Combinations for the treatment of cancer

Abstract

In one aspect, provided herein are methods of treating cancer with a combination therapy comprising an anti-human-HER3 antibody-drug conjugate and a small molecule inhibiting G12C mutant of Kirsten rat sarcoma (KRAS) protein.

Description

Attorney Docket No. 14463-360-228COMBINATIONS FOR THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 728,041, filed December 4, 2024, the disclosure of which is incorporated by reference herein in its entirety.SEQUENCE LISTING

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14463-360-228_SEQ_LISTING.xml”, was created on November 25, 2025, and is 14,324 bytes in size.BACKGROUND

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

[0004] In one aspect, provided is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:1NAI-5006811188and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.2NAI-5006811188

[0005] In some embodiments, provided herein is a method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti- human-HER3 antibody or a functional fragment thereof and a drug-linker of Formula IIIFormula III wherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and3NAI-5006811188b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

[0006] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula III, wherein the number of drug-linkers of Formula III is equal to n, and wherein n represents the drug to antibody ratio.

[0007] In some embodiments of the method provided herein, the compound of Formula I i s (5 aka, 17 a / a)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-4 / 7- 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one.

[0008] Pharmaceutical compositions for use and uses according to the present combinational therapy are also provided herein.

[0009] In some embodiments of the methods, pharmaceutical compositions and uses provided herein, the cancer is a lung cancer. In some embodiments, the cancer is a non-small cell lung cancer.BRIEF DESCRIPTION OF THE DRAWINGS

[0001] FIG. 1 is a schematic diagram showing an exemplary design of a clinical study for the combination of patritumab deruxtecan and MK-1084. As represented in FIG. 1, CNS=central nervous system; DL=dose level; ECOG=Eastern Cooperative Oncology Group; G12C= mutation of glycine to cysteine at codon 12; ILD=interstitial lung disease; I0=immune oncology; KRASi=Kirsten rat sarcoma viral oncogene inhibitor; NSCLC=non-small cell lung cancer; PD=progressive disease; PS=performance status; q2w=every 2 weeks; q3w=every 3 weeks; qd=once daily; R=randomization; RP2D=recommended Phase 2 dose. In Phase lb, DL0 will be the first dose level evaluated. Further escalation, de-escalation, or re-escalation (if the lower dose level is well tolerated) to be determined based on safety data. Dose randomization may not be initiated depending on Phase lb data. If dose randomization is not initiated, randomization will be employed. In Phase 2, participants will continue at the RP2D until PD or toxicity. As denoted by “a” de-escalation to DL-1 will occur if DL0 (the starting dose) is not initially tolerable. DL-1 A (the backup option) may be employed if DLTs (dose limiting toxicity) at the other dose levels are mainly attributable to MK-1084.4NAI-5006811188DETAILED DESCRIPTION1. Definitions

[0010] Unless otherwise defined, terms of art, notations, and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art.

[0011] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise. The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0012] As used herein, the term “comprising” also specifically includes embodiments “consisting of’ and “consisting essentially of’ the recited elements, unless specifically indicated otherwise.

[0013] The term “about” or “approximately” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” or “approximately” indicates the designated value ± 10%. In certain embodiments, where applicable, the term “about” or “approximately” indicates the designated value(s) ± one standard deviation of that value(s).

[0014] In some embodiments, the terms “first,” “second,” “third,” “fourth” and similar in a component name are used to distinguish and identify more than one component sharing certain identity in their names. For example, “first composition” and “second composition” are used to distinguish two compositions.

[0015] It is understood that wherever embodiments are described herein with the term “comprising” otherwise analogous embodiments described in terms of “consisting of’ and / or “consisting essentially of’ are also provided. It is also understood that wherever embodiments are described herein with the phrase “consisting essentially of’ otherwise analogous embodiments described in terms of “consisting of’ are also provided.

[0016] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 95th Ed. Additionally, general principles of organic chemistry are described in "Organic Chemistry,” 2ndEd., Thomas Sorrell, University Science Books, Sausalito: 2006, and "March’s Advanced Organic Chemistry,” 7th Ed., Ed.: Smith, M.B. and March, J., John5NAI-5006811188Wiley & Sons, New York: 2013, the entire contents of which are hereby incorporated by reference.

[0017] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 20 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0018] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch. 5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region typically comprises three domains, abbreviated CHI, CH2, and CH3. Each light chain typically comprises a light chain variable region (VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CL.

[0019] “Antigen” refers to any molecule (e.g., protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, portions thereof, or combinations thereof) that is capable of mediating an immune response. Exemplary immune responses include antibody production and activation of immune cells, such as T cells, B cells or NK cells.

[0020] “Antigen binding fragment” or “antigen binding domain” refers to a portion of a protein that binds the antigen. Antigen binding fragments may be synthetic, enzymatically obtainable or genetically engineered polypeptides and include portions of an immunoglobulin that bind an antigen, such as a VH, a VL, the VH and the VL, Fab, Fab’, F(ab’)2, Fd and Fv fragments, single-domain antibodies (sdAb) consisting of one VH domain or one VL domain, camelized VH domains, VHH domains, minimal recognition units consisting of the amino acid residues that mimic the CDRs of an antibody, such as FR3-CDR3-FR4 portions, the HCDR1, the HCDR2 and / or the HCDR3 and the LCDR1, the LCDR2 and / or the LCDR3, alternative scaffolds that bind an antigen, and multispecific proteins comprising the antigen6NAI-5006811188binding fragments. Antigen binding fragments (such as the VH and the VL) may be linked together via a synthetic linker to form various types of single antibody designs in which the VH / VL domains may pair intramolecularly, or intermolecularly in those cases when the VH and the VL domains are expressed by separate single chains, to form a monovalent antigen binding domain, such as single chain Fv (scFv) or diabody. Antigen binding fragments may also be conjugated to other antibodies, proteins, antigen binding fragments or alternative scaffolds which may be monospecific or multispecific to engineer bispecific and multispecific proteins.

[0021] “Antibody” is meant in a broad sense and includes immunoglobulin molecules including monoclonal antibodies including murine, human, humanized and chimeric monoclonal antibodies, antigen binding fragments, multispecific antibodies, such as bispecific, trispecific, tetraspecific, etc., dimeric, tetrameric or multimeric antibodies, single chain antibodies, domain antibodies and any other modified configuration of the immunoglobulin molecule that comprises an antigen binding site of the required specificity. A full length antibody is comprised of two heavy chains (HC) and two light chains (LC) inter-connected by disulfide bonds as well as multimers thereof (e.g., IgM). Each heavy chain is comprised of a heavy chain variable region (VH) and a heavy chain constant region (comprised of domains CHI, hinge, CH2 and CH3). Each light chain is comprised of a light chain variable region (VL) and a light chain constant region (CL). The VH and the VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with framework regions (FR). Each VH and VL is composed of three CDRs and four FR segments, arranged from amino-to-carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. Immunoglobulins may be assigned to five major classes, IgA, IgD, IgE, IgG and IgM, depending on the heavy chain constant domain amino acid sequence. IgA and IgG are further sub-classified as the isotypes IgAl, IgA2, IgGl, IgG2, IgG3 and IgG4. Antibody light chains of any vertebrate species may be assigned to one of two clearly distinct types, namely kappa (K) and lambda (1), based on the amino acid sequences of their constant domains. An antibody provided herein may include post-translational modifications thereof, e.g., C-terminal lysine clipping in the heavy chain or conversion of glutamine or glutamic acid to pyroglutamate or pyroglutamic acid, which may occur when recombinantly expressed in host cells (e.g., CHO cells), or during purifi cati on / storage .

[0022] “Human antibody” refers to an antibody that is optimized to have minimal immune response when administered to a human subject. Variable regions of human antibody7NAI-5006811188are derived from human immunoglobulin sequences. If human antibody contains a constant region or a portion of the constant region, the constant region is also derived from human immunoglobulin sequences. Human antibody comprises heavy and light chain variable regions that are “derived from” sequences of human origin if the variable regions of the human antibody are obtained from a system that uses human germline immunoglobulin or rearranged immunoglobulin genes. Such exemplary systems are human immunoglobulin gene libraries displayed on phage, and transgenic non-human animals such as mice or rats carrying human immunoglobulin loci. A “human antibody” typically contains amino acid differences when compared to the immunoglobulins expressed in humans due to differences between the systems used to obtain the human antibody and human immunoglobulin loci, introduction of somatic mutations or intentional introduction of substitutions into the frameworks or CDRs, or both. Typically, a “human antibody” is at least about 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical in amino acid sequence to an amino acid sequence encoded by human germline immunoglobulin or rearranged immunoglobulin genes. In some cases, a “human antibody” may contain consensus framework sequences derived from human framework sequence analyses, for example as described in Knappik et al., (2000) J Mol Biol 296:57-86, or a synthetic HCDR3 incorporated into human immunoglobulin gene libraries displayed on phage, for example as described in Shi et al., (2010) J Mol Biol 397:385-396, and in International Publication No. W02009 / 085462. Antibodies in which at least one CDR is derived from a non-human species are not included in the definition of “human antibody.”

[0023] “Humanized antibody” refers to an antibody in which at least one CDR is derived from non-human species and at least one framework region is derived from human immunoglobulin sequences. A humanized antibody may include substitutions in the framework regions so that the framework regions may not be exact copies of expressed human immunoglobulin or human immunoglobulin germline gene sequences.

[0024] The term “Fc region” means the C-terminal region of an immunoglobulin heavy chain that, in naturally occurring antibodies, interacts with Fc receptors and certain proteins of the complement system. The structures of the Fc regions of various immunoglobulins, and the glycosylation sites contained therein, are known in the art.

[0025] The VH and VL regions may be further subdivided into regions of hypervariability (“hypervariable regions (HVRs);” also called “complementarity determining regions” (CDRs)) interspersed with regions that are more conserved. The more conserved regions are called framework regions (FRs). Each VH and VL generally comprises three8NAI-5006811188CDRs and four FRs, arranged in the following order (from N-terminus to C-terminus): FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4. The CDRs are involved in antigen binding, and influence antigen specificity and binding affinity of the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest 5th ed. (1991) Public Health Service, National Institutes of Health, Bethesda, MD.

[0026] A “Complementary Determining Region (CDR)” refers to one of three hypervariable regions (Hl, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH [3-sheet framework, or one of three hypervariable regions (LI, L2 or L3) within the non-framework region of the antibody VL [3-sheet framework. CDRs are variable region sequences interspersed within the framework region sequences. CDRs are well recognized in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable (V) domains. See Kabat et al., J Biol Chem, 1977, 252:6609-6616 and Kabat, Adv Protein Chem, 1978, 32: 1-75.CDRs have also been defined structurally by Chothia as those residues that are not part of the conserved [3-sheet framework, and thus are able to adapt different conformations. See Chothia and Lesk, J Mol Biol, 1987, 196:901-917. Both the Kabat and Chothia nomenclatures are well known in the art. AbM, Contact and IMGT also define CDRs. CDR positions within a canonical antibody variable domain have been determined by comparison of numerous structures. See Morea et al., Methods, 2000, 20:267-279 and Al-Lazikani et al., J Mol Biol, 1997, 273:927-48. Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable domain numbering scheme. Such terminology is well known to those skilled in the art.

[0027] A number of hypervariable region delineations are in use and are included herein.The Kabat CDRs are based on sequence variability and are the most commonly used. See Kabat et al. (1992) Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719. Chothia refers instead to the location of the structural loops (Chothia and Lesk, supra). The AbM hypervariable regions represent a compromise between the Kabat CDRs and Chothia structural loops, and are used by Oxford Molecular’s AbM antibody modeling software. The Contact hypervariable regions are based on an analysis of the available complex crystal structures.

[0028] More recently, a universal numbering system ImMunoGeneTics (IMGT) Information System™ has been developed and widely adopted. See Lefranc et al., Dev Comp9NAI-5006811188Immunol, 2003, 27:55-77. IMGT is an integrated information system specializing in immunoglobulins (IG), T cell receptors (TR) and major histocompatibility complex (MHC) of human and other vertebrates. The IMGT CDRs are referred to in terms of both the amino acid sequence and the location within the light or heavy chain. As the “location” of the CDRs within the structure of the immunoglobulin variable domain is conserved between species and present in structures called loops, by using numbering systems that align variable domain sequences according to structural features, CDR and framework residues are readily identified. Correspondence between the Kabat, Chothia and IMGT numbering is also well known in the art (Lefranc et al., supra). An exemplary system, shown herein, combines Kabat and Chothia CDR definitions.

[0029] The light chain from any vertebrate species can be assigned to one of two types, called kappa (K) and lambda (1), based on the sequence of its constant domain.

[0030] The heavy chain from any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated a, 8, a, y, and p, respectively. The IgG and IgA classes are further divided into subclasses on the basis of differences in sequence and function. Humans express the following subclasses: IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.

