Methods for treating cancer or von-hippel lindau disease using combination of PD-1 antagonist, HIF-2α inhibitor, and lenvatinib or pharmaceutically acceptable salt thereof

Abstract

To provide a method for treating cancer (for example, RCC) or von Hippel-Lindau disease.SOLUTION: A method for treating cancer or von Hippel-Lindau disease is provided, the method comprising administering to a human patient in need of treatment for 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. Also provided are kits containing such agents and uses of therapeutic combinations of such agents for the treatment of cancer.SELECTED DRAWING: Figure 1

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 pharmaceutically acceptable salt thereof. The combination of salts may be used to treat cancer (e.g., renal cell carcinoma (RCC)) or von Hippel-Zachary syndrome (VHS) Provided herein are methods for treating Le Lindau disease.

[0002] Reference to an electronically submitted sequence listing The sequence listing of the present application is available under the file name "25062WOPCT-SEQLIST-09APR 2021_ST25.txt", created on April 9, 2021, size 10KB ASCI Submitted electronically via EFS-Web as a Format I sequence listing. This Sequence Listing, submitted via http: / / www.mcd.gov / sequencelisting, is incorporated herein by reference in its entirety. be incorporated into the book. [Background technology]

[0003] PD-1 is recognized as a key player in immune regulation and the maintenance of peripheral immune tolerance. It is recognized that immune chemotherapies targeting PD-1 or its ligands (e.g., PD-L1) Checkpoint therapy has led to revolutionary improvements in clinical responses in multiple human cancer types ( Brahmer et al.,N Engl J Med,366:2455-246 5(2012);Garon et al.,N Engl J Med,372:20 18-2028(2015);Hamid et al., N Engl J Med, 369:134-144(2013);Robert et al.,Lancet,3 84:1109-1117(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,32:1020-103 0(2014);Wolchok et al.,N Engl J Med,369: 122-133(2013)). Immunotherapy targeting the PD-1 axis involves the PD-1 receptor (e.g., KEYTRUDA®) ) (pembrolizumab), Merck and Co., Inc., Kenilworth h, NJ; OPDIVO® (nivolumab), Bristol-Myers S Quibb Company, Princeton, NJ; LIBTAYO (registered trademark) ) (cemiplimab), Regeneron Pharmaceuticals, Inc. TYVYT® (sintilumab), Innove, Tarrytown, NY; nt Biologics, Inc., Jiangsu, China; tislelizumab; BeiGene, Beijing, China; Camrelizumab, Hengrui Th erapeutics, Inc., Princeton, NJ; and toripalimab, J unshi Biosciences, Shanghai, China); and PD- Those that bind to L1 ligands (e.g., IMFINZI® (durvalumab) , AstraZeneca Pharmaceuticals LP, Wilmingt on, DE; and BAVENCIO® (avelumab), Pfizer Inc. c, New York, NY).

[0004] Hypoxia in tumors is a driving force behind cancer progression and is associated with poor patient prognosis and chemotherapy and It is closely related to resistance to radiation treatment. HIF-2α is a transcription factor that plays a central role in the hypoxia response pathway. Under oxygen conditions, the von Hippel-Lindau (VHL) protein, a tumor suppressor, , which binds to specific hydroxylated proline residues and targets HIF-α for proteasomal degradation It recruits an E3 ubiquitin ligase complex that targets proteins. Under hypoxic conditions, HIF-α protein accumulates and enters the nucleus, where it regulates anaerobic metabolism, angiogenesis, cell proliferation, and cell survival. , extracellular matrix remodeling, pH homeostasis, amino acid and nucleotide metabolism, etc. VHL deficiency also stimulates the expression of genes that regulate genomic instability and oxygen stress. This may result in accumulated HIF expression under hypoxic conditions (pseudohypoxic conditions). Directly targeting the -α protein represents an excellent opportunity to attack tumors on multiple fronts. (Keith, et al., Nature Rev. Cancer 12 :9-22,2012).

[0005] Specifically, HIF-2α is a key player in clear cell renal cell carcinoma (ccRCC). It is a cancer-promoting factor (Kondo, K., et al., Cancer Cell, 1:2 37-246(2002);Maranchie, J. et al, Cancer Ce ll,1:247-255(2002);Kondo,K.,et al.,PLoS Biol., 1:439-444(2003)). In a mouse ccRCC tumor model HIF-2α expression in pVHL (von Hippel-Lindau protein)-deficient cell lines Knockdown of pVHL inhibited tumor growth as effectively as reintroduction of pVHL. Expression of a stabilized mutant form of 2α was able to overcome the tumor-suppressive role of pVHL. Excellent in vitro efficacy, pharmacokinetic profile and in vivo efficacy in mouse models. Belzutifan, a novel HIF-2α inhibitor with potent anti-cancer activity, or its pharmaceutically acceptable salts The compound salts have shown promising results in patients with advanced renal cell carcinoma (Xu, R ui, et al., J.Med.Chem.62:6876-6893(2019).

[0006] HIF-2α is essential for von Hippel-Lindau (VHL)-deficient ccRCC VHL-deficient ccRCC xenograft mouse tumor model has emerged as an essential HIF isoform. In DEL, knockdown of HIF-2α expression was equivalent to reintroduction of functional VHL. Inhibiting VHL formation, overexpression of HIF2α alone rescues the tumor-suppressive effects of VHL. (Kondo K., Klco J, Nakamura E, Lechpamm er M,Kaelin WG Jr..Inhibition of HIF is necessary for tumor suppression by the v on Hippel-Lindau protein.Cancer Cell 200 2;1:237-46;Maranchie JK,Vasselli JR,Riss J, Bonifacino JS, Linehan WM, Klausner RD. The contribution of VHL substrate bindin g and HIF1-alpha to the phenotype of VHL loss in renal cell carcinoma.Cancer Cel l 2002;1:247-55;Kondo K,Kim WY,Lechpamme r M,Kaelin WG Jr..Inhibition of HIF2alph a is sufficient to suppress pVHL-defecti ve tumor growth.PLoS Biol 2003;1:E83;Zim mer 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 is a tumorigenic driver in ccRCC. HIF proteins are also expressed in a variety of ways by the hypoxic tumor microenvironment. It is activated in many other types of cancer (e.g., breast, liver, colon, brain, and pancreatic cancers). These proteins are believed to be involved in the initiation, progression, and metastasis of cancer (Jarman EJ, Ward C, Turnbull AK, Martinez-Perez C, Meehan J ,Xintaropoulou C,Sims AH,Langdon SP.HER2 regulates HIF-2α and drives an increase d hypoxic response in breast cancer.Brea st Cancer Res.2019 Jan 22;21(1):10;Wiger up C, Pahlman S., Bexell D. Therapeutic tar getting of hypoxia and hypoxia-inducible factors in cancer.Pharmacology&Therapeut ics 164(2016)152-169). HIF-2α is involved in endothelial cells, perivascular tumors, and Tumor cells and tumor-associated macrophages (TAMs) play a role in regulating innate immunity It can be stabilized by host tumor cells under tumor hypoxia, including immunosuppressive cell types such as As shown (Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gim otty PA, Keith B, Simon MC. Hypoxia-inducib le factor 2alpha regulates macrophage fu nction in mouse models of acute and tumor r inflammation.J Clin Invest.2010 Aug;12 0(8):2699-714). However, it is unclear which VHL-carrying tumor types and combinations Whether it is logical to investigate a combined strategy using HIF-2α inhibitors is a matter of concern. is little known.

[0007] Von Hippel-Lindau disease (VHL disease) not only predisposes patients to kidney cancer ( Approximately 70% lifetime risk), hemangioblastoma, pheochromocytoma, and pancreatic neuroendocrine tumors. VHL disease is an autosomal dominant syndrome that is easily inherited. These tumors are highly dependent on HIF-2α activity (Maher, et al., 2004). t al.Eur.J.Hum.Genet.19:617-623,2011). HI F-2α contributes to retinal, adrenal, and pancreatic cancers through both VHL disease and activating mutations. Recently, gain-of-function HIF-2α mutations have been reported to cause erythrocytosis and polycythemia. It has been identified in paragangliomas associated with cerebrospinal fluid (Zhuang, et al. NEJM 367 :922-930,2012;Percy,et al.NEJM 358:162-1 68, 2008; and Percy, et al. Am. J. Hematol. 87:4 39-442, 2012). Notably, several known HIF-2α-target genes Gene products (e.g., VEGF, PDGF, and cyclin D1) are expressed in the kidney, liver, and colon. It has been shown to play a crucial role in cancers originating from the lung and brain. , which targets VEGF, one of the key HIF-2α-regulated gene products Therapies have been approved for the treatment of these cancers.

[0008] Tyrosine kinases are involved in the regulation of growth factor signaling and therefore in cancer therapy. Lenvatinib inhibits the vascular endothelial growth factor (VEGF) receptor (VE GFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4) and fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, as well as tumor growth factors. Other pro-angiogenic and oncogenic pathway-related RTKs (platelet-derived growth factor (PD) PDGFRα (GF receptor); kinases including KIT and RET proto-oncogenes (RET) It is a multi-RTK inhibitor that selectively inhibits enzyme activity. The antibody possesses a novel binding mechanism for VEGFR2, as confirmed through X-ray crystallography. (Form V) and exhibits rapid and potent inhibition of kinase activity based on kinetic analysis.

[0009] The efficacy of anti-PD-1 or anti-PD-L1 antagonist antibodies will be compared with other approved or Experimental cancer treatments, such as radiation, surgery, chemotherapy, targeted therapy, and the use of dysregulated genes in tumors In combination with other agents that inhibit other signaling pathways, and other immune-enhancing agents However, it has been suggested that the efficacy of anti-PD-1 or anti-PD-2 antibodies may be enhanced when combined with anti-PD-1 or anti-PD-2 antibodies. Any agent in combination with the D-L1 antibody may be effective or any patient may benefit. There is no clear guidance as to whether the combination may enhance the efficacy of treatment in patients Therefore, highly effective therapeutic compositions capable of generating a robust immune response against cancer are possible. There is an unmet need in the art for combinations. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Brahmer et al.,N Engl J Med,366:2455-2465(2012) [Non-patent document 2] Garon et al.,N Engl J Med,372:2018-2028(2015) [Non-patent document 3] Hamid et al.,N Engl J Med,369:134-144(2013) [Non-patent document 4] Robert et al.,Lancet,384:1109-1117(2014) [Non-licensed document 5] Robert et al.,N Engl J Med,372:2521-2532(2015)

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Summary of the Invention

[0011] The present disclosure relates to a PD-1 antagonist, a HIF-2α inhibitor and lenvatinib or its derivatives. and the like. A method for treating Hippel-Lindau disease is provided.

[0012] The present disclosure further provides PD-1 antagonists, HIF-2α inhibitors and lenvatinib or or a pharmaceutically acceptable salt thereof.

[0013] Therapeutic Combinations for Treating Cancer (e.g., RCC) or Von Hippel-Lindau Disease The therapeutic combination comprises a PD-1 antagonist, a HIF-2 The use of the compound described herein includes a medicament for treating atopic dermatitis, comprising administering to a subject a therapeutically effective amount of a medicament for treating atopic dermatitis anemia, an allergic reaction, or atopic dermatitis, and / or a medicament for treating atopic dermatitis, comprising administering to a subject a therapeutically effective amount of a medicament for treating atopic dermatitis, an allergic reaction, or a medicament for treating atopic dermatitis, comprising administering to a subject a therapeutically effective amount of a medicament for treating It is provided at.

[0014] In one aspect, a method of treating cancer or von Hippel-Lindau disease includes: or von Hippel-Lindau disease, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0015] In some embodiments, the cancer is bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, or Colon cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), pancreatic cancer and melanoma? is selected from the group consisting of:

[0016] In some embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory. is.

[0017] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In one 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 one 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 recurrent and refractory RCC.

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

[0020] In one embodiment, the kit comprises a PD-1 antagonist, a HIF-2α inhibitor and a receptor. and instructions for administering ramvatinib or a pharmaceutically acceptable salt thereof to a human patient. Prepare for.

