A method for treating cancer or von Hippel-Lindau disease using a combination of a PD-1 antagonist, an HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof

Abstract

Provided herein are methods for treating cancer (e.g., RCC) or von Hippel-Lindau disease, comprising administering to a human patient in need of treatment for cancer or von Hippel-Lindau disease (VHD), (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof. Kits containing such agents and the use of therapeutic combinations of such agents for the treatment of cancer are also provided.

Description

Technical Field

[0001] (a) Programmed death 1 protein (PD-1) antagonist, (b) hypoxia-inducible factor 2α (HIF-2α) inhibitor and (c) lenvatinib, or a combination of pharmaceutically acceptable salts thereof, are provided herein for treating cancer (e.g., renal cell carcinoma (RCC)) or von Hippel-Lindau disease.

[0002] Reference to electronically submitted sequence listing The sequence listing for this application has been electronically submitted via EFS-Web as a sequence listing in ASCII format with the file name "25062WOPCT-SEQLIST-09APR2021_ST25.txt", creation date April 9, 2021, and size 10 KB. This sequence listing submitted via EFS-Web is part of this specification and is hereby incorporated by reference in its entirety.

Background Art

[0003] PD-1 is recognized as an important player in immune regulation and maintenance of peripheral immune tolerance. Immune checkpoint therapies targeting PD-1 or its ligands (e.g., PD-L1) have brought revolutionary improvements in clinical responses in multiple human cancer types (Brahmer et al., N Engl J Med, 366:2455-2465 (2012); Garon et al., N Engl J Med, 372:2018-2028 (2015); Hamid et al., N Engl J Med, 369:134-144 (2013); Robert et al., Lancet, 384:1109-1117 (2014); Robert et al., N Engl J Med, 372:2521-2532 (2015); Robert et al., N Engl J Med, 372:320-330 (2015); Topalian et al., N Engl J Med, 366:2443-2454 (2012); Topalian et al., J Clin Oncol, 32:1020-1030 (2014); Wolchok et al., N Engl J Med, 369:122-133 (2013)).Immunotherapies targeting the PD-1 axis include monoclonal antibodies made against 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® (sintilimab), Innovent Biologics, 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, DE; and BAVENCIO® (avelumab), Pfizer Inc, New York, NY).

[0004] Hypoxia within tumors is a driving force in cancer progression and is closely associated with poor patient prognosis and resistance to chemotherapy and radiation treatment. Hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that play a central role in the hypoxia response pathway. Under normoxic conditions, the von Hippel-Lindau (VHL) protein, a tumor suppressor, binds to specific hydroxylated proline residues and recruits an E3 ubiquitin ligase complex that targets the HIF-α protein for proteasomal degradation. Under hypoxic conditions, the HIF-α protein accumulates and enters the nucleus, stimulating 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 the accumulation of HIF expression under oxygen-loaded conditions (pseudohypoxic conditions). Therefore, directly targeting the HIF-α protein presents an excellent opportunity to attack tumors in multiple ways (Keith, et al., Nature Rev. Cancer 12:9-22, 2012).

[0005] Specifically, HIF-2α is an important oncogenic promoter in clear cell renal cell carcinoma (ccRCC) (Kondo, K., et al., Cancer Cell, 1:237-246 (2002); Maranchie, J. et al, Cancer Cell, 1:247-255 (2002); Kondo, K., et al., PLoS Biol., 1:439-444 (2003)). In a mouse ccRCC tumor model, knockdown of HIF-2α expression in a pVHL (von Hippel-Lindau protein)-deficient cell line blocked tumor growth equivalently to reintroduction of pVHL. Furthermore, expression of a stabilized mutant form of HIF-2α was able to overcome the tumor suppressive role of pVHL. Belzutifan, a novel HIF-2α inhibitor with excellent in vitro efficacy, pharmacokinetic profile and in vivo efficacy in a mouse model, or a pharmaceutically acceptable salt thereof, has shown promising results in patients with advanced renal cell carcinoma (Xu, Rui, et al., J. Med. Chem. 62:6876-6893 (2019).

[0006] HIF-2α has emerged as an important HIF isoform that is essential for von Hippel-Lindau (VHL)-deficient ccRCC. In a VHL-deficient ccRCC xenograft mouse tumor model, knockdown of HIF-2α expression inhibits tumor formation equivalently to reintroduction of functional VHL, and overexpression of HIF2α can, by itself, rescue the tumor suppressor 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. Cancer Cell 2002;1:237-46; Maranchie JK, Vasselli JR, Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate binding and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma. Cancer Cell 2002;1:247-55; Kondo K, Kim WY, Lechpammer M, Kaelin WG Jr.. Inhibition of HIF2alpha is sufficient to suppress pVHL-defective tumor growth. PLoS Biol 2003;1:E83; Zimmer M, Doucette D, Siddiqui N, Iliopoulos O. Inhibition of hypoxia-inducible factor is sufficient for growth suppression of VHL- / - tumors. Mol Cancer Res 2004;2:89-95). These data suggest that HIF-2α may be a tumor-promoting factor in ccRCC.HIF proteins can also be activated by the tumor hypoxic microenvironment in many other types of cancer (e.g., breast cancer, liver cancer, colon cancer, brain cancer, pancreatic cancer) and are thought to be involved in cancer initiation, progression, and metastasis (Jarman EJ, Ward C, Turnbull AK, Martinez-Perez C, Meehan J, Xintaropoulou C, Sims AH, Langdon SP. HER2 regulates HIF-2α and drives an increased hypoxic response in breast cancer. Breast Cancer Res. 2019 Jan 22;21(1):10; Wigerup C, Pahlman S., Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacology & Therapeutics 164 (2016) 152-169). HIF-2α has been shown to be stabilized by host tumor cells under tumor hypoxia, including endothelial cells, perivascular tumor cells, and immunosuppressive cell types such as tumor-associated macrophages (TAM) that play a role in the regulation of innate immunity (see Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC. Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest. 2010 Aug;120(8):2699-714). However, little is known about which VHL-bearing tumor types and combination strategies are logically appropriate to investigate using inhibitors of HIF-2α.

[0007] Von Hippel-Lindau disease (VHL disease) is an autosomal dominant syndrome in which patients are not only at high risk of renal cancer (approx. 70% lifetime risk), but also of hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. VHL disease results in tumors with constitutively active HIF-α proteins, most of which are dependent on HIF-2α activity (Maher, et al. Eur. J. Hum. Genet. 19:617-623, 2011). HIF-2α is associated with cancers of the retina, adrenal gland and pancreas via both VHL disease and activating mutations. In recent years, gain-of-function HIF-2α mutations have been identified in erythrocytosis and paragangliomas associated 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). Notably, several known HIF-2α-target gene products (e.g., VEGF, PDGF, and cyclin D1) have been shown to play extremely important roles in cancers derived from the kidney, liver, colon, lung and brain. Indeed, a therapy targeting VEGF, one of the important gene products regulated by HIF-2α, has been approved for the treatment of these cancers.

[0008] Tyrosine kinases are involved in the regulation of growth factor signaling and are therefore important targets for cancer therapy. Lenvatinib is a multi-RTK (multi-receptor tyrosine kinase) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4)), as well as fibroblast growth factor (FGF) receptors FGFR1, 2, 3 and 4, and other angiogenesis-promoting and oncogenic pathway-related RTKs involved in tumor growth (including platelet-derived growth factor (PDGF) receptor PDGFRα; the KIT and RET proto-oncogenes (RET)). In particular, lenvatinib has a new binding mode (type V) to VEGFR2 as confirmed by X-ray crystallographic analysis and shows rapid and potent inhibition of kinase activity according to kinetic analysis.

[0009] The effectiveness of anti-PD-1 or anti-PD-L1 antagonist antibodies has been proposed to be enhanced when administered in combination with other approved or experimental cancer treatments, such as radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways dysregulated in tumors, and other immune enhancers. However, there are no clear guidelines regarding which substances in combination with anti-PD-1 or anti-PD-L1 antibodies may be effective, or in which patients such combinations may enhance the effectiveness of treatment. Thus, there exists an unmet need in the art for highly effective therapeutic combinations that can generate a robust immune response against cancer.

Prior Art Documents

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Summary of the Invention

Problems to be Solved by the Invention

[0011] The present disclosure provides a method for treating cancer (e.g., RCC) or von Hippel-Lindau disease using a combination of a PD-1 antagonist, an HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof.

[0012] The present disclosure further provides a kit comprising a PD-1 antagonist, an HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof.

[0013] Use of a therapeutic combination for treating cancer (e.g., RCC) or von Hippel-Lindau disease, wherein said therapeutic combination comprises a PD-1 antagonist, a HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof, is also provided herein.

[0014] In one aspect, a method of treating cancer or von Hippel-Lindau disease, comprising administering to a human patient in need of treating cancer or von Hippel-Lindau disease (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0015] In some embodiments, 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.

[0016] In one embodiment, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In still other embodiments, the cancer is recurrent and refractory.

[0017] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet 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.

[0018] In one embodiment, the cancer is advanced RCC. In another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. In yet another embodiment, the cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC.

[0019] In another aspect, (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof A kit comprising the same is provided herein.

[0020] In certain embodiments, the kit further comprises instructions for administering the PD-1 antagonist, the HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof to a human patient.

[0021] In yet another aspect, provided herein is the use of a therapeutic combination for treating cancer in a human patient, wherein the therapeutic combination comprises (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0022] In some embodiments, 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.

[0023] In certain embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In still other embodiments, the cancer is recurrent and refractory.

[0024] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet 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.

[0025] In one aspect, the cancer is advanced RCC. In another aspect, the RCC is advanced RCC (ccRCC) having a clear cell component. In yet another aspect, the cancer is metastatic RCC. In yet another aspect, the cancer is recurrent RCC. In yet another aspect, the cancer is refractory RCC. In yet another aspect, the cancer is recurrent and refractory RCC.

[0026] In one aspect, the human patient has not received prior systemic treatment for the advanced disease. In a class of aspects, the human patient has not received prior systemic treatment for advanced RCC.

[0027] In certain aspects of the various methods, kits or uses provided herein, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof. In other aspects of the various methods, kits or uses provided herein, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof.

[0028] In some aspects of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is a humanized antibody.

[0029] In other aspects of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is a human antibody.

[0030] In certain aspects of the various methods, kits or uses provided herein, the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0031] In one aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, semaprilumab, sintilimab, tislelizumab, camrelizumab and toripalimab.

[0032] In one aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is pembrolizumab.

[0033] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is nivolumab.

[0034] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is semiprimab.

[0035] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is sintilimab.

[0036] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is tislelizumab.

[0037] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is camrelizumab.

[0038] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-1 monoclonal antibody is toripalimab.

[0039] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-L1 monoclonal antibody is durvalumab.

[0040] In another aspect of the various methods, kits or uses provided herein, the anti-human PD-L1 monoclonal antibody is avelumab.

