Methods of treating cancer using futibatinib, pembrolizumab and at least one additional chemotherapeutic agent

Abstract

The present disclosure relates to methods of treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.

Description

155792.599942 METHODS OF TREATING CANCER USING FUTIBATINIB AND PEMBROLIZUMAB CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of International Application No. PCT / IB2023 / 058633 filed August 31, 2023, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0002] The disclosure relates to methods of treating a cancer with futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. BACKGROUND OF THE INVENTION

[0003] Despite the huge advances in cancer therapies in recent years, cancer is the second leading cause of death globally, accounting for 9.6 million deaths in 2018, with the most common fatal cancers being lung, colorectal, stomach, liver, and breast cancer. Although cancer incidence was 18.1 million in 2018, it is estimated to increase to 29.5 million by 2040.

[0004] The fibroblast growth factor / fibroblast growth factor receptor (FGF / FGFR) signaling axis has been characterized for its role in the proliferation, differentiation, migration, and survival of cells, and it is fundamental to embryonic development, angiogenesis regulation, and wound healing in adults. Accordingly, the dysregulation of this signaling pathway has been associated with many developmental disorders and cancer.

[0005] Fibroblast growth factors (FGFs) are expressed in various tissues and are one of the growth factors that regulate cell proliferation and differentiation. The physiological activity of the FGFs is mediated by fibroblast growth factor receptors (FGFRs), which are specific cell surface receptors. FGFRs belong to a receptor protein tyrosine kinase family and comprise an extracellular ligand-binding domain, a single transmembrane domain, 1 64309488-v1155792.599942 and an intracellular tyrosine kinase domain. Four types of FGFRs (FGFR1, FGFR2, FGFR3, and FGFR4) have been heretofore identified. FGFRs bind to FGFs to form dimers and are activated by phosphorylation. Activation of the receptors induces mobilization and activation of specific downstream signal transduction molecules, thereby developing physiological functions. Some reports have been made about the relationship between aberrant FGF / FGFR signaling and various human tumors. Aberrant activation of FGF / FGFR signaling in human tumors is considered to be attributable to overexpression of FGFRs and / or gene amplification, gene mutation, chromosomal translocation, insertion, and inversion, gene fusion, or an autocrine or paracrine mechanism by overproduction of FGFs (ligands). (See, e.g., Nat. Rev. Cancer, 10, 116- 129 (2010); J. Clin. Oncol., 24, 3664-3671 (2006); Mol. Cancer Res., 3, 655-667 (2005); Cancer Res., 70, 2085-2094 (2010)).

[0006] Futibatinib (i.e., (S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H- pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)prop-2-en-1-one), which is a 3,5- disubstituted benzene alkynyl compound, or a pharmaceutically acceptable salt thereof, is known as an FGFR inhibitor (see, e.g., WO2017 / 150725, which is incorporated by reference to its entirety). Futibatinib is the first irreversible covalent inhibitor of FGFR that is being tested in humans.

[0007] On the other hand, the development of cancer immunotherapy has progressed as a new cancer treatment method. Recent efforts have focused on therapies that specifically target the immune system, and promising results have been obtained with nivolumab, ipilimumab, pembrolizumab, and atezolizumab, for example. Therapeutic approaches to many types of cancers have thus changed dramatically. However, the survival benefit from these new agents remains limited, and many patients experience disease failure after clinical responses with them.

[0008] Activation of the adaptive immune response is initiated by the binding of antigenic peptide-MHC complexes to T-cell receptors (TCRs). This binding is further defined by costimulation or coinhibition by binding between the costimulatory molecule B7 family and their receptor CD28 family. That is, in order for T cells to activate an antigen specifically, two characteristic signal transduction events are required, and T cells 2 64309488-v1155792.599942 that have received only antigen stimulation without costimulation from the B7 family enter a state of anergy, and immune tolerance is induced.

[0009] Taking advantage of this mechanism to suppress the activation of antigen-specific T cells, cancer cells escape from the immune surveillance system and continue to grow. Therefore, it is considered to be effective for cancer treatment to induce antitumor immune responses in the bodies of cancer patients by strengthening costimulation and blocking coinhibition and to prevent tumor immune escape. Various proposals have been made for cancer immunotherapy targeting costimulatory molecules (stimulatory costimulatory molecules) or coinhibitory molecules (inhibitory costimulatory molecules) (see, e.g., Nat. Rev. Cancer, 12, 252-264 (2012)). For example, nivolumab (human IgG4 monoclonal antibody against human PD-1) is used for the treatment of malignant melanoma, for example, as an immune checkpoint inhibitor that activates T cells by inhibiting the binding of PD-1 with its ligands (PD-L1 and PD-L2) (see WO2004 / 004771; N. Engl. J. Med., 366, 2443-2454 (2012). Further, as an immune checkpoint inhibitor that is different from nivolumab in terms of antibody type, pembrolizumab is used for the treatment of malignant melanoma and non-small cell lung cancer (see, e.g., N. Engl. J. Med., 366, 2443-2454 (2012)).

[0010] Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its interaction with PD-L1 and programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda®(pembrolizumab) is indicated for the treatment of patients across a number of indications.

[0011] The tumor microenvironment (TME) has been recognized as an important factor in disease progression, attracting attention to trials for the development of new anticancer therapies targeting the TME (Breast Cancer Res: BCR.2011;13:227). In the past decade, studies on cancer immunosuppression have shown that bone marrow-derived immunosuppressor cells (MDSCs) are closely involved in the immune evasion of cancer cells (Arthritis Rheumatol.2016;68:2717-2727; Tumour Biol.2016;37:1387-1406). 3 64309488-v1155792.599942

[0012] MDSCs are immature bone marrow cells that are recruited from the bone marrow and spleen into tumors in response to tumor-secreted chemotactic factors. Activated MDSCs can enhance immunosuppression by stimulating the expression of regulatory T cells (Treg) and regulatory B cells (Breg) (Arthritis Rheumatol.2016;68:2717-2727; Immunology.2013;138:105-115). Tregs inhibit the proliferation and activation of effector T cells by secreting interleukin (IL)-10 and transforming growth factor-β cytokines (Genes Immun.2014;15:511-5205) or act through PD-L1 / PD-1-mediated intercellular adhesion (Immunological reviews.2010;236:219-242). Breg inhibits the function of Th1, Th17, monocytes, dendritic cells, and CD8+ T cells while activating Tregs (Immunity. 2015;42:607-612). Breg, MDSCs, and Tregs are immunosuppressor cells that control tissue immunosuppression via anti-inflammatory cytokines such as IL-10, IL-35, and transforming growth factor-β. These cytokines promote immunosuppression in TME because they regulate crosstalk between MDSCs, Tregs, and Bregs (Immunology. 2013;138:105-115; Immunity.2015;42:607-612; The Journal of Immunology. 2007;179:977-983).

[0013] Recent studies have shown that the number of MDSCs in spleen cells and peripheral blood mononuclear cells decreases after administration of FGFR inhibitors to tumor-bearing mice. On the other hand, the percentage of CD4+ and CD8+ T cells in the tumor and spleen increased. This study showed that inhibition of FGFR markedly reduced the number of MDSCs and increased the number of CD4+ and CD8+ T cells (Cell Physiol Biochem.2014;33:633-645). This potentially suggests some intracellular and / or peri-cellular tumor environmental interaction of FGF / FGFR signaling pathway and an immunological responsive cascade, although neither detail of such a mechanism in molecular, cellular or animal experimental level, nor significance in a human clinical situation, is clear.

[0014] Further, even anti-cancer agents having high therapeutic efficacy need to be carefully used, and it may not be possible to use them in some cases where, for example, an anti-cancer agent has severe side effects or is highly toxic. It is also known that anti- cancer agents may differ in effect among patients, or their efficacy may be reduced due to the long-term administration of the same agent. For example, it has been found that continued administration of certain immune checkpoint inhibitors can result in drug 4 64309488-v1155792.599942 resistance. (see, e.g., Cell, 168, 707-723 (2017); N. Engl. J. Med., 375, 819-829 (2016); Sci. Transl. Med.9, eaal 3604 (2017)).

[0015] Additionally, anti-cancer agents are often not effective for all patients, especially when administered individually. Thus, attempts have been made to increase the cure rate of such therapeutic anti-cancer agents by combining them. See, e.g., WO2020 / 175697 and WO2017 / 150725, both of which are incorporated by reference in their entireties.

[0016] Despite the significant advancement in the treatment of cancer, improved therapies are still being sought. An object of the present disclosure is to provide a novel method for treating a cancer. The present disclosure advances the state of the art by providing methods of treating a cancer comprising administering futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. SUMMARY OF THE DISCLOSURE

[0017] The present disclosure provides a method for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.

[0018] The present disclosure also provides a method for treating a cancer in a subject in need thereof, comprising administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a treatment cycle of about 14 to about 28 days; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, or about 240 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject 5 64309488-v1155792.599942 about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2per dose, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

[0019] The present disclosure also provides a kit for treating a cancer in a subject in need thereof comprising futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.

[0020] The present disclosure also provides futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, or use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.

[0021] The present disclosure also provides a pharmaceutical composition comprising a first composition comprising futibatinib or a pharmaceutically acceptable salt thereof, a second composition comprising pembrolizumab or a pharmaceutically acceptable salt thereof, and a third composition comprising at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.

[0022] The present disclosure also provides a use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG.1 is a schematic of the study design expansion phase, according to embodiments of the disclosure. 6 64309488-v1155792.599942

[0024] FIG.2A is a graphical representation showing overall response rate of Cohort D, according to embodiments of the disclosure. FIG.2B is a graphical representation showing median duration of response of Cohort D, according to embodiments of the disclosure.

[0025] FIG.3A is a graphical representation showing overall response rate of Cohort A, according to embodiments of the disclosure. FIG.3B is a graphical representation showing median duration of response of Cohort A, according to embodiments of the disclosure.

[0026] FIG.4A is a graphical representation showing overall response rate of Cohort B, according to embodiments of the disclosure. FIG.4B is a graphical representation showing median duration of response of Cohort B, according to embodiments of the disclosure.

[0027] FIG.5A is a graphical representation showing overall survival of Cohorts A and B, according to embodiments of the disclosure. FIG.5B is a graphical representation showing progression-free survival of Cohorts A and B, according to embodiments of the disclosure.

[0028] FIG.6 is a graphical representation showing certain adverse events of Cohorts A, B, and D, according to embodiments of the disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0029] It is known that methods of treatment of cancer can have undesirable side effects and / or inadequate efficacy. The present disclosure provides novel methods of treatment of a cancer including administering futibatinib or a pharmaceutically acceptable salt thereof and pembrolizumab or a pharmaceutically acceptable salt thereof in combination with at least one additional anti-cancer therapy agent which can advantageously maximize therapeutic efficacy. In some embodiments, the at least one additional anti-cancer therapy agent is a chemotherapeutic agent. Such combination therapies can be potent cancer treatments. For example, the novel methods of the disclosure can provide unexpectedly enhanced efficacy (e.g., an increased overall response rate) relative to administration of any of the anti-cancer therapy agents as a monotherapy or even a combination of only futibatinib and pembrolizumab. In some embodiments, efficacy of 7 64309488-v1155792.599942 the methods using the combination therapy of the disclosure was unexpectedly increased without remarkably exacerbating toxicity.

[0030] In certain embodiments, doses of existing anti-cancer therapy agents, e.g., chemotherapeutic agents, can be reduced or administered less frequently in using the combination therapies disclosed herein, thereby increasing patient compliance, improving therapy and reducing unwanted or adverse effects.

[0031] The present disclosure provides methods for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. In some embodiments, the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.

[0032] In some embodiments, the futibatinib or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. In some embodiments, the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0033] In some embodiments, the at least one additional anti-cancer therapy agent is selected from the group consisting of: an antimetabolite, an alkaloid antitumor agent, a platinum-containing drug, a molecular targeting drug, an antitumor antibiotic, an alkylating agent, a hormonal therapy agent, a folic acid replenisher, an anti-androgen, and any combination thereof. In some embodiments, the at least one additional anti-cancer therapy agent is selected from the group consisting of: fludarabine, cladribine, nelarabine, 5-fluorouracil, tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine / tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, nanoparticle albumin-bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan (CPT-11), nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, trabectedin, lurbinectedin, cisplatin, carboplatin, oxaliplatin, nedaplatin, tretinoin (ATRA), imatinib, gefitinib, erlotinib, lapatinib, sunitinib, dasatinib, everolimus, temsirolimus, selumetinib, trametinib, 8 64309488-v1155792.599942 sorafenib, afatinib, regorafenib, dabrafenib, vemurafenib, pifusertib, MK2206, trastuzumab, cetuximab, bevacizumab, panitumumab, veltuzumab, rituximab, ramucirumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab, abatacept, doxorubicin, daunorubicin, epirubicin, actinomycin D, mitomycin C, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, calcium folinate hydrate, calcium levofolinate hydrate, folinic acid, potassium oxonate, prednisone, megestrol acetate, ethinylestradiol, tamoxifen, 4- hydroxy tamoxifen, toremifene keoxifene, onapristone, raloxifene, anastrozole, letrozole, exemestan, flutamide, nilutamide, bicalutamide, leuprolide, goserelin, palbociclib, abemaciclib, ribocyclib, and any combination thereof. In some embodiments, the at least one additional anti-cancer therapy agent is selected from the group consisting of 5- fluorouracil, cisplatin, oxaliplatin, calcium folinate hydrate, calcium levofolinate hydrate, and any combination thereof.

[0034] In some embodiments, the method comprises administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of oxaliplatin or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, skin cancer, mesothelioma, and cancer of unknown primary. In some embodiments, the cancer is esophageal cancer.

[0036] In some embodiments, the subject has not been previously treated with a chemotherapy agent and / or anti-PD-1 / PD-L1 monoclonal antibody for the esophageal cancer. 9 64309488-v1155792.599942

[0037] In some embodiments, the cancer is an advanced, metastatic, irreversible, resistant, or intractable cancer.

[0038] In some embodiments, the subject is a human.

[0039] In some embodiments, the administering is for at least one treatment cycle. In some embodiments, the treatment cycle is about 14 to about 28 days. In some embodiments, the treatment cycle is about 21 days. In some embodiments, the futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each day of the treatment cycle. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered once during the treatment cycle. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on consecutive days during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 5 days during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once during the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle. 10 64309488-v1155792.599942

[0040] In some embodiments, the administering is for at least one additional treatment cycle. In some embodiments, an amount of the futibatinib or the pharmaceutically acceptable salt thereof being administered is reduced during the at least one additional treatment cycle.

[0041] In some embodiments, an amount of the futibatinib or the pharmaceutically acceptable salt thereof being administered is about 4 mg to about 160 mg per dose, about 4 mg to about 24 mg per dose, about 12 mg to about 24 mg per dose, about 16 mg to about 24 mg per dose, or about 12 mg to about 20 mg per dose. In some embodiments, the amount of the futibatinib or the pharmaceutically acceptable salt thereof is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose. In some embodiments, the amount of the futibatinib or the pharmaceutically acceptable salt thereof is about 20 mg per dose.