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

[0022] In some embodiments, the cancer is bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, or Colon cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), pancreatic cancer and melanoma? is selected from the group consisting of:

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

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

[0025] In one embodiment, the cancer is advanced RCC. In another embodiment, the RCC has a clear cell component. In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. The cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC. .

[0026] In one embodiment, the human patient has not received prior systemic treatment for advanced disease. In a class of embodiments, the human patient has not received prior systemic treatment for advanced RCC. There is no problem.

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

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

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

[0030] In certain embodiments of the various methods, kits, or uses provided herein, HIF-2 The alpha inhibitor is velzutifan or a pharmaceutically acceptable salt thereof.

[0031] In one embodiment of the various methods, kits, or uses provided herein, an anti-human PD- 1 Monoclonal antibodies include pembrolizumab, nivolumab, cemiplimab, and sintilimab , tislelizumab, camrelizumab and toripalimab.

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

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

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

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

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

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

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

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

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

[0041] In yet another embodiment of the various methods, kits or uses provided herein, Vatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate. The capsules for this drug contain 4 mg or 10 mg of lenvatinib, each 4.90 ml g or 12.25 mg of lenvatinib mesylate. A pharmaceutically acceptable salt of lenvatinib, such as lenvatinib mesylate, may be administered and used. If the dose of lenvatinib is 4 mg, healthcare professionals should administer 4.90 mg of lenvatinib. In another embodiment, lenvatinib mesylate is administered. A pharmaceutically acceptable salt of lenvatinib, such as the benzoate salt, may be administered and used. When the dose of lenvatinib is 10 mg, healthcare professionals should administer 12.25 mg of lenvatinib. In various method embodiments described herein, In the study, human patients received 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib is administered once daily.

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

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

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

[0045] In some embodiments of the various methods described herein, the human patient receives 200 mg , received pembrolizumab at 240 mg or 2 mg / kg, and pembrolizumab was administered at 3 In one embodiment, a human patient receives 200 mg of pembrolizumab once weekly. In one embodiment, a human patient receives 240 mg of pembromobenzoate once every three weeks. In one embodiment, a human patient receives 2 mg / kg of tafamidis. Pembrolizumab will be administered once every three weeks.

[0046] In some embodiments of the various methods described herein, the human patient receives 400 mg of Pembroke Breast Milk. Patients will receive lorizumab and pembrolizumab once every six weeks.

[0047] In other embodiments of the various methods described herein, the human patient receives 240 mg or 3 mg / kg nivolumab once every 2 weeks or 480 mg nivolumab every 4 weeks In one particular embodiment, a human patient receives 240 mg of nivolumab. In one particular embodiment, human patients receive 3 mg of fluoxetine once every two weeks. In one particular embodiment, nivolumab is administered at a dose of 100 mg / kg once every two weeks. Patients will receive 480 mg of nivolumab once every four weeks.

[0048] In other embodiments of the various methods described herein, the human patient receives 350 mg of semiprescription Patients will receive limumab and cemiplimab once every three weeks.

[0049] In other embodiments of the various methods described herein, the human patient receives 800 mg of Abel. Patients will receive mab and avelumab once every two weeks.

[0050] In other embodiments of the various methods described herein, the human patient receives 10 mg / kg of Patients will receive durvalumab once every two weeks. In other embodiments of the various methods described, the human patient receives 1500 mg of durvalumab. and durvalumab is administered once every three weeks. In another embodiment of the method, the human patient is administered 1500 mg of durvalumab, Ibuprofen is administered once every four weeks.

[0051] In still other embodiments of the various methods described herein, the HIF-2α inhibitor is a vegetative inhibitor. Luzutifan or its pharmaceutically acceptable salt, and human patients can receive 40 mg to 120 mg g of velzutifan or a pharmaceutically acceptable salt thereof is administered daily. In this study, human patients received 40, 80, or 120 mg of velzutifan or its pharmaceutical equivalents. In one particular embodiment, the human patient is administered a 4 mg or 5 mg once daily of a commercially acceptable salt. 0 mg of belzutifan or a pharmaceutically acceptable salt thereof once daily. In certain embodiments, a human patient receives 80 mg of velzutifan or a pharmaceutically acceptable salt thereof. In another specific embodiment, a human patient receives 120 mg of a vegetative salt once daily. Luzutifan or a pharmaceutically acceptable salt thereof is administered once daily.

[0052] Thus, in some embodiments, the human patient: (a) Pembrolizumab at 200 mg, 240 mg, or 2 mg / kg once every 3 weeks Mab; (b) 40, 80, or 120 mg of belzutifan once daily; and (c) lenvatinib at 8, 10, 12, 14, 18, 20, or 24 mg once daily is administered.

[0053] In one embodiment, the human patient: (a) 200 mg pembrolizumab once every 3 weeks; (b) 120 mg of belzutifan once daily; and (c) lenvatinib 20 mg once daily is administered.

[0054] In one embodiment, the human patient: (a) 240 mg of pembrolizumab once every 3 weeks; (b) 120 mg of belzutifan once daily; and (c) lenvatinib 20 mg once daily is administered.

[0055] In one embodiment, the human patient: (a) pembrolizumab 2 mg / kg once every 3 weeks; (b) 120 mg of belzutifan once daily; and (c) lenvatinib 20 mg once daily is administered.

[0056] In one embodiment, the human patient: (a) 400 mg pembrolizumab once every 6 weeks; (b) 120 mg of belzutifan once daily; and (c) lenvatinib 20 mg once daily is administered.

[0057] In certain embodiments, the method of treating RCC comprises administering to a subject in need of treating RCC. In human patients, (a) 200 mg pembrolizumab once every 3 weeks; (b) 120 mg of belzutifan once daily; and (c) lenvatinib 20 mg once daily Provided herein are methods comprising administering

[0058] In some embodiments of such methods, an anti-human PD-1 monoclonal antibody, HIF-2 The alpha inhibitor and lenvatinib are administered on the same day. PD-1 monoclonal antibody, HIF-2α inhibitor, and lenvatinib are administered sequentially In another embodiment, an anti-human PD-1 monoclonal antibody, a HIF-2α inhibitor, and a receptor Mvastinib is 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 dose of lenvatinib mesylate is 8, A molar equivalent to 10, 12, 14, 18, 20, or 24 mg of lenvatinib The dose is appropriately adjusted to provide lenvatinib. [Brief explanation of the drawings]

[0060] [Figure 1] Figure 1 shows a scheme of the design overview of a phase 1b / 2 study of velzutifan or a pharmaceutically acceptable salt thereof (MK-6482) in combination with pembrolizumab and lenvatinib in patients with primary advanced RCC (experimental group A4). [Figure 2A] Figure 2A shows the antitumor effect of co-administration of the PD-1 antagonist, lenvatinib, and the HIF-2a inhibitor (MK-6482), as indicated by the mean tumor volume in each treatment group. Experimental details are described in Example 2. [Figure 2B]Figure 2B shows the antitumor effect of coadministration of the PD-1 antagonist, lenvatinib, and the HIF-2a inhibitor (MK-6482), as indicated by the mean tumor volume in the individual growth curves for each respective group. Experimental details are described in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0061] 1.Definition Certain technical and scientific terms are specifically defined below. Elsewhere in this specification All other technical and scientific terms used herein unless specifically defined Terms have the meanings commonly understood by those of ordinary skill in the art.

[0062] Numerically defined parameters (e.g., anti-PD-1 antibodies or antigen-binding fragments thereof, The dose of HIF-2α inhibitor or its antigen-binding fragment, or lenvatinib, or When used to modify the duration of treatment with a combination therapy as described herein "About" means that a parameter is within 20% of the stated value or range for that parameter. Within, within 15%, within 10%, within 9%, within 8%, within 7%, within 6%, within 5%, This means that the value is within 4%, 3%, 2%, 1%, or less. In some cases, the stated parameters may be rounded to the nearest whole number. For example, about 5 mg / The dose per kg can vary between 4.5 mg / kg and 5.5 mg / kg.

[0063] As used in this specification, including the appended claims, "a," "an," and "t" refer to The singular forms of words such as "he" and "he" are used interchangeably unless the context clearly dictates otherwise. Contains corresponding multiple mentions of.

[0064] The terms "administration" or "administering" are used when a substance is present outside the body (e.g., anti-PD-1 antibodies, HIF-2α inhibitors, and lenvatinib as described herein) , oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or or any other physical delivery method known in the art. Refers to the act of injecting or other physical delivery.

[0065] "PD-1 antagonist" is a molecule expressed on immune cells (T cells, B cells, or NKT cells). and blocking the binding of PD-L1 expressed on cancer cells to PD-1 expressed on cancer cells, preferably by immunotherapy. It also blocks the binding of PD-L2 expressed on cancer cells to PD-1 expressed by the cells. means any chemical compound or biological molecule. or synonyms include PDCD1, PD1, CD279, and SLEB2 for PD-1; For PD-L1, PDCD1L1, PDL1, B7H1, B7-4, CD274 and and B7-H; and for PD-L2, PDCD1L2, PDL2, B7-DC, The therapeutic methods, medicaments and methods for treating human subjects include Btdc and CD273. In any of the disclosed uses, the PD-1 antagonist is a human PD-L1 antagonist. Human PD-L1 and PD-L2 receptors that block binding to PD-1 and preferably both human PD-L1 and PD-L2. The human PD-1 amino acid sequence is available from NCBI Locus No. Human PD-L1 and PD-L2 amino acids can be found in: The sequences are listed under NCBI Locus No.: NP_054862 and NP_ 079515. PD-1 antagonists include anti-PD-L1 monoclonal antibodies. It is not the monoclonal antibody atezolizumab.

[0066] A "HIF-2α inhibitor" is any chemical compound or biological agent that inhibits the activity of HIF-2α. HIF-2α is a biological molecule. Other names or synonyms for HIF-2α include hypoxia-inducible factor-2α, including, but not limited to, endothelial PAS domain-containing protein 1 and EPAS1 do not have.

[0067] As used herein, the term "antibody" refers to an antibody that has a desired biological or binding activity. The term "antibody" refers to any form of immunoglobulin molecule that exhibits the properties of an antibody. The term is also used in a broad sense and includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and Clonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, and "Parent antibody" specifically includes, but is not limited to, human therapeutic antibodies and chimeric antibodies. Immunoglobulins may be used to identify antibodies prior to modification of the antibody for its intended use, such as humanizing the antibody for use as a drug. Antibodies obtained by exposing the immune system to an antigen. The term "antibody" refers to intact polyclonal or monoclonal antibodies as well as Unless otherwise specified, any antigen-binding portion thereof that competes with the intact antibody for specific binding. , fusion proteins containing antigen-binding portions, and immunoglobulin molecules containing antigen recognition sites. Any other modified forms are also included.

[0068] Generally, the basic antibody structural unit comprises a tetramer. Each tetramer consists of two polypeptide chains. Each pair contains one "light" chain (about 25 kDa) and one "heavy" chain (about 5 kDa). The amino-terminal portion of each chain has approximately 100-1000 kDa, which is primarily responsible for antigen recognition. The variable regions of each light / heavy chain pair comprise a variable region of 10 or more amino acids. The heavy chain forms the binding site. Thus, an intact antibody generally has two binding sites. The carboxy-terminal portion of the ribozyme may define a constant region primarily responsible for effector function. In general, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains are typically Generally, they are classified as mu, delta, gamma, alpha, or epsilon, and the antibody Isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. Within the heavy and variable chains, the variable and constant regions are separated by a "J" sequence of about 12 or more amino acids. The heavy chains are joined by a "D" region of about 10 more amino acids. Generally, see Fundamental Immunology Ch.7 (Paul, W., ed., 2nd ed. Raven Press, NY (1989). I want to be.

