WO2021262562A2 - Méthodes de traitement du cancer ou de la maladie de von hippel-lindau à l'aide d'une combinaison d'un antagoniste de pd-1, d'un inhibiteur de hif-2 alpha et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé - Google Patents

Méthodes de traitement du cancer ou de la maladie de von hippel-lindau à l'aide d'une combinaison d'un antagoniste de pd-1, d'un inhibiteur de hif-2 alpha et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé Download PDF

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WO2021262562A2
WO2021262562A2 PCT/US2021/038171 US2021038171W WO2021262562A2 WO 2021262562 A2 WO2021262562 A2 WO 2021262562A2 US 2021038171 W US2021038171 W US 2021038171W WO 2021262562 A2 WO2021262562 A2 WO 2021262562A2
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human
cancer
lenvatinib
rcc
administered
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PCT/US2021/038171
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English (en)
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WO2021262562A3 (fr
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Rodolfo Fleury Perini
Elaine M. PINHEIRO
Jaqueline WILLEMANN ROGERIO
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Merck Sharp & Dohme Corp.
Eisai R&D Management Co., Ltd.
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Priority to MX2022016410A priority Critical patent/MX2022016410A/es
Priority to KR1020237002564A priority patent/KR20230026492A/ko
Priority to AU2021297151A priority patent/AU2021297151A1/en
Priority to JP2022578934A priority patent/JP2023531930A/ja
Priority to US18/009,109 priority patent/US20230250182A1/en
Priority to CN202180051960.9A priority patent/CN116406288A/zh
Priority to CA3183862A priority patent/CA3183862A1/fr
Priority to BR112022026086A priority patent/BR112022026086A2/pt
Priority to EP21828207.7A priority patent/EP4168016A4/fr
Publication of WO2021262562A2 publication Critical patent/WO2021262562A2/fr
Publication of WO2021262562A3 publication Critical patent/WO2021262562A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered

Definitions

  • a) a programmed death 1 protein (PD-1) antagonist e.g., a programmed death 1 protein (PD-1) antagonist
  • PD-1 programmed death 1 protein
  • HIF-2 ⁇ hypoxia-inducible factor 2 ⁇
  • lenvatinib e.g., lenvatinib, or a pharmaceutically acceptable salt thereof.
  • sequence listing of the present application is submitted electronically via EFS-Web as an ASCII formatted sequence listing with a file name “25062WOPCT-SEQLIST- 09APR2021_ST25.txt”, creation date of April 9, 2021, and a size of 10 KB.
  • This sequence listing submitted via EFS-Web is part of the specification and is herein incorporated by reference in its entirety.
  • PD-1 is recognized as an important player in immune regulation and the maintenance of peripheral tolerance.
  • Immune checkpoint therapies targeting PD-1 or its ligand have resulted in technological improvements in clinical response in multiple human cancer types (Brahmer et al., N Engl JMed, 366: 2455-2465 (2012); Garon el al., N Engl JMed, 372:2018-2028 (2015); Hamid et al, N Engl JMed, 369:134-144 (2013); Robert et al, Lancet, 384:1109-1117 (2014); Robert et al, N Engl JMed, 372: 2521-2532 (2015); Robert et al., N Engl JMed, 372:320-330 (2015); Topalian et al., N Engl JMed, 366:2443-2454 (2012); Topalian et al., JClin Oncol, 32:1020-1030 (2014); Wolchok et al., N Engl JMed, 369:122
  • Immune therapies targeting the PD-1 axis include monoclonal antibodies directed to the PD-1 receptor (e.g., KEYTRUDA ® (pembrolizumab), Merck and Co., Inc., Kenilworth, NJ; OPDIVO ® (nivolumab), Bristol-Myers Squibb Company, Princeton, NJ); LIBTAYO ® (cemiplimab), Regeneron Pharmaceuticals, Inc., Tarrytown, NY; TYVYT ® (sintilmab), Innovent Biologies, Inc., Jiangsu, China; tislelizumab, BeiGene, Beijing, China; camrelizumab, Hengrui Therapeutics, Inc., Princeton, NJ; and toripalimab, Junshi Biosciences, Shanghai, China); and those that bind to the PD-L1 ligand (e.g.,IMFINZI ® (durvalumab), AstraZeneca Pharmaceuticals LP, Wilmington,
  • Intratumoral hypoxia is a driving force in cancer progression and is closely linked to poor patient prognosis and resistance to chemotherapy and radiation treatment.
  • Hypoxia- Inducible Factors HIF-1 ⁇ and HIF-2 ⁇
  • VHL tumor suppressor von Hippel-Lindau
  • HIF-a proteins Under hypoxic conditions, HIF-a proteins accumulate and enter the nucleus to stimulate the expression of genes that regulate anaerobic metabolism, angiogenesis, cell proliferation, cell survival, extracellular matrix remodeling, pH homeostasis, amino acid and nucleotide metabolism, and genomic instability. VHL deficiency can also result in accumulated HIF expression under oxygenated conditions (pseudohypoxic conditions). Accordingly, directly targeting HIF-a proteins offers an exciting opportunity to attack tumors on multiple fronts (Keith, et al, Nature Rev. Cancer 12: 9- 22, 2012).
  • HIF-2 ⁇ is a key oncogenic driver in clear cell renal cell carcinoma (ccRCC) (Kondo, K., et al, Cancer Cell, 1:237-246 (2002); Maranchie, J. et al, Cancer Cell,
  • HIF-2 ⁇ has emerged as a key HIF isoform that is essential for von Hippel Lindau (VHL) deficient ccRCC.
  • VHL deficient ccRCC xenograft mouse tumor models knockdown of HIF-2 ⁇ expression inhibits tumor formation comparable with reintroduction of functional VHL and overexpression of HIF2 ⁇ alone can rescue the tumor-suppressive effect of VHL (see, Kondo K., Klco J, Nakamura E, Lechpammer M, Kaelin WG Jr.. Inhibition of HIF is necessary for tumor suppression by the von Hippel-Lindau protein.
  • Inhibition of HIF2 ⁇ lpha is sufficient to suppress pVHL-defective tumor growth.
  • HIF-2 ⁇ may be the tumorigenic driver in ccRCC.
  • HIF proteins can also be activated in many other types of cancers (ex. breast, liver, colon, brain, pancreatic cancers) due to the tumor hypoxic microenvironment and have been implicated in cancer initiation, progression and metastasis (see, Jarman EJ, Ward C, Turnbull AK, Martinez-Perez C, Meehan J, Xintaropoulou C, Sims AH, Langdon SP.
  • HER2 regulates HIF-2 ⁇ and drives an increased hypoxic response in breast cancer.
  • HIF-2 ⁇ has been shown to be stabilized by host tumor cells under tumor hypoxia, including endothelial cells, perivascular tumor cells, and immune suppressive cell types such as tumor associated macrophages (TAMs) where it plays a role in regulating innate immunity (see, Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC.
  • TAMs tumor associated macrophages
  • VHL disease Von-Hippel Lindau disease
  • kidney cancer -70% lifetime risk
  • hemangioblastomas pheochromocytoma
  • pancreatic neuroendocrine tumors results in tumors with constitutively active HIF-a proteins with the majority of these dependent on HIF-2 a activity (Maher, et al. Eur. J. Hum. Genet. 19: 617-623, 2011).
  • HIF-2 a has been linked to cancers of the retina, adrenal gland and pancreas through both VHL disease and activating mutations.
  • HIF-2 a mutations have been identified in erythrocytosis and paraganglioma with polycythemia (Zhuang, et al. NEJM 367: 922-930, 2012; Percy, et al. NEJM 358: 162-168, 2008; and Percy, et al. Am. J. Hematol. 87: 439-442, 2012).
  • HIF-2 ⁇ -target gene products e.g., VEGF, PDGF, and cyclin Dl
  • Lenvatinib is a multiple RTK (multi-RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4)), and fibroblast growth factor (FGF) receptors FGFR1, 2, 3 and 4 in addition to other proangiogenic and oncogenic pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRa; KIT; and the RET proto-oncogene (RET)) involved in tumor proliferation.
  • VEGF vascular endothelial growth factor
  • FLT1 vascular endothelial growth factor receptors
  • KDR VEGFR2
  • FLT4 fibroblast growth factor receptors FGFR1, 2, 3 and 4
  • PDGF platelet-derived growth factor
  • RET RET proto-oncogene
  • anti -PD-1 or anti-PD-Ll antagonistic antibodies might be enhanced if administered in combination with other approved or experimental cancer therapies, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are deregulated in tumors, and other immune enhancing agents.
  • cancer therapies e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are deregulated in tumors, and other immune enhancing agents.
  • agent combined with the anti-PD-1 or anti-PD-Ll antibodies may be effective or in which patients the combination may enhance the efficacy of treatment.