[0042] In some embodiments, an amount of the pembrolizumab or the pharmaceutically acceptable salt thereof being administered is about 100 mg to about 400 mg per dose or about 200 mg to about 400 mg per dose. In some embodiments, the amount of the pembrolizumab or the pharmaceutically acceptable salt thereof is about 200 mg or about 400 mg per dose. In some embodiments, the amount of the pembrolizumab or the pharmaceutically acceptable salt thereof is about 200 mg per dose.

[0043] In some embodiments, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 10 mg / m2to about 2000 mg / m2, about 10 mg / m2to about 1000 mg / m2, about 40 mg / m2to about 800 mg / m2, about 40 mg / m2to about 400 mg / m2, about 80 mg / m2to about 200 mg / m2, about 200 mg / m2to about 800 mg / m2, about 400 mg / m2to about 1600 mg / m2, or about 400 mg / m2to about 800 mg / m2per dose. In some embodiments, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, about 240 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2per dose. In some embodiments, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable 11 64309488-v1155792.599942 salt thereof is about 80 mg / m2per dose. In some embodiments, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is about 800 mg / m2per dose.

[0044] In some embodiments, the futibatinib or the pharmaceutically acceptable salt thereof is administered orally. In some embodiments, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously.

[0045] In some embodiments, the method achieves an overall response rate of equal to or greater than 50%. In some embodiments, the overall response rate is equal to or greater than 60%. In some embodiments, the overall response rate is equal to or greater than 70%. In some embodiments, the overall response rate is equal to or greater than 80%. In some embodiments, the method achieves an improved overall response rate relative to an overall response rate of administration of futibatinib or pembrolizumab alone. In some embodiments, the method achieves an improved overall response rate relative to an overall response rate of administration of a combination of futibatinib and pembrolizumab.

[0046] The present disclosure also provides a method for treating a cancer in a subject in need thereof, comprising administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a treatment cycle of about 14 to about 28 days; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, or about 240 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, or about 1000 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days, 3 days, 4 days, 5, days, 12 64309488-v1155792.599942 6 days, or 7 days starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

[0047] The present disclosure also provides a kit for treating cancer in a subject in need thereof comprising futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.

[0048] The present disclosure also provides futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, or use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer.

[0049] The present disclosure also provides a pharmaceutical composition comprising a first composition comprising futibatinib or a pharmaceutically acceptable salt thereof, a second composition comprising pembrolizumab or a pharmaceutically acceptable salt thereof, and a third composition comprising at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer. In some embodiments, the first composition further comprises a first pharmaceutically acceptable carrier. In some embodiments, the second composition further comprises a second pharmaceutically acceptable carrier. In some embodiments, the third composition further comprises a third pharmaceutically acceptable carrier.

[0050] The present disclosure also provides a use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancer.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

[0052] As used herein, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. 13 64309488-v1155792.599942

[0053] Except where otherwise indicated, all numbers expressing quantities of ingredients, time periods, and so forth used in the disclosure and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present disclosure. At the very least, and not to be considered as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding conventions.

[0054] Additionally, the disclosure of numerical ranges within this specification is considered to be a disclosure of all numerical values and ranges within that range. For example, if a range is from about 1 to about 50, it is deemed to include, for example, 1, 7, 34, 46.1, 23.7, 50 or any other value or range within the range. Moreover, as used herein, the term “at least” includes the stated number, e.g., “at least 50” includes 50.

[0055] All references cited herein, including patent applications and publications, are incorporated by reference in their entirety for any purpose.

[0056] As used herein, “subject” or “patient” refers to an animal, preferably a mammal, including a human or a non-human animal including livestock animals and domestic animals including, but not limited to, cattle, horses, sheep, swine, goats, rabbits, cats, dogs, and other mammals in need of treatment. In an embodiment, the subject is a human. In an embodiment, the subject is a human who has been diagnosed as needing a treatment for a cancer or a clinical symptom or medical state associated with a cancer. The subject may be in need of, or desire, treatment for an existing cancer or may be in need of, or desire, prophylactic treatment to prevent or reduce the risk of occurrence of a cancer.

[0057] As used herein, a subject “in need” of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment. A subject “in need” of treatment includes a subject having a cancer and / or diagnosed with a cancer.

[0058] As used herein, the term “active agent of the disclosure” or “active agent” or “therapeutic agent” or “pharmaceutical agent” refers to an agent or ingredient with a 14 64309488-v1155792.599942 pharmacological effect, such as a therapeutic effect, at a relevant dose, and includes the pharmaceutically acceptable salt thereof. This includes the anti-cancer therapy agents of the disclosure, including futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. Accordingly, unless indicated to the contrary, the term “active agent” or any reference to a specific anti-cancer therapy agent of the disclosure (i.e., futibatinib, pembrolizumab, and the at least one additional anti-cancer therapy agent) is assumed to include the active agent or the pharmaceutically acceptable salt thereof.

[0059] As used herein, the term “administration” and variants thereof (e.g., “administering”) in reference to an active agent of the disclosure means providing the active agent to a subject in need of treatment. Administering of an active agent of the disclosure to the subject includes both self-administration and administration to the subject by another, including a medical professional. Administration may be via any common route, and in forms suitable for each administration route. Such routes include, but are not limited to, parenteral (e.g., subcutaneous, intramuscular, intraperitoneal or intravenous), oral, nasal, airway (e.g., aerosol), buccal, intradermal, transdermal, sublingual, rectal, and vaginal.

[0060] As used herein, “treat”, “treating”, or “treatment” include treating for the purpose of curing or ameliorating cancer, or for the purpose of suppressing the progression, occurrence, or recurrence of the cancer or alleviating one or more of the associated symptoms.

[0061] Treating cancer can include, for example, reduction in number of cancer cells, reduction in tumor size, reduction in rate of cancer cell infiltration into peripheral organs, reduction in rate of tumor metastasis or tumor growth, increase in overall survival (OS), increase in progression free survival (PFS), increase in disease free survival (DFS), complete response (CR), partial response (PR), stable disease (SD), improvement in duration of response (DOR), decrease in associated symptoms, and / or failure of tumors to reoccur after treatment has stopped. “Treatment” can also mean prolonging survival as compared to expected survival in the absence of treatment. 15 64309488-v1155792.599942

[0062] Positive therapeutic effects in cancer can be measured in a number of ways and would be understood by a person of skill in the art. In some embodiments, the treatment achieved by a therapeutically effective amount is any of progression free survival (PFS), disease free survival (DFS), or overall survival (OS). PFS, also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow and includes the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease. DFS refers to the length of time during and after treatment that the patient remains free of disease. OS typically refers to a time until death from the start of therapy. Methods of the present invention may not be effective in achieving a positive therapeutic effect in every patient, but may do so in a statistically significant number of subjects as determined by any statistical test known in the art such as the Student's t-test, the chi2- test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.

[0063] As used herein, the term “overall response rate” (ORR) is equal to the proportion of patients in an analysis population achieving a best overall response of partial or complete response (PR+CR). For example, ORR can be evaluated according to RECIST v1.1. ORR is an acceptable measure of clinical benefit for screening new agents for evidence of anti-tumor effect, and agents that produce tumor shrinkage in a proportion of patients have a reasonable chance of subsequently demonstrating an improvement in OS.

[0064] As used herein, “therapeutically effective” or “prophylactically effective” in reference to an amount refers to the amount necessary at the intended dosage to achieve the desired therapeutic and / or prophylactic effect for the period of time desired. The desired effect may be, for example, the alleviation, amelioration, reduction or cessation of at least one symptom associated with the treated condition. In an embodiment, the “therapeutically effective amount” coincides with a daily dosage. Amounts may vary, as the ordinarily skilled artisan will appreciate, according to various factors, including but not limited to the disease state and type, age, sex, and weight of the subject, and the ability of the active agent to elicit the desired effect in the individual. The response may be documented, for example, by in vitro assay, in vivo non-human animal studies, and / or further supported from clinical trials. 16 64309488-v1155792.599942

[0065] Dosage and administration may be adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug interaction(s), reaction sensitivities, and tolerance / response to therapy. An effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.

[0066] As used therein, the term “combination” or “combination therapy” is intended to include administration of the active agents of the methods disclosed herein in a sequential manner, wherein each active agent is administered at a different time, as well as administration of these active agents, or at least two of the active agents concurrently or in a simultaneous manner. Thus, “combination therapy”, “combination,” and the use of active agents “in combination” in the present disclosure may mean active agents administered as part of the same overall therapeutic regimen (e.g., during the same treatment cycle or period). The dose of each of the active agents may be different: each may be administered simultaneously (including substantially simultaneously, e.g., at substantially the same time, or at different times. Therefore, it is understood that the active agents of the combination may be administered sequentially (e.g., before or after) or simultaneously or substantially simultaneously, either in the same pharmaceutical formulation or pharmaceutical composition (i.e., formulated together) or in different pharmaceutical formulations or pharmaceutical compositions (i.e., formulated separately).

[0067] Simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed or variable ratio of each therapeutic agent (i.e., simultaneous) or in multiple, single capsules or other dosage forms (e.g., injectable) for each of the therapeutic agents. Sequential or simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. Each of the active agents of the methods of the disclosure can be administered by the same route or by different routes. For example, one active agent(s) of the method may be administered by intravenous injection while at least one other 17 64309488-v1155792.599942 active agent(s) of the method may be administered orally. Alternatively, for example, all active agents may be administered orally or all active agents may be administered by intravenous injection. The sequence in which the active agents are administered can vary.

[0068] As used herein, the terms “regimen” and “therapeutic regimen” refer to an administration plan or schedule that shows, in chronological order, the type and amount of therapeutic agents, the duration, and the procedure in drug treatment, and that shows the dose, administration method, administration order, and administration day of each drug. The treatment in one therapeutic regimen is, for example, a method that starts administration of drugs to be combined, simultaneously or substantially simultaneously on the first day of a treatment cycle (i.e., treatment period). The treatment in one therapeutic regimen also includes, for example, one treatment cycle with three weeks in which administration of drug A is started first, and administration of drug B is started one week later.

[0069] As used herein, the “treatment cycle” or “treatment period” refers to the period of time during which the administration according to the methods of the disclosure takes place. During a treatment cycle, each of the active agents of the method is administered sequentially or simultaneously as described herein.

[0070] As used herein, the term “q.d.” means one a day (from the Latin quaque die). The abbreviation is sometimes written without a period in capital letters as "QD" used to specify the frequency with which therapeutic agents are administered.

[0071] As used herein, the term “Q3W” means once every three weeks and is used to specify the frequency with which therapeutic agents are administered.

[0072] This disclosure provides methods for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.

[0073] The present disclosure includes prodrugs, free-acid, free-base and pharmaceutically acceptable salts of the active agents described herein where applicable. As used herein, the term “pharmaceutically acceptable salts” refers to salts of the one or more compounds of the methods of the disclosure that are substantially non-toxic to 18 64309488-v1155792.599942 living organisms, e.g., subjects in need of methods of treatment. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the one or more active components of the disclosure with an inorganic or organic acid, or an organic base, depending on the substituents present on the one or more active components of the disclosure. The pharmaceutically acceptable salts of the present disclosure are not particularly limited, and include, for example, addition salts with inorganic acids such as hydrochloric acid and sulfuric acid, or with organic acids such as acetic acid, citric acid, tartaric acid, and maleic acid; salts with alkali metals such as potassium and sodium; salts with alkaline earth metals such as calcium and magnesium; salts with organic bases such as ammonium salts, ethylamine salts, and arginine salts; and the like.

[0074] As used herein, an “additional anti-cancer therapy agent” can be any pharmaceutically active agent (or pharmaceutically acceptable salt thereof) that is active in the body against cancer and that is other than the futibatinib and pembrolizumab. The additional anti-cancer therapy agents include prodrugs, free-acid, free-base and pharmaceutically acceptable salts of the additional anti-cancer therapy agents. Generally, any suitable additional anti-cancer therapy agent, including chemotherapeutic agents or therapeutic antibodies, may be used. The additional anti-cancer therapy agent may include an anti-cancer agent (e.g., chemotherapeutic agents and therapeutic antibodies, etc.) that directly or indirectly treats the cancer (i.e., active agents) or a supplemental agent that does not directly or indirectly treat the cancer but is used during anti-cancer treatment, or both.

[0075] In an embodiment, the at least one additional anti-cancer therapy agent is a chemotherapeutic agent. As used herein, “chemotherapeutic agent” refers to cytotoxic anti-cancer agents. Non-limiting examples of chemotherapeutic agents include antimetabolites, alkaloid antitumor agents (i.e., mitotic inhibitors and plant alkaloids), platinum-containing drugs (i.e., platinum analogs), molecular targeting drugs, antitumor antibiotics, alkylating agents, hormonal therapy agents, folic acid replenishers, anti- androgens, enzymes, topoisomerase inhibitors, retinoids, and aziridines. Many anti- cancer agents can be classified within one or more of these groups. While certain anti- cancer agents have been categorized within a specific group(s) or subgroup(s) herein, many of these agents can also be listed within one or more other group(s) or subgroup(s), as would be presently understood in the art. It is to be understood that the 19 64309488-v1155792.599942 classification herein of a particular agent into a particular group is not intended to be limiting.

[0076] Non-limiting examples of mitotic inhibitors and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, nanoparticle albumin- bound paclitaxel, and tesetaxel; demecolcine; epothilone; eribulin; etoposide (VP- 16); etoposide phosphate; lurbinectedin, navelbine; noscapine; teniposide; thaliblastine; trabectedin, vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[0077] Non-limiting examples of alkylating agents include nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, cytophosphane, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozotocin, and TA-07; ethylenimines and methylamelamines such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphaoramide, trietylenephosphoramide, and trimethylolomelamine; ambamustine; bendamustine; dacarbazine; etoglucid; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.

[0078] Non-limiting examples of antimetabolites include folic acid analogues such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs such as 6-mercaptopurine, 6-thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs such as 5-fluorouracil (5- FU), 6-azauridine, ancitabine, azacytidine, capecitabine, carmofur, cytarabine, decitabine, dideoxyuridine, doxifiuridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0079] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate. 20 64309488-v1155792.599942

[0080] Non-limiting examples of enzymes include asparaginase and pegaspargase.

[0081] Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan (CPT-11), lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0082] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, RII retinamide, and tretinoin (ATRA).

[0083] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.

[0084] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and valrubicin; 6-diazo-5-oxo- L-norleucine; aclacinomysins; actinomycin; authramycin; azaserine; bleomycins; cactinomycin; calicheamicin; carabicin; carminomycin; carzinophilin; chromomycins; dactinomycin; detorubicin; esorubicin; esperamicins; geldanamycin; marcellomycin; mitomycins; mitomycin C; mycophenolic acid; olivomycins; novantrone; peplomycin; porfiromycin; potfiromycin; puromycin; quelamycin; rebeccamycin; rodorubicin; streptonigrin; streptozocin; tanespimycin; tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.