[0041] In yet another aspect of the various methods, kits or uses provided herein, lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate. Capsules for oral administration contain 4 mg or 10 mg of lenvatinib, corresponding to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively. In another aspect, when a pharmaceutically acceptable salt of lenvatinib, such as lenvatinib mesylate, is administered and the dose of lenvatinib to be used is 4 mg, a medical practitioner will know to administer 4.90 mg of lenvatinib mesylate. In another aspect, when a pharmaceutically acceptable salt of lenvatinib, such as lenvatinib mesylate, is administered and the dose of lenvatinib to be used is 10 mg, a medical practitioner will know to administer 12.25 mg of lenvatinib mesylate. In aspects of the various methods described herein, a human patient is administered 8, 10, 12, 14, 18, 20 or 24 mg of lenvatinib once daily.

[0042] In one specific aspect of the various methods, kits or uses provided herein, the PD-1 antagonist is pembrolizumab and the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0043] In one specific aspect of the various methods, kits or uses provided herein, the PD-1 antagonist is nivolumab and the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0044] In one specific aspect of the various methods, kits or uses provided herein, the PD-1 antagonist is semiprimab and the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0045] In some aspects of the various methods described herein, a human patient is administered pembrolizumab at 200 mg, 240 mg, or 2 mg / kg, and pembrolizumab is administered once every three weeks. In one aspect, a human patient is administered 200 mg of pembrolizumab once every three weeks. In one aspect, a human patient is administered 240 mg of pembrolizumab once every three weeks. In one aspect, a human patient is administered 2 mg / kg of pembrolizumab once every three weeks.

[0046] In certain aspects of the various methods described herein, a human patient is administered 400 mg of pembrolizumab, and pembrolizumab is administered once every six weeks.

[0047] In other aspects of the various methods described herein, a human patient is administered nivolumab at 240 mg or 3 mg / kg once every two weeks, or 480 mg of nivolumab once every four weeks. In one particular aspect, a human patient is administered 240 mg of nivolumab once every two weeks. In one particular aspect, a human patient is administered 3 mg / kg of nivolumab once every two weeks. In one particular aspect, a human patient is administered 480 mg of nivolumab once every four weeks.

[0048] In other aspects of the various methods described herein, a human patient is administered 350 mg of semiprimab, and semiprimab is administered once every three weeks.

[0049] In other aspects of the various methods described herein, a human patient is administered 800 mg of avelumab, and avelumab is administered once every two weeks.

[0050] In other aspects of the various methods described herein, a human patient is administered 10 mg / kg of durvalumab, and durvalumab is administered once every two weeks. In other aspects of the various methods described herein, a human patient is administered 1500 mg of durvalumab, and durvalumab is administered once every three weeks. In other aspects of the various methods described herein, a human patient is administered 1500 mg of durvalumab, and durvalumab is administered once every four weeks.

[0051] In still other aspects of the various methods described herein, the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof, and a human patient is administered 40 mg to 120 mg of belzutifan or a pharmaceutically acceptable salt thereof daily. In some aspects, a human patient is administered 40, 80, or 120 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily. In one particular aspect, a human patient is administered 40 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily. In another particular aspect, a human patient is administered 80 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily. In another particular aspect, a human patient is administered 120 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily.

[0052] Thus, in some aspects, a human patient is (a) 200 mg, 240 mg, or 2 mg / kg of pembrolizumab once every three weeks; (b) 40, 80, or 120 mg of belzutifan once daily; and (c) 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib once daily administered.

[0053] In one aspect, a human patient is (a) 200 mg of pembrolizumab once every three weeks; (b) 120 mg of belzutifan once daily; and (c) Once daily, 20 mg of lenvatinib is administered.

[0054] In certain embodiments, a human patient is (a) Once every three weeks, 240 mg of pembrolizumab; (b) Once daily, 120 mg of belzutifan; and (c) Once daily, 20 mg of lenvatinib is administered.

[0055] In certain embodiments, a human patient is (a) Once every three weeks, 2 mg / kg of pembrolizumab; (b) Once daily, 120 mg of belzutifan; and (c) Once daily, 20 mg of lenvatinib is administered.

[0056] In certain embodiments, a human patient is (a) Once every six weeks, 400 mg of pembrolizumab; (b) Once daily, 120 mg of belzutifan; and (c) Once daily, 20 mg of lenvatinib is administered.

[0057] In certain embodiments, provided herein is a method of treating RCC, the method comprising administering to a human patient in need of treating RCC (a) Once every three weeks, 200 mg of pembrolizumab; (b) Once daily, 120 mg of belzutifan; and (c) Once daily, 20 mg of lenvatinib Thereby administered.

[0058] In certain embodiments of such methods, the anti-human PD-1 monoclonal antibody, the HIF-2α inhibitor, and lenvatinib are administered on the same day. In some embodiments, the anti-human PD-1 monoclonal antibody, the HIF-2α inhibitor, and lenvatinib are administered sequentially. In other embodiments, the anti-human PD-1 monoclonal antibody, the HIF-2α inhibitor, and lenvatinib are administered simultaneously.

[0059] In some embodiments of the various methods, kits, or uses described herein, a pharmaceutically acceptable salt of lenvatinib - lenvatinib mesylate - can be used. When lenvatinib mesylate is used, the dosage of lenvatinib mesylate is appropriately adjusted to provide a molar amount of lenvatinib equal to that provided by 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib.

Brief Description of the Drawings

[0060]

Figure 1

Figure 2A

Figure 2B

Modes for Carrying Out the Invention

[0061] 1. Definitions The following specifically defines certain technical and scientific terms. Unless otherwise specifically defined elsewhere in this specification, all other technical and scientific terms used in this specification have the meanings generally understood by those skilled in the art.

[0062] When used to modify a numerically defined parameter (e.g., the dose of an anti-PD-1 antibody or its antigen-binding fragment, an HIF-2α inhibitor or its antigen-binding fragment, or lenvatinib, or the length of treatment time by the combination therapies described herein), "about" means that the parameter is within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the numerical value or range described for that parameter, and where appropriate, the described parameter may be rounded to the nearest integer. For example, a dose of about 5 mg / kg can vary between 4.5 mg / kg and 5.5 mg / kg.

[0063] As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural references unless the context clearly indicates otherwise.

[0064] The term "administer" or "administering" refers to the act of injecting or otherwise physically delivering a substance to a patient, when the substance is outside the body (e.g., an anti-PD-1 antibody, an HIF-2α inhibitor, and lenvatinib as described herein), by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0065] "PD-1 antagonist" means any chemical compound or biological molecule that blocks the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells or NKT cells), and preferably also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed by immune cells. Alternative names or synonyms for PD-1 and its ligands include, for PD-1, PDCD1, PD1, CD279 and SLEB2; for PD-L1, PDCD1L1, PDL1, B7H1, B7-4, CD274 and B7-H; and for PD-L2, PDCD1L2, PDL2, B7-DC, Btdc and CD273. In any of the treatment methods, medicaments and disclosed uses in which a human individual is being treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1, and preferably also blocks the binding of both human PD-L1 and PD-L2 to human PD-1. The human PD-1 amino acid sequence can be found at NCBI Locus No.: NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI Locus No.: NP_054862 and NP_079515, respectively. The PD-1 antagonist is not atezolizumab, an anti-PD-L1 monoclonal antibody.

[0066] "HIF-2α inhibitor" means any chemical compound or biological molecule that inhibits the activity of HIF-2α. Alternative names or synonyms for HIF-2α include, but are not limited to, hypoxia-inducible factor-2α, endothelial PAS domain-containing protein 1 and EPAS1.

[0067] As used herein, the term "antibody" refers to any form of immunoglobulin molecule that exhibits the desired biological activity or binding activity. Thus, the term "antibody" is used in the broadest sense and specifically includes, 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. A "parent antibody" is an antibody obtained by exposing the immune system to an antigen prior to modification of the antibody for an intended use such as humanization of the antibody for use as a human therapeutic. As used herein, the term "antibody" refers not only to intact polyclonal or monoclonal antibodies, but also, unless otherwise specified, to any antigen-binding portion thereof that competes with the intact antibody for specific binding, a fusion protein comprising the antigen-binding portion, and any other modified form of the immunoglobulin molecule that comprises an antigen recognition site.

[0068] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer comprises two identical pairs of polypeptide chains, and each pair has one "light" chain (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain comprises a variable region of about 100-110 or more amino acids that is primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair form the antibody binding site. Thus, generally, an intact antibody has two binding sites. The carboxy-terminal portion of the heavy chain may define a constant region that is primarily responsible for effector functions. Typically, human light chains are classified as kappa and lambda light chains. Further, human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the isotypes of the antibody as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, and the heavy chain also includes a "D" region of about 10 additional amino acids. Generally, see Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)).

[0069] As used herein, "variable region" or "V region" or "V chain" means the segment of the IgG chain whose sequence is variable among different antibodies. The "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 "V H ". The variable region of the light chain may be referred to as "V L ". Typically, the variable regions of both the heavy and light chains contain three hypervariable regions, also called complementarity-determining regions (CDRs), which are located within relatively conserved framework regions (FRs). The CDRs are usually aligned by the framework regions and enable binding to specific epitopes. Generally, from the N-terminus to the C-terminus, both the light chain variable domain and the heavy chain variable domain contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The amino acid assignments to each domain generally follow the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al., National Institutes of Health, Bethesda, Md., 5th ed., NIH Publ. No. 91-3242 (1991), Kabat (1978), Adv. Prot. Chem. 32:1-75, Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616, Chothia, et al., (1987) J. Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0070] "CDR" refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the antibody V H β-sheet framework, or one of the antibody V LRefers to one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the β-sheet framework. Thus, the CDR is a variable region array interspersed within the framework region array. CDR regions are well known to those skilled in the art and are defined, for example, by Kabat as the most hypervariable regions within the antibody variable domain. CDR region sequences are also structurally defined by Chothia as residues that are not part of the conserved β-sheet framework and can thus adapt to different conformations. Both nomenclatures are well recognized in the art. CDR region sequences are also defined by AbM, Contact and IMGT. The positions of the CDRs within the canonical antibody variable regions 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). Since the number of residues within the hypervariable regions varies among different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c, etc. adjacent to the residue numbers in the canonical variable region numbering scheme (Al-Lazikani et al., supra). Such nomenclature is likewise well known to those skilled in the art. For example, the correspondence between numbering systems including Kabat numbering and the IMGT-specific numbering system is well known to those skilled in the art and is shown in Table 1 below. In some embodiments, the CDR is as defined by the Kabat numbering system. In other embodiments, the CDR is as defined by the IMGT numbering system. In yet other embodiments, the CDR is as defined by the AbM numbering system. In yet other embodiments, the CDR is as defined by the Chothia numbering system. In yet other embodiments, the CDR is as defined by the Contact numbering system.