  • high efficacy therapeutic combinations that can generate a robust immune response to cancer.
  • the present disclosure provides methods of treating cancer (e.g., RCC) or von- Hippel Lindau disease, using a combination of a PD-1 antagonist, a HIF-2 ⁇ inhibitor, and lenvatinib, or a pharmaceutically acceptable salt thereof.
  • cancer e.g., RCC
  • von- Hippel Lindau disease a combination of a PD-1 antagonist, a HIF-2 ⁇ inhibitor, and lenvatinib, or a pharmaceutically acceptable salt thereof.
  • kits including a PD-1 antagonist, a HIF-2 ⁇ inhibitor, and lenvatinib, or a pharmaceutically acceptable salt thereof.
  • a therapeutic combination for treating cancer e.g., RCC
  • the therapeutic combination includes a PD-1 antagonist, a HIF-2 ⁇ inhibitor, and lenvatinib, or a pharmaceutically acceptable salt thereof.
  • provided herein is a method of treating cancer or von-Hippel Lindau disease, comprising administering to a human patient in need thereof:
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), pancreatic cancer and melanoma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • RRC renal cell carcinoma
  • HCC hepatocellular carcinoma
  • pancreatic cancer pancreatic cancer and melanoma.
  • the cancer is metastatic. In some embodiments, the cancer is relapsed. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory.
  • the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In still another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is melanoma.
  • the cancer is advanced RCC. In another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is relapsed RCC. In still another embodiment, the cancer is refractory RCC. In yet still another embodiment, the cancer is relapsed and refractory RCC.
  • kits comprising:
  • the kit further comprises instructions for administering to a human patient the PD-1 antagonist, the HIF-2 ⁇ inhibitor, and lenvatinib, or a pharmaceutically acceptable salt thereof.
  • a therapeutic combination for treating cancer in a human patient wherein the therapeutic combination comprises:
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), pancreatic cancer and melanoma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • RRC renal cell carcinoma
  • HCC hepatocellular carcinoma
  • pancreatic cancer pancreatic cancer and melanoma.
  • the cancer is metastatic. In some embodiments, the cancer is relapsed. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory.
  • the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In still another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is melanoma.
  • the cancer is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component (ccRCC). In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is relapsed RCC. In still another embodiment, the cancer is refractory RCC. In yet still another embodiment, the cancer is relapsed and refractory RCC.
  • the human patient has not received prior systemic treatment for advanced disease. In a class of the embodiment, the human patient has not received prior systemic treatment for advanced RCC.
  • the PD- 1 antagonist is an anti -human PD-1 monoclonal antibody or antigen binding fragment thereof.
  • the PD-1 antagonist is an anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof.
  • the anti- human PD-1 monoclonal antibody is a humanized antibody.
  • the anti- human PD-1 monoclonal antibody is a human antibody.
  • the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof.
  • the anti- human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, sintilimab, tislelizumab, camrelizumab and toripalimab.
  • the anti- human PD-1 monoclonal antibody is pembrolizumab.
  • the anti- human PD-1 monoclonal antibody is nivolumab. In another embodiment of various methods, kits, or uses provided herein, the anti- human PD-1 monoclonal antibody is cemiplimab.
  • the anti- human PD-1 monoclonal antibody is sintilimab.
  • the anti- human PD-1 monoclonal antibody is tislelizumab.
  • the anti- human PD-1 monoclonal antibody is camrelizumab.
  • the anti- human PD-1 monoclonal antibody is toripalimab. In another embodiment of various methods, kits, or uses provided herein, the anti- human PD-L1 monoclonal antibody is durvalumab.
  • the anti- human PD-L1 monoclonal antibody is avelumab.
  • the lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.
  • Capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively.
  • a pharmaceutically acceptable salt of lenvatinib when administered, such as lenvatinib mesylate, and the dose of lenvatinib to be used is 4 mg, a medical practitioner would know to administer 4.90 mg of lenvatinib mesylate.
  • a pharmaceutically acceptable salt of lenvatinib when administered, such as lenvatinib mesylate, and the dose of lenvatinib to be used is 10 mg, a medical practitioner would know to administer 12.25 mg of lenvatinib mesylate.
  • the human patient is administered 8, 10, 12, 14, 18, 20, or 24 mg lenvatinib once daily.
  • the PD-1 antagonist is pembrolizumab; and the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof.
  • the PD-1 antagonist is nivolumab
  • the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof.
  • the PD-1 antagonist is cemiplimab; and the a HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof.
  • the human patient is administered 200 mg, 240 mg, or 2 mg/kg pembrolizumab, and pembrolizumab is administered once every three weeks. In one embodiment, the human patient is administered 200 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered 240 mg pembrolizumab once every three weeks. In one embodiment, the human patient is administered 2 mg/kg pembrolizumab once every three weeks.
  • the human patient is administered 400 mg pembrolizumab, and pembrolizumab is administered once every six weeks.
  • the human patient is administered 240 mg or 3 mg/kg nivolumab once every two weeks, or 480 mg nivolumab once every four weeks.
  • the human patient is administered 240 mg nivolumab once every two weeks.
  • the human patient is administered 3 mg/kg nivolumab once every two weeks.
  • the human patient is administered 480 mg nivolumab once every four weeks.
  • the human patient is administered 350 mg cemiplimab, and cemiplimab is administered once every three weeks. In other embodiments of various methods described herein, the human patient is administered 800 mg of avelumab, and avelumab is administered once every two weeks.
  • the human patient is administered 10 mg/kg of durvalumab, and durvalumab is administered once every two weeks.
  • the human patient is administered 1500 mg of durvalumab, and durvalumab is administered once every three weeks. In other embodiments of various methods described herein, the human patient is administered 1500 mg of durvalumab, and durvalumab is administered once every four weeks.
  • the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof, and the human patient is administered from 40 mg to 120 mg of belzutifan, or a pharmaceutically acceptable salt thereof daily.
  • the human patient is administered 40, 80, or 120 mg of belzutifan, or a pharmaceutically acceptable salt thereof once daily.
  • the human patient is administered 40 mg of belzutifan, or a pharmaceutically acceptable salt thereof once daily.
  • the human patient is administered 80 mg of belzutifan, or a pharmaceutically acceptable salt thereof once daily.
  • the human patient is administered 120 mg of belzutifan, or a pharmaceutically acceptable salt thereof once daily.
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • RCC RCC-reactive neoplasmic plasminogen activator originating from a human patient in need thereof:
  • the anti -human PD-1 monoclonal antibody, HIF-2 ⁇ inhibitor and lenvatinib are administered on the same day. In some embodiments, the anti-human PD-1 monoclonal antibody, the HIF-2 ⁇ inhibitor, and lenvatinib are administered sequentially. In other embodiments, the anti-human PD-1 monoclonal antibody, the HIF-2 ⁇ inhibitor, and lenvatinib are administered concurrently.
  • the pharmaceutically acceptable salt of lenvatinib — lenvatinib mesylate — can be used.
  • lenvatinib mesylate the dosage of lenvatinib mesylate is appropriately adjusted to provide equal mole of lenvatinib as 8, 10, 12, 14, 18, 20, or 24 mg lenvatinib provides.
  • FIG. 1 illustrates a scheme of the design overview the Phase lb/2 Study of belzutifan, or a pharmaceutically acceptable salt thereof (MK-6482) in combination with pembrolizumab and lenvatinib in patients with 1 st line Advanced RCC (Experimental Arm A4).
  • FIG. 2A illustrates the anti -tumor effect of concurrent administration of a PD-1 antagonist, Lenvatinib and a HIF-2 ⁇ inhibitor (MK-6482) as shown by average tumor volumes in each treatment group. Experimental details are described in Example 2.
  • FIG. 2B illustrates the anti -tumor effect of concurrent administration of a PD-1 antagonist, Lenvatinib and a HIF-2 ⁇ inhibitor (MK-6482) as shown by average tumor volumes in the individual growth curves for each respective group. Experimental details are described in Example 2.
  • “About” when used to modify a numerically defined parameter means that the parameter is within 20%, withinl5%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, within 4%, within 3%, within 2%, within 1%, or less of the stated numerical value or range for that parameter; where appropriate, the stated parameter may be rounded to the nearest whole number. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg.
  • administer refers to the act of injecting or otherwise physically delivering a substance as it exists outside the body (e.g., an anti-PD-1 antibody, HIF-2 ⁇ inhibitor, and lenvatinib as described herein) into a patient, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and/or any other methods of physical delivery described herein or known in the art.
  • a substance as it exists outside the body (e.g., an anti-PD-1 antibody, HIF-2 ⁇ inhibitor, and lenvatinib as described herein) into a patient, such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and/or any other methods of physical delivery described herein or known in the art.
  • PD-1 antagonist means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1.
