Methods for treating cancer or von Hippel-Lindau disease using a combination of a HIF-2α inhibitor and lenvatinib

Abstract

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

Description

[Technical Field]

[0001] Provided herein are methods for treating cancer (e.g., renal cell carcinoma (RCC)) or von Hippel-Lindau disease using a combination of (a) a hypoxia-inducible factor 2α (HIF-2α) inhibitor and (b) lenvatinib, or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Intratumor hypoxia is a driving force for cancer progression and is closely associated with poor patient prognosis and resistance to chemotherapy and radiation treatment. Hypoxia-inducible factors (HIF-1α and HIF-2α) are transcription factors that play a central role in the hypoxia response pathway. Under normoxic conditions, the tumor suppressor von Hippel-Lindau (VHL) protein binds to specific hydroxylated proline residues and recruits an E3 ubiquitin ligase complex that targets HIF-α proteins for proteasomal degradation. Under hypoxic conditions, HIF-α proteins accumulate and enter the nucleus, stimulating the expression of genes that regulate anaerobic metabolism, angiogenesis, cell proliferation, cell survival, extracellular matrix remodeling, pH homeostasis, amino acid and nucleotide metabolism, and genomic instability. VHL deficiency can also result in accumulated HIF expression under oxygenated conditions (pseudohypoxic conditions). Therefore, directly targeting the HIF-α protein offers a great opportunity to attack tumors on multiple fronts (Keith, et al., Nature Rev. Cancer 12:9-22, 2012). Specifically, HIF-2α is a key tumorigenic driver in clear cell renal cell carcinoma (ccRCC) (Kondo, K., et al., Cancer Cell, 1:237-246 (2002); Maranchie, J., et al., Cancer Cell, 1:247-255 (2002); Kondo, K., et al., PLoS Biol., 1:439-444 (2003)). In a murine ccRCC tumor model, knockdown of HIF-2α expression in pVHL (von Hippel-Lindau protein)-deficient cell lines inhibited tumor growth equivalent to reintroduction of pVHL. Furthermore, expression of a stabilized mutant form of HIF-2α was able to overcome the tumor-suppressive role of pVHL. Belzutifan, a novel HIF-2α inhibitor with excellent in vitro potency, pharmacokinetic profile, and in vivo efficacy in mouse models, has shown promising results in patients with advanced renal cell carcinoma (Xu, Rui, et al., J. Med. Chem. 62:6876-6893 (2019)).

[0003] Von Hippel-Lindau disease (VHL disease) is an autosomal dominant syndrome that predisposes patients to kidney cancer (approximately 70% lifetime risk) as well as hemangioblastoma, pheochromocytoma, and pancreatic neuroendocrine tumors. VHL disease results in tumors with constitutively active HIF-α protein, the majority of which are dependent on HIF-2α activity (Maher, et al. Eur. J. Hum. Genet. 19:617-623, 2011). HIF-2α has been linked to cancers of the retina, adrenal gland, and pancreas, both through VHL disease and activating mutations. Recently, HIF-2α gain-of-function mutations have been identified in erythrocytosis and paraganglioma with erythrocytosis (Zhuang, et al. NEJM 367:922-930, 2012; Percy, et al. NEJM 358:162-168, 2008; and Percy, et al. Am.J.Hematol.87:439-442, 2012).Notably, some known HIF-2α-target gene products (such as VEGF, PDGF, and cyclin D1) have been shown to play a crucial role in kidney, liver, colon, lung, and brain cancers.In fact, therapies targeting VEGF, one of the key HIF-2α-regulated gene products, have been approved for the treatment of these cancers.

[0004] Tyrosine kinases are involved in regulating growth factor signaling and are therefore important targets for cancer therapy. Lenvatinib is a multi-RTK inhibitor that selectively inhibits the kinase activity of vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4)) and fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, as well as other RTKs involved in proangiogenic and oncogenic pathways involved in tumor growth, including the platelet-derived growth factor (PDGF) receptor PDGFRα; KIT; and RET proto-oncogene (RET). Specifically, lenvatinib possesses a novel binding mode (V-type) for VEGFR2, as confirmed by X-ray crystallography, and kinetic analysis demonstrates rapid and potent inhibition of its kinase activity.

[0005] The hypoxic response leads to the upregulation of genes that promote angiogenesis and angiogenic responses, increasing oxygen delivery. This includes the transcriptional activation of vascular endothelial growth factor (VEGF), which can regulate several endothelial cell responses, such as activation and proliferation. VEGF tyrosine kinase can systemically block VEGF receptor signaling, while HIF-2α inhibition can block tumor VEGFA expression and secretion. The combination of VEGF TKIs and HIF-2α inhibitors allows for independent inhibition of VEGFA secretion and signaling without overlapping toxicity. Furthermore, HIF-2α inhibition can suppress VEGF TKI-induced HIF-2α activity and antiangiogenic resistance. D.Shweiki,A.Itin,D.Soffer,E.Keshet.Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis.Nature,359(1992),pp.843-845;JAForsythe,BHJiang,NVIyer,F.Agani,SWLeung,RDKoos,GLSemenza.Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol,16(1996),pp.4604-4613;Hypoxic stress:obstacles and opportunities for innovative immunotherapy of cancer.Chouaib S,Noman MZ,Kosmatopoulos K,Curran MA.Oncogene.2017 Jan 26;36(4):439-445.doi:10.1038 / onc.2016.225.Epub 2016 Jun 27.

