Use of an immunoconjugate for the treatment of non-small cell lung cancer

Abstract

The present disclosure relates to methods for treating or preventing non-small cell lung cancer in a patient, wherein the non-small cell lung cancer has an actionable EGFR mutation, the 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. Also disclosed are combination therapies and kits containing such agents for the treatment of cancers.

Description

USE OF AN IMMUNOCONJUGATE FOR THE TREATMENT OF NON-SMALL CELLLUNG CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 586,327, filed September 28, 2023, the disclosure of which is incorporated herein by its entirety.REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby in corporated by reference in its entirety. The XML file, created on July 15, 2024, is named 25839_WO_PCT_SL.XML, and is 10,375 bytes in size.FIELD OF THE DISCLOSURE

[0003] The present disclosure relates to methods for treating or preventing non-small cell lung cancer in a patient, wherein the non-small cell lung cancer has an actionable EGFR mutation, the method comprising administering to the patient an Immunoconjugate.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, 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] In breast cancer specifically, elevated TROP-2 expression has been associated with worse survival. TROP-2 gene expression has been detected in all breast cancer subtypes with higher levels noted in HR+ / HER2-, and triple negative breast cancer (TNBC) compared to HER2+ disease. Genomic analyses of TNBC also identified TROP-2 as an attractive candidate for targeted therapy, and led to further investigation of TROP-2 as a new therapeutic target.

[0007] The success of targeting TROP-2 via antibody -drug conjugates (ADCs) in metastatic breast cancer (MBC), and urothelial cancer and ongoing trials in NSCLC have established TROP-2 targeting as a valid and fruitful strategy, and several TROP-2-targeted therapeutics have recently been developed for clinical use. such as anti-TROP-2 antibodies and TROP-2-targeted ADCs. Subsequently, multiple early-phase clinical trials have demonstrated good safety profiles, and clinical benefit associated with TROP-2-based ADCs across multiple tumor types. This includes clinical benefit, and tolerability in tumor types with limited treatment options, such as triple-negative breast cancer, platinum-resistant urothelial cancer, and non-small cell lung cancer. An example of an immunoconjugate that is currently in early phase clinical trials is Immunoconjugate A:Immunoconjugate A wherein Ab is an anti-TROP-2 antibody (sacituzumab), and n is a decimal or integer from 1 to 10, is described in US Patent Publication No. 20200347075.

[0008] 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. Given TROP-2’ s expression pattern and associated poor prognostic outcomes, TROP-2 is a rational prognostic marker and therapeutic target.SUMMARY OF THE PRESENT DISCLOSURE

[0009] In a first aspect, the present disclosure provides a method of treating non-small cell lung cancer in a patient, comprising administering to the patient an effective amount of an Immunoconjugate of Formula (I):wherein:Ab is an antibody that binds to TROP-2; and n is an integer from 1 to 10.

[0010] In one embodiment of this method (embodiment no. 1), the cancer is non-small cell lung cancer (NSCLC).

[0011] In embodiment no. 2 of this method, the cancer is previously -treated nonsquamous non- small cell lung cancer having an EGFR mutation. In a specific embodiment, the EGFR mutation is exon 19del or exon 21 L858R mutation.

[0012] In embodiment no. 3 of this method, the cancer is previously-treated nonsquamous non- small cell lung cancer having any of the following genomic mutations: ALK gene rearrangements; ROS1 rearrangements; BRAF V600E mutations; NTRK gene fusions: MET exon 14 skipping mutations; RET rearrangements; or EGFR point mutations of exon 20 S7681, exon 21 L861Q, or exon 18 G719X.

[0013] In embodiment no. 4 of this method, the cancer is previously-treated nonsquamous non- small cell lung cancer having an EGFR mutation, wherein the patient has been previous treated with (a) an EGFR-TKI, and (b) platinum-based chemotherapy. In a specific embodiment, the EGFR mutation is exon 19del or exon 21 L858R mutation.

[0014] In embodiment no. 5 of this method, the cancer is previously-treated nonsquamous non- small cell lung cancer having any of the following genomic mutations: ALK gene rearrangements; ROS1 rearrangements; BRAF V600E mutations; NTRK gene fusions: MET exon 14 skipping mutations; RET rearrangements; or EGFR point mutations of exon 20 S7681,exon 21 L861Q, or exon 18 G719X. and wherein the patient has been previous treated with (a) an EGFR-TKI, and (b) platinum-based chemotherapy.

[0015] In embodiment no. 6 of this method, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0016] In embodiment no. 7 of this method, the patient is administered 4 mg / kg of Immunoconjugate A, wherein Immunoconjugate A is administered once every 2 weeks. For instance, a human patient is administered 4 mg / kg of Immunoconjugate A every 2 weeks.

[0017] In embodiment no. 8 of this method, the patient is administered 4 mg / kg of Immunoconjugate A, wherein Immunoconjugate A is administered on days 1, and 15, of a 4- week cycle.

[0018] In embodiment no. 9 of this method, the patient is administered 4 mg / kg of Immunoconjugate A, wherein Immunoconjugate A is administered on days 1, 15, and 29, of a 6- week cycle.

[0019] In embodiment no. 10 of this method, the patient is a human.DETAILED DESCRIPTION OF THE PRESENT DISCLOSUREDefinitions and Abbreviations

[0020] 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.

[0021] 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.

[0022] As used herein, the articles “a” and “an” refer to one or to more than one (z.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.

[0023] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides).

[0024] An “antibody-darug conjugate,” or “ADC,” or “immunoconjugate,” refers to anantibody 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.

[0025] 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.

[0026] The terms “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.

[0027] 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.

[0028] 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., TROP-2). 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 know n. An antigen-binding 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.

[0029] 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.

[0030] ‘‘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).

[0031] As used herein, the term “antibody” refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic. As used herein, the term “antibody” encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.

[0032] 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 Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0033] “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.

[0034] 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.

[0035] 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.