[0031] The terms “constant region” or “constant domain” refer to a carboxy terminal portion of the light and heavy chain which is not directly involved in binding of the antibody to antigen but exhibits various effector function, such as interaction with the Fc receptor. The terms refer to the portion of an immunoglobulin molecule having a more conserved amino acid sequence relative to the other portion of the immunoglobulin, the variable domain, which contains the antigen-binding site. The constant domain contains the CHI, CH2 and CH3 domains of the heavy chain and the CL domain of the light chain.

[0032] “Monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-10NAI-5006811188terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation. Monoclonal antibodies typically bind one antigenic epitope. Monoclonal antibodies may have heterogeneous glycosylation within the antibody population. Monoclonal antibody may be monospecific or multispecific such as trispecific.

[0033] “Polynucleotide” refers to a molecule comprising a chain of nucleotides covalently linked by a sugar-phosphate backbone or other equivalent covalent chemistry. cDNA is a typical example of a polynucleotide.

[0034] “Protein” or “polypeptide” are used interchangeably herein to refer to a molecule that comprises one or more polypeptides each comprised of at least two amino acid residues linked by a peptide bond. Protein may be a monomer, or may be a protein complex of two or more subunits, the subunits being identical or distinct. Small polypeptides of less than 50 amino acids may be referred to as “peptides.” Protein may be a heterologous fusion protein, a glycoprotein, or a protein modified by post-translational modifications such as phosphorylation, acetylation, myristoylation, palmitoylation, glycosylation, oxidation, formylation, amidation, citrullination, polyglutamylation, ADP-ribosylation, pegylation or biotinylation.

[0035] “Recombinant” refers to polynucleotides, polypeptides, vectors, viruses and other macromolecules that are prepared, expressed, created or isolated by recombinant means.

[0036] As used herein, the term “percent (%) amino acid sequence identity” with respect to a sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs or software such as EMBOSS MATCHER, EMBOSS WATER, EMBOSS STRETCHER, EMBOSS NEEDLE, EMBOSS LALIGN, BLAST, BLAST-2, ALIGN or Megalign (DNASTAR). Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0037] “Affinity” refers to the strength of the sum total of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen or epitope). Unless indicated otherwise, as used herein, “affinity” refers to intrinsic11NAI-5006811188binding affinity, which reflects a 1 : 1 interaction between members of a binding pair (e.g., antibody and antigen or epitope). The affinity of a molecule X for its partner Y can be represented by the dissociation equilibrium constant (KD). The kinetic components that contribute to the dissociation equilibrium constant are described in more detail below. Affinity can be measured by common methods known in the art, such as surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®).

[0038] With regard to the binding of an antibody to a target molecule, the terms “bind,” “specific binding,” “specifically binds to,” “specific for,” “selectively binds,” and “selective for” a particular antigen (e.g., a polypeptide target) or an epitope on a particular antigen mean binding that is measurably different from a non-specific or non-selective interaction (e.g., with a non-target molecule). Specific binding can be measured, for example, by measuring binding to a target molecule and comparing it to binding to a non-target molecule. Specific binding can also be determined by competition with a control molecule that mimics the epitope recognized on the target molecule. In that case, specific binding is indicated if the binding of the antibody to the target molecule is competitively inhibited by the control molecule.

[0039] The term “KD” (M), as used herein, refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. KD = kd / ka. In some embodiments, the affinity of an antibody is described in terms of the KD for an interaction between such antibody and its antigen. For clarity, as known in the art, a smaller KD value indicates a higher affinity interaction, while a larger KD value indicates a lower affinity interaction.

[0040] As used herein, the term “anti-human-HER3 antibody” refers to an antibody which binds specifically to HER3, and preferably has an activity of internalization in HER3- expressing cells by binding to HER3. In some embodiments, HER3 is human HER3.

[0041] The term “antibody-drug conjugate” or “ADC” refers to a conjugate comprising an antibody conjugated to one or more cytotoxic agents, optionally through one or more linkers. The terms “anti-human HER3 antibody-drug conjugate,” “anti-human HER3 ADC” are used interchangeably and refer to a conjugate comprising an anti-human HER3 antibody conjugated to one or more cytotoxic agents, optionally through one or more linkers.

[0042] As used herein, the term “functional fragment” of an antibody is also called “antigen binding fragment” of a human HER3 antibody, and is used to mean a partial fragment of the antibody having binding activity against human HER3, and includes, but not limited to, Fab, F(ab’)2, scFv, a diabody, a linear antibody and a multi-specific antibody12NAI-5006811188formed from antibody fragments. In some embodiments, Fab’, which is a monovalent fragment of antibody variable regions obtained by treating F(ab’)2 under reducing conditions, is also included in the antigen-binding fragment of an antibody. The antigen-binding fragment of an antibody is not limited to these molecules, as long as the antigen-binding fragment has HER3 -binding ability. These antigen-binding fragments include not only those obtained by treating a full-length molecule of an antibody protein with an appropriate enzyme, but proteins produced in appropriate host cells using a genetically engineered antibody gene.

[0043] The term “cytotoxic agent,” as used herein, refers to a substance that inhibits or prevents a cellular function and / or causes cell death or destruction. The cytotoxic agent can be an anti-angiogenic agent, a pro-apoptotic agent, an anti-mitotic agent, an anti-kinase agent, an alkylating agent, a hormone, a hormone agonist, a hormone antagonist, a chemokine, a drug, a prodrug, a toxin, an enzyme, an antimetabolite, an antibiotic, an alkaloid, or a radioactive isotope. Exemplary cytotoxic agents include calicheamycin, camptothecin, carboplatin, irinotecan, SN-38, carboplatin, camptothecan, cyclophosphamide, cytarabine, dacarbazine, docetaxel, dactinomycin, daunorubicin, doxorubicin, etoposide, idarubicin, topotecan, vinca alkaloid, maytansinoid, maytansinoid analog, pyrrolobenzodiazepine, taxoid, duocarmycin, dolastatin, auristatin, and derivatives thereof.

[0044] A “linker” refers to a molecule that connects one composition to another, e.g., an antibody to an agent. Linkers described herein can conjugate an antibody to a cytotoxic agent. Exemplary linkers include a labile linker, an acid labile linker, a photolabile linker, a charged linker, a disulfide-containing linker, a peptidase-sensitive linker, a P-glucuronide-linker, a dimethyl linker, a thio-ether linker, and a hydrophilic linker. A linker can be cleavable or non-cleavable.

[0045] As used herein, the term “HER3-DXd” is an antibody-drug conjugate (ADC) comprising a HER3 monoclonal antibody, which is covalently linked to a cytotoxic payload, exatecan, or more preferably, an exatecan derivative deruxtecan (“DXd”). Exatecan is a topoisomerase I inhibitor that leads to apoptosis of the target cells. In some embodiments, HER3-DXd is patritumab deruxtecan.

[0046] As used herein, the term “patritumab deruxtecan” is an antibody-drug conjugate (ADC) comprising the anti-HER3 monoclonal antibody patritumab, which is covalently linked to deruxtecan (“DXd”). Patritumab deruxtecan is also described, e.g., in WHO Drug Information, Vol. 34, No. 1, 2020 (Recommended INN: List 83), which is incorporated by reference herein in its entirety. Patritumab is also described, e.g., in WHO Drug Information,13NAI-5006811188Vol. 26, No. 3, 2012 (Recommended INN: List 68), which is incorporated by reference herein in its entirety. Deruxtecan is also described, e.g., in WHO Drug Information, Vol. 30, No. 4, 2016 (Proposed INN List 116), which is incorporated by reference herein in its entirety.

[0047] As used herein, the term “MK-1084” refers to the compound (5a5a, 17a / L)-20- chl oro-2- [(2S, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2- yl)- 11,12-di [(2H)hydro]( 11 , 12-2H2)-47 - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one. MK-1084 is also described in U.S. Patent No. 11,697,657, which is incorporated herein by reference in its entirety.

[0048] The term “treating” (and variations thereof such as “treat” or “treatment”) refers to clinical intervention in an attempt to alter the natural course of a disease or condition in a subject in need thereof. Treatment can be performed during the course of clinical pathology. Desirable effects of treatment include preventing recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, preventing metastasis, decreasing the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis. In some embodiments, the term “treating” or any grammatical variation thereof refers to reducing and / or ameliorating the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto, such as (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) to improve or enhance the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein).

[0049] The term “pharmaceutically acceptable” as used herein means being approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized Pharmacopeia for use in animals, and more particularly in humans. Additionally or alternatively, the phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problem or complication, commensurate with a reasonable benefit risk ratio.

[0050] The term “pharmaceutically acceptable carrier” includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the14NAI-5006811188ingredients and that is not toxic to the patient to whom it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil / water emulsions, various types of wetting agents, and sterile solutions. Such carriers can be formulated by conventional methods and can be administered to the subject at a suitable dose. Preferably, the compositions are sterile. These compositions may also contain adjuvants such as preservative, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents.

[0051] As used herein, the term “pharmaceutically acceptable salt” refers to a salt that does not have notable toxicity, and can be used as a medicament.

[0052] A compound having an acidic substituent can be formed into a salt by a reaction with a base. Examples include, but are not limited to, alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt, and magnesium salt; metal salts such as aluminum salt, and iron salt; inorganic salts such as ammonium salt; amine salts including organic salts and the like such as tert-butylamine salt, tert-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenetylamine salt, piperazine salt, tetramethylammonium salt, and tri s(hydroxymethyl)aminom ethane salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt.

[0053] A compound having a basic substituent can be formed into a salt by a reaction with an acid. Examples include halide acid salts such as hydrofluoric acid salt, hydrochloric acid salt, hydrobromic acid salt, and hydroiodic acid salt; inorganic acid salts such as nitric acid salt, perchloric acid salt, sulfuric acid salt, and phosphoric acid salt; C1-C6 alkyl sulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, and ethanesulfonic acid salt; aryl sulfonic acid salts such as benzenesulfonic acid salt, and p- toluenesulfonic acid salt; organic acid salts such as acetic acid salt, malic acid salt, fumaric acid salt, succinic acid salt, citric acid salt, ascorbic acid salt, tartaric acid salt, oxalic acid salt, adipic acid salt, and maleic acid salt; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamic acid salt, and aspartic acid salt.

[0054] The term “therapeutically effective amount” as used herein refers to the amount of an agent (e.g., those described herein individually or in combination) that is sufficient to15NAI-5006811188reduce and / or ameliorate the severity and / or duration of a given disease, disorder or condition, and / or a symptom related thereto. A therapeutically effective amount of an agent, including a therapeutic agent, can be an amount necessary for (i) reduction, delay or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction, delay or amelioration of the recurrence, development or onset of a given disease, disorder or conditions, and / or (iii) improvement or enhancement of the prophylactic or therapeutic effect of another therapy (e.g., a therapy other than the administration of an agent described herein). A “therapeutically effective amount” of a substance / molecule / agent of the present disclosure may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the substance / molecule / agent, to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which any toxic or detrimental effects of the substance / molecule / agent are outweighed by the therapeutically beneficial effects. In certain embodiments, the term “therapeutically effective amount” refers to an amount of an agent effective to “treat” a disease, disorder, or condition, in a subject or mammal.

[0055] As used herein, the terms “immune oncology therapy,” “immuno-oncology therapy,” “immuno oncology therapy,” or “IO therapy” comprise administration to the subject of at least one compound capable of recognizing a tumor-cell antigen and / or a cancercell antigen. In some cases, the at least one compound capable of recognizing a tumor-cell antigen and / or a cancer-cell antigen is an engineered protein, a fusion protein, an antibody, or a cytokine. In some cases, the tumor-cell antigen and / or a cancer-cell antigen is selected from the group consisting of: 2B4, 41BB, A2AR, ALK, a B-7 family ligand, BRAF, BTK, BTLA, CCR4, CD19, CD20, CD27, CD28, CD35, CD40, CD50, CD73, CD137, CD160 / By55, CD172a / SIRPa, CD200, CD223, CD244, CEACAM, a CHK 1 kinase, a CHK2 kinase, cMET, CSF1R, CTLA-4, CXCR, DNMT, EGFr, GAL9, GITR, HD AC, HER-2, HVEM, ICOS, IDO, KIR, KRAS, LAG3, MEK, mTor, NKG2A, 0X40, PARP, PD-1, PD-L1, PD-L2, STAT3, TGF-beta, TIGIT, TIM-3, TKI, a TLR (Toll like receptors), and combinations thereof. In some cases, an IO therapy includes an immune checkpoint inhibitor, e.g., a PD-1 antagonist (e.g., an anti-PD-1 antibody) or a PD-Ll antagonist (e.g., an anti-PD-Ll antibody). In various embodiments, the anti-PD-1 antibody is pembrolizumab, cemiplimab, dostarlimab, toripalimab, retifanlimab, tislelizumab, camrelizumab, sintilimab, vopratelimab, spartalizumab, INCMGA00012 (MGA012), AMP-514 (MEDI0680), acrixolimab, or nivolumab. In various embodiments, the anti-PD-Ll antibody is atezolizumab, durvalumab, KN035, cosibelimab, or avelumab. In some cases, the at least one compound is an antibody16NAI-5006811188selected from the group consisting of: nivolumab, pembrolizumab, pidilizumab, RMP1-14, AGEN2034, cemiplimab, ipilimumab, 9D9, tremelimumab, AGEN1884, RG2077, and combinations thereof.

