Combination treatment comprising a FGFR3 inhibitor and a PD-1 / PD-l1 inhibitor 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): Formula (I), or a pharmaceutically acceptable salt thereof, and a PD-1 or PD-L1 antagonist.

Description

COMBINATION TREATMENT REGIMENS CROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of United State Provisional Application No. 63 / 673,215, filed July 19, 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 PD-1 or PD-L1 antagonist. 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] Programmed cell death protein 1 (PD-1) is a checkpoint protein expressed on the surface of T cells. PD-1 plays an important role in immune regulation and the maintenance of peripheral tolerance, by inhibiting T cell proliferation and cytokine production. Upregulation of PD-1 and its ligands (PD-L1 and PD-L2) occurs in some tumors and signaling through this pathway can contribute to inhibition of active T cell immune surveillance of tumors. Antigen binding proteins and antibodies that block the interaction between PD-1 and its ligands may release PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. Immune checkpoint therapies targeting PD-1 (or PD-L1) have resulted in groundbreaking improvements in clinical response in multiple human cancer types (Brahmer et al., N Engl J Med, 366: 2455-2465 (2012); Garon et al., N Engl J Med, 372:2018-2028 (2015); Hamid et al., N Engl J Med, 369:134-144 (2013); Robert et al., Lancet, 384:1109-1117 (2014); Robert et al., N Engl J Med, 372: 2521-2532 (2015); Robert et al., N Engl J Med, 372:320-330 (2015); Topalian et al., N Engl J Med, 366:2443-2454 (2012); Topalian et al., J Clin Oncol, 32: 1020-1030 (2014); Wolchok et al., N Engl J Med, 369:122-133 (2013)).120039.000198 (TYRA.039PCT)

[0005] Immune therapies targeting the PD-1 axis include monoclonal antibodies directed to the PD-1 receptor (e.g, KEYTRUDA® (pembrolizumab), Merck and Co., Inc., Kenilworth, NJ; OPDIVO® (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ) and those that bind to the PD-L1 ligand (e.g, TECENTRIQ® (atezolizumab), Genentech, San Francisco, CA).

[0006] Though there have been many recent advances in the treatment of cancer, there remains a need for more effective treatment options to enhance the depth and duration of responses. Several patents have been filed describing the use of combination targeted therapy plus immunotherapy in cancer (WO202301875, WO2020160365, WO2017205216, WO2021086909). Importantly, clinical studies in several cancer types have demonstrated that the combination of a targeted therapy with a PD-1 or PD-L1 antagonist can enhance responses, such as the combination of erdafitinib with a PD-1 antagonist in bladder cancer (Siefker-Radtke et al., ASCO 2023). The combination and methods herein that relate to combining an FGFR3 inhibitor with a PD-1 antagonist for enhancing anti-tumor immunity address this need. SUMMARY

[0007] 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 PD-1 or PD-L1 antagonist.

[0008] In some aspects, the cancer has an activating FGFR3 gene alteration.120039.000198 (TYRA.039PCT) BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1A shows that the combination Formula I plus anti-PD-1 enhances tumor growth inhibition. See Example 1. Tumor growth curves are shown as mean tumor volume by group (n=8-10 per group). Error bars represent the standard error of the mean. The grey arrows indicates the start of treatment.

[0010] Figure 1B shows that the combination Formula I plus anti-PD-1 enhances tumor growth inhibition. See Example 1. Tumor growth curves are shown as mean tumor volume as individual mice. Error bars represent the standard error of the mean. The grey arrows indicates the start of treatment. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0011] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed 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.

[0012] 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.

[0013] 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.120039.000198 (TYRA.039PCT) 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- C7alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0014] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. It is understood that, in any compound described herein having one or more chiral centers, all possible diastereomers are also envisioned. It is understood that, in any compound described herein all tautomers are envisioned. 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-14, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0015] 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 a120039.000198 (TYRA.039PCT) vehicle, carrier, or diluent to facilitate administration of a compound of Formula (I) and that is compatible therewith.

