Combination of the FGFR 3 inhibitor tyra-300 and a nectin-4 targeting agent-drug conjugate for use in the treatment of cancer

Abstract

Disclosed are methods of treating cancer comprising administering to a subject a treatment regimen comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and a nectin-4 targeting agent-drug conjugate.

Description

COMBINATION TREATMENT REGIMENS CROSS REFERENCE OF RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 549,629, filed February 5, 2024, the entirety of which is incorporated by reference herein. TECHNICAL FIELD

[0002] The disclosure pertains to methods of treating cancer comprising administering to a subject a treatment regimen comprising an FGFR3 inhibitor and a nectin-4 targeting agent-drug conjugate. BACKGROUND

[0003] Genomic alterations in Fibroblast Growth Factor Receptor (FGFR) family members occur in approximately 7% of all human cancers, representing about 126,000 new cases per year. The pan-FGFR inhibitor erdafitinib is currently FDA approved for the treatment of bladder cancer tumors driven by alterations in FGFR3 and FGFR2, and additional FGFR inhibitors are currently under development in several cancer types.

[0004] Though there have been many recent advances in the treatment of cancer, there remains a need for more effective treatment options that enhance the depth and duration of tumor responses to treatment.

[0005] Nectin-4 is a protein expressed in a number of different cancers. Surprisingly, combining an FGFR3 inhibitor with a nectin-4 targeting agent-drug conjugate, as disclosed herein, is unexpectedly effective in enhancing anti-tumor response. SUMMARY

[0006] The disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a treatment regimen comprising: (a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and (b) a nectin-4 targeting agent-drug conjugate.

[0007] In some aspects, the cancer has an activating FGFR3 gene alteration. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG.1 depicts the experimental procedure testing a herein described treatment regimen comprising administration of Formula (I) in combination with a nectin-4 targeting agent-drug conjugate (AGS-22ME).

[0009] FIG.2 shows the average tumor volume from the start of treatment in mice administered the indicated treatment regimen. Nude mice bearing RT112 / 84 bladder carcinoma tumors were treated with vehicle, AGS-22ME, Formula (I), erdafitinib, combination Formula (I) plus AGS-22ME, or combination erdaftinib plus AGS-22ME for 21 days.

[0010] FIG.3 shows the individual tumor volume measurements over time in mice administered the indicated treatment regimen. The gray arrow indicates the start of treatment.

[0011] FIG.4 shows the average change in body weight from the start of treatment in mice administered the indicated treatment regimen.

[0012] FIG.5 shows the percent change in individual tumor volumes from the start of treatment to endpoint (Day 21 of treatment) in mice administered the indicated treatment regimen. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0013] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the - 2 - 4901-4937-2950.1disclosed methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0014] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0015] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, benzenesulfonic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. Particularly preferred salts of the compound of Formula (I) are described in WO2022 / 147246.

[0016] It is understood that, the compound of Formula (I) described herein includes a chiral center. The compound of Formula (I) provided herein may be enantiomerically pure, enantiomerically enriched, or a racemic mixture. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned. For example, any instance of hydrogen, may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon- - 3 - 4901-4937-2950.114, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0017] A “pharmaceutically acceptable excipient” refers to a substance that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of a compound of Formula (I) and that is compatible therewith.

[0018] As used herein, the term “subject” shall be given its ordinary meaning and shall also refer to an organism, or cells from an organism, that have FGFR proteins. This includes mammals, and mammalian cells such as recombinant cells derived from a mammal. Suitable mammals include a human, non-human primate, ungulate, canine, feline, equine, rodent (e.g., mice, rats), and the like. The term “mammal” includes both human and non- human mammals and cells originating from or derived from a mammal.

[0019] The term “treatment” (or “treating,” “treat” and the like) as used herein shall be given its ordinary meaning and shall include any treatment of a disease of an organism or cells from an organism, such as a mammal or mammalian cells, particularly a human and human cells, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and / or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom. Thus, “treatment” generally refers to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease.