[0036] A “CDR” refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH P-sheet framework, or one of three hypervariable regions (LI, L2, or L3) within the non-framework region of the antibody VL P-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability7within 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 havealso been defined by AbM, Contact, and 1MGT. 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 a / ., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is similarly well known to those skilled in the art. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art and shown 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

[0037] ‘‘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, cy toxic / 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, andanti-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.

[0038] ‘‘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.

[0039] As used herein, the terms “combination therapy” and “therapeutic combination” refer to treatments in which an Immunoconjugate of Formula (I), and optionally additional therapeutic agents, are administered to a patient in a coordinated manner, over an overlapping period of time. The period of treatment with the Immunoconjugate of Formula (I) is the period of time that a patient undergoes treatment with the Immunoconjugate of Formula (I); that is, the period of time from the initial dosing with the Immunoconjugate of Formula (I) through the final day of a treatment cycle. In certain embodiments, the administration of the Immunoconjugate of Formula (I) and the optionally additional therapeutic agents are coextensive. In other embodiments, the Immunoconjugate of Formula (I) is administered prior to the optionally additional therapeutic agents. In another embodiment, the Immunoconjugate of Formula (I) is administered after the optionally additional therapeutic agents. In another embodiment, the Immunoconjugate of Formula (I) administration is terminated prior to the administration of the optionally additional therapeutic agents. In another embodiment, the administration of the optionally additional therapeutic agents is terminated prior to the administration of the Immunoconjugate of Formula (1).

[0040] The terms “complementarity -determining region” and “CDR,” which are synonymous with “hypervariable region” or “HVR,” refer to subregions within the antibody variable domains, which confer the antibody's specificity and / or affinity for its antigen. In general, there are three CDRs in each heavy chain variable domain (HCDR1. HCDR2, and HCDR3) and three CDRs in each light chain variable domain (LCDR1, LCDR2, and LCDR3). “Framework regions” (“FRs”) refer to the non-CDR portions of the variable domains. In general, there are four FRs in each full- length heavy chain variable domain and four FRs in each full-length light chain variable domain. The precise amino acid sequence boundaries of a given CDR or FR can be readily determined using any of several well-known schemes, including those described by Kabat et al., 5th Ed., Public Health Sendee, National Institutes of Health, Bethesda, MD (1991) (“Kabat” numberingscheme); Al-Lazikani et al., JMB 273.927-948 (1997) (“Chothia” numbering scheme);MacCallum et al., J. Mol. Biol. 262:732-745 (1996) (‘'contact” numbering scheme); Lefranc et al., Dev Comp Immunol. 27(1): 55-77 (2003) (“IMGT” numbering scheme); and Honegger and Pluckthun, J Mol Biol, 309(3):657-70 (2001) (“Aho” numbering scheme).

[0041] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on sequence alignments, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based upon the most common antibody region sequence lengths, with insertions accommodated by insertion letters, for example, “30a.” The two schemes place certain insertions and deletions (“indels”) at different positions, resulting in differential numbering. The contact scheme is based on analysis of complex crystal structures and is similar in many respects to the Chothia numbering scheme. Unless indicated otherwise, the CDRs of the antibodies referred to herein may be identified according to any of the Kabat, Chothia, IMGT, and contact methods.

[0042] “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, hydrophobicit / hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and / or specificity. Those of skill in this art recognize that, in general, single amino acid substitutions in non-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 2 below.Table 2. Exemplary Conservative Amino Acid Substitutions

[0043] 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, which is a decimal 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 anAntibody-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.

[0044] 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 van’ 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.

[0045] “Homologj'” 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 BLASTalgorithm 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.

[0046] The following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., etal., (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., etal., (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.

[0047] “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.

[0048] “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.

[0049] 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.

[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 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.

[0051] 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.

[0052] 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.

[0053] “Kabat” as used herein means an immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat ((1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Sendee, National Institutes of Health, Bethesda, Md.).

[0054] “Monoclonal antibody” or “mAb” or “Mab”. as used herein, refers to a population of substantially homogeneous antibodies, z.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 typicallyinclude 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.

[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 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, aswell 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 alkyl halides (e.g, methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g, decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g, 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., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.

[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” as used herein means to administer an Immunoconjugate of Formula (I) to a patient having cancer, or diagnosed with cancer, to achieve at least one positivetherapeutic 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 Immunoconjugate of Formula (I) is 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 Immunoconjugate of Formula (I) that is effective to alleviate any particular disease symptom may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapeutic combination to elicit a desired response in the patient. Whether a disease symptom has been alleviated can be assessed by any clinical measurement typically used by physicians or other skilled healthcare providers to assess the severity or progression status of that symptom. “Treatment7’ 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 non-small cell lung 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 an Immunoconjugate of Formula (I), or to each therapeutic agent in a combination therapy of the 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 known inthe 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 amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al. ,' National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32: 1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901- 917 or Chothia, et al., (1989) Nature 342:878-883.

[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- TROP-2 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-TROP-2 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-TROP-2 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.

[0082] The following Abbreviations are used herein, and are defined as follows:ADC Antibody -Drug ConjugateAE Adverse EffectAPaT All patients as treated populationART Antiretroviral therapyBICR Blinded independent central reviewCR Complete responseCTCAE Common terminology criteria for adverse effectsECOG Eastern Cooperative Oncology GroupEGFR Epidermal growth factor receptorEGFR-TKI Epidermal growth factor tyrosine kinase inhibitorEORTC European Organization for Research and Treatment of CancerGy GrayHBsAg Hepatitis B surface antigenHBV Hepatitis B virusHCV Hepatitis C virusHIV Human immunodeficiency virusIA Adverse incidentILD Interstitial lung disease mAb Monoclonal antibodyMPK or mpk Milligram per kilogramNCI National Cancer InstituteNSCLC Non-small cell lung cancerNTRK Neurotrophic tyrosine receptor kinaseOR Overall responseORR Overall response rateOS Overall survivalPD-1 Programmed cell death protein 1PFS Progression free survivalPOCBP Persons of childbearing potentialPR Partial response^-values Calculated probability q2w Once every 2 weeksQTcF QT interval corrected for heart rateRECIST Response Evaluation Criteria in Solid TumorsSAE Serious adverse effectTKI Tyrosine kinase inhibitorVH immunoglobulin heavy chain variable regionVK immunoglobulin kappa light chain variable regionVL immunoglobulin light chain variable region

[0083] Additional abbreviations may be defined throughout this disclosure.