[0071] [Table 1]

[0072] A "chimeric antibody" refers to an antibody in which a part of the heavy chain and / or light chain is derived from a specific species (e.g., human), or contains a sequence belonging to a specific antibody class or subclass, and the remainder of the (one or more) chains is derived from another species (e.g., mouse), or belongs to another antibody class or subclass, as well as fragments of such antibodies, provided that they exhibit the desired biological activity.

[0073] A "human antibody" refers to an antibody that contains a human immunoglobulin protein sequence or a derivative thereof. A human antibody may contain mouse carbohydrate chains when produced in a mouse, in mouse cells, or in a hybridoma derived from mouse cells. Similarly, a "mouse antibody" or a "rat antibody" refers to an antibody that contains only the immunoglobulin sequence of a mouse or a rat, respectively, or a derivative thereof.

[0074] A "humanized antibody" refers to a form of an antibody that contains, in addition to human antibodies, sequences derived from non-human (e.g., mouse) antibodies. Such antibodies contain the minimum sequence derived from non-human immunoglobulins. Generally, a humanized antibody contains substantially all of at least one, typically two, variable domains, and all or substantially all of the hypervariable loops correspond to the hypervariable loops of non-human immunoglobulins, and all or substantially all of the FR regions are the FR regions of human immunoglobulin sequences. A humanized antibody may also contain at least a part of the immunoglobulin constant region (Fc), typically at least a part of the immunoglobulin constant region (Fc) of a human immunoglobulin. If necessary to distinguish a humanized antibody from a parental rodent antibody, the prefix "hum", "hu", or "h" may be added to the name of the antibody clone. The humanized form of a rodent antibody generally contains the same CDR sequences as the parental rodent antibody, but may contain certain amino acid substitutions for the purpose of increasing affinity, increasing the stability of the humanized antibody, or for other reasons.

[0075] As used herein, the term "monoclonal antibody" or "mAb" or "Mab" refers to a substantially homogeneous population of antibodies, i.e., the antibody molecules that make up the population have the same amino acid sequence, except for naturally occurring mutations that may be present in trace amounts. In contrast, conventional (polyclonal) antibody preparations typically contain a number of different antibodies that often have different amino acid sequences in their variable domains, particularly in their CDRs, which are specific for different epitopes. The modifier "monoclonal" indicates the characteristic of the antibody as being obtained from a substantially homogeneous population of antibodies and should not be construed as requiring the production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present disclosure can be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495 or by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567). "Monoclonal antibodies" can also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. Biol. 222:581-597. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0076] As used herein, unless otherwise specified, "antibody fragment" or "antigen-binding fragment" refers to a fragment of an antibody that retains the ability to specifically bind to an antigen, e.g., a fragment that retains 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 compared to other proteins (as appropriate), but this specificity does not require absolute binding specificity. An antibody is considered "specific" for its intended target if its binding determines the presence of the target protein in a sample without producing unwanted results such as false positives. An antibody or its binding fragment binds to the target protein with an affinity that is at least 2-fold greater, preferably at least 10-fold greater, more preferably at least 20-fold greater, and most preferably at least 100-fold greater than its affinity for non-target proteins.

[0077] Examples of antigen-binding portions include, for example, Fab, Fab’, F(ab’)2, Fd, Fv, fragments containing CDRs, and single-chain variable fragment antibodies (scFv), and polypeptides containing at least a portion of an immunoglobulin sufficient to confer a specific antigen that binds to an antigen (e.g., PD-1 or ILT4). An antibody includes antibodies of any class, such as IgG, IgA, or IgM (or subclasses thereof), and the antibody need not be of any particular class. Immunoglobulins can be assigned to different classes according to the amino acid sequence of the constant region of their heavy chains. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant regions corresponding to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional arrangements of the different classes of immunoglobulins are well known.

[0078] As used herein, the terms "at least one" item or "one or more" items each include a single item selected from a list and a mixture of two or more items selected from the list.

[0079] As used herein, the term "immune response" relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific responses, natural response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[0080] As used herein, the term "subject" (or "patient") refers to a mammal that is the subject of treatment, observation, or experiment. The mammal can be male or female. The mammal can be one or more selected from the group consisting of humans, bovines (e.g., dairy cows), porcines (e.g., pigs), ovines (e.g., sheep), caprines (e.g., goats), equines (e.g., horses), canines (e.g., pet dogs), felines (e.g., pet cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), procyon lotor (e.g., raccoons). In certain embodiments, the subject is a human.

[0081] As used herein, the term "subject in need of" refers to a subject diagnosed with or suspected of having a cancer or infectious disease as defined herein.

[0082] The therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral or parenteral route of administration. The term "enteral route" of administration refers to administration through any part of the digestive tract. Examples of enteral routes include oral, mucosal, oral and rectal routes, or intragastric routes. "Parenteral route" of administration refers to a route of administration other than the enteral route. Examples of parenteral route of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal, subcutaneous or topical administration. The therapeutic agents and compositions of the present disclosure can be administered using any suitable method such as oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implanted infusion pump, and osmotic pump. The appropriate route and method of administration may vary depending on several factors such as the specific therapeutic agent being used, the desired absorption rate, the specific formulation or dosage form being used, the type or severity of the disorder being treated, the specific site of action, and the condition of the patient, and can be readily selected by those skilled in the art.

[0083] The term "variant", when used with respect to an antibody (e.g., an anti-PD-1 antibody) or an amino acid region within an antibody, can refer to a peptide or polypeptide that contains one or more (e.g., 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, etc.) amino acid sequence substitutions, deletions and / or additions as compared to the native or unmodified sequence. For example, a variant of an anti-PD-1 antibody can result from one or more (e.g., 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, etc.) changes to the amino acid sequence of a native or previously unmodified anti-PD-1 antibody. Variants can occur naturally or can be artificially constructed. Polypeptide variants can be prepared from the corresponding nucleic acid molecules encoding the variants. In certain embodiments, an antibody variant (e.g., an anti-PD-1 antibody variant) retains at least antibody functional activity. In certain embodiments, an anti-PD-1 antibody variant binds to PD-1 and / or antagonizes PD-1 activity.

[0084] A "conservatively modified variant" or "conservative substitution" refers to a substitution of an amino acid in a protein by another amino acid having similar characteristics (e.g., charge, side chain size, hydrophobicity / hydrophilicity, backbone steric structure and rigidity, etc.) such that changes can be made frequently without altering the biological activity of the protein or other desired properties such as antigenic affinity and / or specificity. Those skilled in the art generally recognize that a single amino acid substitution in a non-essential region of a polypeptide does not substantially alter its biological activity [see, for example, Watson et al., (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)]. Further, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity. Exemplary conservative substitutions are shown in Table 2 below.

[0085]

Table 2

[0086] "Homology" refers to the sequence similarity between two polypeptide sequences when the two polypeptide sequences are optimally aligned. If a position in both of the two compared sequences is occupied by the same amino acid monomer subunit, for example, if the positions in the light chain CDRs of two different Abs are occupied by alanine, the two Abs are homologous at that position. The percent homology is the number of homologous positions shared by the two sequences divided by the total number of positions compared × 100. For example, when the sequences are optimally aligned and 8 out of 10 positions in the two sequences match, the two sequences are 80% homologous. Generally, the comparison is made when the two sequences are aligned so as to give the maximum percent homology. For example, the comparison can be carried out by the BLAST algorithm and the parameters of the algorithm are selected so as to give the maximum match between the respective sequences over the entire length of each reference sequence.

[0087] The following references are related to the 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. 266:131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., ’’A model of evolutionary change in proteins.’’ in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.), pp. 345-352,; Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., ’’Matrices for detecting distant relationships.’’ in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3.’’ M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J. Mol. Biol. 219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S.F., et al.,(1993) J.Mol.Evol. 36:290 - 300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc.Natl.Acad.Sci.USA 87:2264 - 2268; Karlin, S., et al., (1993) Proc.Natl.Acad.Sci.USA 90:5873 - 5877; Dembo, A., et al., (1994) Ann.Prob. 22:2022 - 2039; and Altschul, S.F. ‘‘Evaluating the statistical significance of multiple distinct local alignments.’’ in Theoretical and Computational Methods in Genome Research (S.Suhai, ed.), (1997) pp.1 - 14, Plenum, New York.

[0088] As used herein, the ‘‘Solid Tumor Response Evaluation Criteria in Solid Tumors 1.1 Response Criteria’’ means, as appropriate, the definitions described in Eisenhauer, E.A. et al., Eur.J.Cancer 45:228 - 247 (2009) with respect to target or non - target lesions, based on the circumstances in which the response is being measured.

[0089] ‘‘Durable response’’ means a sustained therapeutic effect after discontinuation of the treatment described herein. In some embodiments, the durable response has a duration that is at least as long as the treatment period or at least 1.5 - fold, 2.0 - fold, 2.5 - fold, or 3 - fold longer than the treatment period.