[0056] As used herein, the term “KRAS inhibitor therapy” is a targeted treatment for certain types of cancers that use Kirsten rat sarcoma virus (KRAS) as an oncogene. Nonlimiting examples of KRAS inhibitor therapy compounds having inhibitory activity against KRAS G12C mutant protein include LY3537982, AZD4625, sotorasib (AMG510), adagrasib (MRTX849), JDQ443, GDC-6036, BI1, 823, and 911, D1553, and JNJ-74699157.

[0057] As used herein, the term “concurrently” means at the same time. For example, if two treatment regimens for a single patient are being conducted concurrently, then they are being conducted at the same time. It will be understood that two treatment regimens happening at the same time does not necessarily mean that actual delivery of two drugs happens at the same time, as each regimen may call for a different dosing schedule and / or different delivery modes.

[0058] As used herein, the terms “subject” or “patient” are used interchangeably and mean a mammalian subject. Exemplary subjects include humans, monkeys, dogs, cats, mice, rats, cows, horses, camels, goats, rabbits, pigs and sheep. In certain embodiments, the subject is a human (e.g., an adult human, / .< ., greater than or equal to 18 years of age). In some embodiments, the subject has a disease or condition that can be treated with an agent provided herein. In some embodiments, the disease or condition is a cancer.

[0059] Cancer” refers to any physiological condition in mammals characterized by unregulated cell growth; in particular, cellular-proliferative disease states. As used herein, “tumor” refers to any neoplastic cell growth or proliferation, whether malignant or benign, and to all pre-cancerous and cancerous cells and tissues.

[0060] The term “administering” refers to the act of delivering a combination or composition described herein into a subject by such routes as oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial administration. Administration may be local or systemic. Administration generally occurs after the onset of the disease, disorder, or condition, or its symptoms but, in certain instances, can occur before the onset of the disease, disorder, or condition, or its symptoms (e.g., administration for patients prone to such a disease, disorder, or condition).17NAI-5006811188

[0061] As used herein, in some embodiments, the terms “administration in combination with” and “administered in combination” are used to represent a form of drug administration in which a plurality of active ingredients are contained or encapsulated in different preparations and administered simultaneously (a person skilled in the art would naturally understand that “simultaneously” or “at the same time” may be or may not be at about the same time) or separately or sequentially in any order at different times, or both contained or encapsulated in the same preparation and administered, unless the context otherwise requires and unless technically inconsistent.

[0062] As used herein, the term “packaging material” refers to a physical structure housing the components of the kit. The packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampoules, vials, tubes, and the like).

[0063] In general, the nomenclature used in this application is based on naming conventions adopted by the international union of pure and applied chemistry (IUPAC). Any open valency appearing on a carbon, oxygen, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom.2. Methods of Treatment

[0064] Provided herein are combinational therapies based on a small molecule inhibitor of G12C mutant of Kirsten rat sarcoma (KRAS) protein and an anti-human-HER3 antibodydrug conjugate, detailed description of each of which is provided in sections below.

[0065] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:18NAI-5006811188(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

[0066] In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.19NAI-5006811188

[0067] In another aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I; and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti- human-HER3 antibody or a functional fragment thereof and a drug-linker of Formula IIIFormula III wherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and20NAI-5006811188b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

[0068] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula III, wherein the number of drug-linkers of Formula III is equal to n, and wherein n represents the drug to antibody ratio.

[0069] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4; wherein the subject has been previously administered with a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:21NAI-5006811188Formula I.

[0070] In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0071] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human- HER3 antibody or a functional fragment thereof and a drug-linker of Formula IIIFormula III wherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4;22NAI-5006811188wherein the subject has been previously administered with a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:

[0072] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula III, wherein the number of drug-linkers of Formula III is equal to n, and wherein n represents the drug to antibody ratio.

[0073] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I; wherein the subject has been previously administered with a therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:23NAI-5006811188Formula II wherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

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

[0075] In one aspect, provided is a method for treating cancer in a subject in need thereof. The method comprises administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:24NAI-5006811188wherein the subject has been previously administered with a therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a drug-linker of Formula IIIFormula III wherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

[0076] In some embodiments of the method provided above, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula III, wherein the number of drug-linkers of Formula III is equal to n, and wherein n represents the drug to antibody ratio.

[0077] In another aspect, provided is a method for treating cancer in a subject in need thereof, wherein the method comprises: (A) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof as described herein; and (B) administering to the subject a second therapeutically effective amount of an anti-human-HER3 antibody-drug conjugate. In some embodiments, the drug in the anti-human-HER3 antibody-drug conjugate is a topoisomerase I inhibitor. In some embodiments, the drug represented by the following formula is released to express an antitumor activity:25NAI-5006811188Formula IV

[0078] In another aspect, provided is a method wherein an antitumor compound represented by the following formula is conjugated to an anti-human-HER3 antibody through a linker with the nitrogen atom of the amino group at position 1 as the connecting position:Formula V

[0079] In some embodiments, the antitumor compound is conjugated to the anti-human- HER3 antibody through the linker via a thioether bond which is formed at a disulfide bond moiety present in the anti-human-HER3 antibody. In some embodiments, the linker comprises a tetrapeptide residue of -Gly-Gly-Phe-Gly- (SEQ ID NO: 11).

[0080] In some embodiments of any of the above methods, the compound of Formula I is (5a5'a,17a7?a)-20-chloro-2-[(25',57?)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16,17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-4 / 7- 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one.

[0081] In some embodiments of any of the above methods, the compound of Formula I is MK-1084.

[0082] In one aspect, the method provided herein is for treating a cancer. In one aspect, the method provided herein is for treating non-small cell lung cancer (NSCLC). In one aspect, the method provided herein is for treating advanced and / or metastatic NSCLC.

[0083] In one embodiment, the subject is a human subject. In one embodiment, the human subject is an adult, / .< ., greater than or equal to 18 years of age.26NAI-5006811188

[0084] In certain embodiments, the combination therapy provided herein is used to treat subjects that have a mutation of glycine to cysteine at codon 12 (G12C) in the Kirsten rat sarcoma (KRAS) protein. In one embodiment of the method provided herein, the human subject has a confirmed diagnosis of Stage IV non-squamous NSCLC. In another aspect of the method provided herein, the human subject has received one prior immuno-oncology (“IO”) therapy with or without chemotherapy, and without prior KRAS inhibitor therapy. In one aspect, the subject has (i) a KRAS G12C mutation; (ii) a confirmed diagnosis of Stage IV non-squamous NSCLC; and (iii) received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

[0085] In certain embodiments, the combination therapy of the disclosure reduces the growth of tumor cells in vivo when administered to the subject. Measurement of the reduction of the growth of tumor cells can be determined by multiple different methodologies well known in the art. Non-limiting examples include direct measurement of tumor dimension, measurement of excised tumor mass and comparison to control subjects, measurement via imaging techniques (e.g., CT or MRI) that may or may not use isotopes or luminescent molecules (e.g., luciferase) for enhanced analysis, and the like.

[0086] In specific embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, with an about 100% reduction in tumor growth indicating a complete response and disappearance of the tumor. In further embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-100%, about 75-100% or about 90-100%. In further embodiments, administration of the combination therapy provided herein results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-60%, about 60-70%, about 70-80%, about 80-90%, or about 90-100%.

[0087] In one aspect, provided herein is use of a compound of Formula I or a pharmaceutically acceptable salt thereof and an anti-human-HER3 antibody-drug conjugate for the manufacture of a medicament for treating NSCLC. In another aspect, provided herein is use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament in combination with an anti-HER3 antibody-drug conjugate for treating NSCLC. In yet another aspect, provided herein is use of an anti-human-HER3 antibody-drug conjugate for the manufacture of a medicament in combination with the compound of Formula I or a pharmaceutically acceptable salt thereof for treating NSCLC.27NAI-5006811188

[0088] In one aspect, provided herein is (5a5'a,17a7?a)-20-chloro-2-[(25',57?)-2,5-dimethyl- 4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use in combination with an anti-human- HER3 antibody-drug conjugate in treating cancer in a subject in need thereof. In one aspect, provided herein is a (5a5'a,17a7?a)-20-chloro-2-[(25',57?)-2,5-dimethyl-4-(prop-2- enoyljpiperazin- 1 -yl] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro]( 11 , 12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6-g] [ 1 , 4,7, 9]benzodi oxadi azacyclododecin-4- one for use in combination with an anti-human-HER3 antibody-drug conjugate in treating NSCLC in a subject in need thereof.

[0089] In one aspect, provided herein is MK-1084 for use in combination with an anti- human-HER3 antibody-drug conjugate in treating cancer in a subject in need thereof. In one aspect, provided herein is MK-1084 for use in combination with an anti-human-HER3 antibody-drug conjugate in treating NSCLC in a subject in need thereof. In one aspect, provided herein is an anti-human-HER3 antibody-drug conjugate for use in combination with MK-1084 in treating cancer in a subject in need thereof. In one aspect, provided herein is an anti-human-HER3 antibody-drug conjugate for use in combination with MK-1084 in treating NSCLC in a subject in need thereof.

[0090] In one aspect, provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in combination with an anti-human-HER3 antibody-drug conjugate in treating cancer in a subject in need thereof, wherein Formula I represents:Formula I; and28NAI-5006811188wherein the anti-human-HER3 antibody-drug conjugate comprises an antibodydrug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL- CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0091] In one aspect, provided herein is a compound of Formula I or a pharmaceutically acceptable salt thereof for use in combination with an anti-human-HER3 antibody-drug conjugate in treating cancer in a subject in need thereof, wherein compound of Formula I comprises (5a5'a,17a7?a)-20-chloro-2-[(25',57?)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]- 16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one; and wherein the anti-human-HER3 antibody-drug conjugate comprises an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:29NAI-5006811188Formula II wherein AB is an anti-human-HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4. In some embodiments, a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond. In some embodiments, the cancer is non-small cell lung cancer.

[0092] In one aspect, provided herein is MK-1084 for use in combination with patritumab deruxtecan in treating cancer in a subject in need thereof. In one aspect, provided herein is MK-1084 for use in combination with patritumab deruxtecan in treating non-small cell lung cancer in a subject in need thereof.

[0093] In one aspect, provided herein is patritumab deruxtecan for use in combination with MK-1084 in treating cancer in a subject in need thereof. In one aspect, provided herein is patritumab deruxtecan for use in combination with MK-1084 in treating non-small cell lung cancer in a subject in need thereof.

[0094] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein, and a second therapeutically effective amount of the antibody-drug conjugate as defined herein in combination. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein, in combination with a second therapeutically effective amount of the antibody-drug conjugate as defined30NAI-5006811188herein. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined herein, in combination with a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein. In some embodiments, the cancer is non-small cell lung cancer.

[0095] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of MK- 1084, in combination with a second therapeutically effective amount of patritumab deruxtecan. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of patritumab deruxtecan, in combination with a second therapeutically effective amount of MK- 1084. In some embodiments, the cancer is non-small cell lung cancer.

[0096] In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of (5a5a,l 7a / a)-20-chloro- 2- [(25, 5R)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- l l,12-di[(2H)hydro](l l,12-2H2)-4Z7-l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one, in combination with a second therapeutically effective amount of patritumab deruxtecan. In some embodiments, provided herein is a pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of patritumab deruxtecan, in combination with a second therapeutically effective amount of (5a5a,17a7?a)-20-chloro-2-[(25,5A)-2,5-dimethyl-4-(prop-2- enoyljpiperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-4 / 7- l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one. In some embodiments, the cancer is non-small cell lung cancer.

[0097] In some embodiments, provided herein is a use of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein for the preparation of a medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined herein. In some embodiments, provided herein is a use of the antibodydrug conjugate as defined herein for the preparation of a medicament for treating cancer, by administration in combination with the compound of Formula I or a pharmaceutically acceptable salt thereof as defined herein. In some embodiments, the cancer is non-small cell lung cancer.

[0098] Any suitable dose(s) of the compound of Formula I or a pharmaceutically acceptable salt thereof may be used in the methods, compositions, and kits described herein.31NAI-5006811188

[0099] In some embodiments, for example, relevant to any method as disclosed herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg.

[0100] In some embodiments, for example, relevant to any method as disclosed herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered daily. In some embodiments, for example, relevant to any method as disclosed herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally.

[0101] An antibody-drug conjugate (e.g., patritumab deruxtecan) as disclosed herein can be administered at any suitable dose, e.g., about 3.2 mg / kg, about 4.8 mg / kg, or about 5.6 mg / kg of the subject’s body weight.

