prophylactic treatment to mitigate the onset and severity of stomatitis/oral mucositis in accordance with published ASCO and MASCC/ISOO guidelines. [0244] It is highly recommended that participants treated with Immunoconjugate A 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.

[0245] 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.

[0246] Oral nystatin suspension or other topical antifungal agent can be used following the steroid-containing mouthwash at the investigator’s discretion and per institutional guidelines. [0247] Participants treated with Immunoconjugate A 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).

• Cry otherapy or ice chip therapy, where patients hold ice chips in their mouth for 30 minutes before and during the infusion.

[0248] Refer to the product labels or local standards of care for the management of AEs associated with trifluridine-tipiracil, irinotecan, paclitaxel, and docetaxel and for premedication recommendations.

[0249] Palliative and supportive care for disease-related symptoms and for toxicities associated with study intervention will be offered to participants treated with trifluridine-tipiracil. irinotecan, paclitaxel, and docetaxel. Supportive care measures may include but are not limited to antidiarrheal agents, antiemetic agents, opiate and non-opiate analgesic agents, appetite stimulants, and granulocyte and erythroid grow th factors. Non-drug supportive care procedures may be performed as medically necessary and appropriate in the opinion of the investigator.

Details of interventions, procedures, or blood products (e.g, blood cells, platelets, or fresh frozen plasma transfusions) should be captured on the appropriate CRF.

[0250] In the event of Grade 3 or 4 diarrhea, supportive measures may include hydration, loperamide, octreotide, and antidiarrheals. If diarrhea is severe (i.e.. requires IV hydration) and associated with fever or severe (Grade 3 or 4) neutropenia, broad-spectrum antibiotics may be prescribed. Participants with severe diarrhea or any diarrhea associated with severe nausea or vomiting must be hospitalized for IV hydration and correction of electrolyte imbalance. In cases of irinotecan-induced diarrhea, antibiotic therapy should be initiated if the participant develops ileus, fever, or severe neutropenia. Dose Modification

[0251] During treatment with study intervention, all participants should be closely monitored for treatment-related AEs and actively treated with supportive care. Dose modifications in response to treatment-related AEs/toxicities are permitted in order to keep the participant on study intervention, when appropriate. Dose modifications must follow official current prescription information and local therapeutic guidelines. Details on the modifications for each study intervention are provided in the sections below.

[0252] If a participant experiences a >10% weight change, the dose of study intervention (Immunoconjugate A or TPC) should be recalculated at the beginning of a cycle only. For weight fluctuation <10%, recalculation may be performed at the discretion of the investigator.

Dose Modification for Immunoconjugate A

[0253] Recommended dose-modification guidelines for Immunoconjugate A are provided in Table 5 Dosing delays for Immunoconjugate A due to an AE should not exceed 28 days from the last administered dose, unless otherwise discussed with, and approved by, the Sponsor.

[0254] If a dose reduction for an AE associated with Immunoconjugate A is needed, the dose can be reduced in 1-mg/kg increments (Table 5). 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.

[0255] 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.

[0256] Participants should receive appropriate supportive care measures as deemed necessary by the treating investigator. If the proposed dose-modification plan is inconsistent with the guidelines provided in Table 5, the investigator should discuss the management details with the Sponsor.

[0257] 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 intervention interruption is to be documented in the participant’s study record. Table 5. Dose Modification and Toxicity Management Guidelines for Adverse Events Associated With Immunoconjugate A Management of Infusion Reactions

[0258] Immunoconjugate A may cause severe or life-threatening 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.

[0259] 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 Hl receptor antagonist [per approved product label]), acetaminophen (or equivalent [per approved product label]), and a corticosteroid (dexamethasone 10 mg IV [or equivalent]). An H2 receptor antagonist, if available, is also recommended for the first 4 administrations of Immunoconjugate A per the approved product label and/or institutional standards. 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 6.

Table 6. Infusion Reaction Dose Modification and Treatment Guidelines for Immunoconjugate A

Recommended Dose-modification Guidelines for Treatment of Physician’s Choice

[0260] Management for participants who experience toxicity due to trifluridine-tipiracil, irinotecan, paclitaxel, or docetaxel will be in accordance with the respective prescribing information in each country /region or local institutional guidelines. These dose modification decisions must be documented in the participant’s study records. Participants should continue on the same chemotherapy regimen chosen before randomization throughout the study. Participants who permanently discontinue treatment with any of these therapies should continue to be monitored in the study.