[0020] As used herein, the term “treatment regimen” refers to coordinated dosages and administration timings of each of Formula (I) (or pharmaceutically acceptable salt thereof) and a nectin-4 targeting agent-drug conjugate such that Formula (I) (or pharmaceutically acceptable salt thereof) and a nectin-4 targeting agent-drug conjugate are administered to the subject during an overlapping period of time. Thus, the “treatment regimen” of the disclosure encompasses both concurrent administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and a nectin-4 targeting agent- drug conjugate; and sequential administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and a nectin-4 targeting agent-drug conjugate. - 4 - 4901-4937-2950.1Moreover, the treatment regimen encompasses administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and a nectin-4 targeting agent-drug conjugate on the same day; on different days; and any permutation thereof.

[0021] The term “administering,” when used in the context of administering a therapeutic agent to a subject, refers to introducing the therapeutic agent into the subject’s body or to cells in vitro. For example, therapeutic agents may be introduced into a subject’s body orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.

[0022] The terms “cancer” and “tumor” are used interchangeably herein and shall be given its ordinary meaning and shall also refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precursors, precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells.

[0023] As used herein, “an activating FGFR3 gene alteration” refers to a mutation or rearrangement of the FGFR3 gene, relative to the wild-type FGFR3 gene, such that the FGFR3 gene having an activating FGFR3 gene alteration encodes an FGFR kinase that has greater FGFR3 kinase activity than the FGFR kinase that is encoded by the wild-type FGFR3 gene.

[0024] As used herein, the term “nectin-4 targeting agent-drug conjugate” refers to any chemical compound (including biological molecules such as antibodies) comprised of a moiety that targets (i.e., binds to) nectin-4 conjugated to (i.e., chemically linked to) a drug. It will be understood by those of skill in the art that the nectin-4 targeting agent may be conjugated to the drug via a linker, i.e., a chemical moiety that attaches to both the nectin-4 targeting agent and the drug. Linkers useful for conjugating targeting molecules to drugs are known to those skilled in the art. Nectin-4 targeting agent-drug conjugates useful in the treatment regimens and related treatment methods of the disclosure include, for example, antibody-drug conjugates, monoclonal antibody (mAb)-drug conjugates, antigen binding fragment-drug conjugates, binding protein-drug conjugates, polypeptide-drug conjugates, or small molecule-drug conjugates.

[0025] As used herein, the term “antibody” shall be given its ordinary meaning and refers to any form of antibody that exhibits the desired biological or binding activity, and includes monoclonal antibodies (including full length monoclonal antibodies), polyclonal - 5 - 4901-4937-2950.1antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single domain antibodies.

[0026] As used herein, the term “monoclonal antibody” or “mAb” or “Mab”, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts.

[0027] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment of an antibody” (or “antigen binding fragment”) refers to antibody fragments that retain the ability to bind specifically to the antigen to which the full-length antibody binds.

[0028] Several clinical trials are currently underway to evaluate ADC combination therapies in patients with metastatic urothelial cancer (NCT03474107, NCT03288545, NCT04223856, NCT03547973, NCT04507166, NCT03523572).

[0029] In some aspects, the disclosure is directed to methods of treating cancer in a subject in need thereof, comprising administering to the subject a treatment regimen comprising: (a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and (b) a nectin-4 targeting agent-drug conjugate.

[0030] In some embodiments, the treatment regimen comprises the administration of a compound of Formula (I) and a nectin-4 targeting agent-drug conjugate. Formula (I) and synthesis of Formula (I) are described in WO2022 / 147246 - 6 - 4901-4937-2950.1

[0031] In some embodiments, the treatment regimen comprises a pharmaceutically acceptable salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. In some embodiments, the pharmaceutically acceptable salt of a compound of Formula (I) is the hydrochloride salt, besylate salt, maleate salt, tosylate salt, sulfate salt, 2- hydroxyethanesulfonate salt, ethanesulfonate (esylate) salt, mesylate salt, di-mesylate salt, R- camsylate salt, S-camsylate salt, or hydrobromide salt.

[0032] The treatment regimen can comprise the hydrochloride salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the besylate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the maleate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the tosylate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the sulfate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the 2- hydroxyethanesulfonate salt of a compound of Formula (I) and the nectin-4 targeting agent- drug conjugate. The treatment regimen can comprise the ethanesulfonate (esylate) salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the mesylate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the di-mesylate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the R-camsylate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the S-camsylate salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate. The treatment regimen can comprise the hydrobromide salt of a compound of Formula (I) and the nectin-4 targeting agent-drug conjugate.

[0033] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the nectin-4 targeting agent-drug conjugate are administered concurrently or sequentially.