[0102] In some embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 3.2 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg. In other embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg.

[0103] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate e.g., patritumab deruxtecan) is administered once every three weeks.

[0104] In some embodiments, for example, relevant to any method as disclosed herein, the second therapeutically effective amount of the antibody-drug conjugate is administered once every three weeks.

[0105] In some embodiments relevant to any method as disclosed herein, the administration of the second therapeutically effective amount of the antibody-drug conjugate is maintained to the completion of the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof.

[0106] Any suitable dose(s) of the antibody-drug conjugate (e.g., patritumab deruxtecan) may be used in the methods, compositions, and kits described herein.

[0107] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 3.2 mg / kg, about 4.8 mg / kg, or about 5.6 mg / kg of the subject’s body weight once every three weeks.32NAI-5006811188

[0108] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 3.2 mg / kg of the subject’s body weight once every three weeks.

[0109] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 4.8 mg / kg of the subject’s body weight once every three weeks.

[0110] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of about 5.6 mg / kg of the subject’s body weight once every three weeks.

[0111] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate e.g., patritumab deruxtecan) is administered at a dose of 3.2 mg / kg of the subject’s body weight once every three weeks.

[0112] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of 4.8 mg / kg of the subject’s body weight once every three weeks.

[0113] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate (e.g., patritumab deruxtecan) is administered at a dose of 5.6 mg / kg of the subject’s body weight once every three weeks.

[0114] In some embodiments of this disclosure, the antibody-drug conjugate is administered intravenously. In one embodiment, the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion. In one embodiment, the antibody-drug conjugate is administered via a 90 ± 10 minute IV fusion.

[0115] In some embodiments, the method provided herein may include administering a premedication with one or more antiemetic agents (e.g., dexamethasone with either a 5-HT3 receptor antagonist (e.g., ondansetron, tropisetron, granisetron, dolasetron, palonosetron, or ramosetron) or an NK-1 receptor antagonist (e.g., aprepitant, casopitant, netupitant, or rolapitant)) to the subject.3. MK-1084

[0116] In one aspect, the method of treating cancer in a subject in need thereof as disclosed herein comprises administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:33NAI-5006811188Formula I

[0117] In one aspect, the method of treating cancer in a subject in need thereof as disclosed herein comprises administering to the subject a first therapeutically effective amount of a compound of Formula I, wherein the compound of Formula I is (5a5a,17a7?a)-20- chloro-2-[(25,5A)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16,17-difluoro-6-(propan-2- yl)- l l , 12-di[(2H)hydro]( l l , 12-2H2)-47 / - l , 18-(ethanediylidene)pyrido[4,3-c]pyrimido[ l ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one.

[0118] In one aspect, the method of treating cancer in a subject in need thereof as disclosed herein comprises administering to the subject a first therapeutically effective amount of a compound of Formula I, wherein the compound of Formula I is MK-1084.

[0119] In some embodiments, the cancer is mediated by a KRAS mutation, e.g., the KRAS G12C mutation. In various embodiments, the cancer is lung cancer. In certain embodiments, the lung cancer is a non-small cell lung carcinoma (NSCLC), for example, adenocarcinoma, squamous-cell lung carcinoma or large-cell lung carcinoma.

[0120] Another embodiment of the present disclosure provides a method for inhibiting tumor metastasis, the method comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof disclosed herein.

[0121] In one aspect, the method of treating NSCLC in a subject in need thereof as disclosed herein comprises administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:34NAI-5006811188Formula I

[0122] In one aspect, the method of treating NSCLC in a subject in need thereof as disclosed herein comprises administering to the subject a first therapeutically effective amount of a compound of Formula I, wherein the compound of Formula I is (5a5a,17a7?a)-20- chloro-2-[(25,5A)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16,17-difluoro-6-(propan-2- yl)- l l , 12-di[(2H)hydro]( l l , 12-2H2)-47 / - l , 18-(ethanediylidene)pyrido[4,3-c]pyrimido[ l ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one.

[0123] In one aspect, the method of treating NSCLC in a subject in need thereof as disclosed herein comprises administering to the subject a first therapeutically effective amount of a compound of Formula I, wherein the compound of Formula I is MK-1084.

[0124] In some embodiments, the present disclosure provides a method of treating a disorder (e.g., cancer) in a subject in need thereof, wherein said method comprises determining if the subject has a KRAS mutation (e.g., KRAS G12C mutation) and if the subject is determined to have the KRAS mutation, then administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0125] Determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12C mutation) can be undertaken by assessing the nucleotide sequence encoding the KRAS protein, by assessing the amino acid sequence of the KRAS protein, or by assessing the characteristics of a putative KRAS mutant protein. The sequences of wild-type human KRAS are known in the art.

[0126] Methods for detecting a mutation in a KRAS nucleotide sequence are also known by those of skill in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays, real-time PCR35NAI-5006811188assays, PCR sequencing, mutant allele-specific PCR amplification (MASA) assays, direct sequencing, primer extension reactions, electrophoresis, oligonucleotide ligation assays, hybridization assays, TaqMan® assays, SNP genotyping assays, high resolution melting assays and microarray analyses. In some embodiments, samples are evaluated for KRAS mutations (e.g., the KRAS G12C mutation) by real-time PCR. In real-time PCR, fluorescent probes specific for the KRAS G12C mutation are used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRAS mutation is identified using a direct sequencing method of specific regions (e.g., exon 2 and / or exon 3) in the KRAS gene.

[0127] Methods for detecting a mutation in a KRAS protein (e.g., the KRAS G12C mutation) are known by those of skill in the art. These methods include, but are not limited to, detection of a KRAS mutant using a binding agent (e.g., an antibody) specific for the mutant protein, protein electrophoresis and Western blotting, and direct peptide sequencing.

[0128] A number of tissue samples can be assessed for determining whether a tumor or cancer comprises a KRAS mutation (e.g., the KRAS G12C mutation). In some embodiments, the sample is taken from a subject having a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin- embedded sample. In some embodiments, the sample is a circulating tumor cell (CTC) sample. In some embodiments, the sample is processed to a cell lysate. In some embodiments, the sample is processed to DNA or RNA.3.1. Pharmaceutical Compositions Comprising MK-1084

[0129] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:36NAI-5006811188Formula I; and at least one pharmaceutically acceptable carrier.

[0130] In some embodiments, for example, relevant to any method as disclosed herein, provided herein are pharmaceutical compositions comprising a compound of Formula I wherein the compound of Formula I is (5a5'a,17a7?a)-20-chloro-2-[(25',5A)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one, and at least one pharmaceutically acceptable carrier.

[0131] In some embodiments, for example, relevant to any method as disclosed herein, provided herein are pharmaceutical compositions comprising a compound of Formula I wherein the compound of Formula I is MK-1084, and at least one pharmaceutically acceptable carrier.

[0132] The pharmaceutical compositions according to the disclosure can be administered orally, for example, in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion.

[0133] Other suitable administration forms are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0134] The amount of active compound of Formula I and / or its pharmaceutically acceptable salts in the pharmaceutical composition normally is from 0.01 to 200 mg, such asNAI-5006811188from 0.1 to 200 mg, preferably from 1 to 200 mg, per dose, but depending on the type of the pharmaceutical composition, it can also be higher. In some embodiments, the amount of active compound of Formula I and / or its pharmaceutically acceptable salts in the pharmaceutical composition is from 0.01 to 10 mg per dose. The pharmaceutical compositions usually comprise 0.5 to 90 percent by weight of the compound of Formula I and / or their pharmaceutically acceptable salts.

[0135] The preparation of the pharmaceutical compositions can be carried out in a manner known per se. For this purpose, one or more compounds of Formula I and / or their pharmaceutically acceptable salts, together with one or more solid or liquid pharmaceutical carrier substances and / or additives (or auxiliary substances) and, if desired, in combination with other pharmaceutically active compounds having therapeutic or prophylactic action, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human or veterinary medicine.

[0136] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch, for example, maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example, of solutions for injection, or of emulsions or syrups are, for example, water, physiologically acceptable sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of Formula I and their pharmaceutically acceptable salts and to use the resulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0137] Besides the active compounds and carriers, the pharmaceutical compositions can also contain customary additives, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.

[0138] The compound of Formula I or a pharmaceutically acceptable salt thereof as described herein is contemplated for use as a medicament. The dosage regimen will be determined by the attending physician and other clinical factors. Dosages for any one patient depends on many factors, including the patient’s size, body surface area, age, sex, the38NAI-5006811188particular compound to be administered, time and route of administration, the kind of therapy, general health and other drugs being administered concurrently.

[0139] In some embodiments, for example, relevant to any method as disclosed herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily.

[0140] The compound of Formula I or a pharmaceutically acceptable salt thereof described herein can be administered using different dosages. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof of this disclosure is administered at a dose of about 50 mg. In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof of this disclosure is administered at a dose of about 100 mg.4. Anti-human-HER3 antibody-drug conjugate

[0141] Antibody-drug conjugates (ADCs) are targeted cancer therapies which comprise or consist of monoclonal antibodies (mAbs) conjugated via a linker component to cytotoxic agents (payloads). The antibody component of the ADC is directed towards a tumor- associated antigen, allowing for tumor specificity and targeted drug delivery to the tumor site. This approach is expected to result in reduced exposure of non-target tissues to the cytotoxic agent and enhanced antitumor potency. Due to the reduced toxicity of ADC-mediated drug delivery, the therapeutic window may be broadened in comparison to traditional chemotherapy.

[0142] Human epidermal growth factor receptor 3 (also known as HER3, and ErbB3) is a transmembrane receptor belonging to an epidermal growth factor receptor subfamily of receptor protein tyrosine kinase together with HER1, HER2, and HER4. HER3 is expressed in many types of cancer such as lung cancer, breast cancer, gastrointestinal cancer, and pancreatic cancer, and is known to be phosphorylated itself by forming a heterodimer together with a tyrosine kinase receptor such as EGFR or HER2 to induce proliferation of cancer cells and an apoptosis-inhibitory signal. The RNA sequence, the cDNA sequence, and the amino acid sequence of HER3 are disclosed in public database, and are available with accession numbers such as AAA35979 (precursor containing a signal sequence consisting of 19 amino terminal amino acid residues), and M34309 (NCBI).

[0143] Anti-human-HER3 antibody-drug conjugates used in the present disclosure are known in the art. Examples of such anti-human-HER3 antibody-drug conjugates include, but39NAI-5006811188are not limited to, DB-1310, IBI-133, SHR-A2009, AMT-562, and HMBD-501. Anti-HER3 antibody-drug conjugates are also described in US2021 / 0353764 (W02020063676), US2024 / 0026028 (WO2022078425), W02023017151, WO2023143365, WO2023031435, W02023041006, WO2023088382, WO2023125530, WO2023138635, WO2023143263, WO2023208216, WO2024077277, WO2024078449, WO2024083166, WO2024088388, CN118662651A, WO2024208881, and WO2024215515, all of which are incorporated herein by reference. An anti-HER3 antibody-drug conjugate is also described in International Application No. PCT / JP2024 / 20005, which is incorporated herein by reference in its entirety.

[0144] In one aspect of the method provided herein, the method comprises administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human-HER3 antibody (in preferred embodiments, an antihuman HER3 antibody) or a functional fragment thereof and a drug-linker is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond.

[0145] In one aspect of the present disclosure, the anti-human-HER3 antibody-drug conjugate is an anti-human-HER3 antibody-drug conjugate, in which a drug-linker represented by the following formula:40NAI-5006811188Formula III wherein A represents a connecting position to an anti-human-HER3 antibody or a functional fragment thereof; is conjugated to the anti-human-HER3 antibody or the functional fragment thereof via a thioether bond. In some embodiments of the method provided herein, the antibody-drug conjugate comprises an anti-human-HER3 antibody or a functional fragment thereof and a number of drug-linkers of Formula III, wherein the number of druglinkers of Formula III is equal to n, and wherein n represents the drug to antibody ratio.

[0146] In one aspect of the present disclosure, n represents the Drug-to- Antibody Ratio (DAR). DAR as used herein: (i) when referring to a composition of the antibody-drug conjugates, is the average number of drug molecules (or units of a drug-linker) that are conjugated to the anti-human-HER3 antibody or functional fragment thereof in the antibodydrug conjugate, and (ii) when referring to a single antibody-drug conjugate, is the discrete integer of drug molecules (or units of a drug-linker) that are conjugated to the anti-human- HER3 antibody or functional fragment thereof in the antibody-drug conjugate. Methods to determine DAR are well known to the skilled person and include methods using reverse phase chromatography, or HPLC-MS.