[0069] As used herein, a "variable region" or "V region" or "V chain" refers to a region that is a variable region between different antibodies. The "variable region" of an antibody refers to the segment of an IgG chain that is variable in sequence. The term "variable region" refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. The variable domain is "V H The variable region of the light chain is sometimes called "V L " Typically, the variable regions of both the heavy and light chains share a relatively conserved framework. Three hypervariable regions, also called complementarity-determining regions (CDRs), are located within the framework region (FR). The CDRs are usually aligned by framework regions and contain specific epitopes. Generally, from N-terminus to C-terminus, the light chain variable domain and the heavy chain variable domain are Each variable domain comprises FR1, CDR1, FR2, CDR2, FR3, CDR3 and The amino acid assignments for each domain are generally shown in Sequences of Proteins of Immunological Interest,Ka bat,et al.,National Institutes of Health ,Bethesda,Md.,5th ed.,NIH Publ.No.91-324 2(1991), Kabat(1978), Adv.Prot.Chem.32:1-7 5, Kabat, et al., (1977) J. Biol. Chem. 252:660 9-6616, Chothia, et al., (1987) J.Mol.Biol.1 96:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0070] "CDR" is antibody V H Three superunits in the non-framework region of the β-sheet framework One of the variable regions (H1, H2, or H3), or antibody V L β-sheet framework One of the three hypervariable regions (L1, L2, or L3) within the non-framework regions of the Thus, CDRs are variable region sequences interspersed within framework region sequences. CDR regions are well known to those skilled in the art and are considered to be the most hypervariable regions within antibody variable domains. CDR region sequences are also conserved base sequences, as defined, for example, by Kabat. residues that are not part of the framework and therefore can adapt to different conformations As a group, it is structurally defined by Chothia. CDR region sequences are also well recognized in AbM, Contact, and IMGT. The positions of the CDRs within the canonical antibody variable region are defined by the ratio of multiple structures. It has been determined by comparison (Al-Lazikani et al., 1997, JM ol.Biol.273:927-48;Morea et al.,2000,Met Hods 20:267-79). The number of residues within the hypervariable regions varies among different antibodies. Therefore, additional residues for canonical positions are, by convention, added to the canonical variable region number. The residue numbers in the ring scheme are numbered a, b, c, etc. (Al-Lazik (Iani et al., supra). Such nomenclature is also well known to those skilled in the art. Numbering, including Kabat numbering and IMGT specific numbering systems The correspondence between these systems is well known to those skilled in the art and is shown in Table 1 below. In the present specification, the CDRs are as defined by the Kabat numbering system. In this embodiment, the CDRs are as defined by the IMGT numbering system. In yet other embodiments, the CDRs are defined by the AbM numbering system. In still other embodiments, the CDRs are as follows: In still other embodiments, the CDRs are as defined by the Contact As defined by the numbering system.

[0071] [Table 1]

[0072] A "chimeric antibody" is an antibody in which part of the heavy and / or light chains are derived from a particular species (e.g., human). or contain sequences belonging to a particular antibody class or subclass, The remainder of the (multiple) chains may be from a different species (e.g., mouse) or may be from a different antibody class. Antibodies belonging to any of the classes or subclasses, as well as any other class of antibodies, are also contemplated as long as they exhibit the desired biological activity. Refers to body parts.

[0073] "Human antibody" refers to an antibody that contains a human immunoglobulin protein sequence or a derivative thereof. Human antibodies are antibodies produced in mice, in mouse cells, or derived from mouse cells. If produced in a hybridoma, it may contain mouse carbohydrate chains. "Rat antibody" refers to a mouse or rat immunoglobulin sequence. or its derivatives.

[0074] A "humanized antibody" is an antibody that contains sequences derived from a non-human (e.g., murine) antibody in addition to a human antibody. This refers to a form of antibody that contains minimal sequence derived from non-human immunoglobulin. Generally, a humanized antibody contains at least one, and typically two, variable domains. Qualitatively, all or substantially all of the hypervariable loops are non-human immunoglobulins. The FR regions correspond to the hypervariable loops of human immunoglobulins, and all or substantially all of the FR regions correspond to the hypervariable loops of human immunoglobulins. Humanized antibodies also contain at least one fragment of the immunoglobulin constant region (Fc). At least a portion of the immunoglobulin constant region (Fc), typically of a human immunoglobulin A prefix may also be included where necessary to distinguish the humanized antibody from the parent rodent antibody. The prefix "hum," "hu," or "h" may be added to the name of the antibody clone. Rodent antibodies Humanized forms of generally contain the same CDR sequences of the parent rodent antibody, but with increased affinity. To increase the stability of the humanized antibody, or for other reasons, certain Amino acid substitutions may be included.

[0075] As used herein, a "monoclonal antibody" or "mAb" or "Mab" refers to a It refers to a population of antibodies that is substantially homogeneous, i.e., the antibody molecules that make up the population are present in minute amounts. The amino acid sequences are identical except for possible naturally occurring mutations. Conventional (polyclonal) antibody preparations typically target multiple, often distinct epitopes. These antibodies have different amino acid sequences in their variable domains, particularly in their CDRs, that are specific for each antibody. The modifier "monoclonal" refers to a substantially homogeneous population of antibodies. characterize the antibody as being obtained from a group and demonstrate its production by any particular method For example, the monoclonal antibodies used in accordance with the present disclosure should not be construed as requiring The antibody was prepared according to Kohler et al. (1975) Nature 256:495. It may be made by the hybridoma method first described by, for example, (See, for example, U.S. Pat. No. 4,816,567.) "Non-specific antibodies" are also described, for example, in Clackson et al. (1991) Nature 352:624-628 and Marks et al. (1991) J. Mol. B Phage antibody live-cell imaging was performed using the technique described in Iol. 222:581-597. Presta (2005) J. Allergy Clin. Im See also munol.116:731.

[0076] As used herein, unless otherwise specified, "antibody fragment" or "antigen-binding fragment" refers to a " refers to a fragment of an antibody that retains the ability to specifically bind to an antigen, e.g., one or more C It refers to a fragment that retains the DR region. Antibodies that "specifically bind" to PD-1 or ILT4 , which preferentially binds to PD-1 or ILT4 (as appropriate) relative to other proteins. Although this specificity is not required for absolute binding specificity, the antibody may be, for example, a pseudotype. The binding is sufficient to confirm the presence of the target protein in the sample without producing negative results such as a positive result. A compound is considered "specific" for its intended target if it determines its presence. The antibody or binding fragment thereof has an affinity for the non-target protein that is at least two-fold greater than the affinity for the non-target protein. Preferably at least 10 times larger, more preferably at least 20 times larger, most preferably or binds to the target protein with at least 100-fold greater affinity.

[0077] Examples of antigen-binding portions include Fab, Fab', F(ab'), Fd, Fv, and C. DR-containing fragments, and single-chain variable fragment antibodies (scFv), as well as antigens (e.g., PD A small amount of immunoglobulin sufficient to provide a specific antigen that binds to the immune system (IL-1 or ILT4) The antibody may be an IgG, IgA, or IgM polypeptide. (or any subclass thereof), and antibodies may be any specific Depending on the antibody amino acid sequence of the constant region of its heavy chain, it is possible to classify it as an immunoglobulin. IgA, IgD, IgE, IgG and IgD are the different classes of antibodies that can be assigned to different antigens. There are five major immunoglobulin classes: IgM, IgA, and IgC. Isoclass (isotype), e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constants corresponding to the different classes of immunoglobulins are The normal regions are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.

[0078] As used herein, "at least one" item or "one or more" items The terms "item" and "item" refer to a single item selected from a list and a list of items selected from a list, respectively. Contains a mixture of two or more items.

[0079] As used herein, the term "immune response" refers to the following: a specific immune response , nonspecific immune response, both specific and nonspecific responses, innate response, primary immune response, adaptive Immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and and cytokine expression.

[0080] As used herein, the term "subject" (or "patient") refers to a subject that is being treated, observed or Refers to the mammal that was the subject of the experiment. The mammal may be male or female. Mammals include 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., domesticated animals) breeding dogs), cats (e.g., domestic cats), lagomorphs (e.g., rabbits), rodents (e.g., rats) rat or mouse), Procyon lotor (e.g., raccoon) In certain embodiments, the subject is a human.

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

[0082] The therapeutic agents and compositions provided by the present disclosure can be administered by any suitable route of enteral or non-enteral administration. It can be administered via the oral route. The term "enteral route" of administration refers to administration via the digestive tract. Examples of enteral routes include oral, mucosal, buccal, and rectal. "Parenteral" administration refers to any route of administration other than the enteral route. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, and intravesical. Intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intra-articular, subcapsular, subarachnoid, intraspinal Therapeutic agents and compositions of the present disclosure include intravenous, intramuscular, intravenous ... The drug is administered by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. The drug can be administered using any suitable method, such as by pump. The administration method will depend on the particular therapeutic agent being used, the desired absorption rate, and the particular formulation being used. the agent or dosage form, the type or severity of the disorder being treated, the specific site of action, and the patient The dosage may vary depending on several factors, such as the patient's condition, and may be readily selected by one skilled in the art.

[0083] When used in reference to an antibody (e.g., an anti-PD-1 antibody) or an amino acid region within an antibody The term "variant" of a gene refers to a gene that has one or more (e.g., For example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5. Peptides or polypeptides containing substitutions, deletions and / or additions to the amino acid sequence of For example, a variant of an anti-PD-1 antibody may refer to a naturally occurring or previously unmodified One or more (e.g., about 1 to about 25, about 1 The variation may be from about 1 to about 20, from about 1 to about 15, from about 1 to about 10, or from about 1 to about 5, etc. Variants can be naturally occurring or artificially constructed. Polypeptide variants are known as variants. In certain embodiments, antibody variants (e.g., For example, the anti-PD-1 antibody variant retains at least the functional activity of the antibody. In this study, the anti-PD-1 antibody variants bind to PD-1 and / or antagonize PD-1 activity. do.

[0084] "Conservatively modified variants" or "conservative substitutions" are those that do not alter the biological activity or or without altering other desired properties such as antigen affinity and / or specificity. Similar characteristics (e.g., charge, side chain size, hydrophobicity) allow for frequent variation. / hydrophilicity, backbone conformation and rigidity) in proteins by other amino acids Those skilled in the art generally recognize that substitution of a single amino acid in a non-essential region of a polypeptide is Recognizing that acid substitutions do not substantially alter biological activity [e.g., Watson et al.,(1987)Molecular Biology of the Ge ne,The Benjamin / Cummings Pub.Co.,p.224(4 (See the th Ed.). Furthermore, substitution of structurally or functionally similar amino acids may result in a loss of function. Exemplary conservative substitutions are shown in Table 2 below.

[0085] [Table 2]

[0086] "Homology" refers to the degree of similarity between two polypeptide sequences when the two polypeptide sequences are optimally aligned. Refers to the sequence similarity between peptide sequences. When the amino acid monomer subunits are occupied, e.g., the light chains of two different Abs If a position in a CDR is occupied by alanine, the two Abs will have complementary amino acids at that position. The percent homology is the number of positions shared by the two sequences divided by the total number of positions compared. For example, when sequences are optimally aligned, if two If 8 of the 10 positions in a sequence match, the two sequences are 80% homologous. Generally, the comparison is made when the two sequences are aligned to give the maximum percent homology. For example, the comparison can be performed by the BLAST algorithm, The algorithm parameters are the maximum difference between each sequence over the entire length of each reference sequence. is chosen to give a match of

[0087] The following references concern the BLAST algorithm, which is often used for sequence analysis: :BLAST ALGORITHMS:Altschul,SF,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 A cids Res.25:3389-3402;Zhang,J.,et al.,(1 997)Genome Res.7:649-656;Wootton,J.C.,et al.,(1993)Comput.Chem.17:149-163;Hancoc k,J.M.et al.,(1994)Comput.Appl.Biosci.10 :67-70;ALIGNMENT SCORING SYSTEMS:Dayhoff ,M.O.,et al.,’’A model of evolutionary c hange in proteins.’’ in Atlas of Protein Sequence and Structure,(1978)vol.5,supp l.3.M.O.Dayhoff(ed.),pp.345-352,;Natl.Bi omed.Res.Found.,Washington,DC;Schwartz,R .M.,et al.,’’Matrices for detecting dist ant relationships.’’ in Atlas of Protein Sequence and Structure,(1978)vol.5,supp l.3.’’ M.O.Dayhoff(ed.),pp.353-358,Natl. Biomed.Res.Found.,Washington,DC;Altschul ,S.F.,(1991)J.Mol.Biol.219:555-565;State s,DJ,et al.,(1991)Methods 3:66-70;Heni koff,S.,et al.,(1992)Proc.Natl.Acad.Sci. USA 89:10915-10919;Altschul,SF,et al., (1993)J.Mol.Evol.36:290-300;ALIGNMENT ST ATISTICS:Karlin,S.,et al.,(1990)Proc.Nat l.Acad.Sci.USA 87:2264-2268;Karlin,S.,et al.,(1993)Proc.Natl.Acad.Sci.USA 90:587 3-5877;Dembo,A.,et al.,(1994)Ann.Prob.22 :2022-2039; and Altschul, S.F.'Evaluating the statistical significance of multiple distinct local alignments.'' in Theoret ical and Computational Methods in Genome Research(S.Suhai,ed.),(1997)pp.1-14,Ple num,New York.