[0034] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the nectin-4 targeting agent-drug conjugate are administered concurrently.

[0035] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the nectin-4 targeting agent-drug conjugate are administered sequentially. - 7 - 4901-4937-2950.1

[0036] In some embodiments, the nectin-4 targeting agent-drug conjugate is an antibody-drug conjugate, i.e., a nectin-4 antibody-drug conjugate. In some embodiments, the nectin-4 antibody is a monoclonal antibody.

[0037] In other embodiments, the nectin-4 targeting agent-drug conjugate is a nectin-4 antigen binding fragment-drug conjugate.

[0038] In other embodiments, the nectin-4 targeting agent-drug conjugate is a peptide-drug conjugate. In some embodiments, the peptide is a bicyclic peptide.

[0039] In some embodiments, the nectin-4 targeting agent-drug conjugate is a Bicycle Toxin Conjugate (BTC), such as, for example, BT8009 or BT7480. See, e.g., J Med Chem., 2022 Nov 10;65(21):14337-14347 and J Immunother Cancer, 2021 Nov;9(11):e002883.

[0040] In some embodiments, the nectin-4 targeting agent-drug conjugate is a nectin-4 targeting agent-immune cell receptor agonist conjugate, such as, for example, a nectin-4 targeting agent-4-1BB agonist conjugate, a nectin-4 targeting agent-Toll-like receptor (TLR) agonist conjugate, or a nectin-4 targeting agent-TLR8 agonist conjugate.

[0041] In some embodiments, the nectin-4 targeting agent-drug conjugate is a nectin-4 targeting agent-topoisomerase I inhibitor conjugate, such as, for example, a nectin-4 targeting agent-deruxtecan conjugate, or a nectin-4 targeting agent-SN-38 conjugate.

[0042] In some embodiments, the nectin-4 targeting agent-drug conjugate is a nectin-4 targeting agent-antibiotic conjugate, such as, for example, a nectin-4 targeting agent- ozogamicin conjugate.

[0043] In some embodiments, the nectin-4 targeting agent-drug conjugate is a nectin-4 targeting agent-anti-microtubule agent conjugate, such as, for example, a nectin-4 targeting agent-monomethyl auristatin E (MMAE) conjugate, a nectin-4 targeting agent- emtansine conjugate, an antibody-MMAE conjugate, or an antibody-emtansine conjugate.

[0044] In some embodiments wherein the nectin-4 targeting agent-drug conjugate is an antibody-drug conjugate, the antibody-drug conjugate is enfortumab vedotin. The enfortumab vedotin can be intravenously administered to the subject in a dose of 1.25 mg / kg. The enfortumab vedotin can be administered over 30 minutes on Days 1, 8, and 15 of a 28- day cycle.

[0045] In other embodiments, the enfortumab vedotin is administered in accordance with the December 2023 revision of the prescribing information for PADCEV® (enfortumab vedotin-ejfv) for injection, for intravenous use, the entirety of which is incorporated by reference herein. - 8 - 4901-4937-2950.1

[0046] In some embodiments, the antibody-drug conjugate is N41mab-vcMMAE. See, e.g., Ann Oncol.2017 Apr 1;28(4):769-776.

[0047] In some embodiments, the antibody-drug conjugate is SBT6290. See, e.g., NCT05234606

[0048] In some embodiments, the antibody drug conjugate is 9MW2821. See, e.g., Mol Cancer Ther., 2023 Aug 1;22(8):913-925.

[0049] In some aspects of the disclosed methods, the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, pancreatic cancer, or non-muscle invasive bladder cancer (NMIBC).

[0050] In some embodiments, the cancer is urothelial cancer.

[0051] In other embodiments, the cancer is urothelial carcinoma.

[0052] In other embodiments, the cancer is breast cancer.

[0053] In other embodiments, the cancer is endometrial cancer.

[0054] In other embodiments, the cancer is lung cancer.

[0055] In other embodiments, the cancer is ovarian cancer.

[0056] In other embodiments, the cancer is bladder cancer.

[0057] In other embodiments, the cancer is gastric cancer.

[0058] In other embodiments, the cancer is esophageal cancer.

[0059] In other embodiments, the cancer is pancreatic cancer.

[0060] In some embodiments, the cancer is non-muscle invasive bladder cancer (NMIBC).