[0147] In some embodiments of the method provided herein, with respect to a composition of antibody-drug conjugates, n (e.g., the number of drug-linkers of Formula III) is from about 2 to about 10, from about 2 to about 8, from about 3 to about 8, from about 3 to about 9, from about 3.5 to about 8.5, from about 4 to about 8, from about 5 to about 8, from about 6 to about 8, from about 7 to about 8, from about 7.5 to about 8, or about 8. In the present disclosure, in some embodiments, the term “about 8” is from 7.8 to 8.2, from 7.9 to 8.1, or 8. In other embodiments, the number of the drug or the drug-linkers conjugated per antibody molecule in the anti-human-HER3 antibody-drug conjugate in the instant method is an integer in the range from 2 to 8, for example, 2, 3, 4, 5, 6, 7, or 8. In a specific embodiment, the number of the drug or the drug-linkers conjugated per antibody molecule in41NAI-5006811188the anti-human-HER3 antibody-drug conjugate is 8. In a specific embodiment, the number of drug-linkers of Formula III conjugated per antibody molecule in the anti-human-HER3 antibody-drug conjugate is 8.

[0148] In the present disclosure, the partial structure consisting of a linker and a drug in the anti-human-HER3 antibody-drug conjugate is referred to as a “drug-linker.” The druglinker is connected to a thiol group (i.e., the sulfur atom of a cysteine residue) formed at an interchain disulfide bond site (two sites between heavy chains, and two sites between a heavy chain and a light chain) in the antibody.

[0149] In particular embodiments, the drug-linker of the present disclosure includes a derivative of exatecan as a component. Exatecan, a camptothecin derivative having an antitumor effect, (IUPAC name: (lS,9S)-l-amino-9-ethyl-5-fhioro-l,2,3,9,12,15-hexahydro- 9-hydroxy-4-methyl- 1 OH, 13H-benzo[de]pyrano[3 ',4' : 6,7]indolizino[ 1 ,2-b]quinolin- 10,13- dione, (also expressed as chemical name: (lS,9S)-l-amino-9-ethyl-5-fhioro-2,3-dihydro-9- hydroxy-4-methyl-lH,12H-benzo[de]pyrano[3',4':6,7]indolizino[l,2-b]quinolin- 10,13(9H,15H)-dione)) is a topoisomerase I inhibitor.

[0150] Exatecan is represented by the following Formula:Formula IV

[0151] After internalization into cancer cells, the anti-human-HER3 antibody-drug conjugate used in the present disclosure releases the compound represented by the following Formula V, and thereby exerts an antitumor effect.Formula V42NAI-5006811188

[0152] The aforementioned compound is inferred to be the original source of the antitumor activity of the anti-human-HER3 antibody-drug conjugate used in the present disclosure, and has a topoisomerase I inhibitory effect (Ogitani Y. et al., Clinical Cancer Research, 2016; 22(20):5097-5108).

[0153] In some embodiments, the anti-human-HER3 antibody-drug conjugate used in the present disclosure has a bystander effect (Ogitani Y. et al., Cancer Science, 2016; 107, 1039- 1046). The bystander effect is considered to be exerted through a process such that the anti- human-HER3 antibody-drug conjugate used in the present disclosure is internalized in cancer cells expressing the target and the aforementioned compound is released and then exerts an antitumor effect also on nearby cancer cells not expressing the target.4.1. Anti-human-HER3 antibody

[0154] In one aspect, for example, relevant to any method as disclosed herein, the anti- human-HER3 antibody (e.g., anti-human HER3 antibody) or a functional fragment thereof in the anti-human-HER3 antibody-drug conjugate used in the present disclosure may be derived from any species, but is preferably an antibody derived from a human, a rat, a mouse, or a rabbit. In cases when the antibody is derived from species other than human species, it is preferably chimerized or humanized using a well-known technique. The antibody of the present disclosure may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. Examples of anti-human-HER3 antibodies include, but are not limited to, patritumab (U3-1287), Ul-59 (International Publication No. W02007 / 077028), AV-203 (International Publication No. WO2011 / 136911), LJM-716 (International Publication No. WO2012 / 022814), duligotumab (MEHD-7945A) (International Publication No. W02010 / 108127), istiratumab (MM-141) (International Publication No. WO2011 / 047180), lumretuzumab (RG-7116) (International Publication No. WO2014 / 108484), setibantumab (MM-121) (International Publication No. W02008 / 100624), REGN-1400 (International Publication No. WO2013 / 048883; U. S. Patent No. 8,791,244 B2), ZW-9 (International Publication No. W02013 / 063702; U.S. Patent No. 9,574,010 B2), and variants, active fragments, modified products and the like thereof, all of which are incorporated herein by reference.

[0155] In the anti-human-HER3 antibody in the anti-human-HER3 antibody-drug conjugate relevant to any method as disclosed herein, modified variants of the antibody are also included. The modified variant refers to a variant obtained by subjecting the antibody according to the present disclosure to chemical or biological modification. Examples of the43NAI-5006811188chemically modified variant include variants including a linkage of a chemical moiety to an amino acid skeleton, variants including a linkage of a chemical moiety to an N-linked or O- linked carbohydrate chain, and the like. Examples of the biologically modified variant include variants obtained by post-translational modification (such as N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomerization of aspartic acid, oxidation of methionine, chemical modifications, such as disulfide bonds, oligosaccharides, N-terminal pyroglutamate or pyroglutamic acid formation, glycation, peptide bond cleavage, non-reducible cross-linking, truncation and others known in the art), and variants in which a methionine residue has been added to the N terminus by being expressed in a prokaryotic host cell. Further, an antibody labeled so as to enable the detection or isolation of the antibody or an antigen according to the present disclosure, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody are also included in the meaning of the modified variant.

[0156] It is known that a lysine residue at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell can be deleted or “clipped” (Journal of Chromatography A, 705: 129-134 (1995)), and it is also known that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of an antibody produced in a cultured mammalian cell can be deleted and a proline residue newly located at the carboxyl terminus can be amidated (Analytical Biochemistry, 360: 75-83 (2007)). However, such deletion and modification of the heavy chain sequence typically do not affect the antigenbinding affinity and the effector function (e.g., complement activation or antibody-dependent cellular cytotoxicity) of the antibody. Therefore, in the anti-human-HER3 antibody according to the present methods, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of the deletion variants (for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included. The type of deletion variant having a deletion at the carboxyl terminus of the heavy chain of the antibody according to the present disclosure is not limited to the above variants as long as the antigen-binding affinity and the effector function are conserved. The two heavy chains constituting the antibody according to the present disclosure may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom.44NAI-5006811188

[0157] In some embodiments, an N-terminal E or Q of the anti-human-HER3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid. In some embodiments, a C-terminal K of the anti-human-HER3 antibody provided herein is removed. In other embodiments, an N-terminal E or Q of the anti-human-HER3 antibody provided herein is substituted with pyroglutamate or pyroglutamic acid and a C-terminal K (e.g., heavy chain C terminal amino acid) of the anti-human-HER3 antibody is removed. The present disclosure includes any of the above described post-translational modifications of any of the anti-human-HER3 antibody provided herein.

[0158] All isotypes of the antibody according to the present disclosure, for example, IgG (IgGl, IgG2, IgG3, IgG4) are exemplified, and IgGl or IgG2 are exemplified preferably. Furthermore, variants of these can be also used as the anti-HER3 antibody of the present disclosure.

[0159] In an embodiment, the anti-human-HER3 antibody comprises: a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a light chain variable region provided herein, or a sequence with 95-99% identity with an amino acid sequence provided herein; and / or a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions) of an amino acid sequence of a heavy chain variable region provided herein, or a sequence with 95-99% identity to an amino acid sequence provided herein. In some embodiments, for example, relevant to any method as disclosed herein, the anti-HER3 binding domain comprises three heavy chain CDRs (VH-CDR1, VH-CDR2, and VH-CDR3), and three light chain CDRs (VL-CDR1, VL-CDR2, and VL-CDR3). In some embodiments, the VH-CDR1 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 5, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 5. In some embodiments, the VH-CDR2 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 6, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 6. In some embodiments, the VH-CDR3 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 7, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 7. In some embodiments, the VL-CDR1 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 8, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 8. In other embodiments, the VL-CDR1 of the anti-human-45NAI-5006811188HER3 antibody comprises the amino acid sequence of SEQ ID NO: 12, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 12. In some embodiments, the VL-CDR2 of the anti-human-HER3 antibody comprises the amino acid sequence of SEQ ID NO: 9, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 9. In some embodiments, the VL-CDR3 of the anti-human- HER3 antibody comprises the amino acid sequence of SEQ ID NO: 10, or a sequence comprising one or more modifications or substitutions in SEQ ID NO: 10.

[0160] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody comprises as a VH, the amino acid sequence of SEQ ID NO: 3, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 3. In some examples, the anti-human-HER3 antibody comprises as a VL, the amino acid sequence of SEQ ID NO: 4, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 4.

[0161] In one aspect, for example, relevant to any method as disclosed herein, the anti- human-HER3 antibody comprises: a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 3. In one aspect, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody comprises: a VL-CDR1, a VL-CDR2, and a VL- CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 4.

[0162] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-HER3 antibody comprises as a heavy chain (HC), the amino acid sequence of SEQ ID NO: 1, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about46NAI-500681118896%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 1. In some examples, the anti-human-HER3 antibody comprises as a light chain (LC), the amino acid sequence of SEQ ID NO: 2, or a sequence that is at least about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 2.4.2. Pharmaceutical Compositions Comprising the anti-human-HER3 ADC

[0163] Also provided, in some embodiments, for example, relevant to any method as disclosed herein, are pharmaceutical compositions comprising the anti-human-HER3 ADC (HER3-DXd) described herein. The pharmaceutical composition of the present disclosure may comprise a plurality of anti-human-HER3 ADCs as disclosed herein.

[0164] The pharmaceutical composition of the present disclosure can be preferably used as an injection, can be more preferably used as an aqueous injection, a lyophilized injection, or a freeze-dried injection, and can be even more preferably used as a freeze-dried injection.

[0165] In the case that the pharmaceutical composition of the present disclosure is an aqueous injection, it can be preferably diluted with a suitable diluent and then given as an intravenous drip. Examples of the diluent include a glucose solution, and a saline solution, a preferable example includes a glucose solution, and a more preferable example includes a 5% glucose solution.

[0166] In the case that the pharmaceutical composition of the present disclosure is a freeze-dried injection, it can be preferably administered by intravenous drip after dissolving it in water for injection, and diluting a necessary amount thereof with a proper diluent. Examples of the diluent include a glucose solution, and a saline solution, a preferable example includes a glucose solution, and a more preferable example includes a 5% glucose solution.

[0167] Administration is effected by different ways, e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, topical or intradermal administration. In some embodiments, the route of administration depends on the kind of therapy and the kind of compound contained in the pharmaceutical composition. The dosage regimen will be determined by the attending physician and other clinical factors. Dosages for any one patient depends on many factors, including the patient’s size, body surface area, age, sex, the particular compound to be administered, time and route of administration, the kind of therapy, general health and other drugs being administered concurrently.47NAI-5006811188

[0168] The anti-human-HER3 ADC described herein can be administered using different dosages. In some embodiments relevant to any method as disclosed herein, the antibody-drug conjugate is administered at a dose of about 3.2 mg / kg. In some embodiments relevant to any method as disclosed herein, the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg. In some embodiments to any method as disclosed herein, the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg. In other embodiments, the antibodydrug conjugate is administered at a dose ranging from about 2 mg / kg to about 6 mg / kg. In some embodiments, for example, relevant to any method as disclosed herein, the dose is about 2.5 mg / kg to about 6 mg / kg, about 3.0 mg / kg to about 5.5 mg / kg, about 4.5 mg / kg to about 6.0 mg / kg, about 5 mg / kg to about 5.5 mg / kg, about 4 mg / kg to about 4.5 mg / kg, or about 4.8 mg / kg to about 5.6 mg / kg.

[0169] In some embodiments, for example, relevant to any method as disclosed herein, the antibody-drug conjugate is administered concurrently with the compound of Formula I or a pharmaceutically acceptable salt thereof of this disclosure.

[0170] In some embodiments, for example, relevant to any method as disclosed herein, the administration of the antibody-drug conjugate is maintained to the completion of the administration of the compound of Formula I or a pharmaceutically acceptable salt thereof of this disclosure.

[0171] In one aspect, the antibody-drug conjugate is administered once every three weeks.

[0172] In some embodiments, for example, relevant to any method as disclosed herein, the anti-human-HER3 ADC is administered intravenously (IV). In some embodiments, the anti-human-HER3 ADC via IV fusion, for example for about 20 minutes to about 120 minutes. In some embodiments, the anti-human-HER3 ADC is administered via a 30 ± 5 minute IV fusion. In some embodiments, the anti-human-HER3 ADC is administered via a 90 ± 10 minute IV fusion.5. Kits

[0173] Also provided herein is a kit comprising (i) the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 ADC as disclosed herein (such as HER3-DXd), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. Also provided herein is a kit comprising (i) the compound (5a5a,17a7?a)-20-chl oro-2 - [(25, 5R)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17 -difluoro-6-(propan-2-yl)- 11,12-48NAI-5006811188di[(2H)hydro](l l,12-2H2)-4Z / -l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 ADC as disclosed herein (such as HER3- DXd), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same. Also provided herein is a kit comprising (i) the compound MK-1084, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 ADC as disclosed herein (such as HER3-DXd), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same.