[0084] The present disclosure relates to methods of treating previously -treated nonsquamous non-small cell lung cancer, having an EGFR mutation, wherein the method comprises administering to a human patient in need thereof an effective amount of an Immunoconjugate of Formula (I).

[0085] In preferred embodiments, the Immunoconjugate of Formula (I) is Immunoconjugate A, which is described in US Patent Publication No. 20200347075. Immunoconjugate A has the structure:wherein n is an integer or decimal from 1 to 10; and Ab is sacituzumab.The Immunoconjugate of Formula (I)

[0086] Immunoconjugates useful in the present disclosure are those immuoconj gates ofwherein Ab is an antibody that binds to TROP-2; and and n is an integer from 1 to 10.

[0087] In certain embodiments, immunoconjugates useful in the present disclosure are those Immuoconj gates 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 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 Immuoconj gates of Formula (I):wherein n is an integer from 1 to 10; and Ab is an antibody that binds to TROP-2 comprising:(a) a heavy chain variable region having the amino acid sequence of SEQ ID No.: 3; and(b) a light chain variable region having the amino acid sequence of SEQ ID No.:4.

[0089] In certain embodiments, immunoconjugates useful in the present disclosure are those Immuoconj gates of Formula (I):wherein n is integer from 1 to 10; and Ab is an antibody that binds to TROP-2 comprising:(a) a heavy chain having the amino acid sequence of SEQ ID No.: 1; and(b) 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 has the structure:wherein n is an integer or decimal from 1 to 10; and Ab is sacituzumab.

[0091] In other preferred embodiments, a composition comprising the Immunoconjugates ofFormula (I) is administered whereinthe average “n’?of the composition is a decimal from 0 to 8 and Ab is sacituzumab.In some embodiments of the present disclosure, the anti-TROP-2 antibody of theImmunoconjugates 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 CN 103476941 A,or can be obtained by screening a G-MAB® library of Sorrento Therapeutics, Inc. Table 5 shows the SEQ ID NOs for the amino acid sequences of the heavy and light chain complementaritydetermining regions (HCDRs and LCDRs), heavy’ and light chain variable domains (VH and VL), and heavy' and light chains (HC and LC) of sacituzumab.Table 5. List of sacituzumab (“Abl”) Amino Acid Sequences

[0092] 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.

[0093] 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.

[0094] 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.Uses of the Therapies of the Present DisclosureTreatment or Prevention of Non-Small Cell Lung Cancer

[0095] The methods disclosed herein are potentially useful in treating diseases or disorders including, but not limited to. cancer. The terms "‘cancer; “cancerous”, or “malignant” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.

[0096] Accordingly, in one aspect, the present disclosure relates to methods of treating cancer, said method comprising administering to a patient in need thereof an Immunoconjugate of Formula (I), wherein the amount administered is effective to treat cancer.

[0097] In a specific embodiment, the amount administered is effective to treat 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 human patient.

[0098] In one embodiment, the cancer is metastatic. In another embodiment, the cancer is relapsed. In another embodiment, the cancer is refractory. In yet another embodiment, the cancer is relapsed and refractor)’.

[0099] In other embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient.

[0100] In a particular embodiment, the cancer being treated is non-small cell lung cancer. In a specific embodiment, the non-small cell lung cancer is previously-treated nonsquamous NSCLC, having an actionable EGFR mutation. Accordingly, in one embodiment, provided herein is a method for treating previously-treated nonsquamous NSCLC, having an actionable EGFR mutation, the method comprising administering to the patient an Immunoconjugate of Formula (I), wherein the amount administered is effective to treat this cancer.

[0101] In a specific embodiment, the cancer being treated is previously -treated nonsquamous NSCLC, having an actionable EGFR mutation, wherein the EGFR mutation is exon 19del or exon 21 L858R mutation.

[0102] In a specific embodiment, the cancer being treated is previously -treated nonsquamous NSCLC, having any of the following genomic mutations: ALK gene rearrangements; ROS1 rearrangements; BRAF V600E mutations; NTRK gene fusions; MET exon 14 skipping mutations; RET rearrangements; or EGFR point mutations of exon 20 S7681, exon 21 L861Q, or exon 18 G719X.

[0103] In a specific embodiment, the non-small cell lung cancer is previously-treated nonsquamous NSCLC, having an actionable EGFR mutation, wherein the patient has been previous treated with (a) an EGFR-TKI, and (b) platinum-based chemotherapy. The compositions, methods, kits, and uses provided herein are useful for the treatment of cancer. Cancers that may be treated using the compositions, methods, kits, and uses disclosed herein include, but are not limited to previously -treated nonsquamous NSCLC, having an actionable EGFR mutation, as described above.

[0104] The term "cancerous cell" as used herein, includes a cell afflicted by any one of the above-identified conditions.

[0105] In particular embodiments, the cancer is classified as stage III cancer or stage IV cancer. In some instances of these embodiments, the cancer is not surgically resectable.Administration and Dosage

[0106] The present disclosure relates to methods of treating 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 cancer.

[0107] The Immunoconjugates of Formula (I) will (with a pharmaceutically acceptable carrier or excipient(s)), be 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 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, z.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, z.e., administration of the Immunoconjugate of Formula (I) only to the portion of the patient's body to be treated; examples of such targetted administration include intratumoral injection.

[0108] In some embodiments, the methods of the present disclosure are administered for a period until the patient shows no symptoms of the diseases or disorders. In some embodiments, the methods of the present disclosure are administered for a period until the patient is cured of the diseases or disorders. In some embodiments, the methods of the present disclosure are administered for a period until the patient shows resistance to the therapy. In some embodiments, the methods of the present disclosure are administered for a period until the patient shows side effects that would require discontinuation of the therapy.