[0061] In other embodiments, the cancer is a locally advanced solid tumor.

[0062] In other embodiments, the cancer is a metastatic solid tumor.

[0063] In some aspects of the disclosed methods, the cancer has an activating FGFR3 gene alteration.

[0064] In some embodiments, the activating FGFR3 gene alteration is a mutation. As used in this context, the term “mutation” refers to a change in the FGFR3 gene that results in the encoded FGFR3 kinase having a different amino acid sequence that the wild-type FGFR3 kinase. Methods of identifying FGFR3 mutations are known in the art.

[0065] In some embodiments, the mutation is any one or more of the following: FGFR3 p.S84L; FGFR3 p.G380R; FGFR3 p.R621H; FGFR3 p.R248C; - 9 - 4901-4937-2950.1FGFR3 p.G380E; FGFR3 p.K650E; FGFR3 p.S249C; FGFR3 p.A391V; FGFR3 p.K650M; FGFR3 p.P250R; FGFR3 p.A391E; FGFR3 p.K650T; FGFR3 p.T264M; FGFR3 p.M528I; FGFR3 p.K650N; FGFR3 p.G370C; FGFR3 p.N540D; FGFR3 p.R669Q; FGFR3 p.S371C; FGFR3 p.N540S; FGFR3 p.G697C; FGFR3 p.Y373C; or FGFR3 p.N540K.

[0066] In other embodiments, the mutation is any one or more of the following: FGFR3 p.V553M; FGFR3 p.V555M; or FGFR3 p.V555L.

[0067] In other embodiments, the activating FGFR3 gene alteration is a fusion gene mutation. As used in this context, a “fusion” is a gene that results from the joining of two previously independent genes.

[0068] In some embodiments, the fusion is an FGFR3 rearrangement with an intact FGFR3 kinase domain and: Breakpoint in intron 17 or exon 18 of FGFR3 and a known partner gene (e.g., TACC3, BAIAP2L1); Breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene; or Breakpoint in intron 17 or exon 18 of FGFR3 and an intra-genic region or out-of-frame partner gene. - 10 - 4901-4937-2950.1

[0069] In some embodiments of the disclosed methods, the cancer is metastatic urothelial cancer.

[0070] In some embodiments, the subject has not received any prior chemotherapy for the cancer.

[0071] In some embodiments, the subject has experienced disease progression during or following a previous chemotherapy regimen.

[0072] In some embodiments, the subject is not eligible for any platinum-containing chemotherapy.

[0073] In some embodiments, the subject has experienced disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

[0074] In some embodiments, the subject has Bacillus Calmette-Guerin (BCG)- unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors and is ineligible for or has elected not to undergo cystectomy.

[0075] In some embodiments, the subject has urothelial carcinoma and is at high risk of recurrence after undergoing radical resection of urothelial carcinoma.

[0076] In some embodiments, the subject has locally advanced or metastatic urothelial carcinoma and has disease progression during or following platinum-containing chemotherapy.

[0077] In some embodiments, the subject has locally advanced or metastatic urothelial carcinoma and has disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

[0078] In some embodiments, the subject is ineligible for treatment of the cancer with any one or more of cisplatin or carboplatin. The subject can be ineligible for treatment of the cancer with cisplatin. The subject can be ineligible for treatment of the cancer with carboplatin.

[0079] In some embodiments, the subject has not been previously treated for the cancer.

[0080] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in combination with a nectin-4 targeting agent drug conjugate in an amount of 10 mg – 1500 mg per day, such as, for example, one of 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 - 11 - 4901-4937-2950.1mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, 250 mg / day, 255 mg / day, 260 mg / day, 265 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395 mg / day, 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day, 470 mg / day, 475 mg / day, 480 mg / day, 485 mg / day, 490 mg / day, 495 mg / day, 500 mg / day, 550 mg / day, 600 mg / day, 650 mg / day, 700 mg / day, 750 mg / day, 800 mg / day, 850 mg / day, 900 mg / day, 950 mg / day, 1000 mg / day, 1050 mg / day, 1150 mg / day, 1200 mg / day, 1250 mg / day, 1300 mg / day, 1350 mg / day, 1400 mg / day, 1450 mg / day, or 1500 mg / day. When the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt that is administered is based on the compound of Formula (I). That is, the amount of the salt that is administered is an amount that contains the specified amount of Formula (I) free base.