[0261] Interruptions may occur for situations other than treatment-related AEs, such as medical or surgical events and/or unforeseen circumstances not related to study intervention. Interruptions from these study interventions of greater than 28 days for trifluridine-tipiracil, irinotecan, and paclitaxel and 42 days for docetaxel from the last administered dose should be discussed with, and approved by, the Sponsor. The reason for any study intervention interruption is to be documented in the participant’s study record.

[0262] 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, it is recommended these supportive care measures be used before implementing dose modifications, when clinically appropriate. Prophylactic use is acceptable.

STUDY ASSESSMENTS AND PROCEDURES

[0263] The investigator is responsible for ensuring that procedures are conducted by appropriately qualified (by education, training, and experience) staff. Delegation of study-site personnel responsibilities will be documented in the Investigator Trial File Binder (or equivalent).

[0264] All study-related medical decisions must be made by an investigator who is a qualified physician.

[0265] All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable.

[0266] Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) and obtained before providing documented informed consent may be used for screening or baseline purposes provided the procedures meet the protocol-specified critena and were performed within a defined time frame.

[0267] Additional evaluations/testing may be deemed necessary’ by the investigator and or the Sponsor for reasons related to participant safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g, HIV, hepatitis C). and thus local regulations may require that additional informed consent be obtained from the participant. In these cases, such evaluations/testing will be performed in accordance with those regulations.

[0268] Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the samples.

Timing of Dose Administration

[0269] Study intervention is to be administered at the study visits. After Cycle 1, Day 1, study intervention may be administered up to 3 days before or after the scheduled day of administration.

[0270] Participants will continue to receive study intervention until any of the protocol- specified conditions for discontinuation of study intervention are met.

Immunoconjugate A

[0271] Immunoconjugate A should be prepared according to the instructions in the Pharmacy Manual.

[0272] Immunoconjugate A will be administered at a dose of 4 mg/kg by IV infusion on Days 1, 15, and 29 of each 42-day cycle.

[0273] 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 timeframe 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.

[0274] 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 should be readily available during the period of drug administration. Treatment of Physician’s Choice

[0275] TPC consists of either trifluridine-tipiracil (35 mg/m² po bid on Days 1-5 and 8-12 of every 28-day cycle), irinotecan (150 mg/m² IV on Days 1 and 15 of even' 28-day cycle), paclitaxel (80 mg/m² IV on Days 1, 8, and 15 of eve ' 28-day cycle), or docetaxel (75 mg/m² IV on Day 1 of every 21 -day cycle).

[0276] The administration procedure should follow the approved prescribing information in each country /region or institutional guidelines.

Discontinuation and Withdrawal

[0277] Participants who discontinue study intervention before completion of the treatment period should be encouraged to continue to be followed for all remaining study visits.

[0278] 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 al the time of withdrawal should be followed in accordance with the safely requirements.

Procedures for Negative Studies Without Safety Concerns

[0279] If the study or one study interv ention group discontinues due to futility' or the study does not demonstrate statistically significant efficacy results per protocol-specified analyses without any urgent safety issues, one or more of the following actions may occur:

• cessation of recruitment

• discontinuation of participants assigned to a specific study intervention group unless participants are deriving clinical benefit

[0280] The investigator or medically qualified designee must rapidly inform each participant of these results and discuss treatment options. Additionally, the protocol is to be amended to reflect any change in the study conduct (e.g., cohort changes and follow-up).

Tumor Tissue for Biomarker Status

[0281] During the screening period, a tumor tissue sample is required for each participant. The most recent tissue sample is preferred. Only tissue samples that have not been previously irradiated should be submitted. Formalin-fixed, paraffin embedded tissue blocks are strongly preferred to slides. Details about collection and submission of tumor tissue samples are provided in the Laboratory Manual.

[0282] 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 patients with gastroesophageal adenocarcinomas screening for the clinical study. TR0P2 status is required for stratification and must be determined by the central laboratory before randomization.

[0283] TROP2 results will be masked to the site.

Tumor Imaging and Assessment of Disease

[0284] 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.

[0285] In addition to survival, efficacy will be assessed based on evaluation of scan changes in tumor burden over time, until the participant is discontinued from the study or goes into survival follow-up. The process for scan collection and transmission to the iCRO can be found in the SIM. Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by local practice. The same scan technique should be used in a participant throughout the study to optimize the reproducibility of the assessment of existing and new tumor burden and improve the accuracy of the response assessment based on scans.