[0085] Non-limiting examples of folic acid replenishers include calcium folinate hydrate, calcium levofolinate hydrate, folinic acid, potassium oxonate, prednisone, megestrol acetate, ethinylestradiol, tamoxifen, 4-hydroxy tamoxifen, toremifene keoxifene, onapristone, raloxifene, anastrozole, letrozole, and exemestane.

[0086] Non-limiting examples of anti-androgens include flutamide, nilutamide, bicalutamide, leuprolide, goserelin, palbociclib, abemaciclib, and ribocyclib.

[0087] In an embodiment, the at least one additional anti-cancer therapy agent is selected from the group consisting of: an antimetabolite, an alkaloid antitumor agent, a platinum- containing drug, a molecular targeting drug, an antitumor antibiotic, an alkylating agent, a hormonal therapy agent, a folic acid replenisher, an anti-androgen, and any combination thereof. 21 64309488-v1155792.599942

[0088] In an embodiment, the at least one additional anti-cancer therapy agent is selected from the group consisting of: fludarabine, cladribine, nelarabine, 5-fluorouracil, tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine / tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, nanoparticle albumin-bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan (CPT-11), nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, trabectedin, lurbinectedin, cisplatin, carboplatin, oxaliplatin, nedaplatin, tretinoin (ATRA), imatinib, gefitinib, erlotinib, lapatinib, sunitinib, dasatinib, everolimus, temsirolimus, selumetinib, trametinib, sorafenib, afatinib, regorafenib, dabrafenib, vemurafenib, pifusertib, MK2206, trastuzumab, cetuximab, bevacizumab, panitumumab, veltuzumab, rituximab, ramucirumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab, abatacept, doxorubicin, daunorubicin, epirubicin, actinomycin D, mitomycin C, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, calcium folinate hydrate, calcium levofolinate hydrate, folinic acid, potassium oxonate, prednisone, megestrol acetate, ethinylestradiol, tamoxifen, 4-hydroxy tamoxifen, toremifene keoxifene, onapristone, raloxifene, anastrozole, letrozole, exemestan, flutamide, nilutamide, bicalutamide, leuprolide, goserelin, palbociclib, abemaciclib, ribocyclib, and any combination thereof.

[0089] In an embodiment, the at least one additional anti-cancer therapy agent includes combinations of two or more selected from fludarabine, cladribine, nelarabine, 5- fluorouracil, tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine / tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, nanoparticle albumin-bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan (CPT-11), nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, trabectedin, lurbinectedin, cisplatin, carboplatin, oxaliplatin, nedaplatin, tretinoin (ATRA), imatinib, gefitinib, erlotinib, lapatinib, sunitinib, dasatinib, everolimus, temsirolimus, selumetinib, trametinib, sorafenib, afatinib, regorafenib, dabrafenib, vemurafenib, pifusertib, MK2206, trastuzumab, cetuximab, bevacizumab, panitumumab, veltuzumab, rituximab, ramucirumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab, abatacept, doxorubicin, daunorubicin, epirubicin, actinomycin D, 22 64309488-v1155792.599942 mitomycin C, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, calcium folinate hydrate, calcium levofolinate hydrate, folinic acid, potassium oxonate, prednisone, megestrol acetate, ethinylestradiol, tamoxifen, 4- hydroxy tamoxifen, toremifene keoxifene, onapristone, raloxifene, anastrozole, letrozole, exemestan, flutamide, nilutamide, bicalutamide, leuprolide, goserelin, palbociclib, abemaciclib, ribocyclib. Combination regimens of chemotherapy can be determined by those skilled in the art, and include, but are not limited to PC (paclitaxel and carboplatin), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R- CHOP (rituximab plus CHOP), RCVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), ICE-V (ICE plus vincristine), R-MCP (rituximab-MCP), and FOLFOX or FLOX (oxaliplatin, 5-fluorouracil (5-FU), and leucovorin calcium (folinic acid)). FOLFOX can encompass certain variations and modifications, e.g., FOLFOX2, FOLFOX3, FOLFOX4, FOLFOX6, mFOLFOX6, FOLFOX7, and so on (Eur J Cancer.33(2): 214-219, 1997; J Clin Oncol.17(11): 3560-3568, 1999; J Clin Oncol. 18(16): 2938-2947, 2000; Eur J Cancer.35(9): 1338-1342, 1999; Eur J Cancer.37(8): 1000, 2001).

[0090] In an embodiment, the at least one additional anti-cancer therapy agent is selected from the group consisting of 5-fluorouracil, cisplatin, oxaliplatin, calcium folinate hydrate, calcium levofolinate hydrate, and any combination thereof. In an embodiment, the at least one additional anti-cancer therapy agent is selected from the group consisting of 5-fluorouracil, cisplatin, and the combination thereof. In an embodiment, the at least one additional anti-cancer therapy agent is selected from the group consisting of 5- fluorouracil, oxaliplatin, and the combination thereof.

[0091] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and a regimen comprising oxaliplatin, 5-fluorouracil (5-FU), and leucovorin calcium (folinic acid). In an 23 64309488-v1155792.599942 embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and FOLFOX.

[0092] The methods of the disclosure may also be administered in combination with non- chemotherapeutic treatments such as radiotherapy, photodynamic therapy, gene therapy, surgery, and controlled diets.

[0093] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof, thereby treating the cancer in the subject.

[0094] In the present disclosure, “cancer” or “tumor” refers to the physiological conditions of a subject (e.g., a human subject) characterized by unregulated cell growth. “Cancer” and “tumor” have the same meaning in the present disclosure and are used interchangeably. Cancers include solid and hematologic cancers. Examples include, but are not limited to, carcinoma, lymphoma, leukemia, blastoma, sarcoma, and borderline malignancy (carcinoid).

[0095] Examples of cancers targeted by the methods of the present disclosure include, but are not limited to, head and neck cancer, digestive organ cancer (esophageal cancer, gastric cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder and cholangiocarcinoma), pancreatic cancer, urothelial cancer, small intestine cancer, large intestine cancer (e.g., colorectal cancer, colon cancer, and rectal cancer)), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, and mesothelioma (e.g., malignant pleural mesothelioma, peritoneal mesothelioma, and pericardial mesothelioma)), breast cancer, genital cancer (ovarian cancer, uterine cancer (e.g., cervical cancer, uterine body cancer, and endometrial cancer), etc.), renal cancer, bladder cancer, prostate cancer, testicular tumor, skin cancer (e.g., malignant melanoma and epidermal cancer), blood cancer (e.g., multiple myeloma and acute myeloid leukemia), bone and soft tissue tumor, rhabdomyosarcoma, brain tumor, malignant schwannoma, neuroendocrine tumor, thyroid cancer, and the like. In an embodiment, the targets are bladder cancer, urothelial cancer, digestive organ cancer (esophageal cancer, gastric 24 64309488-v1155792.599942 cancer, duodenal cancer, liver cancer, biliary tract cancer (e.g., gallbladder and cholangiocarcinoma), pancreatic cancer, small intestine cancer, large intestine cancer (e.g., colorectal cancer, colon cancer, and rectal cancer)), ovarian cancer, head and neck cancer, and uterine cancer (e.g., cervical cancer and uterine body cancer). The cancers mentioned herein include not only the primary lesion, but also cancer metastasized to other organs (e.g., liver). The primary lesion may or may not be known. The at least one additional anti-cancer therapy agent of the present disclosure may also be used in postoperative adjuvant chemotherapy performed in order to prevent recurrence after surgical removal of the tumor, or may be used in preoperative adjuvant chemotherapy performed in order to surgically remove the tumor.

[0096] In an embodiment, the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, skin cancer, mesothelioma, and cancer of unknown primary.

[0097] In an embodiment, the cancer is an advanced, metastatic, irreversible, resistant, or intractable cancer.

[0098] In an embodiment, the cancer is selected from malignant melanoma, non-small cell lung cancer, Hodgkin’s lymphoma, urothelial cancer, solid cancer with high- frequency microsatellite instability (MSI-High), renal cell cancer, head and neck cancer, esophageal cancer, and gastric cancer. In an embodiment, the cancer is an advanced, metastatic, irreversible, resistant, or intractable solid tumor.

[0099] In an embodiment, the cancer is urothelial cancer, esophageal cancer, or non- small cell lung cancer. In an embodiment, the cancer is esophageal cancer or non-small cell lung cancer. In an embodiment, the cancer is esophageal cancer. In an embodiment, the esophageal cancer is an advanced, metastatic, irreversible, resistant, or intractable esophageal carcinoma. 25 64309488-v1155792.599942

[0100] In an embodiment, the methods of the disclosure are used for tumors having aberrations in the FGFR pathway. In an embodiment, the FGFR is selected from the group consisting of FGFR1, FGFR2, FGFR3, and FGFR4.

[0101] In an embodiment, the tumors to which the present disclosure are to be applied are tumors having aberrations in the FGFR pathway. The aberrations in the FGFR pathway include FGFR overexpression, FGFR genetic aberration, and aberrant FGFR signaling.

[0102] In an embodiment, the subject is one having aberrations in the FGFR pathway. In an embodiment, the subject is one having no FGFR aberrations.

[0103] Examples of FGFR overexpression include gene expression and high expression of gene product proteins. The expression of FGFR can be detected by methods known to persons skilled in the art. Gene expression and high expression of gene product proteins can be detected by known methods, such as methods using antibodies (immunohistochemistry, enzyme immunoassay (ELISA), flow cytometry, immunoblotting, etc.), methods using nucleic acids (in situ hybridization, PCR, Northern blotting, etc.), and methods based on a common principle of these methods. The detection device can be any known device (GeneChip, microarray, etc.).

[0104] In an embodiment, the methods of the disclosure are used for tumors having FGFR genetic aberrations. Genetic aberrations in the FGFR pathway include, e.g., gene amplification, gene mutation, chromosomal translocation, insertion, and inversion, gene fusion, genetic rearrangement. Some of the FGFR genetic aberrations in tumors have already been reported in documents available to persons skilled in the art (e.g., The Breast, 37, 126-133 (2018); Oncotarget, 8, 16052-16074 (2017)). FGFR genetic aberrations can be detected by methods known to persons skilled in the art, for example, pyrosequence, DNA sequencing including next-generation sequencing (NGS), PCR- based methods including allele-specific PCR chain reactions, microarray-based comparative genomic hybridization (aCGH), fluorescence in situ hybridization (FISH), and chromogenic in situ hybridization (CISH).

[0105] In an embodiment, the methods of the disclosure are used for tumors with activated FGFR signaling. FGFRs bind to FGFs to form dimers and are activated by 26 64309488-v1155792.599942 phosphorylation, which induces mobilization and activation of specific downstream signal transduction molecules, thereby developing physiological functions.

[0106] Activation of FGFR signaling can be detected by methods known to persons skilled in the art. Signaling activation can be detected, for example, by detecting FGFs, which are substrates for FGFRs; by detecting direct phosphorylation state of FGFRs, which are phosphorylated enzymes, or biological activity including enzymatic activity; by detecting phosphorylation state of intracellular substrates and intracellular proteins existing in the FGFR signaling cascade downstream, or biological activity including enzymatic activity; or by detecting gene products or gene transcripts.

[0107] The anti-cancer therapy agents (including active agents) of the disclosure or their pharmaceutically acceptable salts can be administered as pharmaceuticals by themselves, in mixtures with one another, or in the form of pharmaceutical compositions (by themselves or in mixture with one another).

[0108] The administration form or dosage form of the anti-cancer therapy agents of the disclosure is not limited, and can be appropriately selected depending on the therapeutic purpose. The dosage form will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Examples of dosage forms include oral preparations (e.g., tablets, coated tablets, powders, granules, capsules, solutions), injections, suppositories, patches, ointments, and the like. Such dosage forms can be formed by methods conventionally known to a person skilled in the art.

[0109] The active agents of the present disclosure may be formulated into a plurality of dosage forms, or may be formulated into a single dosage form, based on the administration form and administration schedule of each active agent. Further, formulations may be produced and sold in a single package suitable for combined administration, or formulations may be produced and sold in separate packages. The same applies to the embodiments of the pharmaceutical composition.

[0110] As used herein, a “pharmaceutical composition” or “pharmaceutical preparation” is a formulation containing at least one active ingredient, such as at least one compound of the disclosure, in a form suitable for administration to a subject. When an 27 64309488-v1155792.599942 active agent or a salt thereof of the disclosure is used as a pharmaceutical preparation or pharmaceutical composition, a pharmaceutically acceptable carrier can be added, if required, thereby forming a suitable dosage form for prevention and / or treatment purposes. Examples of the dosage form includes oral preparations, injections, suppositories, ointments, inhalations, patches, and the like. Such dosage forms can be formed by methods conventionally known to a person skilled in the art.

[0111] Depending on the administration form thereof, a pharmaceutically acceptable carrier may be used to prepare a pharmaceutical composition by a generally known method. As the pharmaceutically acceptable carrier, various conventional organic or inorganic carrier materials used as preparation materials may be blended as an excipient, binder, disintegrant, lubricant, or colorant in solid preparations; or as a solvent, solubilizing agent, suspending agent, isotonizing agent, buffer, or soothing agent in liquid preparations. Moreover, pharmaceutical preparation additives, such as antiseptics, antioxidants, colorants, sweeteners, and stabilizers, may also be used, if required.

[0112] Oral solid preparations are prepared as follows, for example. After an excipient is added optionally with a binder, disintegrant, lubricant, colorant, taste-masking or flavoring agent, etc. to the compound or a salt thereof of the disclosure, the resulting mixture is formulated into tablets, coated tablets, granules, powders, capsules, or the like by ordinary methods.

[0113] When an injection agent is prepared, a pH regulator, a buffer, a stabilizer, an isotonizing agent, a local anesthetic, and the like may be added to an active agent of the disclosure; and the mixture may be formulated into a subcutaneous, intramuscular, or intravenous injection according to an ordinary method.

[0114] In an embodiment, futibatinib or a pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously. In an embodiment, the futibatinib or the pharmaceutically acceptable salt thereof is administered orally.

[0115] In an embodiment, pembrolizumab is administered orally, intravenously, or subcutaneously. In an embodiment, pembrolizumab is administered intravenously. In an embodiment, pembrolizumab is administered intravenously by IV infusion. In an embodiment, pembrolizumab is administered by 30-minute IV infusion. It will be understood by the person of skill in the art that, given the variability of infusion pumps, 28 64309488-v1155792.599942 for example, the timing of a 30-minute IV infusion permits a window of between -5 minutes and +10 minutes such that infusion time is about 30 minutes (-5 min / +10min).

[0116] In an embodiment, the at least one additional anti-cancer therapy agent is administered orally, intravenously, or subcutaneously. In an embodiment, the at least one additional anti-cancer therapy agent is administered intravenously. In an embodiment, the at least one additional anti-cancer therapy agent is administered intravenously in IV infusion.