[0081] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in combination with a nectin-4 targeting agent drug conjugate, in an amount of 10 mg – 500 mg per day, such as, for example, one of 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, 200 mg / day, 205 mg / day, 210 mg / day, 215 mg / day, 220 mg / day, 225 mg / day, 230 mg / day, 235 mg / day, 240 mg / day, 245 mg / day, 250 mg / day, 255 mg / day, 260 mg / day, 265 mg / day, 270 mg / day, 275 mg / day, 280 mg / day, 285 mg / day, 290 mg / day, 295 mg / day, 300 mg / day, 305 mg / day, 310 mg / day, 315 mg / day, 320 mg / day, 325 mg / day, 330 mg / day, 335 mg / day, 340 mg / day, 345 mg / day, 350 mg / day, 355 mg / day, 360 - 12 - 4901-4937-2950.1mg / day, 365 mg / day, 370 mg / day, 375 mg / day, 380 mg / day, 385 mg / day, 390 mg / day, 395 mg / day, 400 mg / day, 405 mg / day, 410 mg / day, 415 mg / day, 420 mg / day, 425 mg / day, 430 mg / day, 435 mg / day, 440 mg / day, 445 mg / day, 450 mg / day, 455 mg / day, 460 mg / day, 465 mg / day, 470 mg / day, 475 mg / day, 480 mg / day, 485 mg / day, 490 mg / day, 495 mg / day, or 500 mg / day. When the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt that is administered is based on the compound of Formula (I). That is, the amount of the salt that is administered is an amount that contains the specified amount of Formula (I) free base.

[0082] In other embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in combination with a nectin-4 targeting agent drug conjugate, in an amount of 10 mg – 200 mg per day, such as, for example, one of 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, 120 mg / day, 125 mg / day, 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 195 mg / day, or 200 mg / day. When the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt that is administered is based on the compound of Formula (I). That is, the amount of the salt that is administered is an amount that contains the specified amount of Formula (I) free base.

[0083] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in combination with a nectin-4 targeting agent drug conjugate, in an amount of 10 mg – 120 mg per day, such as, for example, one of 10 mg / day, 15 mg / day, 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 45 mg / day, 50 mg / day, 55 mg / day, 60 mg / day, 65 mg / day, 70 mg / day, 75 mg / day, 80 mg / day, 85 mg / day, 90 mg / day, 95 mg / day, 100 mg / day, 105 mg / day, 110 mg / day, 115 mg / day, or 120 mg / day. When the compound of Formula (I) is administered as a pharmaceutically acceptable salt, the amount of the salt that is administered is based on the compound of Formula (I). That is, the amount of the salt that is administered is an amount that contains the specified amount of Formula (I) free base.

[0084] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt - 13 - 4901-4937-2950.1of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 10 mg per day.

[0085] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 20 mg per day.

[0086] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 25 mg per day.

[0087] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 30 mg per day.

[0088] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 40 mg per day.

[0089] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 50 mg per day.

[0090] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 60 mg per day.

[0091] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 75 mg per day.

[0092] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 80 mg per day. - 14 - 4901-4937-2950.1

[0093] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 90 mg per day.

[0094] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 100 mg per day.

[0095] In some embodiments of the disclosed methods, the treatment regimen comprises administering the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, in an amount of 120 mg per day.

[0096] In some embodiments of the methods of the disclosure, the daily administered amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, is administered in a single dose.

[0097] In other embodiments of the methods of the disclosure, the daily administered amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, is administered in divided doses.

[0098] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), with the nectin-4 targeting agent drug conjugate, is administered daily.

[0099] In some embodiments of the methods of the disclosure, the daily administered amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, is given in multiple doses, wherein each of the multiple doses contains a portion of the total daily amount.

[0100] In some embodiments, the daily administered amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), with the nectin-4 targeting agent drug conjugate, is given in two doses, wherein each of the two doses contains a portion of the total daily amount.

[0101] In some embodiments, the daily administered amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a - 15 - 4901-4937-2950.1Formula (I) basis), with the nectin-4 targeting agent drug conjugate, is given in two doses, wherein each of the two doses contains one half of the total daily amount.

[0102] In the methods of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), with the nectin-4 targeting agent drug conjugate, may be administered in any suitable pharmaceutical dosage form. The pharmaceutical dosage form is typically formulated to provide a therapeutically effective amount of a compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), as the active ingredient. In some embodiments, the pharmaceutical dosage form also contains one or more pharmaceutically acceptable excipients.