  • Alternative names or synonyms for PD-1 and its ligands include: PDCD1, PD1, CD279 and SLEB2 for PD-1; PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H for PD-L1; and PDCD1L2, PDL2, B7-DC, Btdc and CD273 for PD-L2.
  • the PD-1 antagonist blocks binding of human PD-L1 to human PD-1, and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1.
  • Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP 005009.
  • Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515, respectively.
  • the PD-1 antagonist is not anti-PD-Ll monoclonal antibody atezolizumab.
  • HIF-2 ⁇ inhibitor means any chemical compound or biological molecule that inhibits the activity of HIF-2 ⁇ .
  • Alternative names or synonyms for HIF-2 ⁇ include but are not limited to: hypoxia-inducible factor-2 ⁇ lpha, endothelial PAS domain-containing protein 1, and EP AS 1.
  • antibody refers to any form of immunoglobulin molecule that exhibits the desired biological or binding activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and chimeric antibodies. “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic.
  • antibody encompasses not only intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, any antigen binding portion thereof that competes with the intact antibody for specific binding, fusion proteins comprising an antigen binding portion, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site.
  • the basic antibody structural unit comprises a tetramer.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the variable regions of each light/heavy chain pair form the antibody binding site.
  • an intact antibody has two binding sites.
  • the carboxy -terminal portion of the heavy chain may define a constant region primarily responsible for effector function.
  • human light chains are classified as kappa and lambda light chains.
  • human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody’s isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
  • the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).
  • variable regions or “V region” or “V chain” as used herein means the segment of IgG chains which is variable in sequence between different antibodies.
  • a “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination.
  • the variable region of the heavy chain may be referred to as “VH.”
  • the variable region of the light chain may be referred to as “VL.”
  • the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • CDRs complementarity determining regions
  • both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • the assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Rabat, et al:, National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Rabat (1978) Adv. Prot.
  • CDR refers to one of three hypervariable regions (HI, H2, or H3) within the non-framework region of the antibody VH b-sheet framework, or one of three hypervariable regions (LI, L2, or L3) within the non-framework region of the antibody VL b-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Rabat as the regions of most hypervariability within the antibody variable domains. CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved b-sheet framework, and thus are able to adapt to different conformation. Both terminologies are well recognized in the art.
  • CDR region sequences have also been defined by AbM, Contact, and IMGT.
  • the positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (Al- Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea et al., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable region numbering scheme (Al- Lazikani et al., supra). Such nomenclature is similarly well known to those skilled in the art.
  • the CDRs are as defined by the Rabat numbering system.
  • the CDRs are as defined by the IMGT numbering system.
  • the CDRs are as defined by the AbM numbering system.
  • the CDRs are as defined by the Chothia numbering system.
  • the CDRs are as defined by the Contact numbering system.
  • Chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain contains sequences derived from a particular species (e.g ., human) or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • a particular species e.g ., human
  • another species e.g., mouse
  • Human antibody refers to an antibody that comprises human immunoglobulin protein sequences or derivatives thereof.
  • a human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody or rat antibody refer to an antibody that comprises only mouse or rat immunoglobulin sequences or derivatives thereof, respectively.
  • Humanized antibody refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • Fc immunoglobulin constant region
  • the prefix “hum”, “hu” or “h” may be added to antibody clone designations when necessary to distinguish humanized antibodies from parental rodent antibodies.
  • the humanized forms of rodent antibodies will generally comprise the same CDR sequences of the parental rodent antibodies, although certain amino acid substitutions may be included to increase affinity, increase stability of the humanized antibody, or for other reasons.
  • conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, which are often specific for different epitopes.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567).
  • the “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al., (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.
  • antibody fragment or “antigen binding fragment” refers to a fragment of an antibody that retains the ability to bind specifically to the antigen, e.g., fragments that retain one or more CDR regions.
  • An antibody that “specifically binds to” PD-1 or ILT4 is an antibody that exhibits preferential binding to PD-1 or ILT4 (as appropriate) as compared to other proteins, but this specificity does not require absolute binding specificity.
  • An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives.
  • Antibodies, or binding fragments thereof will bind to the target protein with an affinity that is at least two-fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.
  • Antigen binding portions include, for example, Fab, Fab’, F(ab’)2, Fd, Fv, fragments including CDRs, and single chain variable fragment antibodies (scFv), and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the antigen (e.g., PD-1 or ILT4).
  • An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereol), and the antibody need not be of any particular class. Depending on the antibody amino acid sequence of the constant region of its heavy chains, immunoglobulins can be assigned to different classes.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2.
  • the heavy- chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three- dimensional configurations of different classes of immunoglobulins are well known.
  • the terms “at least one” item or “one or more” item each include a single item selected from the list as well as mixtures of two or more items selected from the list.
  • immune response relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non- specific response, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell-proliferation, immune cell differentiation, and cytokine expression.
  • subject alternatively “patient” as used herein refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female.
  • the mammal may be one or more selected from the group consisting of humans, bovine (e.g., cows), porcine (e.g, pigs), ovine (e.g, sheep), capra (e.g, goats), equine (e.g, horses), canine (e.g., domestic dogs), feline (e.g, house cats), lagomorphs (e.g, rabbits), rodents (e.g, rats or mice), Procyon lotor (e.g, raccoons).
  • the subject is human.
  • subject in need thereof refers to a subject diagnosed with or suspected of having cancer or an infectious disease as defined herein.
  • enteral route refers to the administration via any part of the gastrointestinal tract.
  • enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route.
  • Parenteral route refers to a route of administration other than enteral route.
  • parenteral routes of administration examples include intravenous, intramuscular, intradermal, intraperitoneal, intratumor, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal, subcutaneous, or topical administration.
  • the therapeutic agents and compositions of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump.
  • the suitable route and method of administration may vary depending on a number of factors such as the specific therapeutic agent being used, the rate of absorption desired, specific formulation or dosage form used, type or severity of the disorder being treated, the specific site of action, and conditions of the patient, and can be readily selected by a person skilled in the art.
  • variants when used in relation to an antibody (e.g, an anti-PD-1 antibody) or an amino acid region within the antibody may refer to a peptide or polypeptide comprising one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid sequence substitutions, deletions, and/or additions as compared to a native or unmodified sequence.
  • a variant of an anti-PD-1 antibody may result from one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) changes to an amino acid sequence of a native or previously unmodified anti-PD-1 antibody.
  • Variants may be naturally occurring or may be artificially constructed.
  • Polypeptide variants may be prepared from the corresponding nucleic acid molecules encoding the variants.
  • an antibody variant e.g., an anti-PD-1 antibody variant
  • an anti-PD-1 antibody variant binds to PD-1 and/or is antagonistic to PD-1 activity.
  • Constantly modified variants or “conservative substitution” refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g., charge, side-chain size, hydrophobicity/hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity or other desired property of the protein, such as antigen affinity and/or specificity.
  • Those of skill in this art recognize that, in general, single amino acid substitutions in non- essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin/Cummings Pub. Co., p. 224 (4th Ed.)).
  • substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are set forth in Table 2 below.
  • “Homology” refers to sequence similarity between two polypeptide sequences when they are optimally aligned. When a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, e.g., if a position in a light chain CDR of two different Abs is occupied by alanine, then the two Abs are homologous at that position.
  • the percent of homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared x 100. For example, if 8 of 10 of the positions in two sequences are matched when the sequences are optimally aligned then the two sequences are 80% homologous.
  • the comparison is made when two sequences are aligned to give maximum percent homology. For example, the comparison can be performed by a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.
  • BLAST ALGORITHMS Altschul, S.F., et al, (1990) J. Mol. Biol. 215:403-410; Gish, W., et al, (1993) Nature Genet. 3:266-272; Madden, T.L., et al, (1996) Meth. Enzymol.
  • RECIST 1.1 Response Criteria as used herein means the definitions set forth in Eisenhauer, E.A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or nontarget lesions, as appropriate based on the context in which response is being measured.
  • sustained response means a sustained therapeutic effect after cessation of treatment as described herein.
  • the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5 or 3 times longer than the treatment duration.
  • Treat” or “treating” cancer as used herein means to administer a therapeutic combination of an anti -human PD-1 monoclonal antibody or antigen binding fragment thereof, a HIF-2 ⁇ inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof, to a subject having cancer or diagnosed with cancer to achieve at least one positive therapeutic effect, such as, for example, reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell infiltration into peripheral organs, or reduced rate of tumor metastasis or tumor growth.
  • Such “treatment” may result in a slowing, interrupting, arresting, controlling, or stopping of the progression of cancer as described herein but does not necessarily indicate a total elimination of the cancer or the symptoms of the cancer.
  • T/C £ 42% is the minimum level of anti -tumor activity.