[0016] As used herein, the term “subject” shall be given its ordinary meaning and shall also refer to an organism that has FGFR proteins. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, rodents (e.g., mice, rats), and the like. The term “mammal” includes both human and non-human mammals.

[0017] The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer 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. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, 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.

[0018] 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 the PD-1 or PD-L1 antagonist such that Formula (I) (or pharmaceutically acceptable salt thereof) and the PD-1 or PD-L1 antagonist 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 the PD-1 or PD-L1 antagonist; and sequential administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and the PD-1 or PD-L1 antagonist. Moreover, the treatment regimen encompasses administration of the compound of Formula (I) (or a pharmaceutically acceptable salt thereof) and the PD-1 or PD-L1 antagonist on the same day; on different days; and any permutation thereof.

[0019] 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. For example, therapeutic agents may be introduced into a subject’s body orally,120039.000198 (TYRA.039PCT) nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.

[0020] 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.

[0021] 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 that the FGFR kinase that is encoded by the wild-type FGFR3 gene.

[0022] As used herein, the term “PD-1 antagonist” refers to any chemical compound (including biological molecules such as antibodies) that blocks, inhibits, or otherwise interferes with binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1. Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7- DC, Btdc and CD273 for PD-L2. PD-1 antagonists useful in any of the treatment methods of the disclosure include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1. Other PD-1 antagonists useful in any of the treatment method, medicaments and uses of the present invention include an immunoadhesin that specifically binds to PD-1 or PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO2010 / 027827 and WO2011 / 066342.

[0023] As used herein, the term “PD-L1 antagonist” refers to any chemical compound (including biological molecules) that binds to PD-L1 and thereby prevents its binding to PD-1.120039.000198 (TYRA.039PCT)

[0024] 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 antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies, and camelized single domain antibodies.

[0025] 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.

[0026] As used herein, unless otherwise indicated, “antibody fragment” or “antigen binding fragment of an antibody” refers to antibody fragments that retain the ability to bind specifically to the antigen to which the full-length antibody binds.

[0027] 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 PD-1 or PD-L1 antagonist.

[0028] In some embodiments, the treatment regimen comprises the compound of Formula (I) and the PD-1 or PD-L1 antagonist. A method of making the compound of Formula (I) is set forth in WO2025 / 129014.

[0029] In some embodiments, the treatment regimen comprises a pharmaceutically acceptable salt of a compound of Formula (I) and the PD-1 or PD-L1 antagonist. In some120039.000198 (TYRA.039PCT) 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.

[0030] In some embodiments, the treatment regimen comprises the besylate salt of a compound of Formula (I) and the PD-1 or PD-L1 antagonist.

[0031] In some embodiments, the treatment regimen comprises the freebase of a compound of Formula (I) and the PD-1 or PD-L1 antagonist.

[0032] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the PD-1 or PD-L1 antagonist are administered concurrently or sequentially.

[0033] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the PD-1 or PD-L1 antagonist are administered concurrently.

[0034] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the PD-1 or PD-L1 antagonist are administered sequentially.

[0035] In some aspects of the disclosure, the treatment regimen comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a PD-1 antagonist.

[0036] In some embodiments, the PD-1 antagonist is an antibody.

[0037] In some embodiments, the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof.

[0038] In some embodiments, the PD-1 antagonist is administered intravenously. In other embodiments, the PD-1 antagonist is administered subcutaneously.

[0039] In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody.

[0040] In some embodiments, the PD-1 antagonist is pembrolizumab, nivolumab, MEDI0680, or pidilizumab.

[0041] In some embodiments, the PD-1 antagonist is pembrolizumab. Pembrolizumab is marketed in the United States under the trade name Keytruda®(pembrolizumab).

[0042] In some embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is administered in accordance with the January 2024 Revision of the Keytruda®(pembrolizumab) prescribing information, the entirety of which is incorporated by reference herein.120039.000198 (TYRA.039PCT)

[0043] In some embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is intravenously administered to the subject.