[0109] In some embodiments, the patient is fasting for at least 1 hour. 2 hours, 3 hours. 4 hours, 6 hours, 8 hours, 12 hours before one or more components of a combination therapy is administered. In some embodiments, the patient needs to fast for at least 1 hour, 2 hours, 3 hours,4 hours, 6 hours. 8 hours, 12 hours after one or more components of a combination therapy is administered.

[0110] A method 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.

[0111] 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 targetted 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, 4.00 mg / kg, 4.50 mg / kg, 4.75 mg / kg, or 5.00 mg / kg every 2 weeks. In specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every’ 2 w eeks. In other specific embodiments, the Immunoconjugate of Formua (I) is administered at 4.00 mg / kg every 3 weeks, every 4 weeks, or every 6 weeks. In specific embodiments, the Immunoconjugate of Formula (I) is administered at3.00 mg / kg even' 2 weeks. In other specific embodiments, the Immunoconjugate of Formua (1) is administered at 4.00 mg / kg every 3 weeks, every 4 weeks, or every 6 weeks. In specific embodiments, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 2 weeks. In other specific embodiments, the Immunoconjugate of Formula (I) is administered at 3.00 mg / kg every 3 weeks, every 4 weeks, or every 6 weeks. In other specific embodiments, the Immunoconjugate of Formula (I) is administered at 4.00 mg / kg every 3 weeks, every 4 weeks, or every’ 6 weeks. In other specific embodiments, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every' 3 weeks, every' 4 weeks, or every 6 weeks.

[0112] In one embodiment, in the methods of the present disclosure, an Immunoconjugate of Formula (I) is administered at a dose of 0.25 mg / kg to 10 mg / kg. In other embodiments, the Immunoconjugate of Formula (I) may' be administered at a dose 0.25 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.5, 6, 6.5, 7, 8, 9, or 10 mg / kg as a single dose, or in any combination thereof for multiple doses. In certain embodiments, the Immunoconjugate of Formula (I) is administered at a dose of 4. 4.25. 4.5, 4.75. 5, 5.25, 5.5, 5.75, or 6 mg / kg. In other embodiments, the Immunoconjugate of Formula (I) is administered at a dose of 3.00, 3.75, 4.00, 4.25, 4.50, 4.75, or 5.00 mg / kg. In a specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of 3 mg / kg. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at a dose of 5 mg / kg.

[0113] 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 certain embodiment, the cycle is 2 weeks. 3 weeks. 4 weeks, or 6 weeks. In a specific embodiment, the cycle is 6 weeks. 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, 2 or more cycles, or 3 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 two-week cycle). In particular embodiments, the Immunoconjugate of Formula (I) is administered on Days 1, 8, and 15 of each cycle (e.g., a four- week cycle or a six-week cycle).In a specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 2-week cycle. In another specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 3-week cycle. In another specific embodiment, the Immunoconjugate of Formula (I) is administered on the first day of a 4-week cycle. In another embodiment, the Immunoconjugate of Formula (I) is administered on days 1. 15. and 29 of a six- week cycle. In other embodiments, the Immunoconjugate of Formula (I) is administered at 3.50 mg / kg, 3.75 mg / kg, 4.0 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 embodiments, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every72 weeks. In another specific embodiment, the Immunoconjugate of Formula (I) is administered at 5.00 mg / kg every 3 weeks.

[0114] 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 (<?.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 every74 weeks.

[0115] 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 specificembodiment, 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.

[0116] 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.

[0117] In one embodiment, provided is a method treating 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 day 1 of a two-week cycle (“Regimen 1”).

[0118] In a specific embodiment, for Regimen 1, the Immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg per administration.

[0119] In a specific embodiment, for Regimen 1, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0120] In another embodiment, Regimen 1 is administered in from 1 to 4 cycles.

[0121] In one embodiment, Regimen 1 is administered to a patient to treat cancer, wherein the cancer is previously -treated nonsquamous non-small cell lung cancer having an EGFR actionable mutation.

[0122] In a specific embodiment, Regimen 1 is administered to a patient to treat cancer, wherein the cancer is previously-treated nonsquamous non-small cell lung cancer having an EGFR actionable mutation, wherein the patient has been previous treated with (a) an EGFR-TKI, and (b) platinum-based chemotherapy.

[0123] In one embodiment, provided is a method treating 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 and 15 of a four-week cycle (“Regimen 2”).

[0124] In a specific embodiment, for Regimen 2, the Immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg per administration.

[0125] In a specific embodiment, for Regimen 2, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0126] In another embodiment, Regimen 2 is administered in from 1 to 4 cycles.

[0127] In one embodiment. Regimen 2 is administered to a patient to treat cancer, wherein the cancer is previously -treated nonsquamous non-small cell lung cancer having an EGFR actionable mutation.

[0128] In a specific embodiment, Regimen 2 is administered to a patient to treat cancer, wherein the cancer is previously-treated nonsquamous non-small cell lung cancer having an EGFR actionable mutation, wherein the patient has been previous treated with (a) an EGFR-TKI, and (b) platinum-based chemotherapy.

[0129] In one embodiment, provided is a method treating 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 (“Regimen 3”).

[0130] In a specific embodiment, for Regimen 3, the Immunoconjugate of Formula (I) is administered at a dose of 4 mg / kg per administration.

[0131] In a specific embodiment, for Regimen 3, the Immunoconjugate of Formula (I) is Immunoconjugate A.

[0132] In another embodiment, Regimen 3 is administered in from 1 to 4 cycles.

[0133] In one embodiment, Regimen 3 is administered to a patient to treat cancer, wherein the cancer is previously -treated nonsquamous non-small cell lung cancer having an EGFR actionable mutation.