[0286] Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local investigator at the site and/or the radiological reviewer at the site or at an offsite facility. [0287] If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging will be acceptable, if MRI is medically contraindicated.

[0288] Bone scans may be performed to evaluate bone metastases. Any supplemental scans performed to support a positive or negative bone scan, such as plain x-rays acquired for correlation, should also be submitted to the iCRO.

[0289] Other imaging modalities that may be collected, submitted to the iCRO. and included in the response assessment include PET-CT. Other types of medical imaging (such as ultrasound) should not be submitted to the iCRO and will not be included in response assessment.

[0290] Participant eligibility will be determined using investigator assessment. All scheduled scans for participants will be submitted to the iCRO. In addition, a scan that is obtained at an unscheduled time point, for any reason (including suspicion of progression or other clinical reason), should be submitted to the iCRO if it shows disease progression, or if it is used to support a response assessment. All scans acquired within the protocol-specified window of time around a scheduled scan visit are to be classified as pertaining to that visit.

[0291] When the investigator identifies disease progression, the iCRO will verify this progression and email the results to the study site and Sponsor. In clinically stable participants, scans are to continue until disease progression has been verified by BICR. If investigator- assessed progression was not verified by BICR. each subsequent scan must be submitted to the iCRO. Once progression is verified by BICR, subsequent scans (if acquired) should not be submitted to the iCRO.

Initial Tumor Scans

[0292] Initial tumor scans at Screening must be performed within 28 days before randomization. The screening scans must be submitted to the iCRO for retrospective review. [0293] Tumor scans performed as part of routine clinical management are acceptable for screening if they are of acceptable diagnostic quality, are performed within 28 days before randomization, and can be assessed by the iCRO. Any scans obtained after Cycle 1, Day 1 cannot be included in the screening assessment. The site must review screening scans before randomization to confirm the participant has measurable disease per RECIST 1.1.

Tumor Scans During the Study

[0294] The first on-study scan should be performed 6 weeks (42 days+7 days) from the date of randomization. Subsequent tumor scans should be performed every' 6 weeks (42 days±7 days) or more frequently if clinically indicated up to Week 54. After Week 54 (±7 days), tumor scans should be performed every 9 weeks (63 days±7 days). Scan timing should be based off of the date of randomization, should follow calendar days, and should not be adjusted for dosing delays. [0295] 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:

• start of a new anti cancer therapy

• pregnancy

• death

• withdrawal of consent

• the end of the study

[0296] Brain and/or bone scans will be repeated during the study as clinically indicated or to confirm CR (if other lesions indicate CR and brain and/or bone lesions existed at baseline).

[0297] 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 perform 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. End-of-treatment and Follow-up Tumor Scans

[0298] 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.

[0299] If participants discontinue study intervention without documented disease progression, every⁷ effort is to be made to monitor disease status by acquiring tumor scans using the same schedule calculated from the date of randomization.

[0300] 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

• start of a new anti cancer therapy

• pregnancy

• death

• withdrawal of consent

• the end of the study

RECIST 1. 1 Assessment of Disease

[0301] 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). The RECIST 1.1 publication allows a maximum of 5 target lesions and 2 per organ.

[0302] Upon investigator-assessed disease progression, the indicative scan(s) is/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.

[0303] 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 [0304] If the participant is not clinically stable, best medical practice is to be applied. [0305] Before stopping study intervention or imaging or starting new anticancer therapy in a participant who is clinically stable, communication with the Sponsor is required.

[0306] 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

[0307] For the purpose of this decision process, lack of clinical stability is defined as:

• unacceptable toxicity'

• clinical signs or symptoms indicating clinically significant disease progression

• decline in performance 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

[0308] The PRO questionnaires will be administered by trained site personnel and completed electronically by participants in the following order: EORTC QLQ-C30, EORTC QLQ-STO22, and EQ-5D-5L. The questionnaires should be administered before dosing. It is acceptable for laboratory safety tests to be performed before administration of ePROs to accommodate institutional practice.

[0309] It is best practice and strongly recommended that ePROs are administered to randomized participants before drug administration. AE evaluation, and disease status notification. If the participant does not complete the ePROs at a scheduled time point, the MISS_MODE form must be completed to capture the reason the assessment was not performed. [0310] Alternative methods of administering PRO questionnaires may be offered to enable participation of individuals when PRO collection via tablet (i.e., ePRO) is not feasible (e.g., during a global pandemic or with illiterate or visually impaired participants).