[0044] In some embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is intravenously administered to the subject in a dose of 200 mg every 3 weeks, or 400 mg every 6 weeks.

[0045] In some embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is intravenously administered to the subject in a dose of 200 mg every 3 weeks.

[0046] In other embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is intravenously administered to the subject in a dose of 400 mg every 6 weeks.

[0047] In some embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is subcutaneously administered to the subject.

[0048] In some embodiments in which the treatment regimen comprises pembrolizumab, the pembrolizumab is subcutaneously administered to the subject in a dose of 285 mg every 3 weeks.

[0049] In some embodiments, the PD-1 antagonist is nivolumab. Nivolumab is marketed in the United States under the trade name Opdivo® (nivolumab).

[0050] In some embodiments in which the treatment regimen comprises nivolumab, the nivolumab is administered in accordance with the March 2024 Revision of the Opdivo® (nivolumab) prescribing information, the entirety of which is incorporated by reference herein.

[0051] In some embodiments in which the treatment regimen comprises nivolumab, the nivolumab is intravenously administered to the subject.

[0052] In some embodiments in which the treatment regimen comprises nivolumab, the nivolumab is intravenously administered to the subject in a dose of 240 mg every 2 weeks, or 480 mg every 4 weeks.

[0053] In some embodiments in which the treatment regimen comprises nivolumab, the nivolumab is intravenously administered to the subject in a dose of 240 mg every 2 weeks.

[0054] In some embodiments in which the treatment regimen comprises nivolumab, the nivolumab is intravenously administered to the subject in a dose of 480 mg every 4 weeks.120039.000198 (TYRA.039PCT)

[0055] In some embodiments in which the treatment regimen comprises nivolumab, the nivolumab is subcutaneously administered to the subject.

[0056] In some aspects of the disclosure, the treatment regimen comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a PD-L1 antagonist.

[0057] In some embodiments, the PD-L1 antagonist is an antibody.

[0058] In some embodiments, the PD-L1 antagonist is monoclonal antibody, or an antigen binding fragment thereof.

[0059] In some embodiments, the PD-L1 antagonist is BMS-936559, durvalumab, atezolizumab, or avelumab.

[0060] In some embodiments, the PD-L1 antagonist is BMS-936559.

[0061] In some embodiments, the PD-L1 antagonist is durvalumab. Durvalumab is marketed in the United States under the trade name Imfinzi® (durvalumab).

[0062] In some embodiments in which the treatment regimen comprises durvalumab, the durvalumab is administered in accordance with the April 2024 Revision of the Imfinzi®(durvalumab) prescribing information, the entirety of which is incorporated by reference herein.

[0063] In some embodiments in which the treatment regimen comprises durvalumab, the durvalumab is intravenously administered to the subject.

[0064] In other embodiments in which the treatment regimen comprises durvalumab, the durvalumab is subcutaneously administered to the subject.

[0065] In some embodiments, the PD-L1 antagonist is atezolizumab. Atezolizumab is marketed in the United States under the trade name Tecentriq® (atezolizumab).

[0066] In some embodiments in which the treatment regimen comprises atezolizumab, the atezolizumab is administered in accordance with the April 2023 and April 2024 Revisions of the Tecentriq® (atezolizumab) prescribing information, the entirety of which is incorporated by reference herein.

[0067] In some embodiments in which the treatment regimen comprises atezolizumab, the atezolizumab is intravenously administered to the subject.

[0068] In other embodiments in which the treatment regimen comprises atezolizumab, the atezolizumab is subcutaneously administered to the subject.

[0069] In some embodiments, the PD-L1 antagonist is avelumab. avelumab is marketed in the United States under the trade name Bavencio®(avelumab).120039.000198 (TYRA.039PCT)

[0070] In some embodiments in which the treatment regimen comprises avelumab, the avelumab is administered in accordance with the September 2023 and March 2024 Revisions of the Bavencio® (avelumab) prescribing information, the entirety of which is incorporated by reference herein.