[0117] In an embodiment, each of the futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered via the same route. In an embodiment, each of the futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered via a different route. In an embodiment, at least two of the futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered via the same route.

[0118] In an embodiment, the subject has not been treated with hormonal therapy, immunotherapy (cancer peptide vaccine therapy, etc.), surgery, radiation therapy, or chemotherapeutic agents (i.e., a treatment-naive subject). In an embodiment, the subject failed to achieve a sustained response after a previous treatment with at least one chemotherapeutic agent. In an embodiment, the subject has been previously treated with hormonal therapy, immunotherapy (cancer peptide vaccine therapy, etc.), surgery, radiation therapy, or chemotherapeutic agents, with or without a sustained response.

[0119] In an embodiment, the subject is a human. In an embodiment, the subject is a treatment-naive human subject. In an embodiment, the human subject has not been previously treated with an anti-PD-1 / PD-L1 monoclonal antibody for the cancer. In an embodiment, the human subject has not been previously treated with a chemotherapeutic agent for the cancer. In an embodiment, the human subject is chemotherapy and anti-PD- l / PD-L1 monoclonal antibody naive. 29 64309488-v1155792.599942

[0120] In an embodiment, the human subject is refractory to at least one chemotherapeutic agent. In an embodiment, the human subject is refractory to the at least one additional anticancer agent. In an embodiment, the human subject is refractory to an immune checkpoint inhibitor. In an embodiment, the human subject is refractory to an FGFR inhibitor.

[0121] In an embodiment, the subject is a treatment-naive human subject with esophageal cancer. In an embodiment, the subject is a treatment-naive human subject with advanced metastatic, irreversible, resistant, or intractable esophageal carcinoma. In an embodiment, the subject has not been previously treated for the esophageal cancer. In an embodiment, the subject has not been previously treated with an anti-PD-1 / PD-L1 monoclonal antibody for the esophageal cancer. In an embodiment, the subject has not been previously treated with a chemotherapeutic agent for the esophageal cancer.

[0122] In an embodiment, the subject is a treatment-naïve human subject with non- small cell lung cancer. In an embodiment, the subject has not been previously treated for the non-small cell lung cancer. In an embodiment, the subject has not been previously treated with an anti-PD-1 / PD-L1 monoclonal antibody or a chemotherapeutic agent for the non-small cell lung cancer. In an embodiment, the subject has not been previously treated with an anti-PD-1 / PD-L1 monoclonal antibody for the non-small cell lung cancer. In an embodiment, the subject has not been previously treated with a chemotherapeutic agent for the non-small cell lung cancer.

[0123] In an embodiment, the methods of the disclosure comprise administering at least one of the anti-cancer therapy agents of the disclosure (i.e., anti-cancer agents, including futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof) in a therapeutically effective amount. In an embodiment, the futibatinib or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount. In an embodiment, the pembrolizumab or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0124] In an embodiment, the at least one additional anti-cancer therapy agent is administered in a therapeutically effective amount. In an embodiment, the methods of the 30 64309488-v1155792.599942 disclosure comprise administering to the subject a therapeutically effective amount of 5- fluorouracil and a therapeutically effective amount of cisplatin. In an embodiment, the methods of the disclosure comprise administering to the subject a therapeutically effective amount of 5-fluorouracil and a therapeutically effective amount of oxaliplatin.

[0125] In an embodiment, the methods of the disclosure comprise administering to the subject a therapeutically effective amount of the futibatinib or the pharmaceutically acceptable salt thereof, a therapeutically effective amount of the pembrolizumab or the pharmaceutically acceptable salt thereof, and a therapeutically effective amount of the at least one additional anti-cancer therapy agent. In an embodiment, the methods of the disclosure comprise administering to the subject a therapeutically effective amount of the futibatinib or the pharmaceutically acceptable salt thereof, a therapeutically effective amount of the pembrolizumab or the pharmaceutically acceptable salt thereof, a therapeutically effective amount of 5-fluorouracil, and a therapeutically effective amount of cisplatin. In an embodiment, the methods of the disclosure comprise administering to the subject a therapeutically effective amount of the futibatinib or the pharmaceutically acceptable salt thereof, a therapeutically effective amount of the pembrolizumab or the pharmaceutically acceptable salt thereof, a therapeutically effective amount of 5- fluorouracil, and a therapeutically effective amount of oxaliplatin.

[0126] Administered amounts may vary, as the ordinarily skilled artisan will appreciate, according to various factors, including but not limited to the administration route, disease state, age, sex, and weight of the subject, and the ability of the active agent to elicit the desired effect in the subject. The response may be documented, for example, by in vitro assay, in vivo non-human animal studies, and / or further supported from clinical trials.

[0127] Each of the active agents according to a method of the disclosure may be administered at a dose of about 30 to 100%, about 50 to 100%, about 70 to 100%, about 80 to 100%, about 90 to 100%, or 100% of the recommended dose in the case of administering each agent alone as a monotherapy. In an embodiment, each of the active agents according to a method of the disclosure is administered at a dose of about 100% of the recommended dose in the case of administering each agent alone as a monotherapy. In an embodiment, one or more of the active agents of the disclosure is administered at a dose of less than 100% of the recommended dose in the case of administering each agent 31 64309488-v1155792.599942 alone as a monotherapy. In an embodiment, two or more of the active agents of the disclosure are administered at a dose of less than 100% of the recommended dose in the case of administering each agent alone as a monotherapy. In an embodiment, three or more of the active agents of the disclosure are administered at a dose of less than 100% of the recommended dose in the case of administering each agent alone as a monotherapy.

[0128] As used herein, the “recommended dose” is a dose that produces the maximum therapeutic effect within a range that can be safely used without developing serious side effects, determined by clinical trials, etc. Specific examples include doses that are described in package inserts, interview forms, treatment guidelines, etc., and that have been approved, recommended, or advised by public institutions or organizations, such as the Japan Pharmaceuticals and Medical Devices Agency (PMDA), the U.S. Food and Drug Administration (FDA), and the European Medicines Agency (EMA). Doses that have been approved by any of the public agencies PMDA, FDA, and EMA are preferable.

[0129] The active agents of the methods of the disclosure may be administered in any order and according to any administration or dosing schedule. The administration schedule and order of administration may be appropriately selected, for example, according to the type of cancer, the stage of cancer, and other various factors, including, but not limited to the age, sex, and weight of the subject, the ability of the active agent to elicit the desired effect in the subject, and adverse effects in the subject.

[0130] The active agents of the methods of the disclosure may be administered in any combination (e.g., separately or in a single dosage form and sequentially or concurrently). For example, at least two of active agents of the disclosure or all of the active agents of the disclosure may be administered in a single dosage formulation (e.g., a fixed dose drug combination) or in one or more separate dosage forms which allow for concurrent or sequential (or substantially sequential) administration of the active agents (co-administration of the separate active agents) to subjects. In an embodiment, the active agents of the disclosure are included in a pharmaceutical composition as described herein.

[0131] The methods of the disclosure also include administration of the active agents before or after a surgical procedure, or administration of the active agents during, before, or after radiation therapy. 32 64309488-v1155792.599942

[0132] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are each administered separately. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered via a single pharmaceutical preparation further comprising at least one pharmaceutically acceptable carrier. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered substantially simultaneously. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially. In an embodiment, any two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered simultaneously. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered simultaneously. In an embodiment, any two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are 33 64309488-v1155792.599942 administered via a single pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier. In an embodiment, any two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered sequentially. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered sequentially.

[0133] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered before pembrolizumab or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered after pembrolizumab or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered before the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered after the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered before pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered after pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered before the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, futibatinib or the 34 64309488-v1155792.599942 pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof are administered after the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.

[0134] In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered before futibatinib or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered after futibatinib or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered before the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered after the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered before futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered after futibatinib or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered before futibatinib or the pharmaceutically acceptable salt thereof. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered after futibatinib or the pharmaceutically acceptable salt thereof.

[0135] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered at the same frequency, either simultaneously or sequentially. In an embodiment, at least two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are 35 64309488-v1155792.599942 administered at the same frequency, either simultaneously or sequentially. In an embodiment, at least two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered at the same frequency, but not simultaneously, e.g., once every 1 week or 2 weeks or 3 weeks but the administration of each therapy is separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, or 12 hours.

[0136] In an embodiment, at least two of futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof are administered at different frequencies and each independently is administered every day, every other day, every week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, or every 8 weeks.

[0137] In an embodiment, futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof are each administered every day or intermittently.

[0138] In an embodiment, the administration according to the methods of the disclosure is for at least one treatment cycle. In an embodiment, each of the futibatinib or a pharmaceutically acceptable salt thereof, the pembrolizumab or a pharmaceutically acceptable salt thereof, and the at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof is administered every day, intermittently, or once during a treatment cycle.

[0139] In an embodiment, a treatment cycle is 1 – 365 days. In an embodiment, a treatment cycle is 1 day, 2 days, one week (i.e., 7 days), 2 weeks (i.e., 14 days), 3 weeks (i.e., 21 days), 4 weeks (i.e., 28 days), 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or 20 weeks, one month, months , months, 6 months or about one year. As used herein, a “week” means seven consecutive days.

[0140] In an embodiment, the treatment cycle is about 14 to about 28 days. In an embodiment, the treatment cycle is about 21 days (i.e., 3 weeks). 36 64309488-v1155792.599942

[0141] As used herein, “administered every day” or “daily” or “once a day” or “once a day on each day” includes an administration schedule based on a regimen in which dosing is performed on every day of a treatment cycle (i.e., treatment period). For example, an active ingredient may be administered every day (i.e., QD) of a 21-day treatment cycle. In an embodiment, a “drug holiday” may be provided as each treatment cycle ends. In an embodiment, an active agent is administer once during a 21-day treatment cycle (i.e, Q3W).

[0142] As used herein, “administered intermittently” is not particularly limited as long as the conditions of at least twice during the treatment cycle and an administration interval of at least one day between dosing (the number of days between a certain day of administration and the next day of administration) are satisfied.

[0143] In one embodiment, the administration is for 1 treatment cycle. In one embodiment, the administration is for at least one treatment cycle and one additional treatment cycle (i.e., at least two treatment cycles). In one embodiment, the administration is for at least 2 treatment cycles, or at least 3 treatment cycles, or at least 4 treatment cycles, or at least 5 treatment cycles, or at least 6 treatment cycles, or at least 7 treatment cycles, or at least 8 treatment cycles, or at least 9 treatment cycles, or at least 10 treatment cycles, or at least 11 treatment cycles, or at least 12 treatment cycles, or at least15 treatment cycles, or at least 20 treatment cycles, or at least 25 treatment cycles, or at least 30 treatment cycles, or at least 35 treatment cycles, or at least 40 treatment cycles. In an embodiment, the treatment is continuous until an endpoint which may be determined by a medical professional. In an embodiment, the administration is for less than or equal to 35 treatment cycles.

[0144] In an embodiment, the administered amount of an active agent of the disclosure is held constant during one treatment cycle. In an embodiment, the administered amount of an active agent of the disclosure is held constant for at least one treatment cycle and at least one additional treatment cycle (i.e., more than one treatment cycle). In an embodiment, the administered amount of an active agent of the disclosure can be increased in a second or subsequent treatment cycle (i.e., an additional treatment cycle). In an embodiment, the administered amount of an active agent of the disclosure can be held constant for at least two treatment cycles and decreased in a third or subsequent 37 64309488-v1155792.599942 treatment cycle. In an embodiment, the administered amount of an active agent of the disclosure can be held constant for at least two treatment cycles and increased in a third or subsequent treatment cycle.

[0145] In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg to about 160 mg per dose, about 4 mg to about 30 mg per dose, about 12 mg to about 24 mg per dose, about 16 mg to about 24 mg per dose, about 12 mg to about 20 mg per dose. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, about 24 mg, or about 30 mg per dose. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 12 mg per dose. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 16 mg per dose. In an embodiment an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 20 mg per dose.

[0146] In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg to about 160 mg per dose once a day, about 4 mg to about 30 mg per dose once a day, about 12 mg to about 24 mg per dose once a day, about 16 mg to about 24 mg per dose once a day, or about 12 mg to about 20 mg per dose once a day. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, about 24 mg, or about 30 mg per dose once a day. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 12 mg per dose once a day. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 16 mg per dose once a day. In an embodiment, an amount of futibatinib or the pharmaceutically acceptable salt thereof administered is about 20 mg per dose once a day.

[0147] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg to about 160 mg per dose once a day on each day of a treatment cycle, about 4 mg to about 24 mg per dose once a day on each day of a treatment cycle, about 12 mg to about 38 64309488-v1155792.599942 24 mg per dose once a day on each day of a treatment cycle, about 16 mg to about 24 mg per dose once a day on each day of a treatment cycle, or about 12 mg to about 20 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 12 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 16 mg per dose once a day on each day of a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg per dose once a day on each day of a treatment cycle.

[0148] In an embodiment, the amount of futibatinib or the pharmaceutically acceptable salt thereof administered is held constant during a second or subsequent treatment cycle. In an embodiment, the amount of futibatinib or the pharmaceutically acceptable salt thereof administered is increased during a second or subsequent treatment cycle. In an embodiment, the amount of futibatinib or the pharmaceutically acceptable salt thereof administered is decreased during a second or subsequent treatment cycle.

[0149] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose once a day on each day of a first treatment cycle and in an amount of about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose once a day on each day of a second or subsequent treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg per dose once a day on each day of a first treatment cycle and in an amount of about 16 mg per dose once a day on each day of a second or subsequent treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered in an amount of about 20 mg per dose once a day on each day of a first treatment cycle and in an amount of about 16 mg per dose once a day on each day of a second treatment cycle and in an amount of about 12 mg per dose once a day on each day of a third or subsequent treatment cycle. 39 64309488-v1155792.599942

[0150] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-14 of a 14-day treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-21 of a 21-day treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-28 of a 28-day treatment cycle.

[0151] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during at least one 21-day treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during at least two 21-day treatment cycles. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during at least three 21-day treatment cycles. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered once a day during each additional 21-day treatment cycle up to thirty five (35) consecutive 21-day treatment cycles.

[0152] In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle. In an embodiment, futibatinib or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle in an amount of about 2 to 1000 mg per dose, about 10 to 500 mg per dose, about 20 to 200 mg per dose, or about 50 to 160 mg per dose.