[0090] As used herein, "treating" or "treatment" of cancer means, for example, administering to a subject having or diagnosed with cancer a therapeutic combination of an anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof, a HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof, in order to achieve at least one positive therapeutic effect such as a reduced number of cancer cells, a reduced tumor size, a reduced rate of cancer cell infiltration into peripheral organs, or a reduced rate of tumor metastasis or tumor growth. Such "treatment" can result in deceleration, interruption, suppression, control or cessation of cancer progression as described herein, but does not necessarily indicate complete elimination of the cancer or cancer symptoms. Positive therapeutic effects in cancer can be measured in several ways (see W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, with respect to tumor growth inhibition, according to the NCI criteria, T / C ≤ 42% is the minimum level of antitumor activity. T / C < 10% is considered a high level of antitumor activity, where T / C(%) = median tumor volume of treated / median tumor volume of control × 100. In some embodiments, the treatment achieved by the combination therapies of the present 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 length of time the patient experiences CR or PR, as well as the length of time the patient experiences SD. DFS refers to the length of time during and after treatment that the patient remains disease-free. OS refers to an extension of the average life expectancy compared to untreated or non-treated individuals or patients. In some embodiments, the response to the combination therapies of the present disclosure is any of PR, CR, PFS, DFS or OR as evaluated using the solid tumor response evaluation criteria 1.1 response criteria. The treatment regimen for the combination therapies of the present disclosure effective for treating cancer patients can vary depending on factors such as the patient's medical condition, age and weight, and the ability of the therapy to induce an anti-cancer response in the subject.While any aspect of the disclosed aspects may not be effective in achieving a positive therapeutic effect in all subjects, it should achieve a positive therapeutic effect in a statistically significant number of subjects as determined by any statistical test known in the art, such as a Student's t-test, chi-square test, Mann-Whitney U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0091] As used herein, the terms "combination", "combination therapy", and "therapeutic combination" refer to a treatment in which at least one anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof, a HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof, and optionally additional therapeutic agents, are each administered to a patient in a coordinated manner over an overlapping period. The period of treatment with at least one anti-human PD-1 monoclonal antibody (or antigen-binding fragment thereof) ("anti-PD-1 treatment") is the period during which the patient is treated with the anti-human PD-1 monoclonal antibody (or antigen-binding fragment thereof), i.e., the period from the first administration of the anti-human PD-1 monoclonal antibody (or antigen-binding fragment thereof) to the last day of the treatment cycle. Similarly, the period of treatment with a HIF-2α inhibitor ("HIF-2α inhibitor treatment") is the period during which the patient is treated with the HIF-2α inhibitor, i.e., the period from the first administration of the HIF-2α inhibitor to the last day of the treatment cycle. The period of treatment with lenvatinib or a pharmaceutically acceptable salt thereof ("lenvatinib treatment") is the period during which the patient is treated with lenvatinib, i.e., the period from the first administration of lenvatinib to the last day of the treatment cycle. In the methods and therapeutic combinations described herein, the anti-PD-1 treatment overlaps with the HIF-2α inhibitor treatment for at least one day and overlaps with the lenvatinib treatment for at least one day. In one embodiment, the anti-PD-1 treatment, the HIF-2α inhibitor treatment, and the lenvatinib treatment are for the same period. In some embodiments, the anti-PD-1 treatment begins before the HIF-2α inhibitor and / or lenvatinib treatment. In other embodiments, the anti-PD-1 treatment begins after the HIF-2α inhibitor and / or lenvatinib treatment. In yet other embodiments, the HIF-2α inhibitor treatment begins before the anti-PD-1 and / or lenvatinib treatment. In yet other embodiments, the HIF-2α inhibitor treatment begins after the anti-PD-1 and / or lenvatinib treatment. In some embodiments, the lenvatinib treatment begins before the HIF-2α inhibitor and / or anti-PD-1 treatment. In other embodiments, the lenvatinib treatment begins after the HIF-2α inhibitor and / or anti-PD-1 treatment.In certain embodiments, anti-PD-1 treatment ends before the end of HIF-2α inhibitor and / or lenvatinib treatment. In other embodiments, anti-PD-1 treatment ends after the end of HIF-2α inhibitor and / or lenvatinib treatment. In still other embodiments, HIF-2α inhibitor treatment ends before the end of anti-PD-1 and / or lenvatinib treatment. In still other embodiments, HIF-2α inhibitor treatment ends after the end of anti-PD-1 and / or lenvatinib treatment. In certain embodiments, lenvatinib treatment ends before the end of HIF-2α inhibitor and / or anti-PD-1 treatment. In other embodiments, lenvatinib treatment ends after the end of HIF-2α inhibitor and / or anti-PD-1 treatment.

[0092] The terms "treatment regimen", "dosage protocol", and "dosage regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination therapies of the present disclosure.

[0093] "Tumor", when applied to a subject diagnosed with cancer or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or tissue mass of any size, including primary tumors and secondary neoplasms. Non-limiting examples of tumors include solid tumors (e.g., sarcomas (such as chondrosarcoma), carcinomas (such as colon carcinoma), blastomas (such as hepatoblastoma), etc.) and hematological tumors (e.g., leukemias (such as acute myeloid leukemia (AML)), lymphomas (such as DLBCL), multiple myeloma (MM), etc.).

[0094] The term "tumor volume" or "tumor size" refers to the total size of a tumor that can be measured as the length and width of the tumor. Tumor size can be determined by various methods known in the art, for example, by measuring the dimensions of the (one or more) tumors when removed from the subject, using, for example, calipers, or by measuring the dimensions of the (one or more) tumors while present in the body, using imaging techniques such as bone scans, ultrasounds, CT or MRI scans.

[0095] Unless the contrary is explicitly stated, all ranges recited in this specification are inclusive, i.e., the range includes the upper and lower limits of the range, as well as all values therebetween. By way of example, temperature ranges, percentage ranges, equivalent ranges, etc. recited in this specification include the upper and lower limits of the range, as well as any value in the continuous connection therebetween. Numerical values provided in this specification, and the use of the term “about” may include variations of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15% and ±20% and their numerical equivalents. Although not necessarily explicitly recited, all ranges are also intended to include all subranges subsumed therein. For example, a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days. Further, the term “or” as used in this specification indicates alternatives that may be combined where appropriate, i.e., the term “or” includes each of the recited alternatives separately as well as combinations thereof.

[0096] Where aspects or embodiments of the disclosure are described in terms of Markush groups or other groupings of alternatives, the disclosure includes not only the entire recited group as a whole, but also each individual member of the group and all possible subgroups of the main group, including main groups in which one or more of the group members are absent. The disclosure also contemplates any explicit exclusion of one or more of the group members in the claims.

[0097] Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control. Throughout this specification and the claims, the word "comprise", or variations such as "comprises" or "comprising", are to be understood to mean including the recited integer or group of integers but not excluding any other integer or group of integers. Unless the context requires otherwise, singular terms shall include pluralities and plural terms shall include the singular. Any example(s) following the terms "e.g." or "for example" are not meant to be exhaustive or limiting. Exemplary methods and materials are described herein, but methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0098] 2. PD-1 Antagonist Provided herein are 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 the binding of PD-L1 to PD-1 and preferably also blocks the binding of PD-L2 to PD-1.

[0099] Any monoclonal antibody that 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 its ligands PD-L1 or PD-L2 can be used. In some embodiments, 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. In other embodiments, 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. In yet other embodiments, 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.

[0100] Any monoclonal antibody that binds to a PD-L1 polypeptide, a PD-L1 polypeptide fragment, a PD-L1 peptide, or a PD-L1 epitope and blocks the interaction between PD-L1 and PD-1 can also be used.

[0101] In one embodiment, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, semaprilimab, sintilimab, tislelizumab, camrelizumab, toripalimab, pidilizumab (U.S. Patent No. 7,332,582), AMP-514 (MedImmune LLC, Gaithersburg, MD), PDR001 (U.S. Patent No. 9,683,048), BGB-A317 (U.S. Patent No. 8,735,553), and MGA012 (MacroGenics, Rockville, MD). In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab.

[0102] In certain aspects of the various methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable region (V L ) complementary determining region 1 (CDR1), V L CDR2 and V L CDR3, and a heavy chain variable region (V H ) CDR1, V H CDR2 and V H CDR3, which comprise the amino acid sequences shown in SEQ ID NO: 6, 7 and 8 respectively.

[0103] In some aspects of the various methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof comprises a V L region comprising the amino acid sequence shown in SEQ ID NO: 4 and a V H region comprising the amino acid sequence shown in SEQ ID NO: 9.

[0104] In other aspects of the various methods, pharmaceutical compositions, kits or uses provided herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof comprises a light chain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 5 and a heavy chain comprising or consisting of the amino acid sequence shown in SEQ ID NO: 10.

[0105]

Table 3

[0106] In another aspect, the anti-human PD-1 monoclonal antibody is nivolumab. In another aspect, the anti-human PD-1 monoclonal antibody is semipramab. In another aspect, the anti-human PD-1 monoclonal antibody is sintilimab. In another aspect, the anti-human PD-1 monoclonal antibody is tislelizumab. In another aspect, the anti-human PD-1 monoclonal antibody is camrelizumab. In another aspect, the anti-human PD-1 monoclonal antibody is toripalimab. In yet another aspect, the anti-human PD-1 monoclonal antibody is pidilizumab. In one aspect, the anti-human PD-1 monoclonal antibody is AMP-514. In another aspect, the anti-human PD-1 monoclonal antibody is PDR001. In yet another aspect, the anti-human PD-1 monoclonal antibody is BGB-A317. In yet another aspect, the anti-human PD-1 monoclonal antibody is MGA012.

[0107] In some aspects, the anti-human PD-1 monoclonal antibody can be any antibody, antigen-binding fragment thereof, or variant thereof disclosed in U.S. Patent No. 7,488,802, U.S. Patent No. 7,521,051, U.S. Patent No. 8,008,449, U.S. Patent No. 8,354,509, U.S. Patent No. 8,168,757, International Publication No. 2004 / 004771, International Publication No. 2004 / 072286, International Publication No. 2004 / 056875, U.S. Patent Application Publication No. 2011 / 0271358, and International Publication No. 2008 / 156712, the disclosures of which are hereby incorporated by reference in their entirety.

[0108] Examples of monoclonal antibodies that bind to human PD-L1 and can be used in the various methods, kits, and uses described herein are disclosed in U.S. Patent No. 8,383,796, the disclosure of which is hereby incorporated by reference in its entirety. Specific anti-human PD-L1 monoclonal antibodies useful as PD-1 antagonists in the various methods, kits, and uses described include durvalumab, avelumab, and BMS-936559.

[0109] Among the various methods, kits and other PD-1 antagonists useful in the uses described herein are immune adhesion molecules that specifically bind to PD-1 or PD-L1, preferably specifically bind to human PD-1 or human PD-L1, for example, fusion proteins containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as the Fc region of an immunoglobulin molecule. Examples of immune adhesion molecules that specifically bind to PD-1 are described in International Publication No. WO 2010 / 027827 and International Publication No. WO 2011 / 066342, the disclosures of which are incorporated herein by reference in their entirety. Specific fusion proteins useful as PD-1 antagonists in the various methods, kits and uses described herein include the PD-L2-Fc fusion protein and AMP-224 (also known as B7-DCIg) that binds to human PD-1.

[0110] In various embodiments, the anti-human PD-1 or anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof includes a variant of the amino acid sequence of the anti-human PD-1 or anti-human PD-L1 antibody described herein. The 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. In some embodiments, the substitutions, deletions and / or additions are within the CDRs. In some embodiments, the substitutions, deletions and / or additions are within the framework regions. In one embodiment, one, two, three, four or five of the amino acid substitutions are conservative substitutions.

[0111] In one embodiment, the anti-human PD-1 or anti-human PD-L1 monoclonal antibody or antigen-binding fragment thereof has at least 95%, 90%, 85%, 80%, 75% or 50% sequence identity with one of the V L domains of the anti-human PD-1 or anti-human PD-L1 antibody described herein. LIt has a domain and shows specific binding to PD-1 or PD-L1. In another aspect, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof has a V H domain having at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology with one of the V H domains and shows specific binding to PD-1 or PD-L1. In yet another aspect, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof has a V L domain having at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology with one of the V L domains and a V H domain having at least 95%, 90%, 85%, 80%, 75% or 50% sequence homology with one of the V H domains and shows specific binding to PD-1 or PD-L1.