[0006] Recent advances have been made in the treatment of first-line (1L) advanced RCC with combinations of immunomodulatory agents and / or VEGF-TKI(s), and multiple agents are now available for the treatment of patients with second-line (2L) RCC. However, existing data indicate that few patients experience complete remission with these agents, and nearly all progress. While these significant advances have led to a change in the treatment paradigm for these patients, there remains an unmet need to improve outcomes for both the 1L and 2L+ advanced RCC populations. Currently, there is no standard of care (SOC) for post-PD-(L)1 inhibitor / post-VEGF-TKI 2L+ advanced RCC, and no large-scale randomized clinical trials exist in this setting.

[0007] Several drugs are currently available for 2L+ treatment in patients with advanced RCC, including nivolumab, cabozantinib, and lenvatinib in combination with everolimus. Since the RECORD1 trial in 2008, these agents have demonstrated benefits in terms of treatment outcomes compared with single-agent everolimus, previously the standard 2L treatment for advanced RCC. It is noteworthy that all of these studies were conducted at a time when the standard of care for 1L advanced ccRCC was VEGF-TKIs. No clinical studies have been conducted to date to investigate subsequent treatment options after 1L treatment with IO / VEGF-TKIs in combination or sequentially. As a result, there is no standard of care (SOC) for patients with 2L+ post-PD-(L)1 inhibitor / post-VEGF-TKI advanced RCC, and there remains an unmet need to improve treatment outcomes in this population. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Keith,et al.,Nature Rev. Cancer 12:9-22,2012 [Non-patent document 2] Kondo,K.,et al.,Cancer Cell,1:237-246(2002)

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[0009] The present disclosure provides methods of treating cancer (e.g., RCC) or von Hippel-Lindau disease using a combination of a HIF-2α inhibitor and lenvatinib, or a pharmaceutically acceptable salt thereof.

[0010] The present disclosure further provides a kit comprising a HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof.

[0011] Also provided herein is the use of a therapeutic combination for treating cancer (e.g., RCC) or von Hippel-Lindau disease, wherein the therapeutic combination comprises a HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, a method of treating cancer or von Hippel-Lindau disease comprises administering to a human patient in need of treatment for cancer or von Hippel-Lindau disease: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0013] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma.

[0014] 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 both recurrent and refractory.

[0015] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is melanoma.

[0016] In one embodiment, the cancer is advanced RCC. In another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. In yet another embodiment, the cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC. In yet another embodiment, the cancer is VHL-deficient RCC.

[0017] In another aspect, (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Provided herein is a kit comprising:

[0018] In certain embodiments, the kit further comprises instructions for administering the HIF-2α inhibitor and lenvatinib, or a pharmaceutically acceptable salt thereof, to a human patient.

[0019] In yet another aspect, there is provided a use of a therapeutic combination to treat cancer in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0020] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma.

[0021] 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 both recurrent and refractory. In yet another embodiment, the cancer is VHL-deficient RCC.

[0022] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is melanoma.

[0023] In one embodiment, the cancer is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component (ccRCC). In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. In yet another embodiment, the cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC. In yet another embodiment, the cancer is VHL-deficient RCC.

[0024] In one embodiment, the human patient has failed other treatments. In another embodiment, the human patient has advanced RCC with a clear cell component (ccRCC) and has experienced disease progression (2L+RCC) during or after systemic treatment for advanced disease with a PD-(L)1 checkpoint inhibitor and a VEGF-TKI.

[0025] In certain embodiments of the various methods, kits, or uses provided herein, the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof.

[0026] In yet another embodiment of the various methods, kits, or uses provided herein, lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate. Capsules for oral administration contain 4 mg or 10 mg of lenvatinib, corresponding to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively. In another embodiment, when a pharmaceutically acceptable salt of lenvatinib, such as lenvatinib mesylate, is administered and the dose of lenvatinib to be used is 4 mg, a healthcare professional will know to administer 4.90 mg of lenvatinib mesylate. In another embodiment, when a pharmaceutically acceptable salt of lenvatinib, such as lenvatinib mesylate, is administered and the dose of lenvatinib to be used is 10 mg, a healthcare professional will know to administer 12.25 mg of lenvatinib mesylate. In other embodiments of the various methods described herein, the human patient is administered 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib once daily.

[0027] In various embodiments of the methods described herein, the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof, and the human patient is administered about 40 mg to about 120 mg of velzutifan daily. In some embodiments, the human patient is administered 40, 80, or 120 mg of velzutifan once daily. In one specific embodiment, the human patient is administered 40 mg of velzutifan once daily. In another specific embodiment, the human patient is administered 80 mg of velzutifan once daily. In another specific embodiment, the human patient is administered 120 mg of velzutifan once daily.