[0134] In a specific embodiment, Regimen 3 is administered to a patient to treat cancer, wherein the cancer is previously-treated nonsquamous non-small cell lung cancer having an EGFR actionable mutation, wherein the patient has been previous treated with (a) an EGFR TKI (tyrosine kinase inhibitor), and (b) platinum-based chemotherapy.Additional Therapeutic Agents

[0135] The methods disclosed herein may be used in combination with one or more other additional therapeutic agents, including but not limited to, additional anti-cancer agents, wherein said additional anti-cancer agents are used in the prevention, treatment, control, amelioration, orreduction of risk of a cancer, which is previously -treated nonsquamous NSCLC having an EGFR mutation. In one embodiment, an 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 a cancer, which is previously-treated nonsquamous NSCLC having an EGFR mutation. Such additional therepeutic agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a combination therapy of the present disclosure.

[0136] Also provided herein are methods comprising administering to a patient: a pharmaceutical composition comprising: (a) the 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 cancer.

[0137] When co-administered with an additional therapeutic agent, the additional therapeutic agent can be administered in repeated cycles of 1, 2, 3, 4, 5. 6, 7, 8, 9, 10, 11. 12. 13, 14, 15, or 16 weeks. In one specific embodiment, the additional therapeutic agent is administered in three- week cycles. In another specific embodiment, the 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 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 two-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.

[0138] 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 Immunoconjugate of Formula (I), and one or more additional therepeutic agents will be determined based on the individual patient needs.

[0139] When the therapeutic combination disclosed herein is used contemporaneously with one or more additional therapeutic agent(s), the Immunoconjugate of Formula (I) may be administered either simultaneously with, or before or after, one or more additional therapeutic agent(s). Either of the Immunoconjugate of Formula (I) or the additional therapeutic agent(s) may be administered separately, by the same or different route of administration, or together in the same pharmaceutical composition.

[0140] The amounts administered of the Immunoconjugate of Formula (I) and the additional thereapeutic agent(s) 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 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 that the amounts administered are together effective to treat cancer.

[0141] Anti-viral compounds that may be used in the combination therapies disclosed herein include hepatitis B virus (HBV) inhibitors, hepatitis C virus (HCV) protease inhibitors, HCV polymerase inhibitors, HCV NS4A inhibitors. HCV NS5A inhibitors, HCV NS5b inhibitors, and human immunodeficiency virus (HIV) inhibitors.

[0142] Antigens and adjuvants that may be used in the combination therapies disclosed herein include B7 costimulatory molecule, interleukin-2, interferon-' / . GM-CSF, CTLA-4 antagonists, OX-40 / OX-40 ligand, CD40 / CD40 ligand, sargramostim. levamisol, vaccinia virus, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surface active substances such as lipolecithin, pluronic polyols,polyanions, peptides, and oil or hydrocarbon emulsions. Adjuvants, such as aluminum hydroxide or aluminum phosphate, can be added to 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 acidinducible gene I (RIG-I) agonists such as poly I:C, used separately or in combination are also potential adjuvants.

[0143] Additional chemotherapeutic agents that may be used in the combination therapies disclosed herein include abiraterone acetate, altretamine, anhydrovinblastine, aroplatin, asparaginase (also known as L-asparaginase, and Erwinia L-asparaginase), auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin. N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl- 1-Lproline- t-butylamide, cachectin, cemadotin, chlorambucil, cyclophosphamide, 3'.4'-didehydro-4'deoxy- 8'-norvin-caleukoblastine, dinaciclib, docetaxol, doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin, cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC), dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin (adriamycin), etoposide, 5- fluorouracil, finasteride, flutamide, hydroxyurea and hydroxyurea andtaxanes, ifosfamide, liarozole, lonidamine, lomustine, MDV3100, mechlorethamine (nitrogen mustard), melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin, mitomycin, methotrexate, taxanes, nilutamide, olaparib, onapristone, oxaliplatin, paclitaxel, prednimustine, procarbazine, RPR109881, selumetinib, stramustine phosphate, tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine, vindesine sulfate, and vinflunine. and pharmaceutically acceptable salts thereof.

[0144] 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. WOO 1 / 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.

[0145] Examples of topoisomerase II inhibitors, include but are not limited to, etoposide, and teniposide.

[0146] 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 therapeutic agent is a platinum-based chemotherapeutic agent. In a specific embodiment, the additional therapeutic agent is cisplatin. In another specific embodiment, the additional therapeutic agent is carboplatin. In specific embodiments, when co-administered with carboplatin, the dose of carboplatin is from about AUC 1 mg / mL / min to AUC 10 mg / mL / min, administered intravenously. In a specific embodiment, when co-administered with carboplatin, the dose of carboplatin is AUC 5 mg / mL / min, administered intravenously. In other embodiments, when co-administered with cisplatin, the dose of cisplatin is from about 10 mg / m2to 150 mg / m2, administered intravenously. In a specific embodiment, when co-administered with cisplatin, the dose of cisplatin is 75 mg / m2, administered intravenously.

[0147] Examples of anti-tumor antibiotics include, but are not limited to, doxorubicin, bleomycin, daunorubicin daunorubicin liposomal (daunorubicin citrate liposome), mitoxantrone, epirubicin, idarubicin, and mitomycin C.

[0148] Examples of anti-metabolites include, but are not limited to, claribine, 5-fluorouracil, 6- thioguanine, pemetrexed (sold under the tradename ALIMTA®), cytarabine (also known as arabinosylcytosine (Ara-C)). cytarabine liposomal (also known as Liposomal Ara-C. sold under the tradename DEPOCYT™), decitabine (sold under the tradename DACOGEN®), hydroxyurea and fludarabine, floxuridine, cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), methotrexate (also known as amethopterin, methotrexate sodium (MTX)), and pentostatin.Additional Embodiments

[0149] Additional embodiments of the disclosure include the compositions, combinations, uses and methods set forth in above, wherein it is to be understood that each embodiment may be combined with one or more other embodiments, to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that theembodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments.General Methods

[0150] Standard methods in molecular biology are described Sambrook, Fritsch and Maniatis (1982 & 1989 2ndEdition, 2001 3rdEdition) Molecular Cloning. A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Sambrook and Russell (2001) Molecular Cloning, 3rded., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Wu (1993) Recombinant DNA. Vol. 217, Academic Press. San Diego, CA). Standard methods also appear in Ausbel, et al. (2001) Current Protocols in Molecular Biology. Vols.1-4, John Wiley and Sons, Inc. New York, NY, which describes cloning in bacterial cells and DNA mutagenesis (Vol. 1), cloning in mammalian cells and yeast (Vol. 2), glycoconjugates and protein expression (Vol. 3), and bioinformatics (Vol. 4).