[0153] In an embodiment, intermittent administration is according to an administration schedule based on a 1-week (7 day) treatment cycle, in which futibatinib or a pharmaceutically acceptable salt thereof is administered at least twice every one to three days per treatment cycle (with an interval between a certain day of administration and the next day of administration of 1 to 3 days), and this cycle is performed once or repeated twice or more. In an embodiment, intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which futibatinib or a pharmaceutically acceptable salt thereof is administered 4 to 7 times every one to three days per treatment cycle (with an interval between a certain day of administration and the next day of administration of 1 to 3 days), and this cycle is performed once or repeated twice or more. In an embodiment, intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which, among 14 days 40 64309488-v1155792.599942 contained in one treatment cycle, futibatinib or a pharmaceutically acceptable salt thereof is administered on days 1, 4, 8, and 11. In an embodiment, intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which, among 14 days contained in one treatment cycle, futibatinib or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 5, 7, 9, 11, and 13. In an embodiment, intermittent administration is according to an administration schedule based on a 14-day treatment cycle, in which, among 14 days contained in one treatment cycle, futibatinib or a pharmaceutically acceptable salt thereof is administered on days 1, 3, 5, 8, 10, and 12. In an embodiment, an example of the administration schedule is such that 160 mg of futibatinib or a pharmaceutically acceptable salt thereof is administered once a day on days 1, 3, 5, 8, 10, and 12. The dose of futibatinib or a pharmaceutically acceptable salt thereof can be reduced to 120 mg, 80 mg, 56 mg, 36 mg, 24 mg, 16 mg, or 8 mg.

[0154] In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 100 mg to about 400 mg per dose, or about 200 mg to about 400 mg per dose, or about 100 mg to 200 mg per dose, or about 150 mg to 200 mg per dose, or about 200 mg to 300 mg per dose, or about 250 mg to 300 mg per dose, or about 300 mg to 400 mg per dose, or about 350 mg to 400 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 100 mg to about 400 mg per dose, or about 200 mg to about 400 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg or about 400 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg per dose. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 1.0 to 2.0 mg / kg (body weight) per dose, or 2.0 mg / kg (body weight) per dose.

[0155] In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 100 mg to about 400 mg per dose once a day, or about 200 mg to about 400 mg per dose once a day, or about 100 mg to 200 mg per dose once a day, or about 150 mg to 200 mg per dose once a day, or about 200 mg to 300 mg per dose once a day, or about 250 mg to 300 mg per dose once a day, or about 300 mg to 400 mg per dose once a day, or about 350 mg to 400 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt 41 64309488-v1155792.599942 thereof administered is about 100 mg to about 400 mg per dose once a day, or about 200 mg to about 400 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg or about 400 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 200 mg per dose once a day. In an embodiment, an amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is about 1.0 to 2.0 mg / kg (body weight) per dose, or 2.0 mg / kg (body weight) per dose once a day.

[0156] In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered once a day on each day of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered once during a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered more than once during a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on at least day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, or day 10 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, and day 5 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 2 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 3 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 4 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 5 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 6 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 7 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 8 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is 42 64309488-v1155792.599942 administered on day 9 of a treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 10 of a treatment cycle.

[0157] In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of at least one 21-day treatment cycle. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of at least two 21-day treatment cycles. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of at least three 21-day treatment cycles. In an embodiment, pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of each additional 21- day treatment cycle up to thirty five (35) consecutive 21-day treatment cycles.

[0158] In an embodiment, the amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is held constant during a second or subsequent treatment cycle. In an embodiment, the amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is increased during a second or subsequent treatment cycle. In an embodiment, the amount of pembrolizumab or the pharmaceutically acceptable salt thereof administered is decreased during a second or subsequent treatment cycle.

[0159] In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once a day on each day of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered intermittently during a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once during a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered more than once during a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on consecutive days during a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on at least day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, or day 10 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically 43 64309488-v1155792.599942 acceptable salt thereof is administered on each of day 1, day 2, day 3, day 4, and day 5 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 2 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 3 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 4 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 5 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 6 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 7 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 8 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 9 of a treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 10 of a treatment cycle.

[0160] In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1 of the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 2 of the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 3 of the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 4 of the treatment cycle. In an embodiment, the at least 44 64309488-v1155792.599942 one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 5 of the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 6 of the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 7 of the treatment cycle.

[0161] In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for at least 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 2 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 3 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 4 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 5 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 6 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 7 days during the treatment cycle.

[0162] In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1 of the treatment cycle consecutively for 5 days during the treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 2 of the treatment cycle consecutively for 5 days during the treatment cycle.

[0163] In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-14 of a 14-day treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once a day 45 64309488-v1155792.599942 on each of days 1-21 of a 21-day treatment cycle. In an embodiment, at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once a day on each of days 1-28 of a 28-day treatment cycle.

[0164] In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of at least one 21-day treatment cycle. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of at least two 21- day treatment cycles. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of at least three 21-day treatment cycles. In an embodiment, the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of each additional 21-day treatment cycle up to thirty five (35) consecutive 21-day treatment cycles.

[0165] In an embodiment, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof administered is held constant during a second or subsequent treatment cycle. In an embodiment, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof administered is increased during a second or subsequent treatment cycle. In an embodiment, the amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof administered is decreased during a second or subsequent treatment cycle.

[0166] In an embodiment, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 10 mg / m2to about 2000 mg / m2, about 10 mg / m2to about 1000 mg / m2, about 40 mg / m2to about 800 mg / m2, about 40 mg / m2to about 400 mg / m2, about 80 mg / m2to about 200 mg / m2, about 200 mg / m2to about 800 mg / m2, about 400 mg / m2to about 1600 mg / m2, or about 400 mg / m2to about 800 mg / m2per dose. In an embodiment, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, about 240 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 46 64309488-v1155792.599942 mg / m2, about 1000 mg / m2, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2per dose. In an embodiment, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 40 mg / m2per dose. In an embodiment, an amount of the at least one additional anti-cancer therapy agent being administered is about 80 mg / m2per dose. In an embodiment, an amount of the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 120 mg / m2per dose. In an embodiment, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 400 mg / m2per dose. In an embodiment, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 800 mg / m2per dose. In an embodiment, an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 1000 mg / m2per dose.

[0167] The methods of the disclosure can comprise more than one additional anti- cancer therapy agent (i.e., at least two additional anti-cancer therapy agents) or the pharmaceutically acceptable salts thereof where each additional anti-cancer therapy agent may be administered at the same or different amount and at the same or different dosage frequency. When at least two additional anti-cancer therapy agents or the pharmaceutically acceptable salts thereof are administered, it is understood that the additional anti-cancer therapy agents or the pharmaceutically acceptable salts thereof may be administered sequentially (e.g., before or after) or simultaneously or substantially simultaneously, either in the same pharmaceutical formulation or pharmaceutical composition (i.e., formulated together) or in different pharmaceutical formulations or pharmaceutical compositions (i.e., formulated separately).

[0168] In an embodiment, the at least one additional anti-cancer therapy agent is 5- fluorouracil (5-FU) which is administered in an amount of about 800 mg / m2per dose. In an embodiment, the at least one additional anti-cancer therapy agent is 5-fluorouracil (5- FU) which is administered for 5 consecutive days in a treatment cycle in a total amount of about 4000 mg / m2during the treatment cycle. 47 64309488-v1155792.599942

[0169] In an embodiment, the at least one additional anti-cancer therapy agent is cisplatin which is administered in an amount of about 80 mg / m2per dose. In an embodiment, the at least one additional anti-cancer therapy agent is cisplatin which is administered on day 1 of a 21-day treatment cycle.

[0170] In an embodiment, the at least one additional anti-cancer therapy agent is 5- fluorouracil (5-FU) which is administered in an amount of about 400 mg / m2, about 600 mg / m2, about 1000 mg / m2, about 1200 mg / m2, or about 1500 mg / m2per dose. In an embodiment, the at least one additional anti-cancer therapy agent is 5-fluorouracil (5-FU) which is administered for two consecutive days in a treatment cycle in a total amount of about 2000 mg / m2, about 2400 mg / m2, about 2800 mg / m2, or about 3000 mg / m2, or about 3400 mg / m2during the treatment cycle.

[0171] In an embodiment, the at least one additional anti-cancer therapy agent is oxaliplatin which is administered in an amount of about 85 mg / m2or about 100 mg / m2per dose. In an embodiment, the at least one additional anti-cancer therapy agent is oxaliplatin which is administered on day 1 or day 2 of a 14- or 21-day treatment cycle.

[0172] In an embodiment, the at least one additional anti-cancer therapy agent is folinic acid which is administered in an amount of about 200 mg / m2or about 400 mg / m2per dose. In an embodiment, the at least one additional anti-cancer therapy agent is folinic acid which is administered on day 1 or day 2 of a 14- or 21-day treatment cycle.

[0173] In an embodiment, a method of the disclosure comprises at least two additional anti-cancer therapy agents. In an embodiment, the at least two additional anti-cancer therapy agents are 5-fluorouracil and cisplatin. In at embodiment, the at least two additional anti-cancer therapy agents are 5-fluorouracil and oxaliplatin. In at embodiment, the at least two additional anti-cancer therapy agents are 5-fluorouracil, oxaliplatin, and folinic acid.

[0174] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a treatment cycle of about 14 to about 28 days; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of 48 64309488-v1155792.599942 the treatment cycle; administering to the subject about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, or about 240 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

[0175] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a 21-day treatment cycle; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, or about 240 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

[0176] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject a therapeutically effective amount of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of during a 21-day treatment cycle; administering to the subject a therapeutically effective amount of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about a therapeutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, 49 64309488-v1155792.599942 day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

[0177] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject about 20 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a 21-day treatment cycle; administering to the subject about 200 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1 of the treatment cycle; administering to the subject about 80 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1 of the treatment cycle; and administering to the subject about 800 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 5 days starting from day 1 of the treatment cycle.

[0178] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject about 20 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof on each day of a 21-day treatment cycle; administering to the subject about 200 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 2 of the treatment cycle; administering to the subject about 80 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 2 of the treatment cycle; and administering to the subject about 800 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 5 starting from day 2 of the treatment cycle.

[0179] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject about 20 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof on each day of a 21-day treatment cycle; administering to the subject about 200 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1 of the treatment cycle; administering to the subject about 80 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1 of the treatment cycle; and administering to the subject about 5-fluorouracil or a pharmaceutically acceptable salt thereof in a total amount of about 4000 mg / m2during the treatment cycle. 50 64309488-v1155792.599942

[0180] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject about 20 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a 21-day treatment cycle; administering to the subject about 200 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1 of the treatment cycle; administering to the subject about 85 mg / m2per dose of oxaliplatin or a pharmaceutically acceptable salt thereof once on day 1 of the treatment cycle; administering to the subject about 400 mg / m2, about 600 mg / m2, about 1000 mg / m2, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days starting from day 1 of the treatment cycle; and administering to the subject about 200 mg / m2per dose of folinic acid or a pharmaceutically acceptable salt thereof consecutively for 2 days starting from day 1 of the treatment cycle.

[0181] In an embodiment, the method of treatment of the disclosure is evaluated using at least one of overall survival (OS), progression free survival (PFS), disease control rate (DCR), disease free survival (DFS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), duration of response (DOR), time to response (TTR), overall response rate (ORR), patient-reported outcomes, associated symptoms, and the like. For example, tumor evaluation for the combination therapy of the disclosure for solid tumors may be based on the RECIST v1.1 criteria (Response Evaluation Criteria in Solid Tumors), and an antitumor effect may be expressed by SD (stable disease), PR (partial response), CR (complete response), and PD (progressive disease).

[0182] In an embodiment, a method of treating a cancer of the disclosure improves overall survival (OS), progression free survival (PFS), disease control rate (DCR), disease free survival (DFS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), duration of response (DOR), time to response (TTR), overall response rate (ORR), patient-reported outcomes, associated symptoms, and combinations thereof.

[0183] In an embodiment, a method of treating a cancer of the disclosure results in (or achieves or provides) reduction in the number of cancer cells, reduction in tumor size, increase in overall survival, increase in progression free survival, complete response, 51 64309488-v1155792.599942 partial response, stable disease, improved duration of response, decrease in associated symptoms, reduction in the rate of cancer infiltration into peripheral organs, reduction in tumor metastasis, reduction in tumor growth, failure of tumors to reoccur after treatment has stopped, and combinations thereof in the subject.

[0184] In an embodiment, a method of treating a cancer of the disclosure increases the duration of progression free survival of a subject. In an embodiment, a method of treating a cancer of the disclosure increases the duration of progression free survival of a subject compared to another subject treated with monotherapy (e.g., compared to treatment with any one of the active agents of the disclosure alone). For example, a subject’s progression free survival is greater by at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 10 months, at least about 12 months, or at least about 18 months, compared to treatment with monotherapy. In an embodiment, a method of treating a cancer of the disclosure increases the duration of progression free survival of a subject compared to another subject treated with a combination of two of the active agents of the disclosure (i.e., futibatinib and pembrolizumab, or futibatinib and at least one additional anti-cancer therapy agent, or pembrolizumab and at least one additional anti-cancer therapy agent). For example, a subject’s progression free survival is greater by at least about 2 weeks, at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 10 months, at least about 12 months, or at least about 18 months, compared to treatment with a combination of two of the active agents of the disclosure (i.e., futibatinib and pembrolizumab, or futibatinib and at least one additional anti-cancer therapy agent, or pembrolizumab and at least one additional anti-cancer therapy agent).

[0185] In an embodiment, a method of treating a cancer of the disclosure increases the overall survival of a subject. In an embodiment, a method of treating a cancer of the disclosure increases the overall survival of a subject compared to another subject treated with monotherapy or compared to another subject treated with a combination of two of the active agents of the disclosure (i.e., futibatinib and pembrolizumab, or futibatinib and at least one additional anti-cancer therapy agent, or pembrolizumab and at least one additional anti-cancer therapy agent). For example, a subject’s overall survival is increased by at least about 1 month, at least about 2 months, at least about 3 months, at 52 64309488-v1155792.599942 least about 4 months, at least about 6 months, or at least about 1 year when compared to another subject treated with monotherapy (e.g., compared to treatment with any one of the active agents of the disclosure alone) or compared to another subject treated with a combination of two of the active agents of the disclosure. In an embodiment, the overall survival is increased by at least about 4 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 1 year, at least about 18 months or at least about 2 years compared to another subject treated with monotherapy (e.g., compared to treatment with any one of the active agents of the disclosure alone) or compared to another subject treated with a combination of two of the active agents of the disclosure. In an embodiment, the overall survival of the subject is increased by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50% or at least about 75% when compared to another subject treated with monotherapy (e.g., compared to treatment with any one of the active agents of the disclosure alone) or compared to another subject treated with a combination of two of the active agents of the disclosure.

[0186] In an embodiment, a method of treating a cancer of the disclosure achieves an overall response rate of equal to or greater than about 30% to 100%. The overall response rate is assessed in a population of subjects after treatment and can be determined by RECIST v1.1. For example, the population of subjects could be a group of human subjects with the same or substantially the same type of cancer who are treated by the method of the disclosure.

[0187] In an embodiment, the overall response rate is equal to or greater than about 30% 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 92%, 94%, 95%, 96% 97%, 98%, or 99%. In an embodiment, the overall response rate is equal to or greater than 40%. In an embodiment, the overall response rate is equal to or greater than 45%. In an embodiment, the overall response rate is equal to or greater than 50%. In an embodiment, the overall response rate is equal to or greater than 55%. In an embodiment, the overall response rate is equal to or greater than 60%. In an embodiment, the overall response rate is equal to or greater than 65%. In an embodiment, the overall response rate is equal to or greater than 70%. In an embodiment, the overall 53 64309488-v1155792.599942 response rate is equal to or greater than 75%. In an embodiment, the overall response rate is equal to or greater than 80%. In an embodiment, the overall response rate is equal to or greater than 85%. In an embodiment, the overall response rate is equal to or greater than 90%. In an embodiment, the overall response rate is equal to or greater than 95%.