[0071] In some embodiments in which the treatment regimen comprises avelumab, the avelumab is intravenously administered to the subject.

[0072] In some embodiments in which the treatment regimen comprises avelumab, the avelumab is intravenously administered to the subject in a dose of 800 mg every 2 weeks.

[0073] In some embodiments in which the treatment regimen comprises avelumab, the avelumab is subcutaneously administered to the subject.

[0074] In some aspects of the disclosed methods, the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

[0075] In some embodiments, the cancer is urothelial cancer.

[0076] In other embodiments, the cancer is urothelial carcinoma.

[0077] In other me embodiments, the cancer is breast cancer.

[0078] In other embodiments, the cancer is endometrial cancer.

[0079] In other embodiments, the cancer is lung cancer.

[0080] In other embodiments, the cancer is ovarian cancer.

[0081] In other embodiments, the cancer is bladder cancer.

[0082] In some embodiments, the cancer is non-muscle invasive bladder cancer (NMIBC).

[0083] In other embodiments, the cancer is a locally advanced solid tumor.

[0084] In other embodiments, the cancer is a metastatic solid tumor.

[0085] In some aspects of the disclosed methods, the cancer has an activating FGFR3 gene alteration.

[0086] 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.

[0087] In some embodiments, the mutation is any one or more of the following: FGFR3 p.S84L; FGFR3 p.G380R;120039.000198 (TYRA.039PCT) 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; 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.

[0088] In other embodiments, the mutation is any one or more of the following: FGFR3 p.V553M; FGFR3 p.V555M; or FGFR3 p.V555L.

[0089] 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.

[0090] 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);120039.000198 (TYRA.039PCT) 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.

[0091] In some embodiments of the disclosed methods, the cancer is metastatic urothelial cancer.

[0092] In some embodiments, the subject has not received any prior chemotherapy for the cancer.

[0093] In some embodiments, the subject has experienced disease progression during or following a previous chemotherapy regimen.

[0094] In some embodiments, the subject is not eligible for any platinum-containing chemotherapy.

[0095] 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.

[0096] In some embodiments, the subject has experienced disease progression during or following a previous PD-1 antagonist-containing regimen or a previous PD-L1 antagonist- containing regimen.

[0097] 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.

[0098] In some embodiments, the subject has urothelial carcinoma and is at high risk of recurrence after undergoing radical resection of urothelial carcinoma.

[0099] In some embodiments, the subject has locally advanced or metastatic urothelial carcinoma and has disease progression during or following platinum-containing chemotherapy.

[0100] 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.

[0101] In some embodiments, the subject is ineligible for treatment of the cancer with any one or more of cisplatin, carboplatin, enfortumab vedotin, or sacituzumab govitecan.120039.000198 (TYRA.039PCT)

[0102] In some embodiments, the subject is ineligible for treatment of the cancer with any one or more of cisplatin, carboplatin, or enfortumab vedotin.

[0103] In some embodiments, the subject has not been previously treated for the cancer.

[0104] In some embodiments of the disclosed methods, the treatment regimen comprises 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 – 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 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 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.

[0105] In some embodiments of the disclosed methods, the treatment regimen comprises 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 per120039.000198 (TYRA.039PCT) 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 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, 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.

[0106] In other embodiments of the disclosed methods, the treatment regimen comprises 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 – 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.120039.000198 (TYRA.039PCT)

[0107] In some embodiments of the disclosed methods, the treatment regimen comprises 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 – 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.

[0108] In some embodiments of the disclosed methods, the treatment regimen comprises 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.

[0109] In some embodiments of the disclosed methods, the treatment regimen comprises 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.

[0110] In some embodiments of the disclosed methods, the treatment regimen comprises 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 25 mg per day.

[0111] In some embodiments of the disclosed methods, the treatment regimen comprises 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 30 mg per day.

[0112] In some embodiments of the disclosed methods, the treatment regimen comprises 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.