[0088] As used herein, the "Solid Cancer Response Criteria 1.1 Response Criteria" refers to the response criteria, as appropriate. Eisenhau for target or non-target lesions based on the situation in which it is being measured. er,EAet al.,Eur.J.Cancer 45:228-247(20 09).

[0089] "Sustained response" means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, a sustained response lasts for at least as long as or longer than the treatment period. or treatment period at least 1.5, 2.0, 2.5, or 3 times longer than the treatment period. do.

[0090] As used herein, "treating" or "treating" cancer refers to, for example, reducing or reduced number of cancer cells, reduced tumor size, reduced rate of cancer cell invasion into peripheral organs, or tumor size Achieve at least one positive therapeutic effect, such as a reduced rate of tumor metastasis or tumor growth. To achieve this, anti-human PD-1 monoclonal antibody or its antigen-binding fragment, HIF-2α a therapeutic combination of an inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof, "Treatment" refers to administering a compound to a subject who has or has been diagnosed with cancer. as described herein slows, interrupts, inhibits, controls, or stops the progression of cancer. It may be possible to achieve this, but it does not necessarily indicate complete elimination of cancer or cancer symptoms. The therapeutic effect of the drug can be measured in several ways (W.A. Weber, J.N. ucl.Med.50:1S-10S(2009)). For example, According to the NCI criteria, T / C ≦ 42% is the minimum level of antitumor activity. 10% is considered a high level of antitumor activity, and T / C (%) = tumor volume of treated subjects. In some embodiments, the tumor volume of the present disclosure is calculated by dividing the tumor volume by the median tumor volume of the control group by 100. Treatment achieved with combination therapy included PR, CR, OR, PFS, DFS, and OS. PFS, also known as "time to tumor progression," is the difference between the progression of cancer during and after treatment. This indicates the length of time that the patient experienced a CR or PR, as well as the length of time that the patient DFS includes the length of time a patient experiences SD during and after treatment. OS refers to the average time post-treatment compared with untreated or untreated individuals or patients. In some embodiments, the response to the combination therapy of the present disclosure is in the treatment of a solid tumor. Response Criteria1.1 PR, CR, PFS, DFS or O assessed using response criteria R. Treatment regimens for the combination therapy of the present disclosure that are effective in treating cancer patients The treatment may be based on the patient's condition, age, and weight, as well as the ability of the therapy to elicit an anti-cancer response in the subject. The effects of any of the aspects of the present disclosure may vary depending on factors such as the force of the Although it may not be effective in achieving positive therapeutic effects in students, t-test, chi-square test, Mann-Whitney U test, Kruskal-Wallis test (H test), Joncke-Trepstra test, and Wilcoxon test, among others. A statistically significant number of subjects show a significant difference in the probability of a positive outcome as determined by any statistical test of the The therapeutic effect of the drug should be achieved.

[0091] As used herein, "combination," "combination therapy," and "therapeutic combination" refer to The term "anti-human PD-1 monoclonal antibody" refers to a compound that binds to at least one anti-human PD-1 monoclonal antibody or its antigen. a recombinant fragment, a HIF-2α inhibitor, and lenvatinib or a pharmaceutically acceptable salt thereof, and optional additional therapeutic agents are administered to the patient in a coordinated manner over overlapping periods. refers to a treatment administered with at least one anti-human PD-1 monoclonal antibody (or The duration of treatment with an antigen-binding fragment of an anti-human PD-1 molecule ("anti-PD-1 treatment") is determined by the patient's The duration of treatment with anti-human clonal antibodies (or antigen-binding fragments thereof) Treatment cycle from first dose of anti-PD-1 monoclonal antibody (or its antigen-binding fragment) Similarly, the period from the treatment with HIF-2α inhibitors (HIF-2α inhibitors) to the final day of treatment was The period of "inhibitory treatment" is the period during which the patient receives treatment with a HIF-2α inhibitor, i.e. That is, the period from the first administration of a HIF-2α inhibitor to the last day of the treatment cycle. The duration of treatment with lenvatinib or a pharmaceutically acceptable salt thereof ("lenvatinib treatment") The period during which patients receive treatment with lenvatinib, i.e., the first dose of lenvatinib The period from the first day of the treatment cycle to the last day of the treatment cycle. In combination, anti-PD-1 treatment overlaps with HIF-2α inhibitor treatment by at least 1 day and overlaps with the lenvatinib treatment by at least one day. The HIF-2α inhibitor treatment and lenvatinib treatment are for the same duration. In these patients, anti-PD-1 treatment was administered prior to HIF-2α inhibitor and / or lenvatinib treatment. In other embodiments, the anti-PD-1 treatment includes a HIF-2α inhibitor and / or a lenalidomide inhibitor. In yet other embodiments, the HIF-2α inhibitor treatment begins after the vatinib treatment. In yet another embodiment, HIF is initiated prior to D-1 and / or lenvatinib treatment. Treatment with a PD-2α inhibitor begins after treatment with anti-PD-1 and / or lenvatinib. In some embodiments, the lenvatinib treatment is in combination with a HIF-2α inhibitor and / or an anti-PD-1 In other embodiments, lenvatinib treatment begins before treatment with a HIF-2α inhibitor and and / or begins after anti-PD-1 treatment. In some embodiments, anti-PD-1 treatment is initiated after HIF- The treatment is terminated before the end of the 2α inhibitor and / or lenvatinib treatment. Anti-PD-1 treatment should be discontinued after the end of HIF-2α inhibitor and / or lenvatinib treatment. In yet other embodiments, the HIF-2α inhibitor treatment is terminated after anti-PD-1 and / or anti-PD-2α treatment. or terminates before the end of lenvatinib treatment. The alpha inhibitor treatment will be terminated after the end of the anti-PD-1 and / or lenvatinib treatment. In some embodiments, the lenvatinib treatment is in combination with a HIF-2α inhibitor and / or an anti-PD-1 In other embodiments, lenvatinib treatment is terminated prior to the end of treatment. The treatment will be terminated after the end of anti-inflammatory drug and / or anti-PD-1 treatment.

[0092] The terms "treatment regimen," "dosing protocol," and "dosing regimen" are used in the context of this disclosure. are used interchangeably to refer to the dose and timing of administration of each therapeutic agent in a combination therapy. can be.

[0093] "Tumor" refers to a subject diagnosed with or suspected of having cancer. A primary tumor refers to a malignant or potentially malignant neoplasm or mass of tissue of any size. and secondary neoplasms. Non-limiting examples of tumors include solid tumors (e.g., sarcomas (soft osteosarcoma), carcinoma (e.g. colon carcinoma), blastoma (e.g. hepatoblastoma) and hematological tumors ( For example, leukemia (acute myeloid leukemia (AML)), lymphoma (DLBCL), Myeloma (MM), etc.

[0094] The term "tumor volume" or "tumor size" refers to the length and width of a tumor. Tumor size refers to the total size of a tumor that can be measured by various methods known in the art. For example, using a caliper, the (one or more) by measuring the size of the tumor or by imaging techniques, e.g., bone scan, ultrasound (one or more) while in the body using ultrasound, CT or MRI scans It can be determined by measuring the size of the tumor.

[0095] Unless expressly stated to the contrary, all ranges cited herein are inclusive. That is, a range is a set of values ​​that includes the upper and lower limits of the range and all values ​​in between. By way of example, the temperature ranges, percentages, equivalent ranges, etc. set forth herein includes the upper and lower limits of the range and any consecutive values ​​therebetween. Numerical values ​​provided herein, and the use of the term "about," are subject to ±1%, ±2%, ±3% , ±4%, ±5%, ±10%, ±15% and ±20% variations and their numerical equivalents Although not always expressly stated, all ranges are inclusive. For example, the range 3 to 7 days includes 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 6 Additionally, as used herein, the term "or" is intended to include days 6 and 7. Terms indicate combinable options where appropriate, i.e., the use of "or" The term includes each listed option separately as well as any combination thereof. .

[0096] Aspects or embodiments of the present disclosure may be presented in terms of Markush groups or other groupings of alternatives. When listed, the disclosure includes each member of the group as well as the entire group listed as a whole. individually and also includes all possible subgroups of the principal group, where one or more of the group members The present disclosure also encompasses the absence of any main group. Assume one or more explicit exclusions.

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, definitions shall prevail. The present specification, including the present invention, takes precedence. "comprises" or "comprises" Variations such as "rising" include a stated integer or group of integers, but may also include any other integer. It is understood to mean not excluding groups of numbers or integers unless the context requires otherwise. Unless otherwise specified, singular terms shall include the plural and plural terms shall include the singular. The terms "eg" or "for example" Any example(s) that follow are not meant to be exhaustive or limiting. Exemplary methods and materials are described herein, however, the methods and materials described herein Methods and materials similar or equivalent to those described herein may also be used in the practice or testing of this disclosure. The materials, methods, and examples are illustrative only and are intended to be limiting. isn't it.

[0098] 2.PD-1 antagonists Blocks the binding of PD-L1 to PD-1, and preferably also blocks the binding of PD-L2 to PD-1 The various methods disclosed herein include any chemical compound or biological molecule that blocks PD-1 antagonists that can be used in the kits and uses are described herein. It is offered at

[0099] PD-1 polypeptide, PD-1 polypeptide fragment, PD-1 peptide or PD-1 Binding to an epitope, interaction between PD-1 and its ligands PD-L1 or PD-L2 Any monoclonal antibody that blocks the action of The anti-human PD-1 monoclonal antibody is a PD-1 polypeptide. PD-1 and PD-L bind to PD-1 peptide fragments, PD-1 peptides, or PD-1 epitopes. 1. In another embodiment, an anti-human PD-1 monoclonal antibody refers to a PD-1 polypeptide, a PD-1 polypeptide fragment, a PD-1 peptide, or a PD It binds to the PD-1 epitope and blocks the interaction between PD-1 and PD-L2. In one embodiment, the anti-human PD-1 monoclonal antibody is a PD-1 polypeptide, PD- 1. A polypeptide fragment, which binds to a PD-1 peptide or PD-1 epitope and binds to PD-1. It blocks the interaction between PD-L1 and between PD-1 and PD-L2.

[0100] PD-L1 polypeptide, PD-L1 polypeptide fragment, PD-L1 peptide or P Any antibody that binds to the PD-L1 epitope and blocks the interaction between PD-L1 and PD-1 Monoclonal antibodies may also be used.

[0101] In some embodiments, the anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, and pembrolizumab. Mab, cemiplimab, sintilimab, tiselizumab, camrelizumab, toripalimab, Dilizumab (U.S. Patent No. 7,332,582), AMP-514 (MedImmun e LLC, Gaithersburg, MD), PDR001 (U.S. Patent No. 9,683 ,048), BGB-A317 (U.S. Patent No. 8,735,553) and MGA01 2 (MacroGenics, Rockville, MD). In one embodiment, the anti-human PD-1 monoclonal antibody is pembrolizumab.