[0188] In an embodiment, the overall response rate following administration according to the methods of the disclosure in a group of subjects is higher as compared to an overall response rate in another group of subjects treated with standard-of-care therapy. In an embodiment, the overall response rate following administration according to the methods of the disclosure in a group of subjects is higher as compared to an overall response rate of another group of subjects treated with a monotherapy or compared to another group of subjects treated with a combination of two of the active agents of the method of the disclosure. For example, the overall response rate after administration according to a method of the disclosure may be compared to treatment with one of the active agents of the disclosure alone (i.e., futibatinib or the pharmaceutically acceptable salt thereof, pembrolizumab or the pharmaceutically acceptable salt thereof, or the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof) or with at least two of the active agents of the disclosure in combination (i.e., futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof, or futibatinib or the pharmaceutically acceptable salt thereof and at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof, or pembrolizumab or the pharmaceutically acceptable salt thereof and at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof). For example, the overall response rate in a group of subjects is higher by at least about 50%, at least about 40%, at least about at 35%, at least about 30%, least about 25%, at least about 20%, at least bout 15%, at least about 10%, at least about 9%, at least about 8%, at least about 7%, at least about 6%, at least about 5%, at least about 4%, at least about 3%, at least about 2%, or at least about 1% when compared to another group of subjects treated with one of the active agents of the disclosure as a monotherapy or two of the active agents of the disclosure in combination.

[0189] In an embodiment, the overall response rate is improved relative to the overall response rate of administration of futibatinib or the pharmaceutically acceptable salt thereof or pembrolizumab or the pharmaceutically acceptable salt thereof alone (i.e., as a 54 64309488-v1155792.599942 monotherapy). In an embodiment, the overall response rate is improved relative to the overall response rate of administration of a combination of futibatinib or the pharmaceutically acceptable salt thereof and pembrolizumab or the pharmaceutically acceptable salt thereof. In an embodiment, the overall response rate is improved relative to the overall response rate of administration of a combination of futibatinib or the pharmaceutically acceptable salt thereof and at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof. In an embodiment, the overall response rate is improved relative to the overall response rate of administration of a combination of pembrolizumab or the pharmaceutically acceptable salt thereof and at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof.

[0190] The methods of the disclosure can provide a therapeutic effect that cannot be expected from monotherapies separately or even from a combination of any two of the active agents of the disclosure. In an embodiment of the present disclosure, the methods of the disclosure achieve increased therapeutic efficacy as compared to at least one of the measurement results of monotherapy treatment with any of the active agents of the disclosure or treatment with a combination of at least two of the active agents of the disclosure. In an embodiment, the increased therapeutic efficacy is measured by at least one of a reduction in the number of cancer cells, a reduction in tumor size, an increase in overall survival, an increase in progression free survival, a complete response, a partial response, stable disease, improved duration of response, a decrease in associated symptoms, a reduction in the rate of cancer infiltration into peripheral organs, a reduction in tumor metastasis, a reduction in tumor growth, failure of tumors to reoccur after treatment has stopped, and any combination thereof.

[0191] As disclosed herein, administration in accordance with the method of the disclosure can result in synergistic effects in treating cancer. These synergistic effects can be such that the one or more effects of the combination are greater than the one or more effects of each component alone at a comparable dosing level, or they can be greater than the predicted sum of the effects of all of the components at a comparable dosing level, assuming that each component acts independently. In an embodiment, the synergistic effect of the combination therapy can allow for reduced dosing amounts, possibly leading to reduced side effects to the subject and reduced cost of treatment. Furthermore, the 55 64309488-v1155792.599942 synergistic effect can allow for results that are not achievable through any other treatments.

[0192] In an embodiment, a method for treating a cancer in a subject in need thereof, comprises administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof, such that the futibatinib or a pharmaceutically acceptable salt thereof, the pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof act synergistically to treat the cancer.

[0193] Also within the scope of the present disclosure is a kit treating cancer in a subject in need thereof comprising futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. Kits typically include a label indicating the intended use of the contents of the kit and instructions for use. The term label includes any writing, or recorded material supplied on or with the kit, or which otherwise accompanies the kit, including an instruction manual.

[0194] In an embodiment, the kit contains the futibatinib or a pharmaceutically acceptable salt thereof, the pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof as separate compositions for use in any method disclosed herein. In some embodiments, the kit comprises futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof and instructions for administration according to any methods disclosed herein.

[0195] The present disclosure also pertains to futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, or use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of a cancer. 56 64309488-v1155792.599942

[0196] The present disclosure also pertains to a pharmaceutical composition comprising a first composition comprising futibatinib or a pharmaceutically acceptable salt thereof, a second composition comprising pembrolizumab or a pharmaceutically acceptable salt thereof, and a third composition comprising at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of cancer. In some embodiments, the first composition further comprises a first pharmaceutically acceptable carrier. In some embodiments, the second composition further comprises a second pharmaceutically acceptable carrier. In some embodiments, the third composition further comprises a third pharmaceutically acceptable carrier.

[0197] The present disclosure also pertains to a use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a cancer. EXAMPLES

[0198] The following examples are provided for the purpose of further illustration only and are not intended to be limitations on the disclosure.

[0199] Example 1: A Phase 1b Study to Assess the Safety, Tolerability, and Efficacy of Futibatinib in Combination with Pembrolizumab in Patients with Solid Tumors

[0200] 1. Overview of the Study Design

[0201] A phase 1b, open-label, nonrandomized, multicenter study was conducted. The study had two phases: (i) a feasibility phase to assess the safety and tolerability of futibatinib in combination with pembrolizumab in patients with advanced or metastatic solid tumors; and (ii) an expansion phase (having five cohorts) to evaluate the efficacy, safety and pharmacodynamics in patients with advanced or metastatic esophageal carcinoma or NSCLC. In phase (i), a maximum total of 38 patients were planned to be enrolled, where 10 or 14 patients were to be allocated in each dose level. In phase (ii), a maximum total of 185 were planned to be enrolled, 52 patients in Cohort A, 50 patients in Cohort B, 30 patients in Cohort C, 38 patients in Cohort D, and 15 patients in Cohort E. 57 64309488-v1155792.599942

[0202] The study sites were located in Japan. The treatment group in the feasibility phase and Cohort D in the expansion phase included three dose level cohorts where patients received futibatinib and pembrolizumab, or futibatinib, pembrolizumab, fluorouracil, and cisplatin. The safety data was evaluated after the completion of each dose level. The next dose level commenced only after written approval was obtained from the data monitoring committee (DMC).

[0203] 2. Dose Finding in the Feasibility Phase and Cohort D in the Expansion Phase

[0204] In the feasibility phase and Cohort D in the expansion phase of the study, the three dose levels (Table 1) were set to determine the recommended dose (RD), and a target dose limiting toxicity (DLT) rate of less than or equal 30% were applied for confirmation to determine a RD for futibatinib in combination with pembrolizumab or in combination with pembrolizumab, 5-fluorouracil, and cisplatin. A maximum of 10 patients were treated at each dose level prior to the next dose level. In the event DLTs were observed in four or more patients in a given dose level (during feasibility phase and / or Cohort D of the expansion phase) or RD was determined in a given dose level (during the feasibility phase), the enrollment of patients was discontinued in that dose level.

[0205] Table 1: Dosage of each drug used in the clinical study in the feasibility phase and Cohort D in the expansion phase Dose level Pembrolizumab Futibatinib 5-Fluorouracil Cisplatin Level 1 (starting 200 mg Q3W 20 mg QD 4000 mg / m2 / cycle 80 mg / m2Q3W dose) Level−1 200 mg Q3W 16 mg QD 4000 mg / m2 / cycle 80 mg / m2Q3W Level−2 200 mg Q3W 12 mg QD 4000 mg / m2 / cycle 80 mg / m2Q3W

[0206] The starting dose was 20 mg of futibatinib once daily (QD) (level 1). Regarding futibatinib, dose modifications were not allowed during cycle 1 in the feasibility phase and in Cohort D of the expansion phase. The dose of pembrolizumab, 5-fluorouracil, and cisplatin were fixed in all dose levels. The dose of futibatinib was only changed from 20 mg to 16 mg (level−1) and from 16 mg to 12 mg (level−2).

[0207] 3. Definitions of Dose-Limiting Toxicity 58 64309488-v1155792.599942

[0208] The occurrence of any of the following toxicities during cycle 1 was considered a DLT if it was determined to be related to pembrolizumab, futibatinib, 5-fluorouracil, or cisplatin. All toxicities were graded using Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (https: / / ctep.cancer.gov / protocolDevelopment / electronic_applications / ctc.htm#ctc_50). A DLT was defined as shown in the following: (1) Grade 4 nonhematologic toxicity (not laboratory). (2) Grade 4 hematologic toxicity lasting ≥ 7 days, except thrombocytopenia: • Grade 4 thrombocytopenia of any duration. • Grade 3 thrombocytopenia associated with clinically significant bleeding. (3) Any nonhematologic adverse event (AE) ≥ grade 3 in severity was considered a DLT, with the following exceptions: grade 3 fatigue lasting ≤ 3 days; grade 3 diarrhea, nausea, or vomiting without use of antiemetics or antidiarrheals per standard of care; grade 3 diarrhea, nausea, or vomiting lasting ≤ 3 days with the use of antiemetics or antidiarrheals per standard of care; grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard of care. (4) Grade 3 or higher ocular toxicity. (5) Ectopic de novo calcification in soft tissues. (6) Any grade 3 or grade 4 nonhematologic laboratory value if any of the following was met: • Clinically significant medical intervention was required to treat the patient. • The abnormality lead to hospitalization. • The abnormality persisted for > 1 week. • The abnormality resulted in a drug induced liver injury. • Hyperphosphatemia: a. Any increase of serum phosphorus ≥ 10 mg / dL b. An increase of serum phosphorus ≥ 7 mg / dL lasting for 7 days or more despite phosphate-lowering treatments for 7 days. 59 64309488-v1155792.599942 (7) Febrile neutropenia Grade 3 or 4: • Grade 3 was defined as absolute neutrophil count (ANC) < 1000 / mm3with a single temperature > 38.3°C or a sustained temperature ≥ 38°C for more than 1 hour. • Grade 4 was defined as ANC < 1000 / mm3with a single temperature > 38.3°C or a sustained temperature ≥ 38°C for more than 1 hour, with life-threatening consequences and urgent intervention indicated. (8) Prolonged delay (> 2 weeks) in initiating cycle 2 owing to treatment-related toxicity. (9) Any treatment-related toxicity that caused the patient to discontinue treatment during cycle 1. (10) Missing > 25% of futibatinib doses as a result of treatment-related AE(s) during the first cycle. (11) Grade 5 toxicity. Whether abnormal laboratory values (except the hematologic toxicities and nonhematologic toxicities described above) and transient signs or symptoms were DLTs was determined.

[0209] 4. Inclusion Criteria

[0210] Patients were eligible to be included in the study if all of the following criteria were met (the following inclusion criteria were common to all phases): (1) Were willing and able to provide written informed consent for the trial. (2) Were ≥ 20 years of age on day of signing informed consent. (3) Able to take medications orally. (4) A male patient agreed to use contraception during the treatment period and for at least 180 days. A list of effective contraceptive methods for this protocol was provided to the male patient. (5) A female patient was eligible to participate if she was not pregnant, not breastfeeding, and at least one of the following conditions applied: a. Not a women of childbearing potential (WOCBP) 60 64309488-v1155792.599942 b. A WOCBP who agreed to follow contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment. c. A WOCBP who had a negative urine pregnancy test within 7 days prior to treatment. If the urine test was positive or cannot be confirmed as negative, a serum pregnancy test was required. (6) Had a measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 (Eur. J. Cancer. (2009) 45:228-247) as assessed by the local site Investigator / radiology. Lesions situated in a previously irradiated area were considered measurable if progression had been demonstrated in such lesions. (7) Had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. (8) Had an adequate organ function as defined in the following table (Table 2).

[0211] Table 2: Adequate Organ Function Laboratory Values 61 64309488-v1155792.599942 System Laboratory Value Hematological Absolute neutrophil count ≥ 1000 / mm3Platelets ≥ 100000 / mm3Hemoglobin ≥ 9.0 g / dLaRenal Measuredbor calculatedcCrCl ≥ 50 mL / min (GFR can also be used in place of CrCl.) ≥ 60 mL / min (only cohort D) Hepatic Total bilirubin ≤ 1.5 × ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 × ULN AST and ALT ≤ 2.5 × ULN (≤5 × ULN for patients with liver metastases) Coagulation INR or PT ≤ 1.5 × ULN unless the patient is receiving aPTT anticoagulant therapy as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants OthersSerum phosphorus ≤ ULN Serum calcium ≤ ULN a Criteria was met without erythropoietin dependency and without packed RBC transfusion within the last 2 weeks. b CrCl was calculated using the Cockcroft–Gault formula: • Male CrCl (mL / min) = Body weight (kg) × (140 – age) / (72 × creatinine [mg / dL]) • Female CrCl (mL / min) = male CrCl × 0.85 c A measured CrCl value (i.e., not calculated) met this criterion. Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements were adapted according to local regulations and guidelines for the administration of specific chemotherapies. (9) Willing and able to comply with scheduled visits and study procedures. (10) Had histologically confirmed advanced or metastatic esophageal carcinoma regardless of histologic type. (11) Had not received prior treatment with systemic chemotherapy and anti-PD-1 / PD- L1 mAb: 62 64309488-v1155792.599942 a. Patients who had received preoperative or postoperative adjuvant chemotherapy, and had recurrence during or within 6 months of completion of the adjuvant chemotherapy were allowed to count the adjuvant therapy as one prior treatment for advanced or metastatic disease.