[0113] In some embodiments of the disclosed methods, the treatment regimen comprises 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 50 mg per day.

[0114] In some embodiments of the disclosed methods, the treatment regimen comprises 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.120039.000198 (TYRA.039PCT)

[0115] In some embodiments of the disclosed methods, the treatment regimen comprises 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 75 mg per day.

[0116] In some embodiments of the disclosed methods, the treatment regimen comprises 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 80 mg per day.

[0117] In some embodiments of the disclosed methods, the treatment regimen comprises 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.

[0118] In some embodiments of the disclosed methods, the treatment regimen comprises 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 100 mg per day.

[0119] In some embodiments of the disclosed methods, the treatment regimen comprises 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.

[0120] In some embodiments of the methods of the disclosure, the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in a single dose.

[0121] In other embodiments of the methods of the disclosure, the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is administered in divided doses.

[0122] In some embodiments of the methods of the disclosure, the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is given in multiple doses, wherein each of the multiple doses contains a portion of the total daily amount.

[0123] In some embodiments, the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is given in two doses, wherein each of the two doses contains a portion of the total daily amount.

[0124] In some embodiments, the daily amount of the compound of Formula (I), or a pharmaceutically acceptable salt of a compound of Formula (I) (on a Formula (I) basis), is120039.000198 (TYRA.039PCT) given in two doses, wherein each of the two doses contains one half of the total daily amount.

[0125] In the methods of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), may be administered by any suitable route of administration, such as, for example, orally, nasally, subcutaneously, intravenously, intravesically, intramuscularly, transdermally, vaginally, rectally or in any combination thereof.

[0126] In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered orally.

[0127] In the methods of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), may be administered in any suitable pharmaceutical dosage form. Suitable dosage forms include, but are not limited to capsules, tablets, powders, suspensions, solutions, and the like. 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.

[0128] In some embodiments of the disclosure, the treatment regimen is administered for at least 21 days.

[0129] In other embodiments of the disclosure, treatment regimen is administered for 21 days.

[0130] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of disease progression, toxicity, or death.

[0131] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of disease progression.

[0132] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of toxicity.

[0133] In other embodiments of the disclosure, the treatment regimen is administered until the occurrence of death.

[0134] In some embodiments of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered for at least 21 days.120039.000198 (TYRA.039PCT)

[0135] In other embodiments of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered for 21 days.

[0136] In other embodiments of the disclosure, the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered until the occurrence of disease progression, toxicity, or death.

[0137] 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 regimen, as evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

[0138] 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.

[0139] 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.

[0140] 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

[0141] The compound of Formula (I) was tested in combination with a mouse PD-1 antagonist (anti-PD-1; Bio X Cell InVivoMab anti-mouse PD-1 (CD279), Clone: RMP1- 14; Fisher Scientific catalog number: 50-562-454) in the MB49 syngeneic mouse model. MB49 is a mouse bladder carcinoma cell line. Specifically, C57BL / 6 mice were injected subcutaneously in the flank with the mouse bladder carcinoma cell line MB49. Starting on day 4 after inoculation, the mice were randomized into groups of ~80 mm3and were dosed with vehicle, Formula (I) (18 mg / kg QD PO), anti-PD-1 (10 mg / kg twice per week IP), or combination Formula (I) (18 mg / kg QD PO) plus anti-PD-1 (10 mg / kg twice per week IP) for up to 21 days. Tumor growth curves are shown in Figs.1A and 1B as mean tumor volume by group (n=8-10 per group) (Fig.1A) and as individual mice (Fig.1B). Error bars represent the standard error of the mean. The grey arrows in Figs.1A and 1B indicate the start of treatment.120039.000198 (TYRA.039PCT)

[0142] As shown in Figs.1A and 1B, Formula (I) and anti-PD-1 have a slight effect on the tumor growth when dosed alone. However, when dosed in combination, Formula (I) plus anti-PD-1 results in enhanced tumor growth inhibition. The difference in average tumor volume between Formula (I) single agent treatment group versus the Formula (I) plus anti-PD-1 combination treatment group was statistically significant on Days 17 and 19 of the study (p<0.05). These data indicate that administering a treatment regimen comprising Formula (I) and a PD-1 antagonist results in an unexpected enhanced anti- tumor response to therapy.