Safety Assessments

[0311] Details regarding specific safety procedures/assessments to be performed in this study are provided. 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. [0312] Planned time points for all safety assessments are provided in the SoA.

Physical Examinations

[0313] A complete or symptom-directed physical examination will be conducted by an investigator or medically qualified designee (consistent with local requirements) per institutional standards.

[0314] Investigators should pay special attention to clinical signs related to previous serious illnesses.

Full Physical Examination

[0315] 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. The time points for full physical exams are described in Section 1.3. After the first dose of study intervention, new clinically significant abnormal findings should be recorded as AEs.

Directed Physical Examination

[0316] For cycles that do not require a full physical examination as defined in Section 1.3, 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.

Vital Signs

[0317] The investigator or qualified designee will assess vital signs at screening. Vital signs will include heart rate, systolic and diastolic blood pressure, temperature, respiratory rate, height (at screening only), and weight.

Electrocardiograms

[0318] At screening, a single 12-lead ECG with QTcF measurement will be obtained for all participants.

[0319] For participants randomized to Arm 1, ECGs will be performed to better describe cardiac activity during treatment with Immunoconjugate A as follows:

• Before the first dose of Immunoconjugate A on Cycle 1, Day 1, 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.

• Before each subsequent dose of Immunoconjugate A, a single 12-lead ECG with QTcF measurement will be performed. The predose ECG may be obtained within 3 days before the scheduled dose. • A single 12-lead ECG with QTcF measurement will be performed within 30 minutes after the end of the first, second, and fifth Immunoconjugate A infusions (i.e., Cycle 1, Day 1, Cycle 1, Day 15, and Cycle 2, Day 15).

[0320] For participants randomized to Arm 2, ECGs will be performed as clinically indicated after screening.

[0321] ECGs 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 PR, QRS, QT, and QTc intervals.

[0322] 6-lead ECG is allowed per institutional standards.

[0323] Note: Clinically significant abnormal findings are to be evaluated including repeated ECGs if necessary. Additional timepoints may be performed as clinically indicated. Clinically significant abnormal findings should be recorded as AEs.

Echocardiogram or Multigated Acquisition Scan

[0324] An ECHO or a MUGA scan (using technetium-based tracer) will be performed to assess LVEF. ECHO or MUGA 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 used for any subsequent LVEF assessments for that participant. Investigator assessment will be based on institutional reports.

Clinical Safety Laboratory Assessments

[0325] 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 be filed 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.

[0326] 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).

[0327] 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)

[0328] 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

• Pregnancy testing requirements for study inclusion are described above herein.

• POCBP require a negative pregnancy test (urine or serum) within 24 hours (urine) or 72 hours (serum) before the first dose of study intervention and before subsequent doses as follows:

• Arm 1 (Immunoconjugate A): Cycle 1, Day 29, and Day 1 and Day 29 of Cycles >2

• Arm 2 (TPC): Day 1 of Cycles >2

• For treatment delays >28 days, perform pregnancy testing before dosing

• If the screening pregnancy test is performed within 24 hours (urine) or 72 hours (serum) before the first dose of study intervention, repeat testing is not required at Cycle 1, Day 1

[0329] 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, as noted in Section 5.1. The length of time required to continue pregnancy testing after the last dose of study intervention is:

• Arm 1 (Immunoconjugate A): 190 days

• Arm 2 (TPC): 190 days

[0330] 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 anytime during the participant’s participation in the study.

Performance Assessments

Eastern Cooperative Oncology’ Group Performance Status

[0331] 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 abil ity (walking, working, etc.) with Grades 0 to 5.

[0332] The investigator or qualified designee will assess ECOG status (see https://ecog- acrin.org/resources/ecog performance 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

[0333] Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative).

[0334] Progression of the cancer under study is not considered an AE.

KEY STATISTICAL CONSIDERATIONS

[0335] This section outlines the principal statistical analysis strategy and procedures for the study.

Responsibility for Analyses/In-house Blinding

[0336] The statistical analysis of the data obtained from this study will be the responsibility of the Clinical Biostatistics department of the Sponsor.

[0337] 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.