[0028] Thus, in some embodiments, the human patient: (a) 40, 80, or 120 mg of belzutifan once daily; and (b) lenvatinib at 8, 10, 12, 14, 18, 20, or 24 mg once daily is administered.

[0029] In one embodiment, the human patient: (a) 120 mg of belzutifan once daily; and (b) 20 mg of lenvatinib once daily is administered.

[0030] In certain embodiments, a method of treating RCC comprises administering to a human patient in need of treatment for RCC: (a) 120 mg of belzutifan once daily; and (b) 20 mg of lenvatinib once daily Provided herein are methods comprising administering

[0031] In some embodiments of such methods, the HIF-2α inhibitor and lenvatinib are administered on the same day. In some embodiments, the HIF-2α inhibitor and lenvatinib are administered sequentially. In other embodiments, the HIF-2α inhibitor and lenvatinib are administered simultaneously.

[0032] In some embodiments of the various methods, kits, or uses described herein, a pharmaceutically acceptable salt of lenvatinib, lenvatinib mesylate, can be used. When lenvatinib mesylate is used, the dosage of lenvatinib mesylate is appropriately adjusted to provide a mole of lenvatinib equivalent to that provided by 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib. [Brief explanation of the drawings]

[0033] [Figure 1] Figure 1 shows the schematic design of a phase 1b / 2 study of velzutifan (MK-6482) (experimental arm B5) in combination with lenvatinib in patients with advanced RCC (ccRCC) with a clear cell component after second-line plus (2L+) programmed cell death 1 / programmed cell death ligand 1 (PD-[L]1) inhibitor / vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). [Figure 2A]Figure 2A shows the antitumor effect of co-administration of lenvatinib and a 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 co-administration of lenvatinib and a HIF-2a inhibitor (MK-6482), as indicated by the mean tumor volume in each individual growth curve for each group. Experimental details are described in Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0034] 1.Definition Certain technical and scientific terms are specifically defined below. Unless specifically defined elsewhere herein, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art.

[0035] "About," when used to modify a numerically defined parameter (e.g., the dose of an anti-PD-1 antibody or antigen-binding fragment thereof, a HIF-2α inhibitor or antigen-binding fragment thereof, or lenvatinib, or the length of treatment time with a combination therapy described herein), means that the parameter is within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the stated numerical value or range for that parameter, and, where appropriate, the stated parameter may be rounded to the nearest integer. For example, a dose of approximately 5 mg / kg may vary between 4.5 mg / kg and 5.5 mg / kg.

[0036] As used in this specification, including the appended claims, the singular forms of words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0037] The term "administration" or "administering" refers to the act of injecting or otherwise physically delivering a substance to a patient when the substance is present outside the body (e.g., a HIF-2α inhibitor and lenvatinib as described herein), such as by oral, mucosal, intradermal, intravenous, subcutaneous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art.

[0038] "HIF-2α inhibitor" refers to any chemical compound or biological molecule that inhibits the activity of HIF-2α. Alternative names or synonyms for HIF-2α include, but are not limited to, hypoxia-inducible factor-2α, endothelial PAS domain-containing protein 1, and EPAS1.

[0039] As used herein, the terms "at least one" or "one or more" items each include a single item selected from a list and a mixture of two or more items selected from a list.

[0040] As used herein, the term "immune response" relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non-specific responses, innate response, primary immune response, adaptive immunity, secondary immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression.

[0041] The term "subject" (or "patient"), as used herein, refers to a mammal that has been the object of treatment, observation, or experiment. The mammal may be male or female. The mammal may be one or more selected from the group consisting of humans, bovines (e.g., dairy cows), porcines (e.g., pigs), ovines (e.g., sheep), caprines (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), and Procyon lotor (e.g., raccoons). In certain embodiments, the subject is a human.

[0042] As used herein, the term "subject in need" refers to a subject diagnosed with or suspected of having cancer or an infectious disease as defined herein.

[0043] Therapeutic agents and compositions provided by the present disclosure can be administered via any suitable enteral or parenteral route of administration. The term "enteral route" of administration refers to administration via any part of the digestive tract. Examples of enteral routes include oral, mucosal, buccal, and rectal routes, or intragastric routes. "Parenteral route" of administration refers to a route of administration other than enteral routes. Examples of parenteral routes of administration include intravenous, intramuscular, intradermal, intraperitoneal, intratumoral, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal, subcutaneous, or topical administration. Therapeutic agents and compositions of the present disclosure can be administered using any suitable method, such as oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump. The appropriate route and method of administration may vary depending on several factors, such as the particular therapeutic agent being used, the desired rate of absorption, the particular formulation or dosage form being used, the type or severity of the disorder being treated, the particular site of action, and the condition of the patient, and may be readily selected by one of ordinary skill in the art.