[0174] Provided herein is a kit comprising (i) the compound of Formula I, or a pharmaceutically acceptable salt thereof, (ii) an anti-human-HER3 ADC as disclosed herein (such as HER3-DXd), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, and (iii) instructions for use, e.g, in any of the methods disclosed herein.

[0175] Also provided herein are kits comprising (i) the compound of Formula I, or a pharmaceutically acceptable salt thereof, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 ADC as disclosed herein (such as HER3-DXd), or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising same, either or both of which packaged into suitable packaging material. A kit optionally includes a label or packaging insert including a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.

[0176] Kits provided herein can include labels or inserts. Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g, a box), or attached to, for example, an ampoule, tube, or vial containing a kit component. Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM / RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic / optical storage media, FLASH media, or memory type cards. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location, and date.

[0177] Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container, and all of the various containers can be within a single package. Kits can also be designed for cold storage.49NAI-50068111886. Illustrative Embodiments

[0178] Provided below is a list of non-limiting illustrative embodiments according to the present disclosure:

[0179] Embodiment 1. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises:50NAI-5006811188a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

[0180] Embodiment 2. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti-human- HER3 antibody or a functional fragment thereof and a drug-linker of Formula IIIFormula III wherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises:51NAI-5006811188a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

[0181] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the antihuman HER3 antibody or the functional fragment thereof comprises(i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 5,(ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 6,(iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 7,(iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 8 or SEQ ID NO:12,(v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 9, and(vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 10.

[0182] Embodiment 4. The method of any one of embodiments 1-3, wherein the antihuman HER3 antibody or the functional fragment thereof comprises a variable heavy chain (“VH”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 3, and a variable light chain (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 4.

[0183] Embodiment 5. The method of any one of embodiments 1-4, wherein the antihuman HER3 antibody is an IgGl or an IgG2.

[0184] Embodiment 6. The method of any one of embodiments 1-5, wherein the antihuman HER3 antibody or the functional fragment thereof comprises a VH comprising the amino acid sequence of SEQ ID NO: 3, and a VL comprising the amino acid sequence of SEQ ID NO: 4.

[0185] Embodiment 7. The method of any one of embodiments 1-6, wherein the antihuman HER3 antibody comprises a heavy chain (“HC”) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain (“LC”) comprising the amino acid sequence of SEQ ID NO: 2.

[0186] Embodiment 8. The method of any one of embodiments 1-7, wherein a lysine residue at the carboxyl terminus of the HC of the anti-human HER3 antibody is deleted.

[0187] Embodiment 9. The method of any one of embodiments 1 and 3-8, wherein the drug to antibody ratio is in the range of from 2 to 8, optionally wherein the drug to antibody ratio is 8.52NAI-5006811188

[0188] Embodiment 10. The method of any one of embodiments 1-9, wherein the antibody-drug conjugate is patritumab deruxtecan.

[0189] Embodiment 11. The method of any one of embodiments 1-10, wherein the compound of Formula I is (5a5'a,17a7?a)-20-chloro-2-[(25',57?)-2,5-dimethyl-4-(prop-2- enoyljpiperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one.

[0190] Embodiment 12. The method of any one of embodiments 1-11, wherein the first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg.

[0191] Embodiment 13. The method of any one of embodiments 1-11, wherein the first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg.

[0192] Embodiment 14. The method of any one of embodiments 1-13, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily.

[0193] Embodiment 15. The method of any one of embodiments 1-14, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally.

[0194] Embodiment 16. The method of any one of embodiments 1-15, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 3.2 mg / kg.

[0195] Embodiment 17. The method of any one of embodiments 1-15, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 4.8 mg / kg.

[0196] Embodiment 18. The method of any one of embodiments 1-15, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg.

[0197] Embodiment 19. The method of any one of embodiments 1-18, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered once every three weeks.

[0198] Embodiment 20. The method of any one of embodiments 1-19, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered intravenously.53NAI-5006811188

[0199] Embodiment 21. The method of embodiment 20, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion.

[0200] Embodiment 22. The method of embodiment 20, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 90 ± 5 minute IV fusion.

[0201] Embodiment 23. The method of any one of embodiments 1-22, wherein the cancer is a lung cancer.

[0202] Embodiment 24. The method of any one of embodiments 1-23, wherein the cancer is non-small cell lung cancer (“NSCLC”).

[0203] Embodiment 25. The method of any one of embodiments 1-24, wherein the antihuman HER3 antibody or functional fragment thereof is an antibody.

[0204] Embodiment 26. The method of any one of embodiments 1-25, wherein the antihuman HER3 antibody or functional fragment thereof is an antibody comprised of two heavy chains and two light chains.

[0205] Embodiment 27. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of(5 a5a, 17 a / a)-20-chl oro-2- [(25, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

[0206] Embodiment 28. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of(5 a5a, 17 a / L)-20-chl oro-2- [(25, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.54NAI-5006811188

[0207] Embodiment 29. The method of embodiment 27 or embodiment 28, wherein the first therapeutically effective amount of (5a5a,17a7?a)-20-chloro-2-[(25,5 / ?)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered at a dose of about 50 mg.

[0208] Embodiment 30. The method of embodiment 27 or embodiment 28, wherein the first therapeutically effective amount of (5a5a,17a7?a)-20-chloro-2-[(25,5 / ?)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -yl]- 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered at a dose of about 100 mg.

[0209] Embodiment 31. The method of any one of embodiments 27-30, wherein the (5 a5a, 17 a / a)-20-chl oro-2- [(25, 57?)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered once daily.

[0210] Embodiment 32. The method of any one of embodiments 27-31, wherein the (5 a5a, 17 a / a)-20-chl oro-2- [(25, 57?)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered orally.

[0211] Embodiment 33. The method of any one of embodiments 27-32, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 3.2 mg / kg.

[0212] Embodiment 34. The method of any one of embodiments 27-32, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 4.8 mg / kg.

[0213] Embodiment 35. The method of any one of embodiments 27-32, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 5.6 mg / kg.

[0214] Embodiment 36. The method of any one of embodiments 27-35, wherein the second therapeutically effective amount of patritumab deruxtecan is administered once every three weeks.55NAI-5006811188

[0215] Embodiment 37. The method of any one of embodiments 27-36, wherein the second therapeutically effective amount of patritumab deruxtecan is administered intravenously.

[0216] Embodiment 38. The method of embodiment 37, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 30 ± 5 minute IV fusion.

[0217] Embodiment 39. The method of embodiment 37, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 90 ± 5 minute IV fusion.

[0218] Embodiment 40. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 50 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 4.8 mg / kg, once every three weeks, intravenously.

[0219] Embodiment 41. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 100 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 4.8 mg / kg, once every three weeks, intravenously.

[0220] Embodiment 42. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 100 mg, once daily, orally; and56NAI-5006811188(ii) administering to the subject patritumab deruxtecan at a dose of about 5.6 mg / kg, once every three weeks, intravenously.

[0221] Embodiment 43. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl-4- (prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3 -e]pyrimido[ 1 ,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 50 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 5.6 mg / kg, once every three weeks, intravenously.

[0222] Embodiment 44. The method of any one of embodiments 1-43, wherein the subject is administered a premedication with antiemetic agents.

[0223] Embodiment 45. The method of any one of embodiments 1-44, wherein the subject is a human subject.

[0224] Embodiment 46. The method of embodiment 45, wherein the human subject has a mutation of glycine to cysteine at codon 12 (G12C) in the Kirsten rat sarcoma (KRAS) protein (“KRAS G12C mutation”).

[0225] Embodiment 47. The method of embodiment 45 or embodiment 46, wherein the human subject has a confirmed diagnosis of Stage IV non-squamous NSCLC.

[0226] Embodiment 48. The method of any one of embodiments 45-47, wherein the human subject has received one prior immuno-oncology (“IO”) therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

[0227] Embodiment 49. The method of embodiment 45, wherein the human subject has(i) a KRAS G12C mutation;(ii) a confirmed diagnosis of Stage IV non-squamous NSCLC; and(iii) received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

[0228] Embodiment 50. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11, and a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-11 in combination, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of57NAI-5006811188embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0229] Embodiment 51. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11, in combination with a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0230] Embodiment 52. A pharmaceutical composition for use in treating cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of embodiments 1-11, in combination with a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0231] Embodiment 53. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of (5aA'a, l 7a / ?a)-20-chloro-2-[(2A',5 / ?)-2,5- dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4Z / -l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one, in combination with a second therapeutically effective amount of patritumab deruxtecan.

[0232] Embodiment 54. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of patritumab deruxtecan, in combination with a second therapeutically effective amount of (5a5'a,17a7?a)-20-chloro-2-[(25',5A)-2,5- dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4Z / -l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one.

[0233] Embodiment 55. The pharmaceutical composition for use of any one of embodiments 50-54, wherein the cancer is as defined in any one of embodiments 23-24.

[0234] Embodiment 56. Use of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11 for the preparation of a58NAI-5006811188medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined in any one of embodiments 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0235] Embodiment 57. Use of the antibody-drug conjugate as defined in any one of embodiments 1-11 for the preparation of a medicament for treating cancer, by administration in combination with compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0236] Embodiment 58. The use of embodiment 56 or embodiment 57, wherein the cancer is as defined in any one of embodiments 23-24.

[0237] Embodiment 59. A compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11 for use in combination with an antihuman HER3 antibody-drug conjugate as defined in any one of embodiments 1-11 in treating cancer in a subject in need thereof, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0238] Embodiment 60. A compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11 for use in combination with an antihuman HER3 antibody-drug conjugate as defined in any one of embodiments 1-11 in treating NSCLC in a subject in need thereof, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of embodiments 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of embodiments 16-22.

[0239] Embodiment 61. (5a5'a,17a7?a)-20-chloro-2-[(25',5A)-2,5-dimethyl-4-(prop-2- enoyljpiperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one for use in combination with patritumab deruxtecan in treating NSCLC in a subject in need thereof.59NAI-5006811188

[0240] Embodiment 62. Patritumab deruxtecan for use in combination with (5aA'a, l 7a / L)- 20-chloro-2-[(25,5A)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16,17-difluoro-6- (propan-2-yl)- 11,12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1 , 18-(ethanediylidene)pyrido[4,3- e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one in treating NSCLC in a subject in need thereof.

[0241] Embodiment 63. The (5a5'a,17a7?a)-20-chloro-2-[(25',5A)-2,5-dimethyl-4-(prop-2- enoyljpiperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 / - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one for use of embodiment 61, or the patritumab deruxtecan for use of embodiment 61 or embodiment 62, wherein the subject is a human subject.

[0242] Embodiment 64. The (5a5'a,17a7?a)-20-chloro-2-[(25',5A)-2,5-dimethyl-4-(prop-2- enoyljpiperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 / - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one for use, or the patritumab deruxtecan for use of embodiment 63, wherein the human subject has a mutation of glycine to cysteine at codon 12 (G12C) in the Kirsten rat sarcoma (KRAS) protein (“KRAS G12C mutation”).

[0243] Embodiment 65. The (5a£a,17a7?a)-20-chloro-2-[(2£,5A)-2,5-dimethyl-4-(prop-2- enoyl)piperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 / - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one for use, or the patritumab deruxtecan for use of embodiment 63 or embodiment 64, wherein the human subject has a confirmed diagnosis of Stage IV non-squamous NSCLC.