[0151] 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 cd. (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).

[0152] Monoclonal, polyclonal, and humanized antibodies can be prepared {see, e.g., Sheperd and Dean (eds.) (2000) Monoclonal Antibodies, Oxford Univ. Press, New Y ork, 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 el o / . (1999) J. Biol. Chem. 274:27371-27378; Baca / o / . (1997) 7. Biol. Chem. 272: 10678-10684; Chothia eloZ. (1989) Nature 342:877-883; Foote and Winter (1992) 7. Mol. Biol. 224:487-499; U.S. Pat. No. 6,329,511).

[0153] 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 Y ork; 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).

[0154] 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 a , supra:, Kaithamana et al. (1999) 7. Immunol. 163:5157-5164).

[0155] Methods for flow cytometry, including fluorescence activated cell sorting (FACS), are available (see, e.g.. Owens, et al. (1994) Flow Cytometry Principles for Clinical Laboratory Practice. John Wiley and Sons, Hoboken, NJ; Givan (2001) Flow Cytometry. 2nded , Wiley-Liss, Hoboken, NJ; Shapiro (2003) Practical Flow Cytometry, John Wiley and Sons, Hoboken, NJ). Fluorescent reagents suitable for modifying nucleic acids, including nucleic acid primers and probes, polypeptides, and antibodies, for use, e.g., as diagnostic reagents, are available (Molecular Probesy (2003) Catalogue, Molecular Probes. Inc., Eugene, OR; Sigma- Aldrich (2003) Catalogue, St. Louis. MO).

[0156] 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).

[0157] 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 NTI® Suite (Informax, Inc., Bethesda, MD); GCG Wisconsin Package (Accelrys. Inc., San Diego, CA); DeCypher® (TimeLogic Corp., Crystal Bay, Nevada); Menne, et al. (2000) Bioinformatics 16: 741-742; Menne, et al. (2000) Bioinformatics Applications Note 16:741-742; Wren, et al. (2002) Comput. Methods ProgramsBiomed. 68: 177-181; von Heijne (1983) Eur. J. Biochem. 133: 17-21; von Heijne (1986) NucleicAcids Res. 14:4683-4690)Examples

[0158] The following examples illustrate representative embodiments of the present disclosure and are not meant to be limiting in any way.EXAMPLE 1Preparation of Immunoconjugate A

[0159] Immunoconjugate A can be made using the methodology described in US Patent Publication No. US Patent Publication No. 20200347075, wherein Immunoconjugate A is referred to as “BT001021.'’EXAMPLE 2Study of Immunoconjugate A Therapy in Subjects with Nonsquamous NSCLC having an EGFR mutation

[0160] This is a randomized, open-label, multi-site study of Compound A in participants with nonsquamous NSCLC with exon 19del or L858R EGFR mutations or other genomic alterations who have progressed on or following both TKI and platinum-based chemotherapy. The following participants will be enrolled: (a) participants with NSCLC with exon 19del or L858R EGFR mutations, and (b) participants with other genomic alterations.

[0161] Participants will receive Compound A at 4 mg / kg q2w on Days 1, 15, and 29 of every' 6- week cycle.Treatment randomization will be stratified by:• EGFR mutations with prior third generation TKI versus EGFR mutations with no prior third generation TKI versus other genomic alterations• Brain metastasis (yes vs no)• TROP2 expression (low vs medium vs high)

[0162] Participants will receive treatment until any of the pre-set criteria for discontinuation of study intervention are met. Participants will undergo imaging at the timepoints described below. Participants will be followed after discontinuation guidelines outlined in the NCI CTCAE v5.0. Each participant will be monitored for adverse effects (AEs) and serious adverse effects (SAEs).

[0163] Results of the IAS will be reviewed by an external data monitoring committee, which will make recommendations to the Sponsor to continue, modify, or end the study.

[0164] The dual primary endpoints of the study are progression-free survival (PFS) and overall survival (OS) in participants with NSCLC with EGFR mutations. Key secondary endpoints include PFS and OS in all participants with NSCLC and overall response (OR) in participants with NSCLC with EGFR mutations and all participants with NSCLC. AEs will be monitored throughout the study and graded in severity.The dual primary endpoints of the study are OS and PFS

[0165] Overall survival (OS) has been recognized as the gold standard for the demonstration of superiority of a new antineoplastic therapy in randomized clinical studies.

[0166] This study will also use PFS based on RECIST 1.1 criteria as assessed by BICR as a primary endpoint. PFS is an acceptable measure 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 is typically considered acceptable by regulatory authorities. Images will be submitted to an iCRO for a blinded central independent review to minimize bias in response assessments. Expedited verification of radiologic progression as determined by central review will be communicated to the site.

[0167] This study will use overall response rate (ORR) based on RECIST 1. 1 criteria as assessed by BICR as a key secondary endpoint. ORR is an acceptable measure of clinical benefit for a study that is assessing response to a new antineoplastic therapy in areas of high unmet need, especially if the magnitude of the response is large and the therapy has an acceptable risk / benefit profile. The use of BICR and RECIST 1.1 to assess ORR is typically considered acceptable by regulatory authorities.Inclusion Criteria