[0338] In addition, independent central imaging review will be performed without knowledge of treatment group assignment. The participant-level TROP2 biomarker results will be masked in the database to the study team at the Sponsor including clinical, statistical, statistical programming, and data management personnel. Access to the TROP2 participant-level biomarker results will be limited to an unblinded Sponsor clinical scientist, and an unblinded Sponsor statistician who will be responsible for data review to ensure validity of results but who will have no other responsibilities associated with the study. A summary of TROP2 biomarker prevalence may be provided to the study team of the Sponsor by the unblinded Sponsor statistician.

Analysis Endpoints

[0339] Efficacy and safety endpoints that will be evaluated are listed below.

Efficacy Endpoints

Primary

• Overall Survival (OS)

OS is defined as the time from randomization to death due to any cause. Secondary

• Progression-free survival (PFS) PFS is defined as the time from randomization to the first documented disease progression per RECIST 1 . 1 (as assessed by BICR) or death due to any cause, whichever occurs first.

• Objective Response (OR)

OR is defined as a confirmed CR or PR per RECIST 1. 1 as assessed by BICR.

• Duration of Response (DOR)

For participants who demonstrate confirmed CR or PR, DOR is defined as the time from the first documented evidence of confirmed CR or PR until the first documented date of disease progression or death due to any cause, whichever occurs first.

Safety Endpoints

[0340] Safety and tolerability⁷ will be assessed by clinical review of all relevant parameters including AEs, laboratory test results, and vital signs.

PRO Endpoints

The following exploratory PRO endpoints will be evaluated:

• Change from baseline in EORTC QLQ-C30 global health status/quality of life score, physical functioning score, role functioning score, nausea/vomiting score, and appetite loss score

• Change from baseline in EORTC QLQ-STO22 pain score

• Time to deterioration in EORTC QLQ-C30 global health status/QoL score, phy sical functioning score, role functioning score, nausea/vomiting score, and appetite loss score

• Time to deterioration in EORTC QLQ-STO22 pain score

• Change from baseline in EQ-5D-5L visual analog scale (VAS)

Analysis Populations

Efficacy Analysis Populations

[0341] The ITT population which consists of all randomized participants will serve as the primary population for analysis of efficacy data in this study. Participants will be included in the treatment group to which they are randomized for the analysis of efficacy data using the ITT population.

[0342] The analysis population for DOR consists of participants in the analysis population of OR who demonstrate confirmed CR or PR.

Safety⁷ Analysis Populations

[0343] Safety analyses will be conducted in the APaT population, which consists of all randomized participants who received at least 1 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.

[0344] Analyses of laboratory test results, vital signs, and ECG measurements will include only participants with at least 1 measurement obtained after at least 1 dose of study intervention. For analyses that will assess change from baseline, a baseline measurement is also required.

Statistical Methods

Statistical Methods for Efficacy Analyses

[0345] The primary hypothesis will be evaluated by comparing Immunoconjugate A to TPC with respect to OS. The secondary hypotheses are that Immunoconjugate A is superior to TPC with respect to PFS and ORR.

[0346] For both OS and PFS, a stratified log-rank test w ill be used for comparison of the 2 treatment groups. The HR and its 95% CI will be estimated using a stratified Cox regression model with Efron’s method of tie handling. Event rates over time will be estimated within each treatment group using the Kaplan-Meier method.

[0347] The ORR, which is defined as the proportion of participants who have a confirmed CR or PR, will be analyzed using the stratified Miettinen and Nurminen’s method for comparison between 2 treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen and Nurminen method with stratum weighting by sample size will be reported. The stratification factors used for randomization will be applied to the analysis. The point estimates of ORR will be provided by treatment group, together with 95% Cis using the exact binomial method proposed by Clopper and Pearson.

[0348] DOR will be summarized descriptively using Kaplan-Meier medians and quartiles if sample size permits.

[0349] A summary of the analysis strategy for the efficacy endpoints is provided in Table 7. Table 7. Analysis Strategy for Key Efficacy Variables

Statistical Methods for Safety Analyses

[0350] Safety and tolerability will be assessed by clinical review of AEs and other relevant parameters, including laboratory test results, vital signs, and ECG measurements.

[0351] The overall safety evaluation will include a summary of the number and percentage of participants with at least 1 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 by treatment group. 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 Miettinen and Nurminen method.