Claims

120039.000198 (TYRA.039PCT) 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 PD-1 or PD-L1 antagonist.

2. The method of claim 1, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the PD-1 or PD-L1 antagonist are administered concurrently or sequentially.

3. The method of claim 1 or claim 2, wherein the treatment regimen comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a PD-1 antagonist.

4. The method of claim 3, wherein the PD-1 antagonist is a monoclonal antibody, or an antigen binding fragment thereof.

5. The method of claim 4, wherein the PD-1 antagonist is an anti-PD-1 antibody.

6. The method of any one of claims 3 to 5, wherein the PD-1 antagonist is pembrolizumab, nivolumab, MEDI0680, or pidilizumab.120039.000198 (TYRA.039PCT) 7. The method of any one of claims 3 to 6, wherein the PD-1 antagonist is pembrolizumab.

8. The method of claim 7, wherein the pembrolizumab is intravenously administered to the subject in a dose of 200 mg every 3 weeks, or 400 mg every 6 weeks.

9. The method of any one of claims 3 to 6, wherein the PD-1 antagonist is nivolumab.

10. The method of claim 9, wherein the nivolumab is intravenously administered to the subject in a dose of 240 mg every 2 weeks, or 480 mg every 4 weeks.

11. The method of claim 1, wherein the treatment regimen comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a PD-L1 antagonist.

12. The method of claim 11, wherein the PD-L1 antagonist is BMS-936559, durvalumab, atezolizumab, or avelumab.

13. 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.

14. The method of claim 13, 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.

15. The method of claim 13, 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.120039.000198 (TYRA.039PCT) 16. The method of claim 13, 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.

17. The method of claim 13, 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.

18. The method of claim 13, 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.

19. The method of claim 13, 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.

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 orally.

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 daily to the subject as a single dose.

22. 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.

23. 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.120039.000198 (TYRA.039PCT) 24. 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 21 days.

25. The method of claim 24, wherein the compound of Formula (I), or pharmaceutically acceptable salt of a compound of Formula (I), is administered for 21 days.

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

27. The method of any one of claims 1 to 25, wherein the subject is administered a pharmaceutically acceptable salt of a compound of Formula (I).

28. The method of any one of claims 1 to 27, wherein the cancer has an activating FGFR3 gene alteration.

29. The method of any one of claims 1 to 28, wherein the cancer is urothelial cancer, breast cancer, endometrial cancer, lung cancer, ovarian cancer, or bladder cancer.

30. The method of any one of claims 1 to 29, wherein the cancer is a locally advanced solid tumor.

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

32. The method of any one of claims 28 to 31, wherein the activating FGFR3 gene alteration is a mutation.

33. The method of claim 32, wherein the mutation is or comprises one or more of FGFR3 p.S84L; FGFR3 p.G380R;120039.000198 (TYRA.039PCT) 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; 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.

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

35. The method of any one of claims 28 to 31, wherein the activating FGFR3 gene alteration is a fusion.

36. The method of claim 35, wherein the fusion is an FGFR3 rearrangements with an intact FGFR3 kinase domain and:120039.000198 (TYRA.039PCT) 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.

37. The method of any one of claims 28 to 36, wherein the cancer is metastatic urothelial cancer.

38. The method of claim 37, wherein the subject is ineligible for treatment of the cancer with any one or more of cisplatin, carboplatin, enfortumab vedotin, or sacituzumab govitecan.

39. The method of any one of claims 37 to 38, wherein the subject has not been previously treated for the cancer.

40. The method of any one of claims 1 to 39, 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.

41. The method of claim 40, 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.

42. The method of claim 40, 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.

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