[0112] In one aspect, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof has a V L domain having a maximum of one, two, three, four, five or more amino acid substitutions, deletions and / or additions in one of the V L domains and shows specific binding to PD-1 or PD-L1. In another aspect, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof has a V H domain having a maximum of one, two, three, four, five or more amino acid substitutions, deletions and / or additions in one of the V HIt has a domain and exhibits specific binding to PD-1 or PD-L1. In yet another aspect, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof has a V L domain with a maximum of one, two, three, four, five or more amino acid substitutions, deletions and / or additions in one of the V L domains of the anti-human PD-1 or anti-human PD-L1 antibodies described herein, and a V H domain with a maximum of one, two, three, four, five or more amino acid substitutions, deletions and / or additions in one of the V H 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.

[0113] In various aspects, the anti-human PD-1 or anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof is selected from any class of immunoglobulins including IgM, IgG, IgD, IgA and IgE. Preferably, the antibody is an IgG antibody. Any isotype of IgG including IgG1, IgG2, IgG3 and IgG4 can be used. Different constant domains can be added to the V L and V H regions provided herein. For example, if a particular intended use of the antibody (or fragment) of the invention requires altered effector functions, a heavy chain constant domain other than IgG1 can be used. IgG1 antibodies provide a long half-life and effector functions such as complement activation and antibody-dependent cell cytotoxicity, but such activities may not be desirable for all uses of the antibody. In such cases, for example, an IgG4 constant domain can be used. In various aspects, the heavy chain constant domain contains one or more amino acid mutations (e.g., IgG4 with the S228P mutation) to produce the desired characteristics of the antibody. These desired characteristics include, but are not limited to, modified effector functions, physical or chemical stability, half-life of the antibody, and the like.

[0114] Generally, the 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, more preferably at least 80%, more preferably at least 85%, more preferably at least 90%, most preferably at least 95, 98 or 99% amino acid sequence identity with the amino acid sequence of a reference antibody or antigen-binding fragment (e.g., heavy chain, light chain, V H H, V L L or humanized sequence). Identity or homology to a sequence is defined herein as the percentage of amino acid residues in a candidate sequence that are identical to a reference sequence, after aligning the sequences to achieve maximum percent sequence identity and introducing gaps, if necessary, and without considering any conservative substitutions as part of the sequence identity. Neither N-terminal, C-terminal or internal extensions, deletions or insertions into the antibody sequence should be construed to affect sequence identity or homology.

[0115] 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 the BLAST algorithm, and the parameters of the algorithm are selected to give the maximum match between the sequences over the full length of each reference sequence. The following references are for the 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. 266:131-141; Altschul, S.F., et al., (1997) Nucleic Acids Res. 25:3389-3402; Zhang, J., et al., (1997) Genome Res. 7:649-656; Wootton, J.C., et al., (1993) Comput. Chem. 17:149-163; Hancock, J.M. et al., (1994) Comput. Appl. Biosci. 10:67-70; ALIGNMENT SCORING SYSTEMS: Dayhoff, M.O., et al., ’’A model of evolutionary change in proteins.’’ in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3. M.O. Dayhoff (ed.), pp. 345-352,; Natl. Biomed. Res. Found., Washington, DC; Schwartz, R.M., et al., ’’Matrices for detecting distant relationships.’’ in Atlas of Protein Sequence and Structure, (1978) vol. 5, suppl. 3., M.O. Dayhoff (ed.), pp. 353-358, Natl. Biomed. Res. Found., Washington, DC; Altschul, S.F., (1991) J.Mol.Biol.219:555-565; States, D.J., et al., (1991) Methods 3:66-70; Henikoff, S., et al., (1992) Proc. Natl. Acad. Sci. USA 89:10915-10919; Altschul, S.F., et al., (1993) J. Mol. Evol. 36:290-300; ALIGNMENT STATISTICS: Karlin, S., et al., (1990) Proc. Natl. Acad. Sci. USA 87:2264-2268; Karlin, S., et al., (1993) Proc. Natl. Acad. Sci. USA 90:5873-5877; Dembo, A., et al., (1994) Ann. Prob. 22:2022-2039; and Altschul, S.F. ‘‘Evaluating the statistical significance of multiple distinct local alignments.’’ in Theoretical and Computational Methods in Genome Research (S. Suhai, ed.), (1997) pp. 1-14, Plenum, New York。

[0116] In some embodiments, 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.

[0117] In some embodiments, the light chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human κ backbone. In other embodiments, the light chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human λ backbone.

[0118] In some embodiments, the heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human IgG1 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 yet other embodiments, the heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human IgG4 backbone.

[0119] In some embodiments, the heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody has a human IgG1 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 yet 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 having an S228P mutation) backbone.

[0120] 3. HIF-2α Inhibitors Also provided herein are HIF-2α 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-2α.

[0121] In some embodiments, the HIF-2α inhibitor is MK-6482, PT2977, 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluorobenzonitrile, and also known as belzutifan or a pharmaceutically acceptable salt thereof having the following chemical structure: 3-[[(1S,2S,3R)-2,3-difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile.

Chemical Structure

[0122] Beltinib and its synthesis are described in U.S. Patent No. 9,969,689, which is hereby incorporated by reference in its entirety. Beltinib as a potential treatment for clear cell renal cell carcinoma is described in Rui Xu et al., J. Med. Chem. 2019, 62, 6876 - 6893, which is hereby incorporated by reference in its entirety. The combination of a PD - 1 / CTLA - 4 inhibitor and a HIF - 2α inhibitor for treating melanoma, RCC or CRC is described in U.S. Patent No. 10,335,388, which is hereby incorporated by reference in its entirety. U.S. Patent Application Publication No. 2018 - 0042884 describes the treatment of glioblastoma with a HIF - 2α inhibitor, which is hereby incorporated by reference in its entirety. The oral formulation of beltinib is described in International Application No. PCT / US2019 / 57725, filed on October 23, 2019, which is hereby incorporated by reference in its entirety.

[0123] 4. Lenvatinib Also provided herein is lenvatinib, a multi - RTK (multi - receptor tyrosine kinase) inhibitor that selectively inhibits the kinase activity of VEGFR.

[0124] Lenvatinib is also known as LENVIMA (registered trademark), Eisai Inc., Woodcliff Lake, NJ and 4 - [3 - chloro - 4 - (cyclopropylaminocarbonyl) aminophenoxy] - 7 - methoxy - 6 - quinolinecarboxamide and has the following chemical structure.

Chemical Structure

[0125] Lenvatinib, its synthesis and use are described in U.S. Patent Nos. 7,253,286; 7,612,208; 9,006,256; 10,259,791; 10,407,393, which are hereby incorporated by reference in their entirety.

[0126] 5. A method of treating cancer or von Hippel-Lindau disease using a combination of a PD-1 antagonist, a HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof In another aspect, a method of treating cancer (e.g., RCC) or von Hippel-Lindau disease using a combination of a PD-1 antagonist, a HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof as described herein is provided.

[0127] In some embodiments, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0128] In one aspect, a method of treating cancer or von Hippel-Lindau disease comprises administering to a human patient in need of treating cancer or von Hippel-Lindau disease (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof Thereby.

[0129] In some embodiments, 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.

[0130] In one aspect, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In still other embodiments, the cancer is recurrent and refractory.

[0131] In one aspect, the cancer is bladder cancer. In another aspect, the cancer is breast cancer. In yet another aspect, the cancer is NSCLC. In yet another aspect, the cancer is CRC. In one aspect, the cancer is RCC. In another aspect, the cancer is HCC. In yet another aspect, the cancer is pancreatic cancer. In yet another aspect, the cancer is melanoma.

[0132] In one aspect, the cancer is advanced RCC. In another aspect, the RCC is clear cell component having advanced RCC (ccRCC). In yet another aspect, the cancer is metastatic RCC. In yet another aspect, the cancer is recurrent RCC. In yet another aspect, the cancer is refractory RCC. In yet another aspect, the cancer is recurrent and refractory RCC.

[0133] In one aspect, the human patient has not received prior systemic treatment for the advanced disease. In a class of aspects, the human patient has not received prior systemic treatment for advanced RCC.

[0134] In one aspect, a method of treating RCC, comprising administering to a human patient in need of treating RCC (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0135] In some aspects, a method of treating advanced RCC, comprising administering to a human patient in need of treating advanced RCC (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0136] In some embodiments, a method of treating advanced RCC having a clear cell component, the method comprising administering to a human patient in need of treatment of advanced RCC having a clear cell component: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0137] In other embodiments, a method of treating metastatic RCC, the method comprising administering to a human patient in need of treatment of metastatic RCC: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0138] In yet other embodiments, a method of treating recurrent RCC, the method comprising administering to a human patient in need of treatment of recurrent RCC: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0139] In yet other embodiments, a method of treating refractory RCC, the method comprising administering to a human patient in need of treatment of refractory RCC: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0140] In another aspect, a method of treating recurrent and refractory RCC, comprising administering to a human patient in need of treatment for recurrent and refractory RCC, (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0141] In another aspect, a method of treating pancreatic cancer, comprising administering to a human patient in need of treatment for pancreatic cancer, (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0142] In one aspect, a method of treating cancer comprises administering to a human patient in need of treatment for cancer, (a) a PD-1 antagonist; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof comprising.

[0143] In one aspect, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof. In some aspects, the anti-human PD-1 monoclonal antibody is a human antibody. In other aspects, the anti-human PD-1 monoclonal antibody is a humanized antibody.

[0144] In one aspect, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof. In some aspects, the anti-human PD-L1 monoclonal antibody is a human antibody. In other aspects, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

[0145] Thus, in one aspect, a method for treating cancer, comprising administering to a human patient in need of treating cancer: (a) a human or humanized anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0146] In some aspects, a method for treating cancer, comprising administering to a human patient in need of treating cancer: (a) a human anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) belzutifan or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0147] In other aspects, a method for treating cancer, comprising administering to a human patient in need of treating cancer: (a) a humanized anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0148] In one aspect of the various methods provided herein, the anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof is pembrolizumab.

[0149] In another aspect of the various methods provided herein, the anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof is nivolumab.

[0150] In another aspect of the various methods provided herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is semi-purimab.

[0151] Thus, in one particular aspect of the various methods provided herein, a method for treating cancer comprises administering to a human patient in need of treating cancer (a) pembrolizumab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof thereof.

[0152] In one particular aspect of the various methods provided herein, a method for treating cancer comprises administering to a human patient in need of treating cancer (a) nivolumab; (b) belzutifan or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof thereof.

[0153] In one particular aspect of the various methods provided herein, a method for treating cancer comprises administering to a human patient in need of treating cancer (a) semi-purimab; (b) belzutifan or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof thereof.

[0154] In one particular aspect of the various methods provided herein, a method for treating RCC comprises administering to a human patient in need of treating RCC (a) pembrolizumab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof thereof.

[0155] In one particular embodiment of the various methods provided herein, a method for treating RCC comprises administering to a human patient in need of treating RCC, (a) nivolumab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof thereof.

[0156] In one particular embodiment of the various methods provided herein, a method for treating RCC comprises administering to a human patient in need of treating RCC, (a) semiprimab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof thereof.