[0244] Embodiment 66. The (5a£a,17a7?a)-20-chloro-2-[(2£,5A)-2,5-dimethyl-4-(prop-2- enoyl)piperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 / - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one for use, or the patritumab deruxtecan for use of any one of embodiments 63-65, wherein the human subject has received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

[0245] Embodiment 67. The (5a£a,17a7?a)-20-chloro-2-[(2£,5A)-2,5-dimethyl-4-(prop-2- enoyl)piperazin- 1 -yl] - 16, 17 -difluoro-6-(propan-2-yl)- 11 , 12 -di [(2H)hy dro]( 11 , 12-2H2)-47 / - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one for use, or the patritumab deruxtecan for use of embodiment 63, wherein the human subject has(i) a KRAS G12C mutation;(ii) a confirmed diagnosis of Stage IV non-squamous NSCLC; and60NAI-5006811188(iii) received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

[0246] Embodiment 68. A kit comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1-11, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 antibodydrug conjugate as defined in any one of embodiments 1-11, or a second pharmaceutical composition comprising the same, optionally further comprising instructions for treating cancer in a subject in need thereof according to the method of any one of embodiments 1-49.EXAMPLES

[0247] The following are examples of methods and compositions of the disclosure. It is understood that various other embodiments may be practiced, given the general description provided herein. Below are examples of specific embodiments for carrying out the present disclosure. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present disclosure in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, efc.), but some experimental error and deviation should, of course, be allowed for.Example 1: Production of MK-1084

[0248] In accordance with a production method described in United States Patent No. 11,697,657 or Ma et al. (2024) J. Med. Chem. 67(13): 11024-11052, for example, MK-1084 ((5 a5a, 17 a7?a)-20-chloro-2-[(25, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-4 / 7- 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one) can be produced.Example 2: Production of Patritumab Deruxtecan (HER3-DXd)

[0249] In accordance with a production method described in International Publication No. WO2015 / 155998, for example, patritumab deruxtecan (HER3-DXd) can be produced. The average number of units of a drug-linker that are conjugated to the anti-human-HER3 antibody in patritumab deruxtecan is, in one embodiment, 8 as determined by a HPLC method.61NAI-5006811188Example 3: Clinical trial protocol for administration of MK-1084 and PatritumabDeruxtecan (HER3-DXd) to patients with non-small cell lung cancer (NSCLC)

[0250] This Example described a Phase lb / 2, rolling arm, multicenter, open-label, adaptive design study that will evaluate the safety and tolerability, establish the recommended dose, and explore the preliminary efficacy of the combination of MK-1084 and patritumab deruxtecan (HER3-DXd) in participants with metastatic non-squamous NSCLC with Kirsten rat sarcoma viral oncogene (KRAS) G12C mutations (mutation of glycine to cysteine at codon 12), who have received one prior immune oncology (IO) therapy with or without chemotherapy and without prior KRAS inhibitor therapy.

[0251] Primary Objectives'. To characterize the safety and tolerability of MK-1084 ((5 a5a, 17 aRa)-20-chloro-2-[(25, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl]- 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one) administered in combination with HER3-DXd. The primary safety analysis is based on participants who experience toxi cities as defined by CTCAE (Common Terminology Criteria for Adverse Events), Version 5.0. Safety is assessed by quantifying the toxi cities and grades of toxicities experienced by participants. Safety parameters frequently used for evaluating investigational-systemic anticancer treatments are included as safety endpoints including, but not limited to, the incidence of, causality, and outcome of adverse events (AEs) / serious adverse events (SAEs), and changes in vital signs and laboratory values. AEs are assessed as defined by CTCAE, Version 5.0.

[0252] Secondary Objectives'. To characterize the PK (pharmacokinetic) profile of MK- 1084 and HER3-DXd. The concentrations of MK-1084 and HER3-DXd will serve as the primary readout for the PK, and these data will be used to derive PK parameters.Furthermore, the results of these analyses will be used in conjunction with the safety, efficacy, and exploratory endpoints data to help assess dosing strategies for MK-1084 and HER3-DXd.

[0253] Exploratory Objectives'. As an exploratory objective, ADA (anti drug antibodies) response will be determined after administration of MK-1084 and HER3-DXd. Correlations between the presence / absence of positivity for AD As and PK, efficacy, and safety of MK- 1084 and HER3-DXd will be explored.

[0254] Target Population'. Participants at least 18 years of age, with metastatic non- squamous NSCLC with KRAS G12C mutations, who have received one prior immuno-62NAI-5006811188oncology (IO) therapy with or without chemotherapy and without prior KRAS inhibitor therapy.

[0255] Type of Participant and Disease Characteristics'. An individual is eligible for inclusion in the study if the individual meets the following criteria:- Histologically or cytologically confirmed diagnosis of Stage IV (Mia, Mlb, or Mlc per AJCC Staging Manual, Version 8) non-squamous NSCLC. Note: Mixed tumors will be characterized by the predominant cell type (squamous or non-squamous); however, small cell elements are not permitted.Tumor tissue or ctDNA that demonstrates the presence of KRAS G12C mutations as assessed at a local laboratory. Note: Assessment of presence of KRAS G12C mutations must be made before allocation / randomization.- Documented disease progression after receiving 1 prior line of IO therapy with or without chemotherapy.- Measurable disease per RECIST 1.1 (Response Evaluation Criteria in Solid Tumors 1.1) as assessed and verified by BICR (blinded independent central review). Lesions situated in a previously irradiated area are considered measurable if progression has been shown in such lesions.- Life expectancy of at least 3 months.- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 assessed within 7 days before allocation / randomization.Adequate organ function.

[0256] Number of Patients'. Up to 20 patients will be enrolled.

[0257] Duration of Participation'. Each participant will participate in the study for approximately 3 years from the time the participant provides documented informed consent through the final protocol-specified contact. After a screening period of up to 56 days, each participant will be receiving assigned study intervention for approximately 1 year. After the end of treatment each participant will be followed for 2 years. After screening, each participant will be assigned to receive study intervention until one of the conditions for discontinuation of study intervention is met. Participants who discontinue for reasons other than radiographic disease progression will have posttreatment follow-up imaging for disease status until any of the conditions for discontinuation of imaging are met. After the end of treatment, each participant will be followed for the occurrence of AEs, SAEs, and other reportable safety events. All participants will be followed for overall survival until death, withdrawal of consent, the end of the study, or enrollment into an extension study.63NAI-5006811188

[0258] Study Design'. The study design is depicted in FIG. 1.

[0259] Phases of the Study. The study uses a BOIN dose escalation design to identify the preliminary RP2D, then randomizes additional participants in a dose confirmation and expansion phase across selected doses to confirm and establish the RP2D and further evaluate efficacy. This is accomplished in two distinct phases in tandem, the dose escalation phase and randomized dose confirmation and expansion phase, as follows:- Dose Escalation (Phase lb): This phase follows BOIN design and escalates through prespecified dose levels investigating safety and tolerability. Once BOIN concludes, the totality of data will be used to determine which dose levels to investigate in the dose confirmation and expansion phase.- Randomized Dose Confirmation and Expansion (Phase 2): This phase randomizes participants to select dose levels after clearing minimum safety standards according to BOIN rules and will provide additional safety, efficacy, and PK data to determine the RP2D. Upon establishing the RP2D, efficacy will be further evaluated.Treatment Plans:

[0260] MK-1084 will be evaluated in combination with HER3-DXd. The initial dose escalation phase (Phase lb) uses a Bayesian Optimal Interval (BOIN) dose escalation design (see below; Table 4) to identify the preliminary RP2D (Table 1), and then randomizes participants in a dose confirmation expansion phase (Phase 2) across selected doses to confirm and establish the arm-specific RP2D (Table 2).

[0261] Table 1: Treatment Plan for Phase lb (Dose Escalation)64NAI-5006811188

[0262] Table 2 : Treatment Plan for Phase 2 (Randomized Dose Confirmation and Expansion)

[0263] MK- 1084 Administration'. MK-1084 is an oral medication. Participants will be instructed to take tablet(s) every 24 hours, in the morning at approximately the same time each day. During onsite visits, MK-1084 will be administered as described herein. On Day 1 of each cycle, MK 1084 will be dosed in the clinic (approximately 30 minutes before infusion of HER3-DXd). The administration, the dose, the time of administration, as well as any immediate reactions at the time of intake will be documented.

[0264] HER3-DXd Administration'. HER3-DXd will be administered as a continuous IV infusion over approximately 90 minutes on Day 1 of Cycle 1. If there are no IRRs after the initial dose, subsequent doses of HER3 DXd will be infused over approximately 30 minutes on Day 1 of each subsequent cycle q3w. Participants will receive the study intervention on Day 1 of each 21-day cycle. Based on currently available clinical safety data for HER3-DXd, it is recommended that subjects receive premedication with anti emetic agents. Accordingly, participants will be premedicated with a 2- or 3-drug combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK-1 receptor antagonist as well as other drugs as indicated) for prevention of chemotherapy -induced nausea and vomiting (CINV). The participant’s weight at baseline (defined as the last measurement on or before allocation / randomization) will be used to calculate the initial dose. If the participant’s weight changes by ±10% or more of the baseline weight, the dose must be recalculated. After the recalculation, the updated weight of the participant will be used as the new baseline weight.

[0265] If dose reduction is required, HER3-DXd dosing will be reduced by 1 dose level at a time (Table 3). Once the dose of HER3-DXd has been reduced due to an AE, all65NAI-5006811188subsequent cycles will be administered at that lower dose level unless further dose reduction is required. In absence of dose level lower than (-2), HER3-DXd will be discontinued if participant experiences toxicity at dose level (-2) that requires further dose reduction.

[0266] Table 3 : Dose Reduction Levels for 5.6 mg / kg Fixed-dose Regimen of HER3- DXdBayesian Optimal Interval (BOIN) design Dose Escalation Cohorts

[0267] Dose-escalation and de-escalation decisions are based on the Bayesian Optimal Interval (BOIN) design and depend on the number of participants enrolled and number of participants with at least 1 dose-limiting toxicity (DLT) observed at the current dose level.

[0268] A minimum of 3 participants are required at each dose. However, depending on the accrual rate, 3, 4, 5, or 6 participants may be enrolled at the opening of a dose cohort. In Table 4, the columns indicate the numbers of participants treated at the current dose level, and the rows indicate the numbers of participants experiencing DLT. The entries of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and excluding the dose from the study due to unacceptable toxicity, respectively. For example, if 0 of 3 participants at a given dose level develop a DLT, then the dose can escalate to the next level. If 2 of 3 participants develop a DLT, the dose will be deescalated to the next lower dose level. If 3 of 3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose should be de-escalated, and the current dose will not be explored further. If 1 of 3 participants at a given dose level develop a DLT, then additional participants should be enrolled at that dose level following the rules below.

[0269] When adding participants to a dose level, the number of additional participants to be enrolled is capped to minimize the exposure to a dose that may be unacceptably toxic. To determine how many more participants can be enrolled at the dose level, one can count steps in diagonal direction (down and to the right) from the current cell to the first cell marked DU. For example, if 1 of 3 participants have experienced a DLT at a given dose level, no more than an additional 3 participants should be enrolled at this dose level until additional DLT data are available. This is because this dose level would be considered unacceptably toxic if all 3 of the additional participants experience a DLT ( / .< ., 4 / 6 participants with DLT in Table 4).66NAI-5006811188

[0270] A D or DU decision at the lowest dose level will stop the study. An E decision at the highest dose level will result in staying at that level. During dose finding, it may be acceptable to de-escalate to an intermediate dose that was not predefined and not previously studied if evaluation of toxicity at such a dose is desired. If this approach is taken, 3 to 6 new participants may be enrolled at the new intermediate dose, and the aforementioned rules should be used to determine further enrollment at this dose level.

[0271] After 10 participants have been enrolled at any of the tested doses (including intermediate doses), dose finding will stop if the BOIN table indicates “S” for staying at current dose.

[0272] After dose finding stops, the dose with an estimated DLT rate closest to 30% will be treated as a preliminary maximum tolerated dose (MTD). However, the totality of the data will be considered before deciding on the dose(s) to carry forward to dose expansion (Phase 2), and the escalation schedule may be adjusted based on data emerging throughout the study. If needed, dose randomization may be conducted to further confirm the recommended dose to carry forward. Two doses maybe selected for dose randomization in each experimental arm, and update to 15 patients may be enrolled for each dose cohort.

[0273] Note that although 30% was the target DLT rate used to generate the guidelines in Table 4, the observed rate of participants with DLTs at the MTD may be slightly above or below 30%.

[0274] Table 4: Dose-finding Rules per BOIN Design with Target DLT Rate 30%BOIN=Bayesian optimal interval; D=Deescalate to the next lower dose; DLT=dose-limiting toxicity; DU=The current dose is unacceptably toxic; E=Escalate to the next higher dose; S=Stay at the current dose.Dose Limiting Toxicity (DLT)

[0275] The occurrence of any of the following toxicities will be considered a DLT if assessed to be possibly, probably, or definitely related to study intervention administration,67NAI-5006811188excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc. :Grade 4 nonhematologic toxicity (not laboratory).Any nonhematologic AEGrade 3 in severity should be considered a DLT, with the following exceptions:• Grade 3 fatigue lasting ^3 days;• Grade 3 diarrhea, nausea, or vomiting lasting <3 days.• Grade 3 rash lasting <7 days.Any Grade 3 or Grade 4 laboratory value (hematologic or nonhematologic), except for the following:• Grade 3+ electrolyte abnormalities that last <72 hours, are not clinically complicated, and resolve spontaneously or with conventional medical interventions.• Grade 3+ amylase or lipase that is not associated with symptoms or clinical manifestations of pancreatitis.• Grade 3+ anemia or Grade 3 neutropenia or thrombocytopenia (in the absence of clinically significant bleeding) responsive to medical management and that resolves to Grade1 within 7 days.• For participants without hepatic metastases: AST (aspartate aminotransferase) or ALT (alanine aminotransferase) >5x ULN (upper limit of normal) that resolves to Grade1 or baseline within 7 days.• For participants with hepatic metastases: AST or ALT >8x ULN that resolves to Grade1 or baseline within 7 days.Febrile neutropenia Grade 3 or Grade 4:• Grade 3 is defined as ANC (absolute neutrophil count) <1000 / mm3with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of38 degrees C (100.4 degrees F) for more than 1 hour.• Grade 4 is defined as ANC <1000 / mm3with a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of i<38 degrees C (100.4 degrees F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated.68NAI-5006811188Prolonged delay (>2 weeks) in initiating Cycle 2 due to study intervention-related toxicity.Any study intervention-related toxicity that causes the participant to discontinue intervention during Cycle 1.Missing study intervention dosing during Cycle 1 Day 1 (C1D1) or receiving less than 75% of daily oral investigational agent(s) as a result of treatment-related AE(s) during the first cycle.Grade 5 toxicity.