[0044] As used herein, "Solid Tumor Response Criteria 1.1 Response Criteria" means the definitions set forth in Eisenhauer, E. A. et al., Eur. J. Cancer 45:228-247 (2009) for target lesions or non-target lesions, as appropriate, based on the context in which response is being measured.

[0045] "Sustained response" means a sustained therapeutic effect after cessation of treatment as described herein. In some embodiments, a sustained response has a duration at least equal to the treatment period, or at least 1.5, 2.0, 2.5, or 3 times longer than the treatment period.

[0046] As used herein, "treating" or "treating" cancer refers to administering a therapeutic combination of a HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof to a subject with or diagnosed with cancer to achieve at least one positive therapeutic effect, such as a reduced number of cancer cells, a reduced tumor size, a reduced rate of cancer cell infiltration into peripheral organs, or a reduced rate of tumor metastasis or tumor growth. Such "treatment" may result in slowing, interrupting, suppressing, controlling, or stopping the progression of cancer as described herein, but does not necessarily indicate the complete elimination of cancer or cancer symptoms. Positive therapeutic effects in cancer can be measured in several ways (see W.A. Weber, J. Nucl. Med. 50:1S-10S (2009)). For example, with regard to tumor growth inhibition, according to NCI standards, T / C≦42% is the minimum level of antitumor activity. A T / C < 10% is considered a high level of anti-tumor activity, where T / C (%) = median tumor volume of treated / median tumor volume of control × 100. In some embodiments, the treatment achieved by the combination therapy of the present disclosure is any of PR, CR, OR, PFS, DFS, and OS. PFS, also known as "time to tumor progression," refers to the length of time during and after treatment during which cancer does not grow, including the length of time a patient experiences CR or PR, as well as the length of time a patient experiences SD. DFS refers to the length of time a patient remains disease-free during and after treatment. OS refers to the extension of life expectancy compared to an untreated or untreated individual or patient. In some embodiments, the response to the combination therapy of the present disclosure is any of PR, CR, PFS, DFS, or OR, as assessed using the Solid Tumor Response Criteria 1.1 response criteria. The treatment regimen for the combination therapy of the present disclosure that is effective in treating cancer patients can vary depending on factors such as the patient's condition, age, and weight, as well as the ability of the therapy to induce an anti-cancer response in the subject.Any embodiment of the aspects of the present disclosure may not be effective in achieving a positive therapeutic effect in all subjects, but should achieve a positive therapeutic effect in a statistically significant number of subjects as determined by any statistical test known in the art, such as Student's t-test, chi-squared test, Mann-Whitney U test, Kruskal-Wallis test (H test), Joncke-Therapstra test, and Wilcoxon test.

[0047] As used herein, the terms "combination," "combination therapy," and "therapeutic combination" refer to treatment in which at least one HIF-2α inhibitor, lenvatinib or a pharmaceutically acceptable salt thereof, and optionally additional therapeutic agents are administered to a patient in a coordinated manner over overlapping periods. The period of treatment with a HIF-2α inhibitor ("HIF-2α inhibitor treatment") is the period during which a patient receives treatment with a HIF-2α inhibitor, i.e., the period from the first administration of the HIF-2α inhibitor to the last day of the treatment cycle. The period of treatment with lenvatinib or a pharmaceutically acceptable salt thereof ("lenvatinib treatment") is the period during which a patient receives treatment with lenvatinib, i.e., the period from the first administration of lenvatinib to the last day of the treatment cycle. In the methods and therapeutic combinations described herein, the HIF-2α inhibitor treatment overlaps with the lenvatinib treatment for at least one day. In some embodiments, the HIF-2α inhibitor treatment and the lenvatinib treatment are for the same period. In some embodiments, the HIF-2α inhibitor treatment begins before the lenvatinib treatment. In other embodiments, the HIF-2α inhibitor treatment begins after the lenvatinib treatment. In some embodiments, the HIF-2α inhibitor treatment ends before the end of the lenvatinib treatment. In some embodiments, the lenvatinib treatment ends before the end of the HIF-2α inhibitor treatment.

[0048] The terms "treatment regimen," "dosing protocol," and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each therapeutic agent in the combination therapy of the present disclosure.

[0049] "Tumor," when applied to a subject diagnosed with or suspected of having cancer, refers to a malignant or potentially malignant neoplasm or tissue mass of any size, including primary tumors and secondary neoplasms. Non-limiting examples of tumors include solid tumors (e.g., sarcomas (e.g., chondrosarcoma), carcinomas (e.g., colon carcinoma), blastomas (e.g., hepatoblastoma), etc.) and hematologic tumors (e.g., leukemias (e.g., acute myeloid leukemia (AML)), lymphomas (e.g., DLBCL), multiple myeloma (MM), etc.).

[0050] The term " tumor volume " or " tumor size " refers to the total size of a tumor, which can be measured as the length and width of the tumor.Tumor size can be determined by various methods known in the art, for example, by measuring the size of tumor(s) when removed from the subject, for example, using a caliper, or by measuring the size of tumor(s) while it is in the body, using imaging technology, for example, bone scan, ultrasound, CT or MRI scan.