[0103] In some embodiments of the disclosure, the treatment regimen is administered for at least 28 days.

[0104] In other embodiments of the disclosure, treatment regimen is administered for 28 days.

[0105] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of disease progression, toxicity, or death.

[0106] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of disease progression.

[0107] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of toxicity.

[0108] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of death.

[0109] In some embodiments of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), with the nectin-4 targeting agent drug conjugate, is administered for at least 28 days.

[0110] In other embodiments of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), with the nectin-4 targeting agent drug conjugate, is administered for 28 days.

[0111] In other embodiments of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), with the nectin-4 targeting agent drug conjugate, is administered until the occurrence of disease progression, toxicity, or death.

[0112] In some aspects of the methods of the disclosure, the cancer exhibits a complete response (CR) or a partial response (PR) to the administration of the treatment - 16 - 4901-4937-2950.1regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0113] In some embodiments, the cancer exhibits a complete response (CR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0114] In other embodiments, the cancer exhibits a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0115] In some aspects of the methods of the disclosure, the cancer exhibits a response to the administration of the treatment regimen as evaluated by reduction in circulating tumor DNA in the subject’s plasma. Example 1

[0116] The compound of Formula (I) was tested in vivo in combination with Anti- Nectin-4 (enfortumab)-mc-val-cit-PABC-MMAE ADC (AGS-22ME) (Creative Biolabs CAT#: ADC-L004) in the RT112 / 84 xenograft mouse model (see FIG.1). RT112 / 84 is a human bladder carcinoma cell line driven by an FGFR3::TACC3 fusion. Enfortumab vedotin is an antibody-drug conjugate that is approved by the U.S. Food & Drug Administration for the treatment of cancer expressing Nectin-4, including bladder cancer, in adult patients who have previously received a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy. Enfortumab vedotin is a conjugate of a Nectin-4 directed antibody and a microtubule inhibitor. In particular, enfortumab vedotin is a Nectin-4 directed antibody-drug conjugate (ADC) comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody conjugated to monomethyl auristatin E (MMAE), which is a small microtubule disrupting agent. Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody. Enfortumab vedotin is also referred to as “AGS-22ME,” “enfotumab vedotin-ejfv,” and “PADCEV.”

[0117] As shown in FIG.2 and FIG.3, Formula (I) and AGS-22ME both caused tumor regression when dosed as single agents. When dosed in combination, Formula (I) plus AGS-22ME also resulted in tumor regression. The treatment combination did not cause any loss of bodyweight in the study (FIG.4). Notably, the treatment combination resulted in complete regression of 40% of the tumors after 21 days of treatment, while Formula (I) alone and AGS-22ME alone each resulted in complete regression of 10% of the tumors (FIG.5). - 17 - 4901-4937-2950.1The percent tumor regression and percent regression for each treatment are shown in TABLE 1.

[0118] These data indicate that co-administration of the FGFR3 inhibitor Formula (I) with AGS-22ME results in an unexpected enhanced anti-tumor response. TABLE 1 Compound % Tumor Growth Inhibition % Regression (Dose) (D.17, 1-T / C) (D.21, ∆T / T0) Erdafitinib 95% 66% (12.5 mg / kg, BID) Formula (I) 91% 33% (18 mg / kg, QD) AGS-22ME 97% 81% (3 mg / kg, QD) Erdafitinib + AGS-22ME 98% 89% Formula (I) + AGS-22ME 98% 90% - 18 - 4901-4937-2950.1

Claims

What is claimed:

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a treatment regimen comprising: (a) a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof; and (b) a nectin-4 targeting agent-drug conjugate.

2. The method of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the nectin-4 targeting agent-drug conjugate are administered concurrently or sequentially.

3. The method of claim 1 or claim 2, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the nectin-4 targeting agent-drug conjugate are administered concurrently.

4. The method of any one of claims 1-3, wherein the nectin-4 targeting agent of the nectin-4 targeting agent-drug conjugate is a monoclonal antibody, or an antigen binding fragment thereof.

5. The method of any one of claims 1-4, wherein the nectin-4 targeting agent- drug conjugate is an antibody-drug conjugate.