  • the treatment achieved by a combination therapy of the disclosure is any of PR, CR, OR, PFS, DFS, and OS.
  • PFS also referred to as “Time to Tumor Progression” indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time patients have experienced a CR or PR, as well as the amount of time patients have experienced SD.
  • DFS refers to the length of time during and after treatment that the patient remains free of disease.
  • OS refers to a prolongation in life expectancy as compared to naive or untreated individuals or patients.
  • response to a combination therapy of the disclosure is any of PR, CR, PFS, DFS, or OR that is assessed using RECIST 1.1 response criteria.
  • the treatment regimen for a combination therapy of the disclosure that is effective to treat a cancer patient may vary according to factors such as the disease state, age, and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. While an embodiment of any of the aspects of the disclosure may not be effective in achieving a positive therapeutic effect in every subject, it should 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 chi 2 -test, the U-test according to Mann and Whitney, the Kruskal -Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.
  • any statistical test known in the art such as the Student’s t-test, the chi 2 -test, the U-test according to Mann and Whitney, the Kruskal -Wallis test (H-test), Jonckheere-Terpstra-test and the Wilcoxon-test.
  • the terms “combination,” “combination therapy,” and “therapeutic combination” refer to treatments in which at least one anti -human PD-1 monoclonal antibody or antigen-binding fragment thereof, aHIF-2 ⁇ inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof, and optionally additional therapeutic agents, each are administered to a patient in a coordinated manner, over an overlapping period of time.
  • the period of treatment with the at least one anti -human PD-1 monoclonal antibody (or antigen- binding fragment thereol) is the period of time that a patient undergoes treatment with the anti -human PD-1 monoclonal antibody (or antigen-binding fragment thereol); that is, the period of time from the initial dosing with the anti -human PD-1 monoclonal antibody (or antigen-binding fragment thereol) through the final day of a treatment cycle.
  • the period of treatment with the HIF-2 ⁇ inhibitor is the period of time that a patient undergoes treatment with the HIF-2 ⁇ inhibitor; that is, the period of time from the initial dosing with the HIF-2 ⁇ inhibitor through the final day of a treatment cycle.
  • the period of treatment with lenvatinib or a pharmaceutically acceptable salt thereof is the period of time that a patient undergoes treatment with lenvatinib; that is, the period of time from the initial dosing with lenvatinib through the final day of a treatment cycle.
  • the anti- PD-1 treatment overlaps by at least one day with the HIF-2 ⁇ inhibitor treatment and overlaps by at least one day with the lenvatinib treatment.
  • the anti -PD- 1 treatment, the HIF-2 ⁇ inhibitor treatment, and the lenvatinib treatment are the same period of time.
  • the anti-PD-1 treatment begins prior to the HIF-2 ⁇ inhibitor and/or the lenvatinib treatment.
  • the anti-PD-1 treatment begins after the HIF-2 ⁇ inhibitor and/or the lenvatinib treatment.
  • the HIF-2 ⁇ inhibitor treatment begins prior to the anti-PD-1 and/or the lenvatinib treatment.
  • the HIF-2 ⁇ inhibitor treatment begins after the anti-PD-1 and/or the lenvatinib treatment. In some embodiments, the lenvatinib treatment begins prior to the HIF-2 ⁇ inhibitor and/or the anti-PD-1 treatment. In other embodiments, the lenvatinib treatment begins after the HIF-2 ⁇ inhibitor and/or the anti-PD-1 treatment. In certain embodiments, the anti-PD-1 treatment is terminated prior to termination of the HIF-2 ⁇ inhibitor and/or the lenvatinib treatment. In other embodiments, the anti-PD-1 treatment is terminated after termination of the HIF-2 ⁇ inhibitor and/or the lenvatinib treatment.
  • the HIF-2 ⁇ inhibitor treatment is terminated prior to termination of the anti-PD-1 and/or the lenvatinib treatment. In still other embodiments, the HIF-2 ⁇ inhibitor treatment is terminated after termination of the anti-PD-1 and/or the lenvatinib treatment. In certain embodiments, the lenvatinib treatment is terminated prior to termination of the HIF-2 ⁇ inhibitor and/or the anti-PD-1 treatment. In other embodiments, the lenvatinib treatment is terminated after termination of the HIF-2 ⁇ inhibitor and/or the anti-PD-1 treatment.
  • treatment regimen “dosing protocol,” and “dosing regimen” are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy of the disclosure.
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size, and includes primary tumors and secondary neoplasms.
  • tumors include solid tumor (e.g., sarcoma (such as chondrosarcoma), carcinoma (such as colon carcinoma), blastoma (such as hepatoblastoma), etc.) and blood tumor (e.g., leukemia (such as acute myeloid leukemia (AML)), lymphoma (such as DLBCL), multiple myeloma (MM), etc.).
  • solid tumor e.g., sarcoma (such as chondrosarcoma), carcinoma (such as colon carcinoma), blastoma (such as hepatoblastoma), etc.
  • blood tumor e.g., leukemia (such as acute myeloid leukemia (AML)), lymphoma (such as DLBCL), multiple
  • tumor volume refers to the total size of the tumor which can be measured as the length and width of a tumor.
  • Tumor size may be determined by a variety of methods known in the art, such as, e.g., by measuring the dimensions of tumor(s) upon removal from the subject, e.g., using calipers, or while in the body using imaging techniques, e.g., bone scan, ultrasound, CT or MRI scans.
  • a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days.
  • the term “or,” as used herein, denotes alternatives that may, where appropriate, be combined; that is, the term “or” includes each listed alternative separately as well as their combination.
  • PD-1 antagonists that can be used in the various methods, kits, and uses disclosed herein, including any chemical compound or biological molecule that blocks binding of PD-L1 to PD-1 and preferably also blocks binding of PD-L2 to PD-1.
  • any monoclonal antibodies that bind to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and block the interaction between PD-1 and its ligand PD-L1 or PD-L2 can be used.
  • the anti -human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1.
  • the anti- human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L2.
  • the anti-human PD-1 monoclonal antibody binds to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD-1 epitope and blocks the interaction between PD-1 and PD-L1 and the interaction between PD-1 and PD-L2.
  • Any monoclonal antibodies that bind to a PD-L1 polypeptide, a PD-L1 polypeptide fragment, a PD-L1 peptide, or a PD-L1 epitope and block the interaction between PD-L1 and PD-1 can also be used.
  • the anti -human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, sintilimab, tiselizumab, camrelizumab, toripalimab, pidilizumab (U.S. Pat. No. 7,332,582), AMP-514 (Medlmmune LLC, Gaithersburg, MD), PDR001 (U.S. Pat. No. 9,683,048), BGB-A317 (U.S. Pat. No. 8,735,553), and MGA012 (MacroGenics, Rockville, MD).
  • the anti-human PD-1 monoclonal antibody is pembrolizumab.
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof comprises a light chain variable region (VL) complementarity determining region 1 (CDR1), a VL CDR2, and a VL CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 1, 2, and 3, respectively, and a heavy chain variable region (VH) CDRl, a VH CDR2, and a VH CDR3 comprising amino acid sequences as set forth in SEQ ID NOs: 6, 7, and 8, respectively.
  • VL light chain variable region
  • CDR1 complementarity determining region 1
  • VH heavy chain variable region
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof comprises a VL region comprising an amino acid sequence as set forth in SEQ ID NO:4, and a VH region comprising an amino acid sequence as set forth in SEQ ID NO:9.
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof comprises a light chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO:5 and a heavy chain comprising or consisting of an amino acid sequence as set forth in SEQ ID NO: 10.
  • the anti -human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti -human PD-1 monoclonal antibody is cemiplimab. In another embodiment, the anti -human PD-1 monoclonal antibody is sintilimab. In another embodiment, the anti -human PD-1 monoclonal antibody is tiselizumab. In another embodiment, the anti- human PD-1 monoclonal antibody is camrelizumab. In another embodiment, the anti -human PD-1 monoclonal antibody is toripalimab. In yet another embodiment, the anti -human PD-1 monoclonal antibody is pidilizumab.
  • the anti -human PD-1 monoclonal antibody is AMP-514. In another embodiment, the anti-human PD-1 monoclonal antibody is PDR001. In yet another embodiment, the anti-human PD-1 monoclonal antibody is BGB-A317. In still another embodiment, the anti-human PD-1 monoclonal antibody is MGA012.
  • the anti -human PD-1 monoclonal antibody can be any antibody, antigen binding fragment thereof, or variant thereof disclosed in US7488802, US7521051, US8008449, US8354509, US8168757, W02004/004771, W02004/072286, W02004/056875, US2011/0271358, and WO 2008/156712, the disclosures of which are incorporated by reference herein in their entireties.