[0102] In certain embodiments of the various methods, pharmaceutical compositions, kits or uses provided herein, The anti-human PD-1 monoclonal antibody or its antigen-binding fragment is SEQ ID NO: 1. A light chain variable region (V) comprising the amino acid sequences shown in D NOs: 1, 2 and 3 L ) Complementary Determination Constant region 1 (CDR1), V L CDR2 and V L CDR3 and SEQ ID N O: A heavy chain variable region (V) containing the amino acid sequences shown in 6, 7, and 8 H ) CDR1, V H CDR2 and V H CDR3.

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

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

[0105] [Table 3]

[0106] In another embodiment, the anti-human PD-1 monoclonal antibody is nivolumab. In another embodiment, the anti-human PD-1 monoclonal antibody is cemiplimab. In another embodiment, the anti-human PD-1 monoclonal antibody is sintilimab. The PD-1 monoclonal antibody is tiselizumab. In another embodiment, the anti-human PD-1 In another embodiment, the anti-human PD-1 monoclonal antibody is camrelizumab. In yet another embodiment, the monoclonal antibody is toripalimab. In one embodiment, the anti-human PD-1 monoclonal antibody is pidilizumab. In another embodiment, the anti-human PD-1 monoclonal antibody is AMP-514. In yet another embodiment, the anti-human PD-1 monoclonal antibody is BG In yet another embodiment, the anti-human PD-1 monoclonal antibody is M-A317. It is GA012.

[0107] In some embodiments, the anti-human PD-1 monoclonal antibody is a monoclonal antibody as described in U.S. Pat. No. 7,488 802, U.S. Patent No. 7,521,051, U.S. Patent No. 8,008,449, U.S. Patent No. 83 No. 54509, U.S. Patent No. 8168757, International Publication No. 2004 / 004771, International Publication No. 2004 / 072286, International Publication No. 2004 / 056875, U.S. Pat. The present invention is disclosed in International Publication No. 2011 / 0271358 and International Publication No. 2008 / 156712. The present disclosure may be directed to any of the antibodies, antigen-binding fragments thereof, or variants thereof. , which is incorporated herein by reference in its entirety.

[0108] Human PD- Examples of monoclonal antibodies that bind to L1 are disclosed in U.S. Pat. No. 8,383,796. The disclosure of which is incorporated herein by reference in its entirety. Specific anti-human PD-1 antagonists useful in methods, kits and uses -L1 monoclonal antibodies include durvalumab, avelumab, and BMS-93655 Contains 9.

[0109] Other PD-1 antigens useful in the various methods, kits and uses described herein include: The antagonists include those that specifically bind to PD-1 or PD-L1, preferably human PD-1. or an immune adhesion molecule that specifically binds to human PD-L1, e.g., an immunoglobulin molecule Extracellular or PD-L1 or PD-L2 fused to a constant region such as the Fc region 1-binding moiety. Immunoadhesion that specifically binds to PD-1. Exemplary molecules are described in WO 2010 / 027827 and WO 2011 / 0663 No. 42, the disclosure of which is incorporated herein by reference in its entirety. In the various methods, kits and uses described herein, a PD-1 antagonist A specific fusion protein useful as a therapeutic agent is a PD-L2-Fc fusion protein. These include AMP-224 (also known as B7-DCIg), which binds to PD-1.

[0110] In various embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or The antigen-binding fragments may be any of the anti-human PD-1 or anti-human PD-L1 antibodies described herein. The variant amino acid sequence may contain one, two, three, four or more amino acids. is identical to the reference sequence except for having five amino acid substitutions, deletions, and / or additions In some embodiments, the substitutions, deletions and / or additions are in the CDRs. In some embodiments, the substitutions, deletions and / or additions are in framework regions. In some embodiments, one, two, three, four, or five of the amino acid substitutions are conservative substitutions. be.

[0111] In one embodiment, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or These antigen-binding fragments may be used in combination with the anti-human PD-1 or anti-human PD-L1 antibodies described herein. V of antibody L At least 95%, 90%, 85%, 80%, 75% with one of the domains or V with 50% sequence homology L domain and binds to PD-1 or PD-L1 In another embodiment, the anti-human PD-1 or anti-human PD-L1 antibody The monoclonal antibodies or antigen-binding fragments thereof may be used in combination with the anti-human PD-1 antibodies described herein. or V of anti-human PD-L1 antibody H At least 95%, 90%, and one of the domains V with 85%, 80%, 75% or 50% sequence identity H domain, PD- In yet another embodiment, the antibody exhibits specific binding to anti-human PD-L1. 1 or anti-human PD-L1 monoclonal antibodies, or antigen-binding fragments thereof, are described herein. V of anti-human PD-1 or anti-human PD-L1 antibodies described in the literature L One of the domains having at least 95%, 90%, 85%, 80%, 75% or 50% sequence identity with RuV L domains and the anti-human PD-1 or anti-human PD-L1 antibodies described herein. V H At least 95%, 90%, 85%, 80%, 75% or more of one of the domains V with 50% sequence identity H domain and target PD-1 or PD-L1 Specific binding is shown.

[0112] In one embodiment, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or These antigen-binding fragments may be used in combination with the anti-human PD-1 or anti-human PD-L1 antibodies described herein. V of antibody L Up to 1, 2, 3, 4, 5 or more in one domain V with amino acid substitutions, deletions and / or additions L domain, and PD-1 or P In another embodiment, the antibody binds to anti-human PD-1 or anti-human PD-L1. -L1 monoclonal antibody or antigen-binding fragment thereof is an anti-human PD-1 or anti-human PD-L1 antibody V H Maximum of 1, 2, 3, in one of the domains V with four, five or more amino acid substitutions, deletions and / or additions H Do In yet another embodiment, the antibody has a domain and exhibits specific binding to PD-1 or PD-L1. and anti-human PD-1 or anti-human PD-L1 monoclonal antibodies or their antigen binding The binding fragments may be any of the V and VF fragments of the anti-human PD-1 or anti-human PD-L1 antibodies described herein. L Domestic up to one, two, three, four, five or more amino acid substitutions in one of the amino acids, V with deletions and / or additions L domains and anti-human PD-1 as described herein. or V of anti-human PD-L1 antibody H Maximum of 1, 2, 3, 4, 5 in one domain V with one or more amino acid substitutions, deletions and / or additions H Domain and and exhibits specific binding to PD-1 or PD-L1.

[0113] In various embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody or or antigen-binding fragments thereof, may be used in immunological studies including IgM, IgG, IgD, IgA, and IgE. The antibody may be selected from any class of globulin. Preferably, the antibody is an IgG antibody. Use any IgG isotype, including G1, IgG2, IgG3, and IgG4 Different constant domains can be used in the V L and V H Append to Region For example, the particular intended use of an antibody (or fragment) of the present invention may be modified. Where effector functions are required, heavy chain constant domains other than IgG1 may be used. IgG1 antibodies offer a long half-life and are effective against inflammatory cytokines such as complement activation and antibody-dependent cellular cytotoxicity. Although these antibodies provide vector functions, such activities are undesirable for all uses of the antibody. In such cases, for example, an IgG4 constant domain may be used. In various embodiments, the heavy chain constant domains may be one or more of the following to generate desired characteristics of the antibody: or multiple amino acid mutations (e.g., IgG4 with the S228P mutation). These desirable characteristics include modified effector functions, physical or chemical stability, and the ability to differentiate antibodies. These include, but are not limited to, half-life.

[0114] Typically, the anti-human PD-1 or anti-human PD-L1 monoclonal antibodies disclosed herein Amino acid sequence variants of antibodies and antigen-binding fragments thereof may be derived from a reference antibody or antigen-binding fragment (e.g., For example, heavy chain, light chain, V H , V L or humanized sequence) and at least 75% Amino acid sequence identity, more preferably at least 80%, more preferably at least 85% %, more preferably at least 90%, and most preferably at least 95, 98 or 99 % amino acid sequence identity. Homology, as used herein, is determined by aligning sequences to achieve maximum percent sequence identity. and consider any conservative substitutions as part of the sequence identity, after introducing gaps if necessary. Defined as the percentage of amino acid residues in a candidate sequence that are identical to the reference sequence, regardless of Any N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence It should not be construed as affecting sequence identity or homology.

[0115] Sequence identity is the number of amino acid sequences of two polypeptides when the two sequences are optimally aligned. The degree to which sequences are the same at equivalent positions is measured using the BLAST algorithm. The algorithm parameters are determined based on the length of each reference sequence. The sequences are chosen to give the greatest match between the respective sequences across the BLAST A: A frequently used BLAST algorithm for sequence analysis LGORITHMS: Altschul, SF, et al., (1990) JM ol.Biol.215:403-410;Gish,W.,et al.,(1993 )Nature Genet.3:266-272;Madden,TL,et a l.,(1996)Meth.Enzymol.266:131-141;Altsch ul,SF,et al.,(1997)Nucleic Acids Res.2 5:3389-3402;Zhang,J.,et al.,(1997)Genome Res.7:649-656; Wootton, JC, et al., (1993 )Comput.Chem.17:149-163;Hancock,JMet a l.,(1994)Comput.Appl.Biosci.10:67-70;ALI GNMENT SCORING SYSTEMS: Dayhoff,MO,et a l.,''A model of evolutionary change in p roteins.'' in Atlas of Protein Sequence and Structure,(1978)vol.5,suppl.3.MODa yhoff(ed.),pp.345-352,;Natl.Biomed.Res.F ound.,Washington,DC;Schwartz,RM,et al. ,''Matrices for detecting distant relati onships.’’ in Atlas of Protein Sequence and Structure,(1978)vol.5,suppl.3.,M.O.D ayhoff(ed.),pp.353-358,Natl.Biomed.Res.F ound.,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 a l.,(1992)Proc.Natl.Acad.Sci.USA 89:10915 -10919;Altschul,S.F.,et al.,(1993)J.Mol. Evol.36:290-300;ALIGNMENT STATISTICS:Kar lin,S.,et al.,(1990)Proc.Natl.Acad.Sci.U SA 87:2264-2268;Karlin,S.,et al.,(1993)P roc.Natl.Acad.Sci.USA 90:5873-5877;Dembo ,A.,et al.,(1994)Ann.Prob.22:2022-2039;お よびAltschul,S.F.’’Evaluating the statisti cal significance of multiple distinct lo cal alignments.’’ in Theoretical and Com putational Methods in Genome Research(S. Suhai,ed.),(1997)pp.1-14,Plenum,New York 。

[0116] In some embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody is a human antibody. In other embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody The clonal antibody is a humanized antibody.

[0117] In some embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody The light chain of the anti-human PD-1 or anti-human PD-L antibody has a human κ backbone. The light chain of one monoclonal antibody has a human lambda backbone.

[0118] In some embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody The heavy chain of the antibody has a human IgG1 backbone. The heavy chain of the D-L1 monoclonal antibody has a human IgG2 backbone. The heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody is human IgG3 In yet another embodiment, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody The heavy chain of the monoclonal antibody has a human IgG4 backbone.

[0119] In some embodiments, an anti-human PD-1 or anti-human PD-L1 monoclonal antibody The heavy chain of the antibody has a human IgG1 variant backbone. The heavy chain of the human PD-L1 monoclonal antibody has a human IgG2 variant framework. In some embodiments, the heavy chain of the anti-human PD-1 or anti-human PD-L1 monoclonal antibody is human PD-1 or human PD-L1. In yet another embodiment, the anti-human PD-1 or anti-human IgG3 variant has a variant backbone. The heavy chain of the PD-L1 monoclonal antibody is a human IgG4 variant (e.g., S228P variant). It has an IgG4 backbone.

[0120] 3.HIF-2α inhibitors The present invention relates to a method for treating HIF-2α-related diseases, including the treatment of HIF-2α-related diseases, and to a method for treating HIF-2α-related diseases. HIF-2α that can be used in the various methods, kits and uses disclosed in Inhibitors are also provided herein.