[0051] Unless expressly stated to the contrary, all ranges cited herein are inclusive, i.e., include the upper and lower limits of the range, as well as all values ​​therebetween. For example, temperature ranges, percentages, equivalent ranges, and the like described herein include the upper and lower limits of the range, as well as any continuous transitions therebetween. Numerical values ​​provided herein, and the use of the term "about" may include variations of ±1%, ±2%, ±3%, ±4%, ±5%, ±10%, ±15%, and ±20%, and their numerical equivalents. Although not always explicitly stated, all ranges are also intended to include all subranges encompassed therein. For example, a range of 3 to 7 days is intended to include 3, 4, 5, 6, and 7 days. Furthermore, as used herein, the term "or" indicates alternatives that may be combined, where appropriate; i.e., the term "or" includes each listed alternative individually as well as combinations thereof.

[0052] When aspects or embodiments of the present disclosure are described in terms of a Markush group or other grouping of alternatives, the present disclosure encompasses not only the entire group listed as a whole, but also each member of the group individually and all possible subgroups of the main group, including the main group in which one or more of the group members are absent. The present disclosure also envisions the explicit exclusion of one or more of any group members in the claims.

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of conflict, the present specification, including definitions, will control. Throughout this specification and claims, the word "comprise" or variations such as "comprises" or "comprising" are understood to mean the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. Unless otherwise required by context, singular terms shall include the plural, and plural terms shall include the singular. Any example(s) following the term "eg" or "for example" are not meant to be exhaustive or limiting.

[0054] Although exemplary methods and materials are described herein, methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0055] 2.HIF-2α inhibitors Provided herein are HIF-2α inhibitors that can be used in the various methods, kits and uses disclosed herein, including any chemical compound or biological molecule that inhibits the activity of HIF-2α.

[0056] In some embodiments, the HIF-2α inhibitor is velzutifan, also known as MK-6482, PT2977, 3-[(1S,2S,3R)-2,3-difluoro-1-hydroxy-7-methylsulfonyl-indan-4-yl]oxy-5-fluoro-benzonitrile, and 3-[[(1S,2S,3R)-2,3-difluoro-2,3-dihydro-1-hydroxy-7-(methylsulfonyl)-1H-inden-4-yl]oxy]-5-fluorobenzonitrile, or a pharmaceutically acceptable salt thereof, and has the following chemical structure: [ka]

[0057] Belzutifan and its synthesis are described in U.S. Patent No. 9,969,689, which is incorporated herein by reference in its entirety. Belzutifan as a potential treatment for clear cell renal cell carcinoma is described in Rui Xu et al., J. Med. Chem. 2019, 62, 6876-6893, which is incorporated herein by reference in its entirety. The combination of a PD-1 / CTLA-4 inhibitor with a HIF-2α inhibitor for treating melanoma, RCC, or CRC is described in U.S. Patent No. 10,335,388, which is incorporated herein by reference in its entirety. U.S. Patent Application Publication No. 2018-0042884 describes the treatment of glioblastoma with HIF-2α inhibitors, which is incorporated herein by reference in its entirety. Oral formulations of belzutifan are described in International Application No. PCT / US2019 / 57725, filed October 23, 2019, which is incorporated herein by reference in its entirety.

[0058] 3. Lenvatinib Also provided herein is lenvatinib, a multiple RTK (multi-RTK) inhibitor that selectively inhibits the kinase activity of VEGF receptors.

[0059] Lenvatinib is also known as LENVIMA®, Eisai Inc., Woodcliff Lake, NJ, and 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, and has the following chemical structure: [ka]

[0060] Levatinib, its synthesis and uses are described in U.S. Patent Nos. 7,253,286; 7,612,208; 9,006,256; 10,259,791; and 10,407,393, which are incorporated by reference in their entireties.

[0061] 4. A method for treating cancer using a combination of a HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof In another aspect, provided herein are methods of treating cancer (e.g., RCC) using a combination of a HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof as described.

[0062] In some embodiments, the method of treating cancer comprises administering to a human patient in need of cancer treatment: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0063] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma.

[0064] 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 both recurrent and refractory.

[0065] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is melanoma.

[0066] In one embodiment, the cancer is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component (ccRCC). In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. In yet another embodiment, the cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC. In yet another embodiment, the cancer is VHL-deficient RCC.

[0067] In one embodiment, the human patient has failed other treatments. In another embodiment, the human patient has advanced RCC with a clear cell component (ccRCC) and has experienced disease progression (2L+RCC) during or after systemic treatment for advanced disease with a PD-(L)1 checkpoint inhibitor and a VEGF-TKI.