  • Examples of monoclonal antibodies that bind to human PD-L1 that can be used in various methods, kits, and uses described herein are disclosed in US8383796, the disclosures of which are incorporated by reference herein in their entireties.
  • Specific anti -human PD-L1 monoclonal antibodies useful as the PD-1 antagonist in the various methods, kits, and uses described include durvalumab, avelumab, and BMS-936559.
  • PD-1 antagonists useful in various methods, kits, and uses described herein include an immunoadhesion molecule that specifically binds to PD-1 or PD-L1, and preferably specifically binds to human PD-1 or human PD-L1, e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule.
  • immunoadhesion molecules that specifically bind to PD-1 are described in W02010/027827 and WO2011/066342, the disclosures of which are incorporated by reference herein in their entireties.
  • Specific fusion proteins useful as the PD-1 antagonist in various methods, kits, and uses described herein include AMP-224 (also known as B7-DCIg), which is a PD-L2-Fc fusion protein and binds to human PD-1.
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof comprises a variant of the amino acid sequences of the anti-human PD-1 or anti-human PD-L1 antibodies described herein.
  • a variant amino acid sequence is identical to the reference sequence except having one, two, three, four, or five amino acid substitutions, deletions, and/or additions.
  • the substitutions, deletions and/or additions are in the CDRs.
  • the substitutions, deletions and/or additions are in the framework regions.
  • the one, two, three, four, or five of the amino acid substitutions are conservative substitutions.
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof has a VL domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VL domains of the anti-human PD-1 or anti- human PD-L1 antibodies described herein, and exhibits specific binding to PD-1 or PD-L1.
  • the anti-human PD-1 or anti-human PD-L1 monoclonal antibody or antigen binding fragment thereof has a VH domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VH domains of the anti-human PD-1 or anti-human PD-L1 antibodies described herein, and exhibits specific binding to PD-1 or PD-L1.
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof has a VL domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VL domains of the anti -human PD-1 or anti -human PD-L1 antibodies described herein and a VH domain with at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology to one of the VH domains of the anti-human PD-1 or anti-human PD-L1 antibodies described herein, and exhibits specific binding to PD-1 or PD-L1.
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof has a VL domain having up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions and/or additions in one of the VL domains of the anti-human
  • PD-1 or anti -human PD-L1 antibodies described herein exhibits specific binding to PD-1 or
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof has a VH domain having up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and/or additions in one of the VH domains of the anti-human
  • PD-1 or anti -human PD-L1 antibodies described herein exhibits specific binding to PD-1 or
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof has a VL domain having up to 1, 2, 3, 4, 5 or more amino acid substitutions, deletions, and/or additions in one of the VL domains of the anti-human
  • PD-1 or anti-human PD-L1 antibodies described herein and a VH domain having up to 1, 2, 3, 4,
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof is selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA, and IgE.
  • the antibody is an IgG antibody. Any isotype of IgG can be used, including IgGi, IgG2, IgG3, and IgG4. Different constant domains may be appended to the VL and VH regions provided herein. For example, if a particular intended use of an antibody (or fragment) of the present invention were to call for altered effector functions, a heavy chain constant domain other than IgGl may be used.
  • IgGl antibodies provide for long half-life and for effector functions, such as complement activation and antibody-dependent cellular cytotoxicity, such activities may not be desirable for all uses of the antibody.
  • an IgG4 constant domain may be used.
  • the heavy chain constant domain contains one or more amino acid mutations (e.g., IgG4 with S228P mutation) to generate desired characteristics of the antibody. These desired characteristics include but are not limited to modified effector functions, physical or chemical stability, half-life of antibody, etc.
  • amino acid sequence variants of the anti -human PD-1 or anti -human PD-L1 monoclonal antibodies and antigen binding fragments thereof disclosed herein will have an amino acid sequence having at least 75% amino acid sequence identity with the amino acid sequence of a reference antibody or antigen binding fragment (e.g., heavy chain, light chain, VH, VL, or humanized sequence), more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95, 98, or 99%.
  • a reference antibody or antigen binding fragment e.g., heavy chain, light chain, VH, VL, or humanized sequence
  • Identity or homology with respect to a sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. None of N-terminal, C -terminal, or internal extensions, deletions, or insertions into the antibody sequence shall be construed as affecting sequence identity or homology.
  • Sequence identity refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned. Sequence identity can be determined using a BLAST algorithm wherein the parameters of the algorithm are selected to give the largest match between the respective sequences over the entire length of the respective reference sequences.
  • the following references relate to BLAST algorithms often used for sequence analysis: BLAST ALGORITHMS: Altschul, S.F., et al, (1990) J. Mol. Biol. 215:403-410; Gish, W., et al, (1993) Nature Genet. 3:266-272; Madden, T.L., et al, (1996) Meth. Enzymol.
  • the anti -human PD-1 or anti -human PD-L1 monoclonal antibody is a human antibody. In other embodiments, the anti -human PD-1 or anti -human PD- L1 monoclonal antibody is a humanized antibody.
  • the light chain of the anti -human PD-1 or anti-human PD- L1 monoclonal antibody has a human kappa backbone. In other embodiments, the light chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human lambda backbone.
  • the heavy chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human IgGl backbone. In other embodiments, the heavy chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human IgG2 backbone. In yet other embodiments, the heavy chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human IgG3 backbone. In still other embodiments, the heavy chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human IgG4 backbone.
  • the heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human IgGl variant backbone. In other embodiments, the heavy chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human IgG2 variant backbone. In yet other embodiments, the heavy chain of the anti -human PD-1 or anti -human PD-L1 monoclonal antibody has a human IgG3 variant backbone. In still other embodiments, the heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human IgG4 variant (e.g, IgG4 with S228P mutation) backbone.
  • a human IgG4 variant e.g, IgG4 with S228P mutation
  • HIF-2 ⁇ inhibitors that can be used in the various methods, kits, and uses disclosed herein, including any chemical compound or biological molecule that inhibits the activity of HIF-2 ⁇ .
  • the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof, which is also known as MK-6482, PT2977, 3-[(lS,2S,3R)-2,3-difluoro- l-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile, and 3-[[(lS,2S,3R)-2,3- difluoro-2,3-dihydro-l-hydroxy-7-(methylsulfonyl)-lH-inden-4-yl]oxy]-5-fluorobenzonitrile and has the following chemical structure:
  • lenvatinib which is a multiple RTK (multi-RTK) inhibitor that selectively inhibits the kinase activities of VEGF receptors.
  • Lenvatinib which is also known as LENVIMA ® , Eisai Inc., Woodcliff Lake, NJ and 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6- quinolinecarboxamide, has the following chemical structure:
  • provided herein are methods of treating cancer (e.g ., RCC) or von-Hippel Lindau disease, using a combination of a PD-1 antagonist, a HIF-2 ⁇ inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof described.
  • the PD-1 antagonist is an anti-PD-1 antibody or antigen binding fragment thereof.
  • the method of treating cancer or von-Hippel Lindau disease comprises administering to a human patient in need thereof:
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), pancreatic cancer and melanoma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • RRC renal cell carcinoma
  • HCC hepatocellular carcinoma
  • pancreatic cancer pancreatic cancer and melanoma.
  • the cancer is metastatic. In some embodiments, the cancer is relapsed. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory.
  • the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In still another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is melanoma.
  • the cancer is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component (ccRCC). In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is relapsed RCC. In still another embodiment, the cancer is refractory RCC. In yet still another embodiment, the cancer is relapsed and refractory RCC.
  • the human patient has not received prior systemic treatment for advanced disease. In a class of the embodiment, the human patient has not received prior systemic treatment for advanced RCC.
  • provided herein is a method of treating RCC, comprising administering to a human patient in need thereof:
  • provided herein is a method of treating advanced RCC, comprising administering to a human patient in need thereof:
  • (c) lenvatinib, or a pharmaceutically acceptable salt thereof in some embodiments, provided herein is a method of treating advanced RCC with clear cell component, comprising administering to a human patient in need thereof:
  • provided herein is a method of treating metastatic RCC, comprising administering to a human patient in need thereof:
  • provided herein is a method of treating relapsed RCC, comprising administering to a human patient in need thereof:
  • a method of treating refractory RCC comprising administering to a human patient in need thereof:
  • provided herein is a method of treating relapsed and refractory RCC, comprising administering to a human patient in need thereof:
  • lenvatinib or a pharmaceutically acceptable salt thereof.
  • a method of treating pancreatic cancer comprising administering to a human patient in need thereof:
  • the method of treating cancer comprises administering to a human patient in need thereof:
  • the PD-1 antagonist is an anti -human PD-1 monoclonal antibody or antigen binding fragment thereof.
  • the anti -human PD-1 monoclonal antibody is a human antibody.
  • the anti-human PD-1 monoclonal antibody is a humanized antibody.