[0157] In one embodiment, the RCC is advanced RCC. In another embodiment, the RCC is advanced RCC having a clear cell component. In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is recurrent RCC. In yet another embodiment, the RCC is refractory RCC. In yet another embodiment, the RCC is recurrent and refractory RCC.

[0158] In one embodiment, the present invention provides a method for treating von Hippel-Lindau (VHL) disease, the method comprising administering to a human patient in need of treating von Hippel-Lindau (VHL) disease (a) a PD-1 antagonist (e.g., pembrolizumab); (b) a HIF-2α inhibitor (e.g., belzutifan or a pharmaceutically acceptable salt thereof); and (c) lenvatinib, or a pharmaceutically acceptable salt thereof thereof.

[0159] 6. Medication and Administration Also provided herein are dosing regimens and routes of administration for treating cancer (e.g., RCC) using a combination of a PD-1 antagonist (e.g., an anti-PD-1 monoclonal antibody or an antigen-binding fragment thereof), a HIF-2α inhibitor, and a multi-RTK inhibitor (e.g., lenvatinib or a pharmaceutically acceptable salt thereof).

[0160] The anti-PD-1 monoclonal antibody or an antigen-binding fragment thereof, the HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof disclosed herein can be administered, for example, at a dose administered daily, 1 to 7 times a week, weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every other month, every 3 months, every six months, annually, etc. The dose can be administered, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracranially, intraspinally, or by inhalation. In certain embodiments, the dose is administered intravenously. In certain embodiments, the dose is administered subcutaneously. In certain embodiments, the dose is administered orally. The total dose for treatment intervals is generally at least 0.05 μg / kg body weight, more generally at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / 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 than that. Doses can also be provided to achieve a predetermined target concentration of an antibody (e.g., an anti-PD-1 antibody) or an antigen-binding fragment thereof in the serum of the subject, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / mL or more.

[0161] In some embodiments, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously at 10, 20, 50, 80, 100, 200, 300, 400, 500, 1000 or 2500 mg / subject, weekly, every other week, every three weeks, every four weeks, every five weeks, every six weeks, monthly, every other month or every three months. In some specific methods, the dosage of the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is about 0.01 mg / kg to about 50 mg / kg, about 0.05 mg / kg to about 25 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.2 mg / kg to about 9 mg / kg, about 0.3 mg / kg to about 8 mg / kg, about 0.4 mg / kg to about 7 mg / kg, about 0.5 mg / kg to about 6 mg / kg, about 0.6 mg / kg to about 5 mg / kg, about 0.7 mg / kg to about 4 mg / kg, about 0.8 mg / kg to about 3 mg / kg, about 0.9 mg / kg to about 2 mg / kg, about 1.0 mg / kg to about 1.5 mg / kg, about 1.0 mg / kg to about 2.0 mg / kg, about 1.0 mg / kg to about 3.0 mg / kg, or about 2.0 mg / kg to about 4.0 mg / kg. In some specific methods, the dosage of the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 200 mg to about 500 mg, about 150 mg to about 250 mg, about 175 mg to about 250 mg, about 200 mg to about 250 mg, about 150 mg to about 240 mg, about 175 mg to about 240 mg, or about 200 mg to about 240 mg. In some embodiments, the dosage 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.

[0162] In some embodiments of the various methods described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 200 mg, 240 mg or 2 mg / kg of pembrolizumab, and pembrolizumab is administered once every three weeks. In one embodiment, the human patient is administered 200 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 240 mg of pembrolizumab once every three weeks. In one embodiment, the human patient is administered 2 mg / kg of pembrolizumab once every three weeks.

[0163] In certain embodiments of the various methods described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and the human patient is administered 400 mg of pembrolizumab, and pembrolizumab is administered once every six weeks.

[0164] In other embodiments of the various methods described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab, and the human patient is administered 240 mg or 3 mg / kg of nivolumab, and nivolumab is administered once every two weeks. In one particular embodiment, the human patient is administered 240 mg of nivolumab once every two weeks. In one particular embodiment, the human patient is administered 3 mg / kg of nivolumab once every two weeks. In other embodiments of the various methods described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab, and the human patient is administered 480 mg of nivolumab, and nivolumab is administered once every four weeks.

[0165] In still other embodiments of the various methods described herein, the anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof is semiprimab, and the human patient is administered 350 mg of semiprimab, and semiprimab is administered once every three weeks.

[0166] In yet other aspects of the various methods described herein, the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof, and the human patient is administered 40-120 mg once daily. In yet other aspects of the various methods described herein, 40, 80, or 120 mg of belzutifan or a pharmaceutically acceptable salt thereof is administered once daily. In one particular aspect, the human patient is administered 40 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily. In one particular aspect, the human patient is administered 80 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily. In one particular aspect, the human patient is administered 120 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily.

[0167] In one aspect, lenvatinib or a pharmaceutically acceptable salt thereof is administered orally. In some aspects, lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8, 10, 12, 14, 18, 20, or 24 mg as lenvatinib, respectively.

[0168] Thus, in some aspects of the various methods provided herein, the human patient is (a) 200 mg, 240 mg, or 2 mg / kg of pembrolizumab; (b) 40, 80, or 120 mg of belzutifan; and (c) 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib; administered, (a) is administered once every three weeks; (b) and (c) are administered daily.

[0169] In one aspect of the various methods provided herein, the human patient is (a) 200 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; administered, (a) is administered once every three weeks; (b) and (c) are administered daily.

[0170] In certain aspects of the various methods provided herein, a human patient is (a) 240 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; administered (a) is administered once every three weeks; (b) and (c) are administered daily.

[0171] In certain aspects of the various methods provided herein, a human patient is (a) 2 mg / kg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; administered (a) is administered once every three weeks; (b) and (c) are administered daily.

[0172] In certain aspects of the various methods provided herein, a human patient is (a) 400 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; administered (a) is administered once every six weeks; (b) and (c) are administered daily.

[0173] In certain aspects of the various methods provided herein, a human patient is (a) 400 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 14 mg of lenvatinib; administered (a) is administered once every six weeks; (b) and (c) are administered daily.

[0174] In certain aspects of the various methods provided herein, a human patient is administered (a) 400 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 10 mg of lenvatinib; where (a) is administered once every 6 weeks; (b) and (c) are administered daily.

[0175] In certain aspects of the various methods provided herein, a human patient is administered (a) 400 mg of pembrolizumab; (b) 80 mg of belzutifan; and (c) 10 mg of lenvatinib; where (a) is administered once every 6 weeks; (b) and (c) are administered daily.

[0176] In certain aspects of the various methods provided herein, a human patient is administered (a) 200 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; where (a) is administered once every 3 weeks; (b) and (c) are administered daily.

[0177] In certain aspects of the various methods provided herein, a human patient is administered (a) 240 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; where (a) is administered once every 3 weeks; (b) and (c) are administered daily.

[0178] In certain aspects of the various methods provided herein, a human patient is administered (a) 2 mg / kg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; are administered, (a) is administered once every three weeks; (b) and (c) are administered daily.

[0179] In certain aspects of the various methods provided herein, a human patient is (a) 400 mg of pembrolizumab; (b) 120 mg of belzutifan; and (c) 20 mg of lenvatinib; are administered, (a) is administered once every six weeks; (b) and (c) are administered daily.

[0180] In certain aspects, the human patient has not received prior systemic treatment for the advanced disease.

[0181] In some aspects, at least one of the therapeutic agents (e.g., an anti-PD-1 monoclonal antibody or a binding fragment thereof, a HIF-2α inhibitor, or lenvatinib) in the combination therapy is administered using the same dosing regimen (dose, frequency, and duration of treatment) typically used when the agent is used as monotherapy to treat the same condition. In other aspects, the patient receives, in the combination therapy, at least one of the therapeutic agents (e.g., an anti-PD-1 monoclonal antibody or a binding fragment thereof, a HIF-2α inhibitor, or lenvatinib) in a lower total amount than when the agent is used as monotherapy, e.g., a lower dose, a lower frequency of dosing, and / or a shorter treatment duration.

[0182] The combination therapies disclosed herein can be used before or after surgery to remove a tumor and can be used before, during, or after radiation treatment.

[0183] In some embodiments, the combination therapies disclosed herein are administered to patients who have not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., treatment-naïve patients. In other embodiments, the combination therapies are administered to patients who were unable to achieve a durable response after prior treatment with a biotherapeutic or chemotherapeutic agent, i.e., treatment-experienced patients.

[0184] The therapeutic combinations disclosed herein can be used in combination with one or more other active agents including, but not limited to, one or more other anti-cancer agents used in the prevention, treatment, modulation, amelioration, or risk reduction of a particular disease or condition (cancer). Such other active agents can be administered simultaneously or sequentially with one or more of the therapeutic agents in the combinations disclosed herein, by the routes and in the amounts generally used therefor.

[0185] One or more additional active agents can be co-administered with an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof, a HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof. The (one or more) additional active agents can be administered in a single dosage form together with one or more co-administered agents selected from an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof, a HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof. The (one or more) additional active agents can also be administered in a (one or more) dosage form separate from the dosage form containing an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof, a HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof.

[0186] 7. Kit In yet another aspect, provided herein is a kit comprising a therapeutic agent (e.g., a PD-1 antagonist, a HIF-2α inhibitor, and lenvatinib) or a pharmaceutical composition thereof, packaged in a suitable packaging material. The kit may include a label or package insert containing instructions for the components or for the in vitro, in vivo, or ex vivo use of the components in the kit.

[0187] In some embodiments, the kit comprises (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof Thereof.

[0188] In one embodiment, the kit further comprises instructions for administering the PD-1 antagonist, the HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof to a human patient.

[0189] In some embodiments, the PD-1 antagonist is an anti-PD-1 monoclonal antibody or an antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is an anti-PD-L1 monoclonal antibody or an antigen-binding fragment thereof.

[0190] In one embodiment, the kit comprises (a) one or more doses of an anti-PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) one or more doses of a HIF-2α inhibitor; (c) one or more doses of lenvatinib or a pharmaceutically acceptable salt thereof; and (d) instructions for administering the anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof, the HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof to a human patient.

[0191] In some embodiments, 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 semaprimab.

[0192] In various kits herein, dosages for an anti-PD-1 monoclonal antibody, an HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof can be used. In some embodiments, the kit includes dosages of each component sufficient for a period of treatment (e.g., 3, 6, 12, or 24 weeks, etc.). For example, the kit can comprise 1 dosage of 200 mg of pembrolizumab, 21 dosages of 120 mg of belzutifan or a pharmaceutically acceptable salt thereof, and 21 dosages of 20 mg of lenvatinib (or an equivalent amount of a pharmaceutically acceptable salt of lenvatinib), which are sufficient for a 3-week treatment. Alternatively, the kit can comprise 1 dosage of 400 mg of pembrolizumab, 42 dosages of 120 mg of belzutifan or a pharmaceutically acceptable salt thereof, and 42 dosages of 20 mg of lenvatinib (or an equivalent amount of a pharmaceutically acceptable salt of lenvatinib), which are sufficient for a 6-week treatment.