[0068] In one embodiment, a method of treating RCC comprises administering to a human patient in need of treatment for RCC: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0069] In some embodiments, the method of treating advanced RCC comprises administering to a human patient in need thereof: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0070] In some embodiments, the method of treating advanced RCC with a clear cell component comprises administering to a human patient in need of treatment for advanced RCC with a clear cell component: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0071] In other embodiments, the method of treating metastatic RCC comprises administering to a human patient in need of treatment for metastatic RCC: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0072] In yet another embodiment, a method of treating recurrent RCC comprises administering to a human patient in need thereof: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0073] In yet another embodiment, a method of treating refractory RCC comprises administering to a human patient in need of treatment for refractory RCC: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0074] In other embodiments, a method of treating relapsed and refractory RCC comprises administering to a human patient in need thereof: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0075] In another embodiment, a method of treating VHL-deficient RCC comprises administering to a human patient in need of treatment for VHL-deficient RCC: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof

[0013] Methods are provided herein that include administering

[0076] In some embodiments, the method of treating cancer comprises administering to a human patient in need of cancer treatment: (a) velzutifan, or a pharmaceutically acceptable salt thereof; and (b) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0077] In one particular embodiment of the various methods provided herein, the method for treating RCC comprises administering to a human patient in need of treatment for RCC: (a) velzutifan, or a pharmaceutically acceptable salt thereof; and (b) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0078] In one embodiment, the RCC is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component. In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is recurrent RCC. In yet another embodiment, the RCC is refractory RCC. In yet another embodiment, the RCC is recurrent and refractory RCC. In yet another embodiment, the RCC is VHL-deficient RCC.

[0079] In one aspect, the present invention provides a method of treating von Hippel-Lindau (VHL) disease, comprising administering to a human patient in need of treatment for von Hippel-Lindau (VHL) disease: (a) a HIF-2α inhibitor (e.g., velzutifan or a pharmaceutically acceptable salt thereof); and (b) lenvatinib or a pharmaceutically acceptable salt thereof The method includes administering

[0080] 5. Medication and Administration Further provided herein are dosing regimens and routes of administration for treating cancer (e.g., RCC) or von Hippel-Lindau (VHL) disease using a combination of a HIF-2α inhibitor and a multi-RTK inhibitor (e.g., lenvatinib or a pharmaceutically acceptable salt thereof).

[0081] The HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof disclosed herein, can be administered, for example, at a dose administered daily, 1 to 7 times per week, weekly, every other week, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, monthly, every other month, every 3 months, every 6 months, every 6 months, annually, etc. The dose can be administered, for example, intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscularly, intracerebrally, intraspinally, 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 a treatment interval will generally be at least 0.05 μg / kg body weight, more usually at least 0.2 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 100 μg / kg, 0.25 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 5.0 mg / ml, 10 mg / kg, 25 mg / kg, 50 mg / kg, or more. Doses may also be provided to achieve a predetermined target concentration of an antibody (e.g., an anti-PD-1 antibody) or antigen-binding fragment thereof in the subject's serum, e.g., 0.1, 0.3, 1, 3, 10, 30, 100, 300 μg / mL or more.

[0082] In some embodiments of the various methods described herein, the HIF-2α inhibitor is velzutifan or a pharmaceutically acceptable salt thereof, and the human patient is administered 40 to 120 mg once daily. In other embodiments of the various methods described herein, 40, 80, or 120 mg of velzutifan is administered once daily. In one particular embodiment, the human patient is administered 40 mg of velzutifan once daily. In one particular embodiment, the human patient is administered 80 mg of velzutifan once daily. In one particular embodiment, the human patient is administered 120 mg of velzutifan once daily.

[0083] In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof is orally administered. In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof is administered at a daily dose of 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib, respectively.

[0084] Thus, in some embodiments of the various methods provided herein, the human patient is (a) 40, 80, or 120 mg of belzutifan; and (b) 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib; was administered, (a) and (b) are administered daily.

[0085] In certain embodiments of the various methods provided herein, the human patient is (a) 120 mg of verzucifan; and (b) 20 mg lenvatinib; was administered, (a) and (b) are administered daily.

[0086] In certain embodiments of the various methods provided herein, the human patient is (a) 120 mg of verzucifan; and (b) 14 mg lenvatinib; was administered, (a) and (b) are administered daily.

[0087] In certain embodiments of the various methods provided herein, the human patient is (a) 120 mg of verzucifan; and (b) 10 mg lenvatinib; was administered, (a) and (b) are administered daily.

[0088] In certain embodiments of the various methods provided herein, the human patient is (a) 80 mg of verzucifan; and (b) 10 mg lenvatinib; was administered, (a) and (b) are administered daily.

[0089] In one embodiment, the human patient has failed other treatments. In another embodiment, the human patient has advanced RCC with a clear cell component (ccRCC) and has experienced disease progression (2L+RCC) during or after systemic treatment for advanced disease with a PD-(L)1 checkpoint inhibitor and a VEGF-TKI.

[0090] In some embodiments, at least one of the therapeutic agents (e.g., HIF-2α inhibitors or lenvatinib) in the combination therapy is administered using the same dosing regimen (dose, frequency, and duration of treatment) as typically used when the agent is used as a monotherapy to treat the same condition. In other embodiments, the patient receives a lower total amount of at least one of the therapeutic agents (e.g., HIF-2α inhibitors or lenvatinib) in the combination therapy than when the agent is used as a monotherapy, e.g., a lower dose, a less frequent dose, and / or a shorter treatment duration.