  • the PD-1 antagonist is an anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof.
  • the anti-human PD-L1 monoclonal antibody is a human antibody.
  • the anti -human PD-L1 monoclonal antibody is a humanized antibody.
  • provided herein is a method for treating cancer, comprising administering to a human patient in need thereof:
  • provided herein is a method for treating cancer, comprising administering to a human patient in need thereof: (a) a human anti -human PD-1 monoclonal antibody or antigen binding fragment thereof;
  • provided herein is a method for treating cancer, comprising administering to a human patient in need thereof:
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab.
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab.
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.
  • the method for treating cancer comprises administering to a human patient in need thereof:
  • the method for treating cancer comprises administering to a human patient in need thereof:
  • the method for treating cancer comprises administering to a human patient in need thereof:
  • the method for treating RCC comprises administering to a human patient in need thereof:
  • the method for treating RCC comprises administering to a human patient in need thereof:
  • the method for treating RCC comprises administering to a human patient in need thereof:
  • the RCC is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component. In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is relapsed RCC. In still another embodiment, the RCC is refractory RCC. In yet still another embodiment, the RCC is relapsed and refractory RCC.
  • the present invention provides a method of treating von
  • VHL disease comprising administering to a human patient in need thereof: (a) a PD-1 antagonist (e.g., pembrolizumab);
  • a PD-1 antagonist e.g., pembrolizumab
  • HIF-2 ⁇ inhibitor e.g., belzutifan, or a pharmaceutically acceptable salt thereof
  • dosing regimens and routes of administration for treating cancer e.g., RCC
  • a PD-1 antagonist e.g., an anti-PD-1 monoclonal antibody or antigen binding fragment thereof
  • HIF-2 ⁇ inhibitor e.g., a HIF-2 ⁇ inhibitor
  • a multi-RTK inhibitor e.g., lenvatinib or a pharmaceutically acceptable salt thereof
  • the anti-PD-f monoclonal antibody or antigen binding fragment thereof, the H1F- 2a inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof disclosed herein may be administered by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, tri- weekly, every four weeks, every five weeks, every 6 weeks, monthly, bimonthly, quarterly, semiannually, annually, etc.
  • Doses may be administered, e.g., intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation.
  • the doses are administered intravenously. In certain embodiments, the doses are administered subcutaneously. In certain embodiments, the doses are administered orally.
  • a total dose for a treatment interval is generally at least 0.05 ⁇ g/kg body weight, more generally at least 0.2 fig/kg, 0.5 ⁇ g/kg, 1 ⁇ g/kg, 10 ⁇ g/kg, 100 ⁇ g/kg, 0.25 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 5.0 mg/ml, 10 mg/kg, 25 mg/kg, 50 mg/kg or more. Doses may also be provided to achieve a pre-determined target concentration of the antibody (e.g. , anti-PD-1 antibody) or antigen binding fragment thereof in the subject’s serum, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300 pg/mL or more.
  • the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is administered subcutaneously or intravenously, on a weekly, biweekly, triweekly , every 4 weeks, every 5 weeks, every 6 weeks, monthly, bimonthly, or quarterly basis at 10, 20, 50, 80, 100, 200, 300, 400, 500, 1000 or 2500 mg/subject.
  • the dose of the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is from about
  • 0.01 mg/kg to about 50 mg/kg from about 0.05 mg/kg to about 25 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, from about 0.2 mg/kg to about 9 mg/kg, from about 0.3 mg/kg to about 8 mg/kg, from about 0.4 mg/kg to about 7 mg/kg, from about 0.5 mg/kg to about 6 mg/kg, from about 0.6 mg/kg to about 5 mg/kg, from about 0.7 mg/kg to about 4 mg/kg, from about 0.8 mg/kg to about 3 mg/kg, from about 0.9 mg/kg to about 2 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.0 mg/kg to about 2.0 mg/kg, from about 1.0 mg/kg to about 3.0 mg/kg, or from about 2.0 mg/kg to about 4.0 mg/kg.
  • the dose of the anti-PD- 1 monoclonal antibody or antigen binding fragment thereof is from about 10 mg to about 500 mg, from about 25 mg to about 500 mg, from about 50 mg to about 500 mg, from about 100 mg to about 500 mg, from about 200 mg to about 500 mg, from about 150 mg to about 250 mg, from about 175 mg to about 250 mg, from about 200 mg to about 250 mg, from about 150 mg to about 240 mg, from about 175 mg to about 240 mg, or from about 200 mg to about 240 mg.
  • the dose of the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 240 mg, 250 mg, 300 mg, 400 mg, or 500 mg.
  • the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab
  • the human patient is administered 200 mg, 240 mg, or 2 mg/kg pembrolizumab
  • pembrolizumab is administered once every three weeks.
  • the human patient is administered 200 mg pembrolizumab once every three weeks.
  • the human patient is administered 240 mg pembrolizumab once every three weeks.
  • the human patient is administered 2 mg/kg pembrolizumab once every three weeks.
  • the anti-human PD- 1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab
  • the human patient is administered 400 mg pembrolizumab
  • pembrolizumab is administered once every six weeks.
  • the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab
  • the human patient is administered 240 mg or 3 mg/kg nivolumab
  • nivolumab is administered once every two weeks.
  • the human patient is administered 240 mg nivolumab once every two weeks.
  • the human patient is administered 3 mg/kg nivolumab once every two weeks.
  • the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab
  • the human patient is administered 480 mg nivolumab
  • nivolumab is administered once every four weeks.
  • the anti-human PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab
  • the human patient is administered 350 mg cemiplimab
  • cemiplimab is administered once every three weeks.
  • the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof, and the human patient is administered from 40 to 120 mg once-daily.
  • 40, 80 or 120 mg of belzutifan, or a pharmaceutically acceptable salt thereof is administered once-daily.
  • the human patient is administered 40 mg of belzutifan, or a pharmaceutically acceptable salt thereof once-daily.
  • the human patient is administered 80 mg of belzutifan, or a pharmaceutically acceptable salt thereof once-daily.
  • the human patient is administered 120 mg of belzutifan, or a pharmaceutically acceptable salt thereof once-daily.
  • lenvatinib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8, 10, 12, 14, 18, 20, or 24 mg, each as lenvatinib.
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient is administered:
  • the human patient has not received prior systemic treatment for advanced disease.
  • At least one of the therapeutic agents (e.g., the anti -PD- 1 monoclonal antibody or binding fragment thereof, the HIF-2 ⁇ inhibitor, or lenvatinib) in the combination therapy is administered using the same dosage regimen (dose, frequency, and duration of treatment) that is typically employed when the agent is used as monotherapy for treating the same condition.
  • the patient receives a lower total amount of at least one of the therapeutic agents (e.g., the anti -PD- 1 monoclonal antibody or binding fragment thereof, the HIF-2 ⁇ inhibitor, or lenvatinib) in the combination therapy than when the agent is used as monotherapy, e.g., smaller doses, less frequent doses, and/or shorter treatment duration.
  • a combination therapy disclosed herein may be used prior to or following surgery to remove a tumor and may be used prior to, during, or after radiation treatment.
  • a combination therapy disclosed herein is administered to a patient who has not previously been treated with a biotherapeutic or chemotherapeutic agent, i. e.. is treatment-naive.
  • the combination therapy is administered to a patient who failed to achieve a sustained response after prior therapy with the biotherapeutic or chemotherapeutic agent, i.e., is treatment-experienced.
  • the therapeutic combination disclosed herein may be used in combination with one or more other active agents, including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cancer).
  • active agents including but not limited to, other anti-cancer agents that are used in the prevention, treatment, control, amelioration, or reduction of risk of a particular disease or condition (e.g., cancer).
  • Such other active agents may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with one or more of the therapeutic agents in the combinations disclosed herein.
  • the one or more additional active agents may be co-administered with the anti- PD-1 monoclonal antibody or antigen binding fragment thereof, the HIF-2 ⁇ inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof.
  • the additional active agent(s) can be administered in a single dosage form with one or more co-administered agent selected from the anti-PD-1 monoclonal antibody or antigen binding fragment thereof, the HIF-2 ⁇ inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof.
  • the additional active agent(s) can also be administered in separate dosage form(s) from the dosage forms containing the anti-PD-1 monoclonal antibody or antigen binding fragment thereof, the HIF-2 ⁇ inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof.
  • kits comprising the therapeutic agents disclosed herein (e.g., aPD-1 antagonist, a HIF-2 ⁇ inhibitor, and lenvatinib) or pharmaceutical compositions thereof, packaged into suitable packaging material.
  • a kit optionally includes a label or packaging insert that include a description of the components or instructions for use in vitro, in vivo, or ex vivo, of the components therein.
  • the kit comprises
  • the kit further comprises instructions for administering to a human patient the PD-1 antagonist, the HIF-2 ⁇ inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof.