[0212] 5. Exclusion Criteria

[0213] Patients were excluded from the study if any of the following criteria applied: Medical conditions 1. History and / or current evidence of clinically significant nontumor related alteration of calcium–phosphorus homeostasis. 2. History and / or current evidence of clinically significant ectopic mineralization / calcification. 3. History and / or current evidence of clinically significant retinal disorder confirmed by retinal examination. 4. History and / or current evidence of serious uncontrolled ventricular arrhythmias. 5. Fridericia’s corrected QT interval > 470 msec on electrocardiogram conducted during screening. Prior / concomitant therapy 6. Had received prior therapy with anti-PD-1, anti-PD-L1 / L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137), and was discontinued from that treatment owing to a grade 3 or higher immune-related adverse event (irAE). Note: This criterion was applied for patients who have received anti-PD-1, anti- PD-L1 / L2 agent. 7. Had received prior treatment with any of the following within the specific time frame prior to the first dose of study treatment: 63 64309488-v1155792.599942 a. If the patient received major surgery within the previous 4 weeks. b. Any noninvestigational anticancer therapy within 3 weeks (mitomycin within prior 5 weeks) c. Targeted therapy or immunotherapy within 3 weeks or within 5 half-lives (whichever is shorter) d. Any investigational agent received within 5 half-lives of the drug or 4 weeks, whichever was shorter. Concurrent participation in an observational study was allowed after review. Note: Patients must have recovered from all AEs due to previous therapies to ≤ grade 1 or baseline. Patients with ≤ grade 2 neuropathy, anemia, alopecia, and skin pigmentation were eligible. Patients with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement were eligible. 8. Had received prior radiotherapy within 2 weeks of start of study treatment or had had a history of radiation pneumonitis. Note: Patients must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout was permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-central nervous system disease. 9. Had received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment examples of live vaccines including but not limited to the following: measles, mumps, rubella, varicella / zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and were allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and were not allowed. 10. Had prior FGFR-directed therapy including futibatinib. 11. Had received radiation therapy to the lung that is >30Gy within 6 months of the first dose of study treatment. 64 64309488-v1155792.599942 Prior / concurrent clinical study experience 12. Was currently participating in or had participated in a study of an investigational agent or had used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who had entered the follow-up phase of an investigational study participated as long as it has been 4 weeks after the last dose of the previous investigational agent. Diagnostic assessments 13. Had a diagnosis of immunodeficiency or was receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment. 14. History of other primary malignancy in the last 5 years (except Cohort E). Patients with prior history of localized other primary malignancies such as in situ cancer, basal / localized squamous cell skin cancer, or others were eligible if they were considered curable by surgery alone or surgery plus radiotherapy. Note: Gonadotropin-releasing hormone or luteinizing hormone–releasing hormone was allowed. 15. Had known active central nervous system metastases and / or carcinomatous meningitis. Patients with previously treated brain metastases participated provided they were radiologically stable, i.e., without evidence of progression for at least 8 weeks by repeat imaging (note that the repeat imaging was performed during study screening), clinically stable, and without steroid treatment requirement for at least 1 month prior to the first dose of study treatment. 16. Had severe hypersensitivity (≥ grade 3) to pembrolizumab and / or any of its excipients. Note: This criterion was applied for patients who have received pembrolizumab. 65 64309488-v1155792.599942 17. History of allergic reactions attributed to compounds of similar chemical or biologic composition to futibatinib and any drug similar to futibatinib in structure or class. 18. Had an active autoimmune disease that had required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) was not considered a form of systemic treatment and was allowed. 19. Had a history of (noninfectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. 20. Had an active infection requiring systemic therapy. 21. With known human immunodeficiency virus (HIV) and / or history of hepatitis B or C infections or known to be positive for hepatitis B antigen / hepatitis B virus deoxyribonucleic acid (DNA) or hepatitis C antibody or ribonucleic acid (RNA). 22. Active hepatitis C was defined by a known positive hepatitis C mAb result and known quantitative hepatitis C virus-RNA results greater than the lower limits of detection of the assay. 23. Had a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that confounded the results of study or interfere with the patient's participation for the full duration of the study, such that it was not in the best interest of the patient to participate. 24. Had a known psychiatric or substance abuse disorder that would interfere with the patient’s ability to cooperate with the requirements of the study. 25. Myocardial infarction, severe / unstable angina, symptomatic congestive heart failure (New York Heart Association class III or IV) within the previous 2 months; if > 2 months, cardiac function was within normal limits, and the patient was free of cardiac-related symptoms. 66 64309488-v1155792.599942 26. Pleural effusion, ascites, or pericardial effusion requiring drainage within 4 weeks prior to enrollment. 27. Chronic nausea, vomiting, or diarrhea that was considered clinically significant. 28. Congenital long QT syndrome, any known history of torsade de pointes, or family history of unexplained sudden death. 29. Known severe chronic kidney disease. 30. Diseases that affect the gastrointestinal absorption of the compound or resection of the stomach or small intestine. 31. Had a history of serious hypersensitivity to any ingredient of 5-fluorouracil (only Cohort D). 32. Had a history of hypersensitivity to cisplatin or other platinum-containing drugs (only Cohort D) Other exclusions 33. Had had an allogenic tissue / solid organ transplant. 34. Otherwise determined to be ineligible as a patient of the study.

[0214] 6. Estimation of the Sample Size

[0215] In Cohort D, a statistical rationale did not exist. A sample size that was considered sufficient to evaluate the tolerability of futibatinib in combination with pembrolizumab, fluorouracil, and cisplatin was determined.

[0216] 7. Results

[0217] As of March 15, 2023, 11 patients (Cohort D) were enrolled. As to the results of the analysis for cut-off data, DLT was observed in one patient (Grade 3, Stomatitis). RD of futibatinib in combination with pembrolizumab and chemotherapy was determined as 20 mg QD. In Cohort D, the most common treatment-related adverse events (TRAEs) 67 64309488-v1155792.599942 (N=11; all grade, grade ≥3) were hyperphosphatemia (82%, 0%) and stomatitis (82%, 9.1%). Among the eight patients evaluated for efficacy in Cohort D, confirmed partial responses (cPRs) and unconfirmed partial responses (uPRs) were observed in two patients and five patients, respectively. Five patients were undergoing ongoing treatment. The percentage of 30% decrease in the sum of diameters of target lesions was 87.5% (7 / 8).

[0218] Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters (Eur. J. Cancer. (2009) 45:228- 247).

[0219] Example 2: A Phase 1b Study of Futibatinib Plus Pembrolizumab with or without Chemotherapy in Patients with Esophageal Carcinoma: Antitumor Activity

[0220] Background: Futibatinib (Futi) has been approved for the treatment of patients with advanced (adv) intrahepatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement based on the results of the pivotal phase 2 study (NCT02052778). Combination therapy using FGFR inhibitors and Immune checkpoint inhibitors (ICIs) are being explored as a novel strategy for cancer patients (pts). Previously, we reported the preliminary encouraging antitumor activity of Futi 20 mg once daily (QD) that is a highly selective and irreversible FGFR inhibitor plus pembrolizumab (Pem) with or without chemotherapy in pts with adv or metastatic esophageal carcinoma (EC). Here, updated results are being presented. Methods: In cohort D (COD), 1st line pts who were chemotherapy and ICI naïve for adv or metastatic EC received Futi 20mg QD plus Pem 200 mg / q3w, fluorouracil 800 mg / m2 on days 1-5 and cisplatin 80 mg / m2 every 3weeks. In cohort A (COA) and B (COB), adv or metastatic EC pts with at least one prior therapy with a fluorouracil and platinum-based drug received Futi 20mg QD plus Pem 200mg / q3w if ICI naïve or ICI refractory, respectively. Primary endpoint was dose- limiting toxicity (DLT) in COD, and overall response rate (ORR) in COA and B. Secondary endpoints included disease control rate (DCR), duration of response (DOR) and treatment-related adverse events (TRAEs). Results: As of October 31, 2023, 36 pts (COA), 50 pts (COB) and 21 pts (COD) were enrolled and the treatments are ongoing in 20 pts (COA: 12 pts and COD: 8 pts). In COD (n=19), confirmed partial responses (cPRs) were observed in 13 pts (12 pts were squamous cell carcinoma [scc]; 1 pt was 68 64309488-v1155792.599942 adenocarcinoma [adeno]); ORR was 68.4% (95% CI: 43.4, 87.4) with DCR of 89.5% and median DOR (mDOR) was 5.6 months (median follow up [mfu]: 3.9 months). One pt became resectable due to tumor shrinkage. In COA (n=35), confirmed complete response and cPRs were observed in 1 and 14 pts (all pts were scc), respectively; ORR was 42.9% (95% CI: 26.3, 60.6) with DCR of 71.4% and mDOR was 16.0 months (mfu: 6.2 months). In COB (n=49), cPRs were observed in 3 pts (2 pts were scc; 1 pt was adeno); ORR was 6.1% (95% CI: 1.3, 16.9) with DCR of 51.0% and mDOR was 4.7 months (mfu: 4.7 months). In COD, common TRAEs (all grade, grade $3) were hyperphosphatemia (85.7%, 0%), Neutrophil count decreased (66.7%, 57.1%) and stomatitis (66.7%, 14.3%). One DLT was observed in COD (Grade 3, Stomatitis), In COA, common TRAEs were hyperphosphatemia (91.7%, 0%), diarrhea, stomatitis and nail disorder (22.2%, 0%) and in COB, hyperphosphatemia (80.0%, 0%), stomatitis (20.0%, 2.0%) and diarrhea (20.0%, 0%). Conclusions: Futi plus Pem with or without chemotherapy showed promising antitumor activity in adv or metastatic EC pts with both histology of scc and adeno. Futi plus Pem and chemotherapy was safe and manageable with no new safety signals observed in 1st line pts with adv or metastatic EC.

[0221] Introduction

[0222] Esophageal carcinoma (EC) is an aggressive malignancy with a poor survival outcome; 5-year survival rates range from 15% to 20%. Platinum plus fluorouracil–based chemotherapy, with or without an anti–programmed cell death protein 1 antibody, is the preferred standard of care for the first-line treatment of EC; immune checkpoint inhibitors (ICIs), including pembrolizumab and nivolumab, have shown survival benefits in this setting. In preclinical mouse models, the combination of ICIs with fibroblast growth factor receptor (FGFR) inhibitors enhanced antitumor immunity and improved survival; combination therapy with FGFR inhibitors and ICIs is therefore being explored as a novel strategy for patients with cancer. Futibatinib is an oral, highly selective, potent, irreversible inhibitor of FGFR1–4 that has been approved in the United States, European Union, United Kingdom, and Japan for the treatment of patients with advanced cholangiocarcinoma harboring an FGFR2 fusion or rearrangement based on the results of the pivotal Phase 2 FOENIX-CCA2 study. The safety and tolerability of futibatinib plus pembrolizumab in Japanese patients with advanced or metastatic solid tumors, together 69 64309488-v1155792.599942 with preliminary antitumor activity in patients with EC, has previously been reported. Preliminary results from the study is presented.

[0223] Methods

[0224] This open-label, multicenter, nonrandomized, Phase 1b study (jRCT2080224975) consisted of a feasibility phase and an expansion phase; here, we present the three-cohort expansion phase (FIG.1). Anti-tumor activity was assessed by CT / MRI imaging every 6 weeks according to Response evaluation criteria in solid tumors (RECIST) v1.1. Safety was assessed using Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 for grading of AEs. The central laboratory of programmed cell death ligand 1 (PD-L1) expression was evaluated by immunohistochemistry using the 22C3 assay. The test was performed voluntarily.

[0225] The full analysis set (FAS) comprised all enrolled patients, including those who met the following criteria: Received futibatinib, pembrolizumab (Cohorts A and B) or futibatinib, pembrolizumab, fluorouracil, and cisplatin (Cohort D). RECIST v1.1 was performed at baseline and at least one tumor evaluation while on treatment.

[0226] Cohorts A and B: The primary objective was to evaluate the antitumor activity of futibatinib plus pembrolizumab in patients with advanced or metastatic EC. Patients were previously treated with ≥1 prior fluorouracil and platinum–based regimen and were either ICI-naïve (Cohort A) or ICI-refractory (Cohort B).

[0227] Cohort D: The primary objective was to evaluate tolerability and identify the recommended dose (RD) of futibatinib plus pembrolizumab and chemotherapy in patients with advanced or metastatic EC who were chemotherapy- and ICI-naïve. At each dose level, ≤10 patients were evaluated before moving to the next dose; if dose-limiting toxicity (DLT) was observed in ≥4 patients or the RD was determined, patient enrollment was discontinued. After the RD was determined, ≤38 patients were enrolled to evaluate efficacy and safety.

[0228] Results

[0229] Patient Population

[0230] As of February 29, 2024, 36 patients (Cohort A), 50 patients (Cohort B), and 21 patients (Cohort D) had been enrolled, 35 patients (Cohort A), 49 patients (Cohort B), and 20 patients (Cohort D) was in the FAS. Most patients were male (78.8%) and had an 70 64309488-v1155792.599942 ECOG PS of 0 (75.0%).90.4% of patients had esophageal squamous cell carcinoma (ESCC) and 8.7% had adenocarcinoma (Ad) were included in the FAS (Table 3)

[0231] Table 3: Baseline Demographics and Disease Characteristics (FAS) Cohort ACohort B Cohort D (n=35) (n=49) (n=20) Age Median (range), years 66.0 (42–79) 63.0 (47–81) 68.0 (43–78) <65 years, n (%) 17 (48.6) 31 (63.3) 9 (47.4) ≥65 years, n (%) 18 (51.4) 18 (36.7) 10 (52.6) Sex, n (%) Male 29 (82.9) 39 (79.6) 14 (70.0) Female 6 (17.1) 10 (20.4) 6 (30.0) ECOG PS, n (%) 0 26 (74.3) 35 (71.4) 17 (85.0) 1 9 (25.7) 14 (28.6) 3 (15.0) Histological type, n (%) Squamous cell carcinoma 33 (94.3) 44 (89.8) 17 (85.0) Adenocarcinoma 2 (5.7) 4 (8.2) 3 (15.0) Adenosquamous carcinoma 0 1 (2.0) 0 No. of metastatic sites, n (%) 0 1 (2.9) 2 (4.1) 0 1 14 (40.4) 17 (34.7) 5 (25.0) 2 13 (37.1) 14 (28.6) 11 (55.0) ≥3 7 (20.0) 16 (32.7) 4 (20.0) Type of cancer, n (%) Esophageal 34 (97.1) 46 (93.9) 19 (95.0) Gastroesophageal junction 1 (2.9) 3 (6.1) 1(5.0) No. of prior therapies, n (%) 1 21 (60.0) 9 (18.4) 0 2 13 (37.1) 11 (22.4) 0 ≥3 1 (2.9) 29 (59.2) 0 Prior therapies, n (%) Neo-adjuvant chemotherapy 8 (22.9) 8 (16.3) 0 Adjuvant chemotherapy 3 (8.6) 8 (16.3) 0 Palliative chemotherapy 29 (82.9) 47 (95.9) 0 Prior surgery, n (%) Yes17 (48.6) 30 (61.2) 2 (10.0)71 64309488-v1155792.599942 Prior radiotherapy, n (%) Yes25 (71.4) 30 (61.2) 2 (10.0)FGFR mRNA overexpression level (designated central ※ laboratory data) Negative 7 (20.0) 5 (10.2) 3 (15.0) Positive 28 (80.0) 44 (89.8) 17 (85.0) FGFR 1 4 (11.4) 8 (16.3) 3 (15.0) FGFR 2 15 (42.9) 21 (42.9) 9 (45.0) FGFR 3 16 (45.7) 31 (63.3) 9 (45.0) FGFR 4 11 (31.4) 20 (40.8) 5 (25.0) PD-L1 (CPS) local＋central data ≥10 8 (22.9) 11 (22.4) 7 (35.0) <10 9 (25.7) 8 (16.3) 2 (10.0) NE 1 (2.9) 0 0 No data 17 (48.6) 30 (61.2) 11 (55.0) Data cutoff February 29, 2024. CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; FAS, full analysis set; FGFR, fibroblast growth factor receptor; NA, not available; NE, not estimable; PD-L1, programmed cell death ligand 1. ※The subtype in which the expression was higher than the cut-off value was considered be positive. If all FGFRs were not overexpressed or not tested, the total result was considered to be negative.