[0091] The combination therapies disclosed herein may be used before or after surgery to remove the tumor, and may be used before, during, or after radiation treatment.

[0092] In some embodiments, the combination therapy disclosed herein is administered to patients who have not been previously treated with a biotherapeutic or chemotherapeutic agent, i.e., treatment-naive patients. In other embodiments, the combination therapy is administered to patients who have failed to achieve a sustained response after previous treatment with a biotherapeutic or chemotherapeutic agent, i.e., treatment-experienced patients.

[0093] The therapeutic combinations disclosed herein may be used in combination with one or more other active agents, including, but not limited to, other anti-cancer agents used in the prevention, treatment, modulation, amelioration, or reduction of risk of a particular disease or condition (cancer). Such other active agents may be administered simultaneously or sequentially with one or more of the therapeutic agents in the combinations disclosed herein, by a route and in an amount commonly used therefor.

[0094] One or more additional active agents may be co-administered with a HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof. The(one or more) additional active agents may be administered in a single dosage form together with a HIF-2α inhibitor and one or more co-administered agents selected from lenvatinib or a pharmaceutically acceptable salt thereof. The(one or more) additional active agents may also be administered in a dosage form(s) separate from the dosage form containing the HIF-2α inhibitor, or lenvatinib or a pharmaceutically acceptable salt thereof.

[0095] 6. Kit In yet another aspect, provided herein is a kit comprising a therapeutic agent (e.g., a HIF-2α inhibitor and lenvatinib) or a pharmaceutical composition thereof disclosed herein, packaged in suitable packaging. The kit may include a label or package insert containing a description of the components or instructions for in vitro, in vivo, or ex vivo use of the components in the kit.

[0096] In some embodiments, the kit comprises: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Equipped with.

[0097] In certain embodiments, the kit further comprises instructions for administering the HIF-2α inhibitor and lenvatinib, or a pharmaceutically acceptable salt thereof, to a human patient.

[0098] In one aspect, the kit comprises: (a) one or more doses of a HIF-2α inhibitor; (b) one or more doses of lenvatinib or a pharmaceutically acceptable salt thereof; and (c) instructions for administering the HIF-2α inhibitor and lenvatinib or a pharmaceutically acceptable salt thereof to a human patient.

[0099] In various kits herein, the dosage of HIF-2α inhibitor or lenvatinib or its pharmaceutically acceptable salt can be used.In some embodiments, the kit contains the dosage of each component sufficient for a certain period of treatment (for example, 3, 6, 12 or 24 weeks).For example, the kit can contain 21 doses of 120mg velzutifan and 21 doses of 20mg lenvatinib (or equivalent amount of lenvatinib pharmaceutically acceptable salt), which are sufficient for 3 weeks of treatment.Alternatively, the kit can contain 42 doses of 120mg velzutifan and 42 doses of 20mg lenvatinib (or equivalent amount of lenvatinib pharmaceutically acceptable salt), which are sufficient for 6 weeks of treatment.

[0100] In some embodiments, the kit comprises a means for keeping the components separate, such as a container, divided bottle, or divided foil packet, etc. The kits of the present disclosure can be used for administration of different dosage forms, e.g., oral and parenteral, for administration of separate compositions at different dosage intervals, or for titrating separate compositions relative to one another.

[0101] 7. Use of the therapeutic combination to treat cancer or von Hippel-Lindau (VHL) disease In yet another aspect, there is provided a use of a therapeutic combination for treating cancer (e.g., RCC) or von Hippel-Lindau (VHL) disease in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) Lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0102] In some embodiments, the cancer is selected from the group consisting of bladder cancer, breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer (CRC), renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and melanoma.

[0103] 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 both recurrent and refractory.

[0104] In one embodiment, the cancer is bladder cancer. In another embodiment, the cancer is breast cancer. In yet another embodiment, the cancer is NSCLC. In yet another embodiment, the cancer is CRC. In one embodiment, the cancer is RCC. In another embodiment, the cancer is HCC. In yet another embodiment, the cancer is melanoma.

[0105] In one embodiment, the cancer is advanced RCC. In another embodiment, the cancer is advanced RCC with clear cell component. In yet another embodiment, the cancer is metastatic RCC. In yet another embodiment, the cancer is recurrent RCC. In yet another embodiment, the cancer is refractory RCC. In yet another embodiment, the cancer is recurrent and refractory RCC. In yet another embodiment, the RCC is VHL-deficient RCC.