[0352] 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, Version 5.0 for each gradable laboratory’ test. [0353] For continuous safety measures, such as change from baseline in laboratory, vital signs, and ECG parameters, summary statistics for baseline, on-treatment, and change from baseline values will be provided.

Demographic and Baseline Characteristics

[0354] The comparability of the treatment group for each relevant demographic and baseline characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis tests will be performed on these characteristics. The number and percentage of participants screened and randomized and the primary reasons for screening failure and discontinuation will be displayed. Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be summarized by treatment either by descriptive statistics or categorical tables.

Interim Analyses (IAs)

[0355] There are 2 planned IAs. Inferential analyses for OS, PFS, and ORR will be provided to evaluate efficacy/futility. Interim results will be reviewed by an eDMC.

[0356] Study enrollment may be ongoing at the time of the futility IA. The results of IAs will not be shared with the investigators until the study objectives have been achieved. Access to the allocation schedule and the participant-level 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.

[0357] The eDMC will perform periodic interim safety reviews as specified in the eDMC charter.

Multiplicity

[0358] The overall Type-I error rate over the primary and secondary hypotheses is strongly- controlled at 2.5% (1-sided), with an initial alpha allocation of 2.5% for OS (Hl), 0% for PFS (H2) and 0% for ORR (H3). The study uses the graphical method of Maurer and Bretz to provide strong multiplicity control for multiple hypotheses as well as IAs. According to this approach, study hypotheses may be tested more than once, and when a particular null hypothesis is rejected, the alpha allocated to that hypothesis can be reallocated to other hypothesis tests.

Sample Size and Power Calculations

[0359] Approximately 450 participants will be randomized 1 : 1 to either Immunoconjugate A or TPC. OS is the primary endpoint, PFS and OR are secondary endpoints.

[0360] For the OS endpoint, based on a target number of 346 events at the final analysis, the study has approximately 91% pow er to detect an HR of 0.70 at the initially allocated alpha=0.025 (1 -sided). [0361] For the PFS endpoint, based on a target number of 375 events, the study has approximately 96% power to detect an HR of 0.68 at alpha=0.025 (1-sided).

[0362] For the OR endpoint, with 450 participants, the study has 96% power to detect a 10% difference in ORR (14% vs. 4%) at alpha=0.025 (1-sided) if both OS and PFS null hypotheses are rejected.

Claims

WHAT IS CLAIMED IS:

1. A method of treating gastric cancer in a human patient, said method comprising administering to the patient 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 amount of Immunoconjugate (I) administered is effective to treat gastric 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:

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: 3, and

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: 1, and

(ii) a light chain comprising the amino acid sequence of SEQ ID NO: 2.

6. The method of any of claims 1-5, wherein the antibody that binds to Trop-2 is sacituzumab, and n is an integer from 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 claim 7, wherein the Immunoconjugate of Formula (I) is administered at a dose of about 4 mg/kg.

9. The method of any of claims 1-8, wherein the Immunoconjugate of Formula (I) is administered in two week cycles, and administered on day 1 of each two-week cycle.

10. The method of any of claims 1-9, wherein the Immunoconjugate of Formula (I) is administered in six-week cycles, and administered on days 1. 15. and 29 of each six -week cycle.

11. The method of claim 9 or 10, wherein the number of cycles is from 1-18.

12. The method of any of claims 1-11. wherein the gastric cancer is locally advanced or metastatic.

13. The method of any of claims 1-12, wherein the gastric cancer has been previously treated.

14. The method of claim 13, wherein the gastric cancer was previously treated with systemic therapy.

15. The method of any of claims 1-14, further comprising administering to the patient an additional anticancer agent.

16. The method of any of claims 1-15 wherein the gastric cancer being treated is gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma.

17. A pharmaceutical composition comprising:

(a) a pharmaceutically acceptable carrier; and

(b) a plurality of Immunoconjugates of Formula (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 1 to 10; and wherein the amounts of Immunoconjugate (I) present in the composition is effective to treat gastric cancer.

18. The pharmaceutical composition of claim 17, wherein the antibody that binds to Trop-2 is Sacituzumab, and n is a real number from 1 to 8.

19. A kit comprising 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 Immunoconjugate (I) present in the kit is effective to treat gastric cancer.

20. The kit of claim 19, further comprising instructions for administering the Immunoconjugate of Formula (I) to a human patient.

21. The kit of claim 19 or 20, wherein the Immunoconjugate of Formula (I) is Immunoconjugate A.