[0193] In some embodiments, the kit comprises means for separately holding the components, such as a container, a divided vial, or a divided foil wrap. The kits of the present disclosure can be used for administration of different dosage forms, e.g., oral and parenteral, for administration of separate compositions at different dosing intervals, or for dose setting of separate compositions relative to each other.

[0194] 8. Use of a therapeutic combination for treating cancer or von Hippel-Lindau disease In yet another aspect, use of a therapeutic combination for treating cancer (e.g., RCC) or von Hippel-Lindau disease in a human patient, wherein the therapeutic combination comprises (a) A PD-1 antagonist; (b) A HIF-2α inhibitor; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof The use thereof is provided herein.

[0195] In some embodiments, 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.

[0196] In one embodiment, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In still other embodiments, the cancer is recurrent and refractory.

[0197] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In still 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 still another embodiment, the cancer is melanoma.

[0198] In one embodiment, the cancer is advanced RCC. In another embodiment, the cancer is advanced RCC having a clear cell component. In still another embodiment, the cancer is metastatic RCC. In still another embodiment, the cancer is recurrent RCC. In still another embodiment, the cancer is refractory RCC. In still another embodiment, the cancer is recurrent and refractory RCC.

[0199] In one embodiment, it is the use of a therapeutic combination for treating RCC in a human patient, wherein the therapeutic combination (a) A PD-1 antagonist; (b) A HIF-2α inhibitor; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof The use thereof is provided herein.

[0200] In some embodiments, the use of a therapeutic combination for treating advanced RCC in a human patient, wherein said therapeutic combination comprises: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0201] In some embodiments, the use of a therapeutic combination for treating advanced RCC having a clear cell component in a human patient, wherein said therapeutic combination comprises: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0202] In other embodiments, the use of a therapeutic combination for treating metastatic RCC in a human patient, wherein said therapeutic combination comprises: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0203] In yet other embodiments, the use of a therapeutic combination for treating recurrent RCC in a human patient, wherein said therapeutic combination comprises: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0204] In yet other embodiments, the use of a therapeutic combination for treating refractory RCC in a human patient, wherein said therapeutic combination comprises: (a) A PD-1 antagonist; (b) A HIF-2α inhibitor; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof (are) provided herein for use.

[0205] In another aspect, there is provided herein for use a therapeutic combination for treating recurrent and refractory RCC in a human patient, wherein said therapeutic combination (a) A PD-1 antagonist; (b) A HIF-2α inhibitor; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof (are) provided herein for use.

[0206] In yet another aspect, there is provided herein for use a therapeutic combination for treating cancer, wherein said therapeutic combination (a) A PD-1 antagonist; (b) Bazedoxifene, or a pharmaceutically acceptable salt thereof; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof (are) provided herein for use.

[0207] In one aspect, the PD-1 antagonist is an anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof. In some aspects, the anti-human PD-1 monoclonal antibody is a human antibody. In other aspects, the anti-human PD-1 monoclonal antibody is a humanized antibody.

[0208] In one aspect, the PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or an antigen-binding fragment thereof. In some aspects, the anti-human PD-L1 monoclonal antibody is a human antibody. In other aspects, the anti-human PD-L1 monoclonal antibody is a humanized antibody.

[0209] In one aspect, the HIF-2α inhibitor is belzutifan or a pharmaceutically acceptable salt thereof.

[0210] Accordingly, in one aspect, there is provided the use of a therapeutic combination for treating cancer, wherein the therapeutic combination comprises: (a) a human or humanized anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0211] In some aspects, there is provided the use of a therapeutic combination for treating cancer, wherein the therapeutic combination comprises: (a) a human anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0212] In other aspects, there is provided the use of a therapeutic combination for treating cancer, wherein the therapeutic combination comprises: (a) a humanized anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0213] In some aspects of the various uses provided herein, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is pembrolizumab. In some aspects of the various uses provided herein, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab. In some aspects of the various uses provided herein, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is semiprimab.

[0214] Accordingly, in one particular aspect, there is provided herein a use of a therapeutic combination for treating cancer, wherein said therapeutic combination comprises (a) pembrolizumab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0215] In one particular aspect, there is provided herein a use of a therapeutic combination for treating cancer, wherein said therapeutic combination comprises (a) nivolumab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0216] In one particular aspect, there is provided herein a use of a therapeutic combination for treating cancer, wherein said therapeutic combination comprises (a) semiprimab; (b) belzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof is provided herein.

[0217] In one particular aspect, there is provided herein a use of a therapeutic combination for treating RCC, wherein said therapeutic combination comprises (a) Pembrolizumab; (b) Belzutifan, or a pharmaceutically acceptable salt thereof; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof The use comprising the same is provided herein.

[0218] In one particular aspect, there is provided the use of a therapeutic combination for treating RCC, wherein the therapeutic combination comprises (a) Nivolumab; (b) Belzutifan, or a pharmaceutically acceptable salt thereof; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof The use comprising the same is provided herein.

[0219] In one particular aspect, there is provided the use of a therapeutic combination for treating RCC, wherein the therapeutic combination comprises (a) Semiprimab; (b) Belzutifan, or a pharmaceutically acceptable salt thereof; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof The use comprising the same is provided herein.

[0220] In one aspect, the human patient has not received prior systemic treatment for advanced disease.

[0221] In one aspect, the RCC is advanced RCC. In another aspect, the RCC is advanced RCC having a clear cell component. In yet another aspect, the RCC is metastatic RCC. In yet another aspect, the RCC is recurrent RCC. In yet another aspect, the RCC is refractory RCC. In yet another aspect, the RCC is recurrent and refractory RCC.

[0222] Some aspects of the present invention have been described. It will be understood that various modifications can be made without departing from the spirit and scope of the present invention. It will be further understood that each aspect can be combined with one or more other embodiments to the extent such combinations are consistent with the description of those aspects. [Examples]

[0223] I. Examples The examples in this section (Section VI) are provided as illustrative, not limiting.

[0224] [Example 1] A clinical trial (experimental group A4) in which pembzutifan (MK-6482) and an anti-PD-1 antibody are administered in combination with lenvatinib to patients with primary (1L) advanced RCC (ccRCC) having a clear cell component.

[0225] A total of 34 healthy volunteers and 185 patients were being treated with MK-6482 in five ongoing clinical trials.

[0226] In an ongoing randomized, single-dose, phase 2, two-group crossover phase 1 study in 16 healthy adult female volunteers, the effect of food on the PK of a single 120 mg dose of MK-6482 was investigated. This study showed that a high-fat, high-calorie meal does not affect the extent of MK-6482 exposure, but decreases the maximum plasma MK-6482 concentration by approximately 35% and delays the time to peak MK-6482 exposure by a median difference of 2 hours (fed - fasted). These data are not considered clinically meaningful and support dosing of MK-6482 with or without food. The most common adverse event (AE) reported was headache (12.5%).

[0227] A Phase 1 FIH study designed to evaluate the tolerability, safety, PK, and PD characteristics of MK-6482 in participants with various advanced solid tumors is ongoing. As of September 6, 2019, a total of 104 participants, including 43 participants with various advanced solid tumors in the dose-escalation portion (Part 1A) ranging from 20 to 240 mg QD and 120 mg BID, had been enrolled. The MTD was not reached, and two treatment-related DLTs were observed: one event of grade 4 thrombocytopenia in the 240 mg QD cohort and one event of grade 3 hypoxia in the 120 mg BID cohort. Based on favorable PK, pharmacodynamic, and safety findings, the 120 mg QD dose was selected for further clinical development. At the clinical dose of 120 mg QD, 52 additional participants with advanced RCC were treated in an expansion cohort (Part 1B). In the combination of dose escalation and expansion cohort, the most common AEs (occurring in more than 20% of participants) were anemia, fatigue, dyspnea, nausea, and peripheral edema. The most common grade 3 AEs were anemia and hypoxia (more than 5% of participants). The t max median was 1 to 2.8 hours, and exposure increased with dose. The mean steady-state t 1 / 2 in the 120 mg QD expansion cohort (Part 1B) on Day 15 was 15.4 hours, resulting in 1.5-fold accumulation from Day 1 to Day 15. The mean steady-state C max in the 120 mg QD expansion cohort (Part 1B) on Day 15 was 1.79 μg / mL (4.67 μM). The estimated CL / F was 5.22 to 14.4 L / hr. The estimated Vz / F was 106 to 266 L, suggesting extensive distribution to peripheral tissues. The CV was 32 to 59% for C max after single-dose administration and 24 to 48% for AUC, and for C maxIt was 27 - 56% for [specific parameter] and 30 - 64% for AUC. In total, 55 participants with previously treated advanced RCC are being treated with MK - 6482 at 120 mg QD in this study (3 patients during the dose escalation part of this study and 52 participants during the dose expansion part of this study). When evaluated by Response Evaluation Criteria in Solid Tumors v1.1, the best responses among these 55 participants included 11 participants (20%) with PR and 32 participants (58%) with SD.

[0228] A phase 2 open - label efficacy and safety trial in participants with VHL - associated RCC is ongoing. As of September 6, 2019, 61 participants had been enrolled at a dose of 120 mg QD. Efficacy data are not yet available. Fatigue was the most common grade 3 or higher toxicity AE (reported by more than 5% of participants).

[0229] Furthermore, 20 patients with ccRCC are being evaluated in a phase 2 trial and 18 healthy adult volunteers are being evaluated in a phase 1 bioavailability trial.

[0230] Based on the data from these studies, a combination of 120 mg of MK6482, 400 mg of pembrolizumab, and 20 mg of lenvatinib is evaluated as first - line treatment in patients (1L) with advanced renal cell carcinoma (ccRCC) having a clear cell component.

[0231] The primary objective of this study is to evaluate the safety, tolerability, and antitumor efficacy of the combination of MK6482, pembrolizumab, and lenvatinib in patients with advanced ccRCC. In this study, the ORR is used as the primary efficacy endpoint. The ORR is defined as the proportion of participants who achieve a confirmed CR or PR according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as evaluated by the BICR. Responses are based on the BICR using RECIST 1.1 modified to follow up to a maximum of 10 target lesions and a maximum of 5 target lesions per organ. The ORR is an appropriate endpoint for evaluating the antitumor activity of the reference and experimental groups. The treatment effect measured by the ORR can represent a direct clinical benefit based on specific diseases, usage situations, effect sizes, number of CRs, durability of responses, disease situations, tumor locations, available treatments, and risk-benefit relationships.