  • the PD-1 antagonist is an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD- L1 monoclonal antibody or antigen-binding fragment thereof.
  • the kit comprises: (a) one or more dosages of an anti-PD-1 monoclonal antibody or antigen binding fragment thereof; (b) one or more dosages of a HIF-2 ⁇ inhibitor; (c) one or more dosages of lenvatinib or a pharmaceutically acceptable salt thereof; and (d) instructions for administering to a human patient the anti -human PD-1 monoclonal antibody or antigen binding fragment thereof, the HIF-2 ⁇ inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof.
  • the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab. In some embodiments, the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.
  • kits for the anti-PD-1 monoclonal antibody, the HIF-2 ⁇ inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof can be used in various kits herein.
  • a kit comprises dosages of each component sufficient for a certain period of treatment (e.g., 3, 6, 12, or 24 weeks, etc.).
  • a kit can comprise a dosage of 200 mg pembrolizumab, 21 dosages of 120 mg belzutifan, or a pharmaceutically acceptable salt thereof, and 21 dosages of 20 mg lenvatinib (or equivalent amount of a pharmaceutically acceptable salt of lenvatinib), which are sufficient for a 3-week treatment.
  • kits can also comprise a dosage of 400 mg pembrolizumab, 42 dosages of 120 mg belzutifan, or a pharmaceutically acceptable salt thereof, and 42 dosages of 20 mg lenvatinib (or equivalent amount of a pharmaceutically acceptable salt of lenvatinib), which are sufficient for a 6-week treatment.
  • the kit comprises means for separately retaining the components, such as a container, divided bottle, or divided foil packet.
  • a kit of this disclosure can be used for administration of different dosage forms, for example, oral and parenteral, for administration of the separate compositions at different dosage intervals, or for titration of the separate compositions against one another.
  • a therapeutic combination for treating cancer e.g., RCC
  • von-Hippel Lindau disease in a human patient, wherein the therapeutic combination comprises:
  • the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma.
  • NSCLC non-small cell lung cancer
  • CRC colorectal cancer
  • RRC renal cell carcinoma
  • HCC hepatocellular carcinoma
  • the cancer is metastatic. In some embodiments, the cancer is relapsed. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory.
  • the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In still another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is melanoma.
  • the cancer is advanced RCC. In another embodiment, the cancer is advanced RCC with clear cell component. In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is relapsed RCC. In still another embodiment, the cancer is refractory RCC. In yet still another embodiment, the cancer is relapsed and refractory RCC.
  • a therapeutic combination for treating RCC in a human patient wherein the therapeutic combination comprises:
  • a therapeutic combination for treating advanced RCC in a human patient wherein the therapeutic combination comprises:
  • a therapeutic combination for treating advanced RCC with clear cell component in a human patient wherein the therapeutic combination comprises:
  • a therapeutic combination for treating metastatic RCC in a human patient wherein the therapeutic combination comprises:
  • a therapeutic combination for treating relapsed RCC in a human patient, wherein the therapeutic combination comprises:
  • a therapeutic combination for treating refractory RCC in a human patient, wherein the therapeutic combination comprises:
  • a therapeutic combination for treating relapsed and refractory RCC in a human patient, wherein the therapeutic combination comprises:
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises:
  • the PD-1 antagonist is an anti -human PD-1 monoclonal antibody or antigen binding fragment thereof.
  • the anti -human PD-1 monoclonal antibody is a human antibody.
  • the anti -human PD-1 monoclonal antibody is a humanized antibody.
  • the PD-1 antagonist is an anti -human PD-L1 monoclonal antibody or antigen binding fragment thereof.
  • the anti-human PD-L1 monoclonal antibody is a human antibody.
  • the anti -human PD-L1 monoclonal antibody is a humanized antibody.
  • the HIF-2 ⁇ inhibitor is belzutifan, or a pharmaceutically acceptable salt thereof.
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises:
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises:
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises:
  • the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is pembrolizumab. In some embodiments of various uses provided herein, the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is nivolumab. In some embodiments of various uses provided herein, the anti-PD-1 monoclonal antibody or antigen binding fragment thereof is cemiplimab.
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises: (a) pembrolizumab;
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises:
  • a therapeutic combination for treating cancer wherein the therapeutic combination comprises:
  • a therapeutic combination for treating RCC wherein the therapeutic combination comprises:
  • a therapeutic combination for treating RCC wherein the therapeutic combination comprises:
  • a therapeutic combination for treating RCC wherein the therapeutic combination comprises: (a) cemiplimab;
  • the human patient has not received prior systemic treatment for advanced disease.
  • the RCC is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component. In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is relapsed RCC. In still another embodiment, the RCC is refractory RCC. In yet still another embodiment, the RCC is relapsed and refractory RCC.
  • a FIH Phase 1 study designed to assess the tolerability, safety, PK, and PD properties of MK-6482 in participants with various advanced solid tumors is ongoing.
  • a total of 104 participants had been enrolled, including 43 participants with various advanced solid tumors in the dose-escalation portion (Part 1 A) ranging from 20 to 240 mg QD and 120 mg BID.
  • the MTD was not reached and 2 treatment-related DLTs were observed: 1 Grade 4 event of thrombocytopenia in the 240 mg QD cohort, and 1 Grade 3 event of hypoxia in the 120 mg BID cohort.
  • the 120 mg QD dose was selected for further clinical development based on favorable PK, pharmacodynamic, and safety findings.
  • Part IB 52 additional participants with advanced RCC were treated in an expansion cohort (Part IB) at the clinical dose of 120 mg QD.
  • the most common AEs (occurring in ⁇ 20% of participants) were anemia, fatigue, dyspnea, nausea, and peripheral edema.
  • the most common Grade 3 AEs were anemia and hypoxia (in ⁇ 5% of participants).
  • the median tmax for MK-6482 was 1 to 2.8 hours and exposure increased with dose.
  • the mean steady state ti/2 in the 120 mg QD expansion cohort (Part IB) on Day 15 was 15.4 hours, resulting in a 1.5-fold accumulation from Day 1 to Day 15.
  • the mean steady state Cmax in the 120 mg QD expansion cohort (Part IB) on Day 15 was 1.79 ⁇ g/mL (4.67 mM).
  • the estimated CL/F was 5.22 to 14.4 L/hr.
  • the estimated Vz/F was 106 to 266 L, which suggests extensive distribution to peripheral tissues.
  • the CV was 32 to 59% for Cmax and 24 to 48% for AUC after a single dose, and 27 to 56% for Cmax and 30 to 64% for AUC at steady state.
  • 55 participants with previously treated advanced RCC have been treated in this study with MK-6482 at 120 mg QD (3 patients in the dose-escalation portion of the study and 52 participants in the dose expansion portion of the study). Best response among these 55 participants included 11 participants (20%) with PR and 32 participants (58%) with SD as assessed by RECIST vl.l.
  • ORR is defined as the percentage of participants who achieve a confirmed CR or PR per RECIST 1.1 as assessed by BICR. Responses are based on BICR using RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. ORR is an appropriate endpoint to evaluate the antitumor activity of reference and experimental arms. Treatment effect measured by ORR can represent direct clinical benefit based on the specific disease, context of use, magnitude of the effect, number of CRs, durability of response, disease setting, location of the tumors, available therapy, and risk-benefit relationship.
  • the secondary objective is to evaluate DOR, PFS, OS, and CBR as secondary efficacy endpoints.
  • DOR is defined as the time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
  • DOR per RECIST 1.1 modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, assessed by BICR will serve as an additional measure of efficacy and is a commonly accepted endpoint by both regulatory authorities and the oncology community.
  • PFS is defined as the time from the date of randomization to the first documented PD per RECIST 1.1 by BICR, or death due to any cause, whichever occurs first. Images will be read by a BICR to minimize bias in the response assessments.
  • a PFS event can reflect tumor growth and be assessed before the determination of a survival benefit. Its determination is not confounded by subsequent therapy.
  • Treatment effect measured by PFS can be a surrogate endpoint to represent direct clinical benefit based on the specific disease, context of use, magnitude of the effect, the disease setting, location of metastatic sites, available therapy, the risk-benefit relationship, and the clinical consequences of delaying or preventing progression in key disease sites (eg, delay of new lesions in the brain or spine) or delaying administration of more toxic therapies.
  • OS has been recognized as the gold standard for the demonstration of superiority of a new antineoplastic therapy in randomized clinical studies. OS is defined as the time from the date of randomization to the date of death from any cause.
  • CBR is a secondary endpoint commonly used in many cancer clinical trials ⁇ 059M4P ⁇ and is defined as the percentage of participants who have achieved SD of >6 months or CR or PR based on assessments by BICR per RECIST 1.1.