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

[0122] Verzutiphane and its synthesis are described in US Pat. No. 6,233,999, which is incorporated herein by reference in its entirety. It is described in Japanese Patent No. 9,969,689. Belzutifan as a treatment is described in Rui et al., herein incorporated by reference in its entirety. Xu et al., J.Med.Chem.2019,62,6876-6893 PD-1 / CTLA-4 for treating melanoma, RCC or CRC The combination of an inhibitor with a HIF-2α inhibitor is incorporated herein by reference in its entirety. No. 10,335,388, filed on May 1, 2014. No. 18-0042884 describes the treatment of glioblastoma with HIF-2α inhibitors. , the entire contents of which are incorporated herein by reference. Oral formulations of velzutifan have been described in Described in International Application No. PCT / US2019 / 57725, filed October 23, 2019 and is incorporated herein by reference in its entirety.

[0123] 4. Lenvatinib Multi-RTK inhibitors selectively inhibit the kinase activity of VEGF receptors Also provided herein is lenvatinib, which is

[0124] Lenvatinib is marketed under the trademark LENVIMA® by Eisai Inc., Woodcroft, MD iff Lake, NJ and 4-[3-chloro-4-(cyclopropylaminocarbonyl Also known as [[(aminophenoxy)aminophenoxy]-7-methoxy-6-quinolinecarboxamide and has the following chemical structure: [ka]

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

[0126] 5. PD-1 antagonist, HIF-2α inhibitor, and lenvatinib or pharmaceuticals thereof US201301229634A1 - Treating cancer or von Hippel-Lindau disease using a combination of environmentally acceptable salts - Google Patents How to place In another aspect, a PD-1 antagonist, a HIF-2α inhibitor, and lenvatinib or a combination of pharmaceutically acceptable salts thereof as described can be used to treat cancer (e.g. Provided herein are methods for treating rheumatoid arthritis (RCC) or von Hippel-Lindau disease. can be.

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

[0128] In some embodiments, the method of treating cancer or von Hippel-Lindau disease comprises administering to a subject a cancer or in a human patient in need of treatment for von Hippel-Lindau disease, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0129] In some embodiments, the cancer is bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, or Colon cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), pancreatic cancer and melanoma? is selected from the group consisting of:

[0130] In some embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory. is.

[0131] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In one 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 one embodiment, the cancer is pancreatic cancer. In yet another embodiment, the cancer is melanoma.

[0132] In one embodiment, the cancer is advanced RCC. In another embodiment, the RCC has a clear cell component. In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. The cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC. .

[0133] In one embodiment, the human patient has not received prior systemic treatment for advanced disease. In a class of embodiments, the human patient has not received prior systemic treatment for advanced RCC. There is no problem.

[0134] In some embodiments, the method of treating RCC comprises administering to a patient in need of treating RCC. In human patients, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0135] In some embodiments, the method of treating advanced RCC comprises treating advanced RCC. to human patients in need thereof, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

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

[0013] Methods are provided herein that include administering

[0137] In another embodiment, the method of treating metastatic RCC comprises treating metastatic RCC. and to human patients in need thereof, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0138] In yet another embodiment, the method of treating recurrent RCC comprises: In a human patient in need of (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0139] In yet another embodiment, the method of treating refractory RCC comprises: In a human patient in need of (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0140] In another embodiment, the method of treating relapsed and refractory RCC comprises: In a human patient in need of treatment for curable RCC, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0141] In another embodiment, a method of treating pancreatic cancer comprises administering to a subject in need of treating pancreatic cancer. In human patients, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0142] In some embodiments, the method of treating cancer comprises administering to a human patient in need of cancer treatment: (a) PD-1 antagonist; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

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

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

[0145] Thus, in one embodiment, a method for treating cancer comprises treating the cancer. to a human patient in need thereof, (a) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0146] In some embodiments, the method for treating cancer comprises administering to a subject in need of treating the cancer. In human patients, (a) a human anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) velzutifan or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0147] In another embodiment, a method for treating cancer involves treating the cancer. In human patients, (a) a humanized anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

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

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

[0150] In another embodiment of the various methods provided herein, an anti-human PD-1 monoclonal The antibody or antigen-binding fragment thereof is cemiplimab.

[0151] Thus, in one particular embodiment of the various methods provided herein, cancer is treated The method for administering to a human patient in need of cancer treatment comprises administering to the patient: (a) Pembrolizumab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0152] In one particular embodiment of the various methods provided herein, the method is for treating cancer. The method comprises administering to a human patient in need of treating cancer: (a) Nivolumab; (b) velzutifan or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0153] In one particular embodiment of the various methods provided herein, the method is for treating cancer. The method comprises administering to a human patient in need of treating cancer: (a) Cemiplimab; (b) velzutifan or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0154] In one particular embodiment of the various methods provided herein, for treating RCC The method comprises administering to a human patient in need of treating RCC: (a) Pembrolizumab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

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

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

[0157] In one embodiment, the RCC is advanced RCC. In another embodiment, the RCC is clear cell In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is recurrent RCC. The CC is refractory RCC. In yet another embodiment, the RCC is relapsed and refractory RCC. is.

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

[0159] 6. Medication and Administration PD-1 antagonists (e.g., anti-PD-1 monoclonal antibodies or antigen-binding fragments), HIF-2α inhibitors and multi-RTK inhibitors (e.g., lenvatinib or its and pharmaceutically acceptable salts thereof) to treat cancer (e.g., RCC). Further provided herein are dosing regimens and routes of administration for the treatment of rheumatoid arthritis.

[0160] anti-PD-1 monoclonal antibody or its antigen-binding fragment, HIF-2α inhibitor, or Lenvatinib or a pharmaceutically acceptable salt thereof disclosed herein may be used in combination with, for example, Daily, 1-7 times a week, weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks and may be administered in doses administered monthly, bimonthly, quarterly, semi-annually, annually, etc. Dosage may be administered, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, or intravenously. or by inhalation. In some embodiments, the dose is administered intravenously. In some embodiments, the dose is administered subcutaneously. In some embodiments, the dose is administered orally. The total dose for each interval is generally at least 0.05 μg / kg body weight, more usually less. Spider: 0.2μg / kg, 0.5μg / kg, 1μg / kg, 10μg / kg, 100μ g / kg, 0.25mg / kg, 1.0mg / kg, 2.0mg / kg, 5.0mg / m l, 10 mg / kg, 25 mg / kg, 50 mg / kg or more. A predetermined target concentration of an antibody (e.g., an anti-PD-1 antibody) or antigen-binding fragment thereof in the serum of a subject. Degree, e.g., 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / mL or Doses to achieve greater amounts may also be provided.

[0161] In some embodiments, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof 10, 20, 50, 80, 100, 200, 300, 400, 500, 1000 or 2 500 mg / subject, weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, or every other week The drug is administered subcutaneously or intravenously every month or every three months. The dose of the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is about 0.01 mg / kg. ~50mg / kg, approx. 0.05mg / kg~25mg / kg, approx. 0.1mg / kg~ Approximately 10mg / kg, approximately 0.2mg / kg to approximately 9mg / kg, approximately 0.3mg / kg to approximately 8m g / kg, about 0.4 mg / kg to about 7 mg / kg, about 0.5 mg / kg to about 6 mg / kg , about 0.6mg / kg to about 5mg / kg, about 0.7mg / kg to about 4mg / kg, about 0. 8mg / kg to approximately 3mg / kg, approximately 0.9mg / kg to approximately 2mg / kg, approximately 1.0mg / kg to approximately 1.5 mg / kg, approximately 1.0 mg / kg to approximately 2.0 mg / kg, approximately 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, an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof The dose is about 10 mg to about 500 mg, about 25 mg to about 500 mg, about 50 mg to about 50 0mg, about 100mg to about 500mg, about 200mg to about 500mg, about 150mg to about 250mg, about 175mg to about 250mg, about 200mg to about 250mg, about 150mg about 175 mg to about 240 mg, about 175 mg to about 240 mg, or about 200 mg to about 240 mg In some embodiments, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof Doses are 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, and 200mg. mg, 225mg, 240mg, 250mg, 300mg, 400mg, or 500m g.

[0162] In some embodiments of the various methods described herein, an anti-human PD-1 monoclonal antibody The monoclonal antibody or antigen-binding fragment thereof is pembrolizumab, and human patients receive 200 mg, Patients received pembrolizumab at 240 mg or 2 mg / kg, with pembrolizumab administered for 3 weeks. In one embodiment, a human patient receives 200 mg of pembrolizumab In one embodiment, a human patient receives 240 mg of pembrolizumab once every three weeks. In one embodiment, a human patient receives 2 mg / kg of pembrolizumab once every three weeks. Mubrolizumab is administered once every three weeks.

[0163] In certain embodiments of the various methods described herein, an anti-human PD-1 monoclonal antibody The antibody or antigen-binding fragment thereof is pembrolizumab, and human patients receive 400 mg of pembrolizumab. Patients will receive lorizumab and pembrolizumab once every six weeks.

[0164] In other embodiments of the various methods described herein, an anti-human PD-1 monoclonal The antibody or antigen-binding fragment thereof is nivolumab, and human patients receive either 240 mg or 3 mg / kg. kg of nivolumab, which is administered once every 2 weeks. In an embodiment, a human patient receives 240 mg of nivolumab once every two weeks. In one particular embodiment, human patients receive 3 mg / kg of nivolumab every two weeks. In other embodiments of the various methods described herein, the anti-human PD-1 monoclonal antibody is administered once. The monoclonal antibody or antigen-binding fragment thereof is nivolumab, and human patients receive 480 mg of Patients will receive nivolumab, which will be administered once every four weeks.

[0165] In still other embodiments of the various methods described herein, an anti-human PD-1 monoclonal antibody The monoclonal antibody or antigen-binding fragment thereof is cemiplimab, and human patients receive 350 mg of cemiplimab. Patients will receive primab and cemiplimab once every three weeks.

[0166] In still other embodiments of the various methods described herein, the HIF-2α inhibitor is a vegetative inhibitor. Luzutifan or its pharmaceutically acceptable salt, and human patients receive 40 to 120 mg. In still other embodiments of the various methods described herein, 40 , 80 or 120 mg of belzutifan or a pharmaceutically acceptable salt thereof once a day. In one particular embodiment, a human patient receives 40 mg of velzutifan or is administered once daily as a pharmaceutically acceptable salt thereof. Patients will receive 80 mg of velzutifan or its pharmaceutically acceptable salt once daily. In one particular embodiment, a human patient receives 120 mg of velzutifan or The pharmaceutically acceptable salt is administered once daily.

[0167] In certain embodiments, lenvatinib or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof Daily doses of lenvatinib are 8, 10, 12, 14, 18, 20 or 24 mg, respectively. It is administered at .

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

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

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

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

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

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

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

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

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

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

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

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

[0180] In some embodiments, the human patient has received prior systemic treatment for advanced disease. do not have.

[0181] In some embodiments, the therapeutic agent in the combination therapy (e.g., an anti-PD-1 monoclonal antibody) antibody or its binding fragment, HIF-2α inhibitor, or lenvatinib One is typically when the drug is used as monotherapy to treat the same condition. It is administered using the same dosing regimen (dose, frequency and duration of treatment) used in other In embodiments, the patient is more likely to receive the agent in combination therapy than if the agent were used as monotherapy. a smaller total dose of therapeutic agent (e.g., anti-PD-1 monoclonal antibody or its binding fragment) than , HIF-2α inhibitor, or lenvatinib), e.g., less use receive lower doses, less frequent doses, and / or shorter treatment durations.

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

[0183] In some embodiments, the combination therapy disclosed herein includes a biotherapeutic or a chemotherapy agent. It is administered to patients who have not been previously treated with other drugs, i.e., treatment-naive patients. In embodiments, the combination therapy is continued after prior treatment with a biotherapeutic or chemotherapeutic agent. It is administered to patients who have failed to achieve a response, ie, treatment-experienced patients.