[0232] The secondary objectives are to evaluate DOR, PFS, OS, and CBR as secondary efficacy endpoints. "DOR" is defined as the time from the first documentation of CR or PR to the earlier of disease progression or death from any cause. DOR, as evaluated by BICR and modified from solid tumor response criteria 1.1 to follow up to a maximum of 10 target lesions and a maximum of 5 target lesions per organ, serves as an additional measure of efficacy and is an assessment generally recognized by both regulatory authorities and oncology groups. "PFS" is defined as the time from the date of randomization to the earlier of the first documentation of PD or death from any cause according to solid tumor response criteria 1.1 by BICR. To minimize bias in efficacy assessment, images are read by BICR. PFS events can reflect tumor growth and can be evaluated prior to the determination of survival benefit. That determination will not be confounded by subsequent treatment. The treatment effect measured by PFS can be a surrogate endpoint representing direct clinical benefit based on the clinical outcome of delaying or preventing progression in a particular disease, context of use, magnitude of effect, disease situation, location of metastatic sites, available treatments, risk-benefit relationship, and important disease sites (e.g., delaying new lesions in the brain or spine) or delaying the administration of more toxic treatments. "OS" is recognized as the gold standard for demonstrating the superiority of new antineoplastic therapies in randomized clinical trials. OS is defined as the time from the date of randomization to the date of death from any cause. "CBR" is a secondary assessment commonly used in many cancer clinical trials and is defined as the proportion of participants who achieve SD for 6 months or more or CR or PR based on BICR evaluation according to solid tumor response criteria 1.1.

[0233] The tertiary / exploratory objectives of this study include the evaluation of the correlation between tumor size changes and DOR, PFS, and OS; the characterization of the pharmacokinetic (PK) profile of the investigational drug and the formation of anti-drug antibodies (ADA); and the identification of molecular (genomic, metabolic, and / or proteomic) biomarkers that may indicate the clinical response / resistance, safety, and / or mechanism of action of the test treatment combinations with pembrolizumab, lenvatinib, and MK6482. Tumor size changes are an exploratory efficacy assessment item and a proposed intermediate assessment item that can detect signals of initial anti-tumor activity, and are defined as the sum of the target lesions' longest diameters and the change (and % change) from baseline at each post-baseline assessment.

[0234] Male and female patients at least 18 years of age with progressive ccRCC who have not received prior systemic treatment for the advanced disease (1L RCC) are enrolled in this study. Patients must have a histologically confirmed diagnosis of locally advanced / metastatic ccRCC (with or without sarcomatoid features), i.e., stage IV RCC according to AJCC, and must not have received prior systemic treatment for advanced RCC. Furthermore, patients must not have measurable disease according to the solid tumor response criteria 1.1 as evaluated by BICR.

[0235] The reference groups for this study are described below.

[0236] [Table 4]

[0237] [Table 5]

[0238] [Table 6]

[0239] [Example 2] A combination of a VHL-bearing mouse syngeneic pancreatic tumor model with an anti-PD-1 murine surrogate antibody (muDX400) and lenvatinib, a VEGF tyrosine kinase inhibitor, combined with MK-6482, an HIF-2α inhibitor.

[0240] In this example, the inventors provide preclinical data using a VHL-bearing mouse syngeneic pancreatic tumor model to demonstrate the antitumor benefit obtained from combining an anti-PD-1 murine surrogate antibody (muDX400) and lenvatinib, a VEGF tyrosine kinase inhibitor, with MK-6482, an HIF-2α inhibitor.

[0241] Before the start of treatment, 7-week-old female C57BL / 6J mice weighing 18 - 21 grams were anesthetized and injected with 0.5 × 10 6 log-phase sub-confluent KPC-2838c3 cells into the posterior flank. Ten (10) days after the average tumor volume of the inoculated animals reached approximately 95 mm 3 eight (8) treatment groups of 10 mice per group were matched. The treatment groups consisted of: 1) 0.5% methylcellulose (vehicle) + isotype murine IgG1 antibody (mIgG1); 2) MK-6482 + mIgG1; 3) lenvatinib + mIgG1; 4) vehicle + anti-mouse PD-1 IgG1 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 administered orally by gavage twice a day (BID) at 3 mg / kg body weight. Lenvatinib was administered orally once a day (QD) at 10 mg / kg body weight. The isotype control, a mouse monoclonal antibody specific for the adenovirus hexon of isotype IgG1, and the anti-PD-1 antibody were administered intraperitoneally every 5 days at 10 mg / kg body weight. The start of treatment was considered day 0, and dosing based on the schedule continued as described until day 45. Tumor and body weight caliper measurements were taken twice a week. Statistical analysis was performed by one-way ANOVA using Tukey's multiple comparison test at the designated time points when the treatment groups reached the endpoint.

[0242] Triple combination treatment with MK-6482, anti-PD-1, and lenvatinib showed a significant anti-tumor effect (Figure 2A), with one complete remission and one partial tumor regression with no measurable tumors remaining (Figure 2B). Complete and partial tumor regressions were not observed in any of the other treatment groups. The mean anti-tumor response of the triple combination treatment was greater than the anti-tumor responses observed with MK-6482 monotherapy, anti-PD-1 monotherapy, or vehicle control (p<0.0001, day 24). The triple combination group was also significantly improved compared to lenvatinib monotherapy (p=0.0002, day 45). The mean anti-tumor response of the triple combination was improved compared to MK-6482+anti-PD-1 (p<0.0001, day 31), but not improved compared to lenvatinib+anti-PD-1 (p=0.247, day 45) or lenvatinib+MK-6482 (p=0.404, day 45). A summary of tumor growth inhibition (TGI) on day 24 and observations of partial tumor regression (PR) or complete tumor regression (CR) when the vehicle treatment group ended the study are shown in the following table:

[0243]

Table 7

[0244] CR was defined as the absence of observable tumors, while PR was a tumor with a volume smaller than the original tumor size at the start of treatment. No significant weight loss or adverse events were observed in any of the animals treated with the above treatments, indicating that the treatments were well tolerated.

[0245] As shown by the above study, treatment with a combination of therapeutic agents is advantageous over treatment with each agent administered alone.

[0246] II. Sequence Listing The following table summarizes all the sequences disclosed in this specification.

[0247]

Table 8

Claims

1. A pharmaceutical composition for treating advanced RCC in a human patient in need of treatment, wherein the pharmaceutical composition comprises the following: (a) a PD-1 antagonist that is pembrolizumab; (b) a HIF-2α inhibitor; and (c) lenvatinib, or a pharmaceutically acceptable salt thereof comprising at least one component selected from the group consisting of, wherein the treatment is performed using a combination of (a), (b) and (c), wherein the PD-1 antagonist is pembrolizumab, wherein the HIF-2α inhibitor is belzutifan: 【Chemical Formula 1】 or a pharmaceutically acceptable salt thereof, wherein the human patient has not received prior systemic treatment for the advanced disease, here, wherein the patient is administered 400 mg of pembrolizumab, and pembrolizumab is administered once every 6 weeks, here, wherein the patient is administered about 40 mg to about 120 mg of belzutifan, and belzutifan is administered once daily, and here, wherein the patient is administered 8, 10, 12, 14, 18, 20 or 24 mg of lenvatinib, and lenvatinib is administered once daily, pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the advanced RCC is clear cell component-containing advanced RCC (ccRCC).

3. (a) A PD-1 antagonist; (b) A HIF-2α inhibitor; and (c) Lenvatinib, or a pharmaceutically acceptable salt thereof comprising a kit for treating advanced RCC, wherein the PD-1 antagonist is pembrolizumab, wherein the HIF-2α inhibitor is belzutifan: 【Chemical 2】 or a pharmaceutically acceptable salt thereof, kit.

4. The kit according to claim 3, further comprising instructions for administering the PD-1 antagonist, the HIF-2α inhibitor and lenvatinib, or a pharmaceutically acceptable salt thereof to a human patient.

5. Use of a PD-1 antagonist in the manufacture of a medicament for treating advanced RCC in a human patient in a combination use with (b) a HIF-2α inhibitor and (c) lenvatinib or a pharmaceutically acceptable salt thereof, wherein the PD-1 antagonist is pembrolizumab, wherein the HIF-2α inhibitor is belzutifan: or a pharmaceutically acceptable salt thereof, 【Chemical Formula 3】 wherein the human patient has not received prior systemic treatment for the advanced disease, use.

6. ​ Use in combination of (a) a PD-1 antagonist and (c) lenvatinib or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of advanced RCC in a human patient, use of (b) a HIF-2α inhibitor, wherein the PD-1 antagonist is pembrolizumab, wherein the HIF-2α inhibitor is belzutifan: 【Chemical Formula 4】 or a pharmaceutically acceptable salt thereof, wherein the human patient has not received prior systemic treatment for the advanced disease, use.

7. Use in combination of (a) a PD-1 antagonist and (b) a HIF-2α inhibitor, for the manufacture of a medicament for the treatment of advanced RCC in a human patient, use of (c) lenvatinib or a pharmaceutically acceptable salt thereof, wherein the PD-1 antagonist is pembrolizumab, wherein the HIF-2α inhibitor is belzutifan: 【Chemical Formula 5】 or a pharmaceutically acceptable salt thereof, wherein the human patient has not received prior systemic treatment for the advanced disease, use.

8. The use according to any one of claims 5 to 7, wherein the advanced RCC is clear cell component-containing advanced RCC (ccRCC).

9. The pharmaceutical composition according to claim 1, wherein the human patient is administered 40, 80 or 120 mg of belzutifan, and belzutifan is administered once daily.

10. The pharmaceutical composition according to claim 9, wherein the human patient is administered 120 mg of belzutifan.

11. A pharmaceutical composition for treating advanced RCC in a human patient in need of treatment, the pharmaceutical composition comprising the following: (a) 400 mg of pembrolizumab; (b) 120 mg of belzutifan: [[Chemical Formula 6]] or a pharmaceutically acceptable salt thereof; and (c) 20 mg of lenvatinib comprising at least one component selected from the group consisting of, wherein the treatment is carried out using a combination of (a), (b) and (c), wherein the human patient has not received prior systemic treatment for the advanced disease, pharmaceutical composition.

12. The pharmaceutical composition according to claim 11, wherein pembrolizumab is administered once every 6 weeks.

13. The pharmaceutical composition according to claim 11, wherein (b) and (c) are administered once daily.

14. The pharmaceutical composition according to claim 11, wherein (a), (b) and (c) are administered on the same day, and (a), (b) and (c) are administered sequentially or simultaneously.

15. The pharmaceutical composition according to any one of claims 1 to 2 or 9 to 14, wherein the pharmaceutically acceptable salt thereof is lenvatinib mesylate.

16. The kit according to claim 3 or 4, wherein the pharmaceutically acceptable salt thereof is lenvatinib mesylate.

17. The use according to any one of claims 5 to 8, wherein the pharmaceutically acceptable salt thereof is lenvatinib mesylate.

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