  • the tertiary/exploratory objectives of the study include evaluation of the correlation of tumor size change with DOR, PFS, and OS; characterization of the pharmacokinetic (PK) profiles and anti-drug antibody (ADA) formation for the investigational agents; and to identify molecular (genomic, metabolic, and/or proteomic) biomarkers that may be indicative of clinical response/resistance, safety, and/or the mechanism of action of study treatment combinations with pembrolizumab, lenvatinib and MK6482.
  • Tumor size change will be an exploratory efficacy endpoint and is a proposed intermediate endpoint that may detect signals of early antitumor activity and is defined as the sum of target lesions in longest diameter at each post-baseline assessment and change (and % change) from baseline.
  • VHL proficient mouse syngeneic pancreatic tumor model combining combining an anti- PD-1 mouse surrogate antibody (muDX400) and a VEGF tyrosine kinase inhibitor, lenvatinib, with a HIF-2 ⁇ inhibitor, MK-6482.
  • mice Prior to treatment initiation, female C57BL/6J mice aged 7 weeks weighing between 18 to 21 grams were anesthetized and injected into the rear flank with 0.5 x 10 6 log-phase sub- confluent KPC-2838c3 cells. Ten (10) days later when the mean tumor volume of inoculated animals reached approximately 95mm 3 , mice were pair-matched into 8 treatment groups consisting of 10 mice per group.
  • Treatment groups consisted of: 1) 0.5% methylcellulose (Vehicle) + Isotype mouse IgGl antibody (mlgGl); 2) MK-6482 + mlgGl; 3) Lenvatinib + mlgGl; 4) Vehicle + anti-mouse PD-1 IgGl antibody; 5) MK-6482 + anti-PD-1; 6) Lenvatinib + anti-PD-1; 7) MK-6482 + Lenvatinib; 8) MK-6482 + Lenvatinib + anti-PD-1. Vehicle and MK- 6482 were orally gavage-dosed twice daily (BID) at 3 mg/kg body weight.
  • BID gavage-dosed twice daily
  • Lenvatinib was orally dosed once daily (QD) at 10 mg/kg body weight.
  • Isotype control, a mouse monoclonal antibody specific for adenoviral hexon of the isotype IgGl, and anti-PD-1 antibodies were dosed intraperitoneally every 5 days at 10 mg/kg body weight. Start of treatments was considered Day 0 and dosing based on schedules continued as described until Day 45. Caliper measurements of tumors and body weights were captured twice weekly. Statistical analyses were performed by one-way ANOVA with Tukey multiple comparison tests at the timepoints specified when treatment groups reached endpoints.
  • Triple combination treatment with MK-6482, anti-PD-1 and lenvatinib demonstrated notable anti-tumor efficacy (FIG. 2A) such that one complete response was observed where no measurable tumor remained as well as one partial tumor regression (FIG. 2B). Complete and partial tumor regressions were not observed in any other treatment groups.
  • the mean anti-tumor response of the triple combination treatment was greater than the anti-tumor response observed with either MK-6482 monotherapy , anti-PD-1 monotherapy, or vehicle control (p ⁇ 0.0001, Day 24).
  • the triple combination group was also significantly improved over lenvatinib monotherapy
  • TGI tumor growth inhibition
  • CRs were defined as no observable tumor whereas PRs were tumors whose volume was lower than the original tumor size when treatment began. There was no significant body weight loss or adverse events observed in any animals treated with the above therapies, indicating the treatments were well tolerated. As shown by the study above, treatment with the combination of therapeutic agents is advantageous over treatment with each agent when administered alone.

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Abstract

L'invention concerne des méthodes de traitement du cancer (par exemple un hypernéphrome) ou de la maladie de von Hippel-Lindau, qui comprend l'administration à un patient humain qui en a besoin : (a) d'un antagoniste de PD-1 ; (b) d'un inhibiteur de HIF-2α ; et (c) de lenvatinib, ou d'un sel pharmaceutiquement acceptable associé. L'invention concerne également des kits contenant de tels agents et des utilisations de combinaisons thérapeutiques desdits agents pour le traitement du cancer.
PCT/US2021/038171 2020-06-17 2021-06-21 Méthodes de traitement du cancer ou de la maladie de von hippel-lindau à l'aide d'une combinaison d'un antagoniste de pd-1, d'un inhibiteur de hif-2 alpha et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé WO2021262562A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
MX2022016410A MX2022016410A (es) 2020-06-22 2021-06-21 Metodos para tratar el cancer o enfermedad de von-hippel lindau usando una combinacion de un antagonista del pd-1, inhibidor de hif-2 alpha y lenvatinib o una sal aceptable farmeuticamente de estos.
KR1020237002564A KR20230026492A (ko) 2020-06-22 2021-06-21 Pd-1 길항제, hif-2 알파 억제제 및 렌바티닙 또는 그의 제약상 허용되는 염의 조합물을 사용하여 암 또는 폰-히펠 린다우병을 치료하는 방법
AU2021297151A AU2021297151A1 (en) 2020-06-17 2021-06-21 Methods for treating cancer or von-Hippel Lindau disease using a combination of a PD-1 antagonist, a HIF-2 alpha inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof
JP2022578934A JP2023531930A (ja) 2020-06-22 2021-06-21 ＰＤ－１アンタゴニスト、ＨＩＦ－２α阻害剤およびレンバチニブまたはその薬学的に許容され得る塩の組み合わせを使用して、癌またはフォンヒッペル・リンダウ病を処置するための方法
US18/009,109 US20230250182A1 (en) 2020-06-22 2021-06-21 Methods for treating cancer or von-hippel lindau disease using a combination of a pd-1 antagonist, a hif-2 alpha inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof
CN202180051960.9A CN116406288A (zh) 2020-06-17 2021-06-21 使用PD-1拮抗剂、HIF-2α抑制剂、以及乐伐替尼或其药学上可接受的盐的组合，用于治疗癌症或冯-希佩尔-林道病的方法
CA3183862A CA3183862A1 (fr) 2020-06-22 2021-06-21 Methodes de traitement du cancer ou de la maladie de von hippel-lindau a l'aide d'une combinaison d'un antagoniste de pd-1, d'un inhibiteur de hif-2 alpha et de lenvatinib ou d'un sel pharmaceutiquement acceptable associ
BR112022026086A BR112022026086A2 (pt) 2020-06-22 2021-06-21 Métodos para tratar câncer ou doença de von-hippel lindau e para tratar carcinoma de célula renal, kit, e, uso de uma combinação terapêutica
EP21828207.7A EP4168016A4 (fr) 2020-06-22 2021-06-21 Méthodes de traitement du cancer ou de la maladie de von hippel-lindau à l'aide d'une combinaison d'un antagoniste de pd-1, d'un inhibiteur de hif-2 alpha et de lenvatinib ou d'un sel pharmaceutiquement acceptable associé

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Cited By (2)

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WO2022258066A1 (fr) * 2021-06-11 2022-12-15 深圳埃格林医药有限公司 Utilisation de caproate d'hydroxyprogestérone pour améliorer l'effet d'un traitement anti-tumoral
WO2023235236A1 (fr) * 2022-06-02 2023-12-07 Merck Sharp & Dohme Llc Méthodes de traitement du cancer, ou de la maladie de von hippel-lindau à l'aide d'une association d'un antagoniste de tigit, d'un antagoniste de pd-1 et d'un inhibiteur de hif-2-alpha

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AU2017249459A1 (en) * 2016-04-15 2018-10-25 Eisai R&D Management Co., Ltd. Treatment of renal cell carcinoma with lenvatinib and everolimus
CA3020749A1 (fr) * 2016-04-15 2017-10-19 Exelixis, Inc. Procede de traitement du cancer a cellules renales a l'aide de n-(4-(6,7-dimethoxyquinolin-4-yloxy) phenyl)-n'-(4-fluoropheny)cyclopropane-1,1-dicarboxamide, (2s)-hydroxybutanedioate
US10098860B2 (en) * 2016-07-20 2018-10-16 Cipla Limited Bezafibrate for the treatment of cancer
WO2018031680A1 (fr) * 2016-08-10 2018-02-15 Fronthera U.S. Pharmaceuticals Llc Nouveaux composés, leurs utilisations et procédés de préparation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022258066A1 (fr) * 2021-06-11 2022-12-15 深圳埃格林医药有限公司 Utilisation de caproate d'hydroxyprogestérone pour améliorer l'effet d'un traitement anti-tumoral
WO2023235236A1 (fr) * 2022-06-02 2023-12-07 Merck Sharp & Dohme Llc Méthodes de traitement du cancer, ou de la maladie de von hippel-lindau à l'aide d'une association d'un antagoniste de tigit, d'un antagoniste de pd-1 et d'un inhibiteur de hif-2-alpha

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