[0168] An individual is eligible for inclusion in the study if the individual meets all of the following criteria: i) Type of Participant and Disease Characteristics1. Histologically- or cytologically-documented advanced (Stage III not eligible for resection or curative radiation) or metastatic non-squamous NSCLC with exon 19del or exon 21 L858R EGFR mutations or other genomic alterations in ALK, ROS1, BRAF V600E, NTRK, MET exon14 skipping, or RET. and those with less common EGFR mutations (exon 20 S768I, exon 21 L861Q, and / or exon 18 G719X) as determined by the local laboratory.2. Documentation of locally assessed radiological disease progression while on or after last treatment based on RECIST 1.1.3. Participants with exon 19del or exon 21 L858R EGFR mutations must have received both of the following treatments: a. One or 2 prior lines of EGFR-TKI, which also includes a third generation TKI for participants with a T790M mutation. For those who progressed on a first and / or second generation EGFR-TKI and then received platinum-based therapy, negative T790M mutation should be documented. b. One platinum-based therapy (treatment regimen may contain anti-PD-l / PD-Ll mAb) after progression on or after EGFR-TKI.4. Participants with other genomic alterations must have received both of the following treatments: a. One or 2 prior lines of locally recommended TKIs for the respective genomic alteration. b. One platinum-based therapy (treatment regimen may contain anti-PD-l / PD-Ll mAb) after progression on or after TKI). ii) Demographics5. Is an individual of any sex / gender of at least 18 years of age at the time of providing the informed consent. iii) Additional Categories6. Measurable disease per RECIST 1.1 as assessed by the local site investigator. Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.7. Archival tumor tissue sample or newly obtained core, incisional, or excisional biopsy of a tumor lesion not previously irradiated has been providedTissue is required for determination of TROP2 status by central vendor before randomization.8. Participants who have AEs due to previous anticancer therapies must have recovered to Grade <1 or baseline (except alopecia or vitiligo). Participants with endocnne-related AEs who are adequately treated with hormone replacement are eligible.9. Adequate organ function. Specimens are collected within 10 days before the start of study intervention. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.10. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.Note: Participants must have completed curative antiviral therapy at least 4 weeks prior to randomization.11. HIV -infected participants must have well controlled HIV on ART, defined as: a. Having a CD4+ count >350 cells / mm3 at the time of screening. b. Having achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening. c. Have not had any AIDS-defining opportunistic infections within the past 12 months. d. Have been on a stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before randomization and agree to continue ART throughout the study.Note: the ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors / inducers / substrates.12. Have a life expectancy of at least 3 months.13. Have an ECOG performance status of 0 or 1 within 3 days before randomization.Exclusion Criteria

[0169] An individual will be excluded from the study if the individual meets any of the following criteria: i) Medical Conditions1. Has predominantly squamous cell histology NSCLC.2. Participants with mixed tumors with small cell elements.3. 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).4. Has Grade >2 peripheral neuropathy.5. Has history of documented severe dry eye syndrome, severe Meibomian gland disease and / or blepharitis, or corneal disease that prevents / delays comeal healing.6. Has uncontrolled, significant cardiovascular disease or cerebrovascular disease including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, uncontrolled symptomatic arrhythmia, prolongation of QTcF interval to >480 ms. and / or other serious cardiovascular and cerebrovascular diseases within the 6 months preceding study intervention. ii) Prior / Concomitant Therapy7. Has an EGFR T790M mutation and has not received a third generation EGFR-TKI (eg, osimertinib).8. Received prior systemic anticancer therapy including investigational agents within 4 weeks or 5 half-lives (whichever is shorter) before randomization.9. Received a live or live-attenuated vaccine within 30 days before the first dose of studyintervention. Administration of killed vaccines are allowed.10. Completed palliative radiotherapy within 7 days of the first dose. Participants must have recovered from all radiation-related toxi cities and not require corticosteroids.11. Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study intervention.12. Received prior treatment with a TROP2-targeted ADC.13. Received prior treatment with a topoisomerase I-containing ADC.14. Requires treatment with a strong inhibitor or inducer of CYP3A4 within 2 weeks before the first dose of study intervention and throughout the study.Note: A list of strong inhibitors or inducers of CYP3A4 can be found at the following website: https: / / www.fda.gov / drugs / drug-interactions-labeling / drug-development-and-druginteractions- table-substrates-inhibitors-and-inducers.Hi) Prior / Concurrent Clinical Study Experience15. Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration. iv) Diagnostic Assessments16. Known additional malignancy that is progressing or has required active treatment within the past 3 years.Note: Participants w ith basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.17. Active infection requiring systemic therapy.18. History of noninfectious pneumonitis / ILD that required steroids or has current pneumonitis / ILD.Note: Lymphangitic spread ofthe NSCLC is not exclusionary’.19. Has known active central nervous system metastases and / or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are clinically stable for at least 2 w eeks, and are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication. Participants with known untreated, asymptomatic brain metastases not needing immediate local therapy (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate. Note: records of any CNS treatment must be documented to allow' for classification of target and non-target lesions20. HIV -infected participants with a history of Kaposi’s sarcoma and / or Multicentric Castleman’s Disease.21. Concurrent active Hepatitis B (defined as HBsAg positive and / or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.22. History or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.23. Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study. v) Other Exclusions24. Participants who have not adequately recovered from major surgery or have ongoing surgical complications.Dose Modification for Compound A

[0170] Recommended dose modification guidelines for Compound A are provided in Table 1. Dosing delays for Compound A due to an AE should not exceed 28 days of the last administered dose, unless otherwise discussed the Sponsor.

[0171] If a dose reduction for an AE associated with Compound A is needed, the dose can be reduced in 1 mg / kg increments. 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.

[0172] Once the Compound 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 Compound A should be permanently discontinued.

[0173] 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 1, the investigator should discuss the management details with the Sponsor.

[0174] Compound 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. However, 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.Management of Infusion Reactions

[0175] Compound A may cause severe or fatal infusion-related reactions, including severe hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion.

[0176] Premedication to prevent hypersensitivity and / or infusion reactions is required prior to each dose of Compound A. Participants should be premedicated 1.5 hours (±30 min) prior to infusion of Compound A. For the first 4 administrations, participants should be premedicated with diphenhydramine (or equivalent [per approved product label]), H2 receptor antagonist (per approved product label), acetaminophen (or equivalent [per approved product label]), and a corticosteroid (dexamethasone 10 mg IV [or equivalent]). After the fourth infusion, in the absence of prior infusion-related or hypersensitivity AEs, participants should be premedicatedwi th diphenhydramine (or equivalent [per approved product label]) and acetaminophen (or equivalent [per approved product label]) with the addition of a corticosteroid at the discretion of the investigator.Timing of Dose Administration

[0177] After Day 1 of Cycle 1, study intervention may be administered up to 3 days before or after the scheduled day of administration. Participants will continue receiving study intervention until one of the criteria for treatment discontinuation are met.Compound A

[0178] Compound A will be administered intravenously on Days 1, 15, and 29 of each 6-week cycle. The duration of the Compound 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. After at least 4 administrations and in the absence of either infusion-related AEs or anaphylactic reactions,the infusion of Compound A may be shortened at the discretion of investigator but cannot be shorter than 60 minutes.