[0184] The therapeutic combinations disclosed herein are useful for the prevention, treatment, and / or prophylaxis of certain diseases or conditions, including cancer. including, but not limited to, other anti-cancer drugs used in the regulation, amelioration, or risk reduction of The compound may be used in combination with one or more other active agents that are not intended to be used in combination with other active agents. The active agent of is one or more of the therapeutic agents in the combination disclosed herein. They can be administered simultaneously or sequentially by a route and in an amount commonly used therefor.

[0185] The one or more additional active agents may be an anti-PD-1 monoclonal antibody or its antigen-binding fragment, HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof The additional active agent(s) may be co-administered with an anti-PD-1 moiety. monoclonal antibody or its antigen-binding fragment, HIF-2α inhibitor, and lenvatinib or or a pharmaceutically acceptable salt thereof; The additional active agent(s) may be administered in a single dosage form together with the active agent(s). The substance also contains an anti-PD-1 monoclonal antibody or its antigen-binding fragment, a HIF-2α inhibitor, or a dosage form containing lenvatinib or a pharmaceutically acceptable salt thereof It may be administered in one or more dosage forms.

[0186] 7. Kit In yet another aspect, a therapeutic agent disclosed herein (e.g., a steroid or steroid drug) packaged in a suitable packaging material is provided. For example, PD-1 antagonists, HIF-2α inhibitors, and lenvatinib) or Kits are provided herein that include pharmaceutical compositions. The kits may include a description of the components or Instructions for in vitro, in vivo or ex vivo use of the components in the kit The label or package insert may include:

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

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

[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 It 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; (b) one or more therapeutic doses of a HIF-2α inhibitor; (c) one or more doses of lenvatinib or a pharmaceutically acceptable salt thereof; and (d) an anti-human PD-1 monoclonal antibody or its antigen-binding fragment, a HIF-2α inhibitor, and a method for administering lenvatinib or a pharmaceutically acceptable salt thereof to a human patient. Comes with instructions.

[0191] In some embodiments, the anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is In some embodiments, the anti-PD-1 monoclonal antibody or The antigen-binding fragment is nivolumab. In some embodiments, the anti-PD-1 monoclonal antibody The monoclonal antibody or antigen-binding fragment thereof is cemiplimab.

[0192] In various kits herein, anti-PD-1 monoclonal antibodies, HIF-2α inhibitors, the dosage for lenvatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the kit includes a period of treatment (e.g., 3, 6 For example, the kit may contain a dosage of each ingredient sufficient for one medicinal use. 200 mg pembrolizumab, 21 doses of 120 mg velzutifan or other and 21 doses of 20 mg lenvatinib (or equivalent , a pharmaceutically acceptable salt of lenvatinib), which may be administered for 3 weeks. Alternatively, the kit contains one 400 mg dose of pembrolizumab, 42 doses an amount of 120 mg of velzutifan or a pharmaceutically acceptable salt thereof, and 42 doses 20 mg of lenvatinib (or an equivalent amount of a pharmaceutically acceptable salt of lenvatinib) These are sufficient for six weeks of treatment.

[0193] In some embodiments, the kit comprises a container, a divided bottle, or a divided foil packet. The kits of the present disclosure may comprise a means for keeping the components separate, such as a box. administration of separate compositions at different dosage intervals for oral and parenteral administration, for example; or for titrating the separate compositions relative to each other.

[0194] 8. Use of the therapeutic combination to treat cancer or von Hippel-Lindau disease In yet another aspect, a method for treating cancer (e.g., RCC) or von Hippel-Zoster disease in a human patient is provided. Use of a therapeutic combination for treating Le-Lindau disease, comprising: Seha, (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0195] In some embodiments, the cancer is bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, or A group consisting of colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma is selected from.

[0196] In some embodiments, the cancer is metastatic. In some embodiments, the cancer is recurrent. In other embodiments, the cancer is refractory. In yet other embodiments, the cancer is relapsed and refractory. is.

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

[0198] In one embodiment, the cancer is advanced RCC. In another embodiment, the cancer has a clear cell component. In yet another embodiment, the cancer is metastatic RCC. In one 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.

[0199] In one embodiment, the use of the therapeutic combination to treat RCC in a human patient. wherein said therapeutic combination comprises: (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

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

[0201] In some embodiments, the method comprises treating advanced RCC with a clear cell component in a human patient. 1. Use of a therapeutic combination for treating a patient suffering from atopic dermatitis, said therapeutic combination comprising: (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

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

[0203] In yet another embodiment, a therapeutic combination for treating recurrent RCC in a human patient is provided. The therapeutic combination comprises: (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0204] In yet another embodiment, a therapeutic combination for treating refractory RCC in a human patient is provided. The therapeutic combination comprises: (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0205] In other embodiments, a therapeutic agent for treating recurrent and refractory RCC in a human patient is provided. The use of a combination, wherein the therapeutic combination comprises: (a) PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0206] In yet another embodiment, there is provided a use of a therapeutic combination for treating cancer, comprising: The therapeutic combination is (a) PD-1 antagonist; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

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

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

[0209] In certain embodiments, the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. It is a salt that can be used.

[0210] Thus, in one embodiment, the use of a therapeutic combination to treat cancer is , the therapeutic combination comprising: (a) a human or humanized anti-human PD-1 monoclonal antibody or antigen-binding fragment thereof; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0211] In some embodiments, the use of a therapeutic combination to treat cancer, The therapeutic combination is (a) a human anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0212] In another embodiment, there is provided a use of a therapeutic combination for treating cancer, wherein said therapeutic combination The combination is: (a) a humanized anti-human PD-1 monoclonal antibody or an antigen-binding fragment thereof; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0213] In some embodiments of the various uses provided herein, an anti-PD-1 monoclonal antibody The antibody or antigen-binding fragment thereof is pembrolizumab. In some embodiments of the use, an anti-PD-1 monoclonal antibody or antigen-binding fragment thereof is nivolumab. In some embodiments of the various uses provided herein, anti-P The D-1 monoclonal antibody or antigen-binding fragment thereof is cemiplimab.

[0214] Thus, in one particular embodiment, the use of the therapeutic combination to treat cancer wherein the therapeutic combination comprises: (a) Pembrolizumab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0215] In one particular embodiment, the use of a therapeutic combination to treat cancer, The therapeutic combination is (a) Nivolumab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0216] In one particular embodiment, the use of a therapeutic combination to treat cancer, The therapeutic combination is (a) Cemiplimab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0217] In one particular embodiment, the use of the therapeutic combination to treat RCC comprises , the therapeutic combination comprising: (a) Pembrolizumab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0218] In one particular embodiment, the use of the therapeutic combination to treat RCC comprises , the therapeutic combination comprising: (a) Nivolumab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0219] In one particular embodiment, the use of the therapeutic combination to treat RCC comprises , the therapeutic combination comprising: (a) Cemiplimab; (b) velzutifan, or a pharmaceutically acceptable salt thereof; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

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

[0221] In one embodiment, the RCC is advanced RCC. In another embodiment, the RCC is clear cell In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is recurrent RCC. The CC is refractory RCC. In yet another embodiment, the RCC is relapsed and refractory RCC. is.

[0222] Several aspects of the present invention have been described. It will be understood that various modifications may be made without departing from the spirit and scope of the present invention. To the extent consistent with the description, each aspect may be combined with one or more other embodiments. It will be further understood that [Example]

[0223] I. Working Example The examples in this section (Section VI) are provided by way of illustration and not by way of limitation. There are.

[0224] [Example 1] In patients with primary (1L) advanced RCC with clear cell component (ccRCC), Administering an anti-PD-1 antibody in combination with ruzutifan (MK-6482) and lenvatinib Clinical trial (experimental group A4).

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

[0226] An ongoing randomized, single-dose, two-period, two-arm study in 16 healthy female adult volunteers. In a Phase 1 study, the PK of a single dose of 120 mg MK-6482 was The effect of food was investigated. This study showed that a high-fat, high-calorie diet did not affect the level of MK-6482 exposure. Although it had no effect on MK-6482, it reduced the maximum plasma MK-6482 concentration by approximately 35%, resulting in peak MK-6 482 demonstrated a median difference (fed minus fasted) of 2 hours delay in time to exposure. These data are not considered clinically meaningful and do not support the efficacy of MK-6 with or without food. Supporting 482 medications. The most common adverse events (AEs) reported were headache (12.5%) and ) was.

[0227] Tolerability, safety, PK and efficacy of MK-6482 in participants with various advanced solid tumors An FIH Phase 1 trial designed to evaluate the efficacy and PD characteristics is ongoing. As of September 6, dose escalation was available, ranging from 20 to 240 mg QD and 120 mg BID. A total of 10 participants, including 43 participants with various advanced solid tumors, were included in the expansion portion (Part 1A). Four participants were enrolled. The MTD was not reached and there were two treatment-related DLTs: One grade 4 thrombocytopenic event in the gQD cohort, and one grade 4 thrombocytopenic event in the 120 mg BI One grade 3 hypoxic event was observed in the D cohort. Based on kinetics and safety findings, the 120mg QD dose was selected for further clinical development The clinical dose of 120 mg QD was expanded to 52 additional participants with advanced RCC. In the large cohort (Part 1B), a combination of dose escalation and expansion cohorts was performed. The most common AEs (occurring in ≥20% of participants) were anemia, fatigue, dyspnea, nausea, and and peripheral edema. The most common grade 3 AEs were anemia and hypoxia. (More than 5% of participants). MK-6482 max The median exposure time was 1 to 2.8 hours. increased with dose. The average steady state t 1 / 2 The time was 15.4 hours, which means that there was a 1.5-fold accumulation from day 1 to day 15. Mean steady-state response in the 120 mg QD expansion cohort (Part 1B) at day 15 Condition C max The estimated CL / F was 5.2. The estimated Vz / F was 106 to 266 L, and the amount of blood entering the peripheral tissues was 2 to 14.4 L / hr. This suggests a wide distribution. max 32-59% and The C and AUC were 24-48% at steady state. max 27-56% and AUC ranged from 30 to 64%. Fifty-five participants with MK-6482 were treated with 120 mg QD in this study. (3 patients in the dose-escalation portion of the study and 52 patients in the dose-expansion portion of the study) Participants). As assessed by Solid Tumor Response Criteria v1.1, these 55 participants The best responses among those included 11 participants (20%) with PR and 10 with SD. Thirty-two participants (58%) were included.

[0228] Phase 2 open-label efficacy and safety study in participants with VHL-associated RCC is progressing As of September 6, 2019, 61 participants were enrolled at the 120 mg QD dose. Efficacy data are not yet available. Fatigue was the most common grade 3 or higher toxicity. were common AEs (reported by ≥5% of participants).

[0229] Additionally, 20 patients with ccRCC are being evaluated in a phase 2 trial, with 18 healthy subjects It is being evaluated in a Phase 1 bioavailability study in healthy adult volunteers.

[0230] Based on the data from these studies, 120 mg of MK6482, 400 mg of Pem The combination of brolizumab and 20 mg of lenvatinib was administered as first-line therapy in a To be evaluated in patients (1L) with advanced RCC with cystic component (ccRCC).

[0231] The primary objective of this study is to evaluate the efficacy and safety of MK6482, pembromodiazole, in patients with advanced ccRCC. The safety, tolerability, and antitumor efficacy of the combination of lizumab and lenvatinib were evaluated. In this study, ORR will be used as the primary efficacy endpoint. is a confirmed CR by Solid Tumor Response Criteria 1.1 as assessed by BICR Response is defined as the proportion of participants achieving a PR or PR. and Solid Cancer Response Criteria modified to track up to five target lesions per organ. Based on BICR using 1.1. ORR evaluates the antitumor activity of the reference and experimental arms. The treatment effect measured by ORR is a measure of the efficacy of a given disease, Use status, magnitude of effect, number of CRs, durability of response, disease status, tumor location, availability can express direct clinical benefit based on available treatments and risk-benefit relationships .