6. The method of claim 5, wherein the antibody-drug conjugate is an antibody- monomethyl auristatin E (MMAE) conjugate. - 19 - 4901-4937-2950.

17. The method of claim 5 or claim 6, wherein the antibody-drug conjugate is enfortumab vedotin.

8. The method of claim 7, wherein the enfortumab vedotin is intravenously administered to the subject in a dose of 1.25 mg / kg.

9. The method of claim 8, wherein the dose of enfortumab vedotin is administered over 30 minutes on Days 1, 8, and 15 of a 28-day cycle.

10. The method of any one of the preceding claims, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 10 mg – 500 mg per day.

11. The method of claim 10, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 10 mg per day.

12. The method of claim 10, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 20 mg per day.

13. The method of claim 10, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 40 mg per day.

14. The method of claim 10, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 60 mg per day.

15. The method of claim 10, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 90 mg per day. - 20 - 4901-4937-2950.

116. The method of claim 10, wherein the subject is administered the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), in an amount of 120 mg per day.

17. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered orally.

18. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered daily to the subject as a single dose.

19. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered daily to the subject in divided doses.

20. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered daily.

21. The method of any one of the preceding claims, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered for at least 28 days.

22. The method of claim 21, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered for 28 days.

23. The method of any one of the preceding claims, wherein the subject is administered a compound of Formula (I).

24. The method of any one of claims 1 to 22, wherein the subject is administered a pharmaceutically acceptable salt of a compound of Formula (I). - 21 - 4901-4937-2950.

125. The method of claim 24, wherein the pharmaceutically acceptable salt of a compound of Formula (I) is the besylate salt.

26. The method of any one of the preceding claims, wherein the cancer has an activating FGFR3 gene alteration.

27. The method of any one of the preceding claims, wherein the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, bladder cancer, gastric cancer, esophageal cancer, or pancreatic cancer.

28. The method of any one of the preceding claims, wherein the cancer is a locally advanced solid tumor.

29. The method of any one of claims 1 to 27, wherein the cancer is a metastatic solid tumor.

30. The method of any one of claims 27 to 29, wherein the activating FGFR3 gene alteration is a mutation.

31. The method of claim 30, wherein the mutation is or comprises one or more of FGFR3 p.S84L; FGFR3 p.G380R; FGFR3 p.R621H; FGFR3 p.R248C; FGFR3 p.G380E; FGFR3 p.K650E; FGFR3 p.S249C; FGFR3 p.A391V; FGFR3 p.K650M; FGFR3 p.P250R; FGFR3 p.A391E; FGFR3 p.K650T; FGFR3 p.T264M; FGFR3 p.M528I; - 22 - 4901-4937-2950.1FGFR3 p.K650N; FGFR3 p.G370C; FGFR3 p.N540D; FGFR3 p.R669Q; FGFR3 p.S371C; FGFR3 p.N540S; FGFR3 p.G697C; FGFR3 p.Y373C; or FGFR3 p.N540K.

32. The method of claim 30, wherein the mutation is or comprises one or more of FGFR3 p.V553M; FGFR3 p.V555M; or FGFR3 p.V555L.

33. The method of any one of claims 26 to 29, wherein the activating FGFR3 gene alteration is a fusion.

34. The method of claim 33, wherein the fusion is an FGFR3 rearrangements with an intact FGFR3 kinase domain and: Breakpoint in intron 17 or exon 18 of FGFR3 and a known partner gene (e.g., TACC3, BAIAP2L1); Breakpoint in intron 17 or exon 18 of FGFR3 and an in-frame novel partner gene; or Breakpoint in intron 17 or exon 18 of FGFR3 and an intra-genic region or out-of- frame partner gene.

35. The method of any one of claims 26 to 34, wherein the cancer is metastatic urothelial cancer.

36. The method of claim 35, wherein the subject is ineligible for treatment of the cancer with cisplatin or carboplatin.

37. The method of any one of claims 35 to 36, wherein the subject has not been previously treated for the cancer. - 23 - 4901-4937-2950.

138. The method of any one of the preceding claims, wherein the cancer exhibits a complete response (CR) or a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

39. The method of claim 38, wherein the cancer exhibits a complete response (CR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

40. The method of claim 38, wherein the cancer exhibits a partial response (PR) to the administration of the treatment regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. - 24 - 4901-4937-2950.1

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