[0276] The present disclosure relates to the combination of MK-1022 (HER3-DXd) with MK-1084 (KRAS G12C inhibitor), as well as related dosing regimens and patient populations. The KRAS G12C mutation is an oncogenic alteration found in about 14% of lung adenocarcinoma. Recently, two KRAS G12C inhibitors received accelerated approval for patients with KRAS G12C-mutated non-small cell lung cancer (NSCLC) who have undergone at least one prior treatment. However, resistance to KRAS G12C inhibitors often occurs, highlighting the need for combination therapies to improve patient survival. The present disclosure believes that the combination of MK-1084 with an anti-HER3 antibodydrug conjugate (e.g., patritumab deruxtecan (HER3-DXd)) may be more efficacious than either treatment alone. Additionally, the present disclosure believes that the combination may not result in cumulative toxicities such that it will be better tolerated than existing therapies.

[0277] While the present disclosure has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the claims appended hereto.

[0278] All references, issued patents and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.69NAI-5006811188SEQUENCES70NAI-500681118871NAI-5006811188

Claims

CLAIMS1. A method for treating cancer in a subj ect in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I; and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate of Formula II or a pharmaceutically acceptable salt thereof, wherein Formula II represents:Formula II wherein AB is an anti-human HER3 antibody or a functional fragment thereof, n represents the drug to antibody ratio, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises:72NAI-5006811188a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

2. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein Formula I represents:Formula I; and(ii) administering to the subject a second therapeutically effective amount of an antibody-drug conjugate, wherein the antibody-drug conjugate comprises an anti- human-HER3 antibody or a functional fragment thereof and a drug-linker of Formula III73NAI-5006811188Formula III wherein A represents a connecting position to the anti-human-HER3 antibody or a functional fragment thereof, and wherein the anti-human-HER3 antibody or the functional fragment thereof comprises: a) a VH-CDR1, a VH-CDR2, and a VH-CDR3, comprising the amino acid sequence of the VH-CDR1, VH-CDR2, and the VH-CDR3, respectively, within SEQ ID NO: 3; and b) a VL-CDR1, a VL-CDR2, and a VL-CDR3, comprising the amino acid sequence of the VL-CDR1, VL-CDR2, and the VL-CDR3, respectively, within SEQ ID NO: 4.

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

4. The method of any one of claims 1-3, wherein the anti-human HER3 antibody or the functional fragment thereof comprises a variable heavy chain (“VH”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 3, and a variable light chain (“VL”) comprising an amino acid sequence having 90% or more amino acid sequence identity with SEQ ID NO: 4.74NAI-50068111885. The method of any one of claims 1-4, wherein the anti-human HER3 antibody is anIgGl or an IgG2.

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

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

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

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

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

11. The method of any one of claims 1-10, wherein the compound of Formula I is (5 a5a, 17 a / C)-20-chl oro-2- [(25, 57Q-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17- difluoro-6-(propan-2-yl)- 11 , 12 - di [(2H)hy dro] (11,12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one.

12. The method of any one of claims 1-11, wherein the first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg.

13. The method of any one of claims 1-11, wherein the first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg.75NAI-500681118814. The method of any one of claims 1-13, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily.

15. The method of any one of claims 1-14, wherein the compound of Formula I or a pharmaceutically acceptable salt thereof is administered orally.

16. The method of any one of claims 1-15, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 3.2 mg / kg.

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

18. The method of any one of claims 1-15, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered at a dose of about 5.6 mg / kg.

19. The method of any one of claims 1-18, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered once every three weeks.

20. The method of any one of claims 1-19, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered intravenously.

21. The method of claim 20, wherein the second therapeutically effective amount of the antibody-drug conjugate is administered via a 30 ± 5 minute IV fusion.

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

23. The method of any one of claims 1-22, wherein the cancer is a lung cancer.

24. The method of any one of claims 1-23, wherein the cancer is non-small cell lung cancer (“NSCLC”).

25. The method of any one of claims 1-24, wherein the anti-human HER3 antibody or functional fragment thereof is an antibody.76NAI-500681118826. The method of any one of claims 1-25, wherein the anti-human HER3 antibody or functional fragment thereof is an antibody comprised of two heavy chains and two light chains.

27. A method for treating cancer in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of(5 a5a, 17 a / a)-20-chl oro-2- [(2S, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] -16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin- 4-one; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

28. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject a first therapeutically effective amount of(5 a5a, 17 a / a)-20-chl oro-2- [(2S, 5A)-2, 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] -16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin- 4-one; and(ii) administering to the subject a second therapeutically effective amount of patritumab deruxtecan.

29. The method of claim 27 or claim 28, wherein the first therapeutically effective amount of (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered at a dose of about 50 mg.

30. The method of claim 27 or claim 28, wherein the first therapeutically effective amount of (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl-4-(prop-2-enoyl)piperazin-l-yl]-16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18-77NAI-5006811188(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered at a dose of about 100 mg.

31. The method of any one of claims 27-30, wherein the (5a5a,17a7?a)-20-chl oro-2 -[(25, 57?)-2,5-dimethyl-4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4J / -l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered once daily.

32. The method of any one of claims 27-31, wherein the (5a5a,17a7?a)-20-chl oro-2 -[(25, 57?)-2,5-dimethyl-4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4J / -l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one is administered orally.

33. The method of any one of claims 27-32, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 3.2 mg / kg.

34. The method of any one of claims 27-32, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 4.8 mg / kg.

35. The method of any one of claims 27-32, wherein the second therapeutically effective amount of patritumab deruxtecan is administered at a dose of about 5.6 mg / kg.

36. The method of any one of claims 27-35, wherein the second therapeutically effective amount of patritumab deruxtecan is administered once every three weeks.

37. The method of any one of claims 27-36, wherein the second therapeutically effective amount of patritumab deruxtecan is administered intravenously.

38. The method of claim 37, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 30 ± 5 minute IV fusion.

39. The method of claim 37, wherein the second therapeutically effective amount of patritumab deruxtecan is administered via a 90 ± 5 minute IV fusion.78NAI-500681118840. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl- 4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4Z7-l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 50 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 4.8 mg / kg, once every three weeks, intravenously.

41. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl- 4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4Z7-l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 100 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 4.8 mg / kg, once every three weeks, intravenously.

42. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl- 4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4Z7-l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 100 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 5.6 mg / kg, once every three weeks, intravenously.

43. A method for treating NSCLC in a subject in need thereof, wherein the method comprises:(i) administering to the subject (5a5a, 17aRa)-20-chloro-2-[(25,5A)-2,5-dimethyl- 4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12-79NAI-5006811188di[(2H)hydro](l l,12-2H2)-4J / -l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one at a dose of about 50 mg, once daily, orally; and(ii) administering to the subject patritumab deruxtecan at a dose of about 5.6 mg / kg, once every three weeks, intravenously.

44. The method of any one of claims 1-43, wherein the subject is administered a premedication with antiemetic agents.

45. The method of any one of claims 1-44, wherein the subject is a human subject.

46. The method of claim 45, wherein the human subject has a mutation of glycine to cysteine at codon 12 (G12C) in the Kirsten rat sarcoma (KRAS) protein (“KRAS G12C mutation”).

47. The method of claim 45 or claim 46, wherein the human subject has a confirmed diagnosis of Stage IV non-squamous NSCLC.

48. The method of any one of claims 45-47, wherein the human subject has received one prior immuno-oncology (“IO”) therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

49. The method of claim 45, wherein the human subject has(i) a KRAS G12C mutation;(ii) a confirmed diagnosis of Stage IV non-squamous NSCLC; and(iii) received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

50. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11, and a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-11 in combination, wherein optionally the compound of Formula I or a pharmaceutically80NAI-5006811188acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

51. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11, in combination with a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

52. A pharmaceutical composition for use in treating cancer, comprising a second therapeutically effective amount of the antibody-drug conjugate as defined in any one of claims 1-11, in combination with a first therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

53. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of (5a5'a,17a7?a)-20-chloro-2-[(25',5A)-2,5-dimethyl-4-(prop- 2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one, in combination with a second therapeutically effective amount of patritumab deruxtecan.

54. A pharmaceutical composition for use in treating cancer, comprising a first therapeutically effective amount of patritumab deruxtecan, in combination with a second therapeutically effective amount of (5a£a,17a7?a)-20-chloro-2-[(2£,5A)-2,5-dimethyl-4-(prop- 2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 - l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4- one.

55. The pharmaceutical composition for use of any one of claims 50-54, wherein the cancer is as defined in any one of claims 23-24.81NAI-500681118856. Use of the compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11 for the preparation of a medicament for treating cancer, by administration in combination with the antibody-drug conjugate as defined in any one of claims 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

57. Use of the antibody-drug conjugate as defined in any one of claims 1-11 for the preparation of a medicament for treating cancer, by administration in combination with compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

58. The use of claim 56 or claim 57, wherein the cancer is as defined in any one of claims 23-24.

59. A compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11 for use in combination with an anti-human HER3 antibody-drug conjugate as defined in any one of claims 1-11 in treating cancer in a subject in need thereof, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

60. A compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11 for use in combination with an anti-human HER3 antibody-drug conjugate as defined in any one of claims 1-11 in treating NSCLC in a subject in need thereof, wherein optionally the compound of Formula I or a pharmaceutically acceptable salt thereof is administered as defined in any one of claims 12-15, and / or the antibody-drug conjugate is optionally administered as defined in any one of claims 16-22.

61. (5 a5a, 17 a / ?a)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 - 1,18-82NAI-5006811188(ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use in combination with patritumab deruxtecan in treating NSCLC in a subject in need thereof.

62. Patritumab deruxtecan for use in combination with (5a5a,17a7?a)-20-chloro-2-[(25, 5A)-2,5-dimethyl-4-(prop-2-enoyl)piperazin- 1 -y 1 ] - 16, 17-difluoro-6-(propan-2-yl)- 11,12- di[(2H)hydro](l l,12-2H2)-4Z7-l,18-(ethanediylidene)pyrido[4,3-e]pyrimido[l,6- g][l,4,7,9]benzodioxadiazacyclododecin-4-one in treating NSCLC in a subject in need thereof.

63. The (5 a5a, 17 a / L)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] -16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use of claim 61, or the patritumab deruxtecan for use of claim 61 or claim 62, wherein the subject is a human subject.

64. The (5 a5a, 17 a / L)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] -16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use, or the patritumab deruxtecan for use, of claim 63, wherein the human subject has a mutation of glycine to cysteine at codon 12 (G12C) in the Kirsten rat sarcoma (KRAS) protein (“KRAS G12C mutation”).

65. The (5 a5a, 17 a / L)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] -16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use, or the patritumab deruxtecan for use, of claim 63 or claim 64, wherein the human subject has a confirmed diagnosis of Stage IV non-squamous NSCLC.

66. The (5 a5a, 17 a / L)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] -16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use, or the patritumab deruxtecan for use, of any one of claims 63-65, wherein the human83NAI-5006811188subject has received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

67. The (5 a5a, 17 a / a)-20-chl oro-2- [(25, 57?) -2 , 5 -dimethyl-4-(prop-2-enoyl)piperazin- 1 -yl] - 16, 17-difluoro-6-(propan-2-yl)- 11,12-di [(2H)hydro](l 1 , 12-2H2)-47 / - 1,18- (ethanediylidene)pyrido[4,3-e]pyrimido[l,6-g][l,4,7,9]benzodioxadiazacyclododecin-4-one for use, or the patritumab deruxtecan for use, of claim 63, wherein the human subject has(i) a KRAS G12C mutation;(ii) a confirmed diagnosis of Stage IV non-squamous NSCLC; and(iii) received one prior IO therapy with or without chemotherapy, and without prior KRAS inhibitor therapy.

68. A kit comprising (i) a compound of Formula I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1-11, or a first pharmaceutical composition comprising the same, and (ii) an anti-human-HER3 antibody-drug conjugate as defined in any one of claims 1-11, or a second pharmaceutical composition comprising the same, optionally further comprising instructions for treating cancer in a subject in need thereof according to the method of any one of claims 1-49.84NAI-5006811188

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