[0232] Secondary objectives include evaluating DOR, PFS, OS, and CBR as secondary efficacy endpoints. "DOR" is the first documented evidence of a CR or PR that has led to the diagnosis of a disease. Defined as the time to disease progression or death from any cause, whichever occurs first. Up to 10 target lesions and up to 5 target diseases per organ, as assessed by BICR DOR according to the Solid Tumor Response Evaluation Criteria 1.1, modified to track changes in It serves as a benchmark for clinical outcomes and is generally accepted by both regulatory agencies and the oncology community. "PFS" is the endpoint for progression-free survival (PFS) measured by BICR from the date of randomization. First documented PD or death from any cause according to efficacy criterion 1.1 This is defined as the time to either the first or second dose, whichever comes first. To minimize this, images are read by BICR. PFS events reflect tumor growth. This can be assessed before determining survival benefit, which can be assessed by subsequent treatment. Treatment efficacy as measured by PFS is not affected by the specific disease, setting of use, or , magnitude of effect, disease status, location of metastatic sites, available treatments, risk-benefit relationships, and and slowing or preventing progression at key disease sites (e.g., in the brain or spine). delaying the development of new lesions in the setting of steroid therapy or delaying the administration of more toxic treatments It may be a surrogate endpoint for direct clinical benefit based on clinical outcomes. "S" is a goal to demonstrate the superiority of new anti-neoplastic therapies in randomized clinical trials. OS is the number of deaths from any cause from the date of randomization. "CBR" is defined as the time to the date of death. This is a secondary endpoint, and is based on the Solid Tumor Response Evaluation Criteria 1.1. Participants who achieved SD for 6 months or more, or CR or PR based on ICR assessment It is defined as the proportion of people

[0233] The tertiary / exploratory objectives of this study include correlation between tumor size change and DOR, PFS and OS. Evaluation of the pharmacokinetic (PK) profile of the investigational drug and characteristics of anti-drug antibody (ADA) formation and study treatment combinations with pembrolizumab, lenvatinib, and MK6482 Molecules (genomic, metabolic, etc.) that may demonstrate combined clinical response / tolerance, safety, and / or mechanism of action and / or proteomic biomarkers. The change is an exploratory efficacy endpoint and is a proposed test that may detect signals of early antitumor activity. The interim endpoint was the sum and baseline of the longest diameter target lesions at each post-baseline assessment. It is defined as the change (and % change) from baseline.

[0234] Advanced ccR with no prior systemic treatment for advanced disease (1L RCC) Male and female patients with CC who are at least 18 years old will be enrolled in this study. Locally advanced / metastatic ccRCC (with or without sarcomatoid features), i.e. Must have a histologically confirmed diagnosis of stage IV RCC by AJCC Patients must not have received prior systemic treatment for advanced RCC. , measurable disease by Solid Tumor Response Criteria 1.1 as assessed by BICR must have it.

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

[0236] [Table 4]

[0237] [Table 5]

[0238] [Table 6]

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

[0240] In this example, we investigated the effects of anti-PD-1 mouse surrogate antibody (muDX400) and V Lenvatinib, an EGF tyrosine kinase inhibitor, was administered in combination with MK-6, an HIF-2α inhibitor. To demonstrate the antitumor benefit from combining 482 with VHL-bearing mice, Preclinical data using syngeneic pancreatic tumor models are provided.

[0241] Before the start of the procedure, 7-week-old female C57BL / 6J mice weighing 18–21 grams were anesthetized. 0.5×10 6 Log-phase subconfluent KPC-2838c3 cells were injected into the posterior flank. The average tumor volume of the inoculated animals was approximately 95 mm 3 Ten days after reaching this point, Mice were matched into eight treatment groups of 10 mice per group. Treatment groups consisted of: 1) 0.5% methylcellulose (vehicle) + isotype mouse 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) Re 6) MK-6482 + lenvatinib; 7) MK-6482 + lenvatinib; 8) MK-6482 + lenvatinib Vehicle and MK-6482 were administered twice daily at 3 mg / kg body weight. Lenvatinib was administered by oral gavage once daily (QD) at 10 mg / kg body weight. ) were orally administered. A mouse monoclonal antibody specific for PD-1 and an anti-PD-1 antibody were administered at a dose of 10 mg / kg. The dose was administered intraperitoneally every 5 days at a dose of 0.001 mg / kg / day. The start of treatment was considered as day 0, and the administration was based on the schedule. Drugs were continued as described until day 45. Caliper measurements of tumors and body weights were taken twice weekly. Statistical analysis was performed using Tukey's multiple comparison test at designated time points when treatment groups reached the endpoint. The results were analyzed by one-way ANOVA.

[0242] Triple combination treatment with MK-6482, anti-PD-1, and lenvatinib demonstrated significant antitumor effects The tumor response (Figure 2A) was demonstrated, with one complete response and one partial response with no measurable tumor remaining. Complete and partial tumor regression was observed (Fig. 2B). The mean antitumor response of the triple combination treatment was 1.0% in the MK-6482 group. Antitumor responses observed with either monotherapy, anti-PD-1 monotherapy, or vehicle control The triple combination group also showed a greater improvement in serotoninib-dependent progression than lenvatinib alone (p<0.0001, day 24). The mean improvement was significantly greater than that of the triple combination (p=0.0002, day 45). The overall antitumor response was improved compared to MK-6482 plus anti-PD-1 (p<0.0001, Day 31), lenvatinib + anti-PD-1 (p=0.247, Day 45) or lenvatinib The improvement was not greater than that seen with MK-6482 (p=0.404, day 45). Summary of tumor growth inhibition (TGI) and partial tumor growth at the end of the study for the vehicle-treated group. Observations of tumor regression (PR) or complete tumor regression (CR) are shown in the table below:

[0243] [Table 7]

[0244] CR was defined as the absence of observable tumor, whereas PR was defined as the time treatment was initiated. The tumor volume was smaller than the original tumor size. No significant weight loss or adverse events were observed in any of the animals, and treatment was well tolerated. This shows that...

[0245] As demonstrated by the studies above, treatment with a combination of therapeutic agents is more effective than treatment with a single agent. This is advantageous over treatment with each drug when

[0246] II. SEQUENCE LISTING The table below summarizes all the sequences disclosed herein.

[0247]

Table 8

Claims

1. 1. A method of treating cancer or von Hippel-Lindau disease, comprising: to a human patient in need of treatment for 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 administering The method, wherein the PD-1 antagonist is not atezolizumab.

2. The cancer is bladder cancer, breast cancer, non-small cell lung cancer, colorectal cancer, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), or bladder cancer.

10. The method of claim 1, wherein the cancer is selected from the group consisting of carcinoma, pancreatic cancer, and melanoma.

3. The method of claim 2, wherein the cancer is RCC.

4. 4. The method of claim 3, wherein the RCC is advanced RCC.

5. The method according to claim 4, wherein the RCC is advanced RCC with clear cell component (ccRCC). How to post.

6. 5. The human patient has not received prior systemic treatment for advanced disease. The method described below.

7. The method of claim 3, wherein the RCC is metastatic RCC.

8. The method of claim 2 , wherein the cancer is pancreatic cancer.

9. (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Equipped with The PD-1 antagonist is not atezolizumab, kit.

10. the PD-1 antagonist, the HIF-2α inhibitor and lenvatinib, or 9. The method of claim 8, further comprising administering the pharmaceutically acceptable salt of The kit according to claim 1.

11. Therapeutic combinations for treating cancer or von Hippel-Lindau disease in human patients The use of a combination of: (a) a PD-1 antagonist; (b) a HIF-2α inhibitor; and (c) lenvatinib or a pharmaceutically acceptable salt thereof Including, The PD-1 antagonist is not atezolizumab.

12. The cancer is bladder cancer, breast cancer, non-small cell lung cancer, colorectal cancer, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), or bladder cancer.

12. The use according to claim 11, wherein the cancer is selected from the group consisting of carcinoma, pancreatic cancer and melanoma.

13. The use according to claim 12, wherein the cancer is RCC.

14. 14. The use of claim 13, wherein the RCC is advanced RCC.

15. 15. The method of claim 14, wherein the RCC is advanced RCC with clear cell component (ccRCC). Use as described.

16. 10. The human patient has not received prior systemic treatment for advanced disease.

5. Use according to claim 5.

17. 17. The use of claim 16, wherein the RCC is metastatic RCC.

18. The use according to claim 12, wherein the cancer is pancreatic cancer.

19. The PD-1 antagonist is an anti-human PD-1 monoclonal antibody or its antigen binding molecule. The method, kit or use according to any one of claims 1 to 18, wherein the fragment is a combination fragment.

20. The PD-1 antagonist is an anti-human PD-L1 monoclonal antibody or an antigen thereof. The method, kit or use according to any one of claims 1 to 18, which is a binding fragment.

21. 20. The method of claim 19, wherein the anti-human PD-1 monoclonal antibody is a humanized antibody. , kit or use.

22. 20. The method of claim 19, wherein the anti-human PD-1 monoclonal antibody is a human antibody. Kit or use.

23. the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof; The method, kit or use according to any one of claims 1 to 18.

24. The anti-human PD-1 monoclonal antibody is selected from the group consisting of pembrolizumab, nivolumab, and cempirumab. from the group consisting of imabu, sintilimab, tislelizumab, camrelizumab, and toripalimab 20. The method, kit or use of claim 19, wherein the method, kit or use is selected from the group consisting of:

25. The method of claim 24, wherein the anti-human PD-1 monoclonal antibody is pembrolizumab. Methods, kits or uses of.

26. 25. The method of claim 24, wherein the anti-human PD-1 monoclonal antibody is nivolumab. , kit or use.

27. The method of claim 24, wherein the anti-human PD-1 monoclonal antibody is cemiplimab. Method, kit or use.

28. (a) the PD-1 antagonist is pembrolizumab; and (b) The HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. The method, kit or use according to any one of claims 1 to 18.

29. (a) the PD-1 antagonist is nivolumab; and (b) The HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. The method, kit or use according to any one of claims 1 to 18.

30. (a) the PD-1 antagonist is cemiplimab; and (b) The HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof. The method, kit or use according to any one of claims 1 to 18.

31. The human patient received 200 mg, 240 mg, or 2 mg / kg of pembrolizumab.

29. The method of claim 28, wherein pembrolizumab is administered once every three weeks.

32. The human patient is administered 400 mg of pembrolizumab, and the pembrolizumab is administered for 6 weeks.

29. The method of claim 28, wherein the dose is administered once per day.

33. The human patient receives 240 mg or 3 mg / kg of nivolumab once every two weeks; or 480 mg of nivolumab administered once every four weeks. 。

34. The human patient is administered 350 mg of cemiplimab, the cemiplimab being administered once every three weeks.

31. The method of claim 30, wherein the dose is administered once.

35. The human patient is administered about 40 mg to about 120 mg of belzutifan, 35. The method of any one of claims 31 to 34, wherein the compound is administered once daily.

36. The human patient is administered 40, 80 or 120 mg of velzutifan, 36. The method of claim 35, wherein the fan is administered once daily.

37. 37. The method of claim 36, wherein the human patient is administered 120 mg of belzutifan.

38. The human patient is administered 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib. and lenvatinib is administered once daily. method.

39. 1. A method of treating RCC comprising administering to a human patient in need thereof: (a) 200 mg pembrolizumab; (b) 120 mg of velzutifan or a pharmaceutically acceptable salt thereof; and (c) 20 mg of lenvatinib The method of claim 1, wherein the

40. 40. The method of claim 39, wherein pembrolizumab is administered once every three weeks.

41. 40. The method of claim 39, wherein (b) and (c) are administered once daily.

42. (a), (b) and (c) are administered on the same day, and (a), (b) and (c) are administered sequentially.

40. The method of claim 39, wherein the administration is to or simultaneously with

43. 43. The compound according to claim 1, wherein the pharmaceutically acceptable salt thereof is lenvatinib mesylate.

10. The method, kit or use according to any one of claims 1 to 9.

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