[0179] All participants are to be premedicated as outlined in the “Management of Infusions Section" above. Participants are to be closely monitored during the infusion for the development of a hypersensitivity reaction and / or infusion reaction. Emergency rescue medications (including epinephrine) and appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.Efficacy EndpointsPrimary• Progression-free survival (PFS)

[0180] PFS is defined as the time from randomization to the first documented disease progression per RECIST 1.1 based on blinded independent central review (BICR) or death due to any cause, whichever occurs first.• Overall Survival (OS)

[0181] OS is defined as the time from randomization to death due to any cause.Secondary• Objective Response (OR)

[0182] The OR is defined as a confirmed complete response (CR) or partial response (PR) per RECIST 1.1 as assessed by BICR.• Duration of Response (DOR)

[0183] For participants who demonstrate confirmed CR or PR per RECIST 1. 1 as assessed by BICR, duration of response is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.Safety Endpoints

[0184] Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, laboratory test results, and vital signs.Patient-reported Outcomes (PRO) Endpoints

[0185] The following secondary PRO endpoints will be evaluated as described in Section4.2. 1.3 and analyzed as described in Section 9.5.3:Change from baseline in• Global health status / QoL score (EORTC QLQ-C30 items 29 and 30)• Dyspnea score (EORTC QLQ-C30 item 8)• Cough (EORTC QLQ-LC13 item 31)• Chest pain (EORTC QLQ-LC13 item 40)Time to deterioration in• Global health status / QoL score (QLQ-C30 items 29-30)• Dyspnea score (EORTC QLQ-C30 item 8)• Cough (EORTC QLQ-LC13 item 31)• Chest pain (EORTC QLQ-LC13 item 40)

[0186] In addition, change from baseline and time to deterioration in EORTC QLQ-C30 phy sical functioning and role functioning scores, and change from baseline in NSCLC-SAQ total score, and EQ-5D-5L VAS will be analyzed as exploratory PRO endpoints. The PGIC-LC and PGIS-LC questionnaires will be used to investigate clinically meaningful thresholds for change in the lung cancer symptoms as measured with the NSCLC-SAQ.Analysis Populations i) Efficacy Analysis Populations

[0187] The Intention-to-Treat (ITT) population will sen e as the population for primary' efficacy analysis. All randomized participants will be included in this population. Participants will be included in the treatment group to which they are randomized. ii) Safety Analysis Populations

[0188] Safety Analyses will be conducted in the APaT population, which consists of all randomized participants who received at least one dose of study intervention. Participants will be included in the treatment group corresponding to the study intervention they actually received for the analysis of safety7data 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. Analyses of laboratory test results, vital signs, and ECG measurements will include only participants with at least one measurement obtained after at least one dose of study intervention. If the analysis will assess change from baseline, a baseline measurement is also required. in) Patient-reported Outcomes Analysis Populations

[0189] The PRO analyses are based on the PRO Full Analysis Set (PRO FAS) population, defined as all randomized participants who have at least one PRO assessment available for the specific endpoint and have received at least one dose of the study intervention. Participants will be analyzed in the treatment group to which they are randomized.Statistical Methods iv) Statistical Methods for Efficacy Analyses

[0190] For both PFS and OS, stratified log-rank tests will be used for comparison of the two groups. The hazard ratio 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 with respect to both primary endpoints. The objective response rate (ORR), defined as the proportion of participants who have an OR, will be analyzed using the stratified Miettinen and Nurminen’s method for comparison between two treatment groups. The difference in ORR and its 95% CI from the stratified Miettinen andNurminen method [Miettinen. O. and Nurminen, M. 1985] with stratum weighting by sample size will be reported.

[0191] The point estimate of ORR will be provided by treatment group, together with 95% CI using exact binomial method proposed by Clopper and Pearson [Clopper, C. J. and Pearson, E. S. 1934], If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians and quartiles.

[0192] While preferred embodiments of the present disclosure have been show n and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in practicing the methods and uses disclosed herein.

Claims

WHAT IS CLAIMED IS:

1. A method of treating previously -treated nonsquamous non-small cell lung cancer in a patient, wherein the nonsquamous non-small cell lung cancer has an EGFR mutation, the method comprising administering to the patient an effective amount of an Immunoconjugate of Formula (I):(I), wherein:Ab is an antibody that binds to TROP-2; and n is an integer from 1 to 10.

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

3. The method of any one of claims 1 - 2. wherein the 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(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.

4. The method of any one of claims 1-3, wherein the 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 ammo acid sequence of SEQ IDNO: 4.

5. The method of any one of claims 1-4, wherein the 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.

6. The method of any one of claims 1-5, wherein the antibody is sacituzumab.

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

8. The method of claim 7. wherein the Immunoconjugate of Formula (I) is administered to the patient at a dose of about 4.0 mg / kg.

9. The method of any one of claims 1-8, wherein the Immunoconjugate of Formula (I) is administered in six- week cycles, and administered on days 1, 15 and 29 of each six- eek cycle.

10. The method of claim 9, wherein the number of cycles is from 1-4.

11. The method of any one of claims 1-10. further comprising administering to the patient an additional anticancer agent, w herein the amounts of the Immunoconjugate of Formula (I) and the additional anti cancer agent are together effective to treat nonsquamous non-small cell lung cancer having an actionable EGFR mutation.

12. The method of claim any of claims 1-11, wherein the patient has been previously- treated with (a) an EGFR-TKI, and (b) platinum-based chemotherapy.

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