[0232] Antitumor Activity

[0233] In Cohort D, the confirmed overall response rate (ORR) was 14 / 20 (70.0%, 95%CI：45.7, 88.1) (FIG.2A), disease control rate (DCR) was 18 / 20 (90.0%, 95%CI:68.3, 98.8), and median duration of response (mDOR) was 6.5 months (median follow-up 5.6 months, range 0.9-10.5) (FIG.2B). Confirmed partial responses (PRs) 72 64309488-v1155792.599942 were observed in 13 patients with ESCC and 1 patient with Ad. The ORR was 12 / 17 (70.6%) in FGFR mRNA overexpression–positive patients and 2 / 3 (66.7%) in negative patients (FIG.2A).

[0234] In Cohort A, the ORR was 15 / 35 (42.9%, 95%CI：26.3, 60.6) (FIG.3A), DCR was 25 / 35 (71.4%, 95%CI:53.7,85.4), and mDOR was 14.1 months (median follow-up 13.5 months, range 3.0-32.9) (FIG.3B). The median overall survival (OS) was 11.9 months (95%CI:8.3,－）(FIG.5A), and the median progression-free survival (PFS) was 5.8 months（95%CI：3.2,10.6）(FIG.5B). Most of the enrolled patients had ESCC (33 among 35), while only 2 patients had Ad. PRs were observed in patients with ESCC. The ORR was 11 / 28 (39.3%) in FGFR mRNA overexpression–positive patients and 4 / 7 (57.1%) in negative patients (FIG.3A).

[0235] In Cohort B, the ORR was 3 / 49 (6.1%, 95%CI:1.3,16.9) (FIG.4A), DCR was 25 / 49 (51.0%, 95%CI:36.3-65.6), and mDOR was 6.0 months (median follow up 6.0 months, range 3.4-9.0) (FIG.4B). The median OS was 8.8 months（95%CI：5.5,9.9）(FIG. 5A), and the median PFS was 3.0 months（95%CI：1.8, 3.4）(FIG.5B).

[0236] Safety and DLT (Cohort D)

[0237] Safety among patients is summarized in FIG.6; the analyses were performed for all treated patients (36 patients in Cohort A, 50 patients in Cohort B and 21 patients in Cohort D).

[0238] In Cohort D, DLT was observed in 1 patient (Grade 3 stomatitis).2 patients resulted in death and discontinuation due to treatment related adverse events (TRAE). 2 patients died due to multiple organ dysfunction syndrome and pneumonia (1 each). 2 patients discontinued the treatment due to mucosal inflammation and encephalitis (1 each). Most common TREAs (grade ≥3) were neutrophil count decreased (57.1%) and anaemia (23.8%).

[0239] Conclusions

[0240] The first-line combination of futibatinib plus pembrolizumab / chemotherapy was safe and tolerable with no new safety signals observed relative to treatment with futibatinib or pembrolizumab / chemotherapy alone. 73 64309488-v1155792.599942

[0241] Futibatinib plus pembrolizumab / chemotherapy demonstrated antitumor activity exceeding historical efficacy data for 1st line pembrolizumab / chemotherapy in 1st line advanced or metastatic EC (70% ORR vs 45% ORR in KEYNOTE 590).

[0242] Futibatinib plus pembrolizumab showed encouraging antitumor activity in patients with ICI-naïve, advanced or metastatic EC (43% ORR).

[0243] Anti-tumor activity was observed regardless of FGFR mRNA overexpression.

[0244] Further development of futibatinib plus ICIs ± chemotherapy in western and Japanese patients are underway in patients with ICI-naïve advanced or metastatic EC. 74 64309488-v1

Claims

155792.599942 WE CLAIM:

1. A method for treating a cancer in a subject in need thereof, comprising administering to the subject futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the at least one additional anti-cancer therapy agent is a chemotherapeutic agent.

3. The method of claim 1 or 2, wherein the futibatinib or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

4. The method of any one of claims 1-3, wherein the pembrolizumab or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

5. The method of any one of claims 1-4, wherein the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

6. The method of any one of claims 1-5, wherein the at least one additional anti- cancer therapy agent is selected from the group consisting of: an antimetabolite, an alkaloid antitumor agent, a platinum-containing drug, a molecular targeting drug, an antitumor antibiotic, an alkylating agent, a hormonal therapy agent, a folic acid replenisher, an anti-androgen, and any combination thereof.

7. The method of any one of claims 1-6, wherein the at least one additional anti- cancer therapy agent is selected from the group consisting of: fludarabine, cladribine, nelarabine, 5-fluorouracil, tegafur / gimeracil / oteracil potassium, tegafur / uracil, trifluridine / tipiracil hydrochloride, capecitabine, doxifluridine, 5-fluoro-2'-deoxyuridine, 75 64309488-v1155792.599942 gemcitabine, cytarabine, pemetrexed, methotrexate, paclitaxel, nanoparticle albumin- bound paclitaxel, docetaxel, cabazitaxel, eribulin, irinotecan (CPT-11), nogitecan (topotecan), etoposide, teniposide, vinorelbine, vincristine, vinblastine, trabectedin, lurbinectedin, cisplatin, carboplatin, oxaliplatin, nedaplatin, tretinoin (ATRA), imatinib, gefitinib, erlotinib, lapatinib, sunitinib, dasatinib, everolimus, temsirolimus, selumetinib, trametinib, sorafenib, afatinib, regorafenib, dabrafenib, vemurafenib, pifusertib, MK2206, trastuzumab, cetuximab, bevacizumab, panitumumab, veltuzumab, rituximab, ramucirumab, nivolumab, atezolizumab, durvalumab, avelumab, ipilimumab, tremelimumab, abatacept, doxorubicin, daunorubicin, epirubicin, actinomycin D, mitomycin C, cyclophosphamide, dacarbazine, temozolomide, nimustine, busulfan, procarbazine, melphalan, calcium folinate hydrate, calcium levofolinate hydrate, folinic acid, potassium oxonate, prednisone, megestrol acetate, ethinylestradiol, tamoxifen, 4- hydroxy tamoxifen, toremifene keoxifene, onapristone, raloxifene, anastrozole, letrozole, exemestan, flutamide, nilutamide, bicalutamide, leuprolide, goserelin, palbociclib, abemaciclib, ribocyclib, and any combination thereof.

8. The method of any one of claims 1-7, wherein the at least one additional anti- cancer therapy agent is selected from the group consisting of 5-fluorouracil, cisplatin, oxaliplatin, calcium folinate hydrate, calcium levofolinate hydrate, and any combination thereof.

9. The method of any one of claims 1-8, comprising administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of cisplatin or a pharmaceutically acceptable salt thereof. 76 64309488-v1155792.599942 10. The method of any one of claims 1-8, comprising administering to the subject a therapeutically effective amount of 5-fluorouracil or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of oxaliplatin or a pharmaceutically acceptable salt thereof.

11. The method of any one of claims 1-10, wherein the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, duodenum cancer, liver cancer, hepatocellular cancer, biliary tract cancer, pancreatic cancer, colorectal cancer, breast cancer, uterine cancer, ovarian cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, thyroid cancer, bone or soft tissue tumor, leukemia, malignant lymphoma, multiple myeloma, head and neck cancer, brain tumor, skin cancer, mesothelioma, and cancer of unknown primary.

12. The method of claim 11, wherein the cancer is esophageal cancer.

13. The method of claim 12, wherein the subject has not been previously treated with a chemotherapy agent and / or anti-PD-1 / PD-L1 monoclonal antibody for the esophageal cancer.

14. The method of claim 11, wherein the cancer is an advanced, metastatic, irreversible, resistant, or intractable cancer.

15. The method of any one of claims 1-14, wherein the subject is a human.

16. The method of any one of claims 1-15, wherein the administering is for at least one treatment cycle.

17. The method of claim 16, wherein the treatment cycle is about 14 to about 28 days.

18. The method of claim 16 or 17, wherein the treatment cycle is about 21 days. 77 64309488-v1155792.599942 19. The method of any one of claims 16-18, wherein the futibatinib or the pharmaceutically acceptable salt thereof is administered once a day on each day of the treatment cycle.

20. The method of any one of claims 16-19, wherein the pembrolizumab or the pharmaceutically acceptable salt thereof is administered once during the treatment cycle.

21. The method of claim 20, wherein the pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle.

22. The method of claim 21, wherein the pembrolizumab or the pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle.

23. The method of any one of claims 16-22, wherein the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on consecutive days during the treatment cycle.

24. The method of claim 23, wherein the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days during the treatment cycle.

25. The method of claim 24, wherein the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered for 5 days during the treatment cycle.

26. The method of any one of claims 23-25, wherein the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle. 78 64309488-v1155792.599942 27. The method of claim 26, wherein the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered starting from day 1 of the treatment cycle.

28. The method of any one of claims 16-22, wherein the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered once during the treatment cycle.

29. The method of claim 28, wherein the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle.

30. The method of claim 29, wherein the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof is administered on day 1 of the treatment cycle.

31. The method of any one of claims 16-30, wherein the administering is for at least one additional treatment cycle.

32. The method of claim 31, wherein an amount of the futibatinib or the pharmaceutically acceptable salt thereof being administered is reduced during the at least one additional treatment cycle.

33. The method of any one of claims 1-32, wherein an amount of the futibatinib or the pharmaceutically acceptable salt thereof being administered is about 4 mg to about 160 mg per dose, about 4 mg to about 24 mg per dose, about 12 mg to about 24 mg per dose, about 16 mg to about 24 mg per dose, or about 12 mg to about 20 mg per dose.

34. The method of any one of claims 1-33, wherein the amount of the futibatinib or the pharmaceutically acceptable salt thereof is about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose. 79 64309488-v1155792.599942 35. The method of claim 34, wherein the amount of the futibatinib or the pharmaceutically acceptable salt thereof is about 20 mg per dose.

36. The method of any one of claims 1-35, wherein an amount of the pembrolizumab or the pharmaceutically acceptable salt thereof being administered is about 100 mg to about 400 mg per dose or about 200 mg to about 400 mg per dose.

37. The method of any one of claims 1-36, wherein the amount of the pembrolizumab or the pharmaceutically acceptable salt thereof is about 200 mg or about 400 mg per dose.

38. The method of claim 37, wherein the amount of the pembrolizumab or the pharmaceutically acceptable salt thereof is about 200 mg per dose.

39. The method of any one of claims 1-38, wherein an amount of the at least one additional anti-cancer therapy agent or the pharmaceutically acceptable salt thereof being administered is about 10 mg / m2to about 2000 mg / m2, about 10 mg / m2to about 1000 mg / m2, about 40 mg / m2to about 800 mg / m2, about 40 mg / m2to about 400 mg / m2, about 80 mg / m2to about 200 mg / m2, about 200 mg / m2to about 800 mg / m2, about 400 mg / m2to about 1600 mg / m2, or about 400 mg / m2to about 800 mg / m2per dose.

40. The method of claim 39, wherein the amount of the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, about 240 mg / m2, about 300 mg / m2, about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, about 1000 mg / m2, about 1100 mg / m2, about 1200 mg / m2, about 1300 mg / m2, about 1400 mg / m2, about 1500 mg / m2, or about 1600 mg / m2per dose. 80 64309488-v1155792.599942 41. The method of claim 40, wherein the amount of the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is about 80 mg / m2per dose.

42. The method of claim 40, wherein the amount of the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is about 800 mg / m2per dose.

43. The method of any one of claims 1-42, wherein the futibatinib or the pharmaceutically acceptable salt thereof is administered orally.

44. The method of any one of claims 1-43, wherein the pembrolizumab or the pharmaceutically acceptable salt thereof is administered intravenously.

45. The method of any one of claims 1-44, wherein the at least one additional anti- cancer therapy agent or the pharmaceutically acceptable salt thereof is administered orally, intravenously, or subcutaneously.

46. The method of any one of claims 1-45, wherein the method achieves an overall response rate of equal to or greater than 50%.

47. The method of claim 46, wherein the overall response rate is equal to or greater than 60%.

48. The method of claim 47, wherein the overall response rate is equal to or greater than 70%.

49. The method of claim 48, wherein the overall response rate is equal to or greater than 80%.

50. The method of any one of claims 1-49, wherein the method achieves an improved overall response rate relative to an overall response rate of administration of futibatinib or pembrolizumab alone. 81 64309488-v1155792.599942 51. The method of any one of claims 1-50, wherein the method achieves an improved overall response rate relative to an overall response rate of administration of a combination of futibatinib and pembrolizumab.

52. A method for treating a cancer in a subject in need thereof, comprising: administering to the subject about 4 mg, about 8 mg, about 12 mg, about 16 mg, about 20 mg, or about 24 mg per dose of futibatinib or a pharmaceutically acceptable salt thereof once a day on each day of a treatment cycle of about 14 to about 28 days; administering to the subject about 200 mg or about 400 mg per dose of pembrolizumab or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; administering to the subject about 40 mg / m2, about 80 mg / m2, about 120 mg / m2, about 160 mg / m2, about 200 mg / m2, or about 240 mg / m2per dose of cisplatin or a pharmaceutically acceptable salt thereof once on day 1, day 2, day 3, day 4, or day 5 of the treatment cycle; and administering to the subject about 400 mg / m2, about 500 mg / m2, about 600 mg / m2, about 700 mg / m2, about 800 mg / m2, about 900 mg / m2, or about 1000 mg / m2per dose of 5-fluorouracil or a pharmaceutically acceptable salt thereof consecutively for 2 days, 3 days, 4 days, 5, days, 6 days, or 7 days starting from day 1, day 2, day 3, day 4, day 5, day 6, or day 7 of the treatment cycle.

53. A kit for treating cancer in a subject in need thereof comprising futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof. 82 64309488-v1155792.599942 54. Futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer, or use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of cancer.

55. A pharmaceutical composition comprising a first composition comprising futibatinib or a pharmaceutically acceptable salt thereof, a second composition comprising pembrolizumab or a pharmaceutically acceptable salt thereof, and a third composition comprising at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the treatment of cancer.

56. The pharmaceutical composition of claim 55, wherein the first composition further comprises a first pharmaceutically acceptable carrier.

57. The pharmaceutical composition of claim 55 or 56, wherein the second composition further comprises a second pharmaceutically acceptable carrier.

58. The pharmaceutical composition of any one of claims 55-57, wherein the third composition further comprises a third pharmaceutically acceptable carrier.

59. Use of futibatinib or a pharmaceutically acceptable salt thereof, pembrolizumab or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer therapy agent or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of cancer. 83 64309488-v1

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