[0106] In one embodiment, there is provided a use of a therapeutic combination for treating RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0107] In some embodiments, there is provided a use of a therapeutic combination for treating advanced RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0108] In some embodiments, there is provided a use of a therapeutic combination to treat advanced RCC with a clear cell component in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0109] In another embodiment, there is provided a use of a therapeutic combination to treat metastatic RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0110] In yet another embodiment, there is provided a use of a therapeutic combination for treating recurrent RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0111] In yet another embodiment, there is provided a use of a therapeutic combination for treating refractory RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0112] In another embodiment, there is provided a use of a therapeutic combination for treating relapsed and refractory RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0113] In another embodiment, there is provided a use of a therapeutic combination for treating VHL-deficient RCC in a human patient, said therapeutic combination comprising: (a) a HIF-2α inhibitor; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0114] In yet another embodiment, there is provided a use of a therapeutic combination for treating cancer or von Hippel-Lindau (VHL) disease, said therapeutic combination comprising: (a) velzutifan, or a pharmaceutically acceptable salt thereof; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0115] In one particular embodiment, the use of a therapeutic combination for treating RCC, wherein said therapeutic combination comprises: (a) velzutifan, or a pharmaceutically acceptable salt thereof; and (b) lenvatinib or a pharmaceutically acceptable salt thereof Uses are provided herein, including

[0116] In one embodiment, the human patient has failed other treatments. In another embodiment, the human patient has advanced RCC with a clear cell component (ccRCC) and has experienced disease progression (2L+RCC) during or after systemic treatment for advanced disease with a PD-(L)1 checkpoint inhibitor and a VEGF-TKI.

[0117] In one embodiment, the RCC is advanced RCC. In another embodiment, the RCC is advanced RCC with clear cell component. In yet another embodiment, the RCC is metastatic RCC. In yet another embodiment, the RCC is recurrent RCC. In yet another embodiment, the RCC is refractory RCC. In yet another embodiment, the RCC is recurrent and refractory RCC. In yet another embodiment, the RCC is VHL-deficient RCC.

[0118] Having described several aspects of the present invention, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. It will be further understood that each aspect may be combined with one or more other embodiments to the extent that such combination is consistent with the description of those aspects.

[0119] [Example] The examples in this section (Section VI) are provided by way of illustration and not limitation.

[0120] [Example 1] A clinical trial of velzutifan (MK-6482) and lenvatinib in patients with advanced RCC with a clear cell component (ccRCC) who have previously experienced disease progression (2L+RCC) on or after systemic treatment for advanced disease with a PD-(L)1 checkpoint inhibitor and a VEGF-TKI.

[0121] As of September 6, 2019, a total of 34 healthy volunteers and 185 patients were being treated with MK-6482 in five ongoing clinical trials.

[0122] An ongoing randomized, single-dose, two-period, two-arm crossover Phase 1 study in 16 healthy female adult volunteers investigated the effect of food on the pharmacokinetics of a single 120 mg dose of MK-6482. This study demonstrated that a high-fat, high-calorie meal did not affect the extent of MK-6482 exposure, but reduced maximum plasma MK-6482 concentrations by approximately 35% and delayed the time to peak MK-6482 exposure by a median difference of 2 hours (fed vs. fasted). These data were not considered clinically meaningful and support the dosing of MK-6482 with or without food. The most common adverse event (AE) reported was headache (12.5%).

[0123] An FIH Phase 1 study designed to evaluate the tolerability, safety, PK, and PD characteristics of MK-6482 in participants with various advanced solid tumors is ongoing. As of September 6, 2019, a total of 104 participants had been enrolled, including 43 participants with various advanced solid tumors in the dose-escalation portion (Part 1A) ranging from 20 to 240 mg QD and 120 mg BID. The MTD was not reached, and two treatment-related DLTs were observed: one Grade 4 thrombocytopenia event in the 240 mg QD cohort and one Grade 3 hypoxia event in the 120 mg BID cohort. Based on favorable PK, pharmacodynamic, and safety findings, the 120 mg QD dose was selected for further clinical development. Fifty-two additional participants with advanced RCC were treated at the 120 mg QD clinical dose in the expansion cohort (Part 1B). In the combined dose escalation and expansion cohorts, the most common AEs (occurring in ≥20% of participants) were anemia, fatigue, dyspnea, nausea, and peripheral edema. The most common grade 3 AEs were anemia and hypoxia (occurring in ≥5% of participants). maxMedian steady-state t values ​​ranged from 1 to 2.8 hours, and exposure increased with dose. Mean steady-state t values ​​in the 120 mg QD expansion cohort (Part 1B) on Day 15 1 / 2 was 15.4 h, resulting in a 1.5-fold accumulation from day 1 to day 15. Mean steady-state C in the 120 mg QD expansion cohort (Part 1B) on day 15 max The CV was 1.79 μg / mL (4.67 μM). The estimated CL / F was 5.22-14.4 L / hr. The estimated Vz / F was 106-266 L, suggesting widespread distribution to peripheral tissues. The CV was 0.0199 μg / mL (0.0199 μM) after a single dose. max The C max The response rates were 27-56% for RR and 30-64% for AUC. In total, 55 participants with previously treated advanced RCC were treated with MK-6482 at 120 mg QD in this study (3 patients in the dose-escalation portion of the study and 52 participants in the dose-expansion portion of the study). As assessed by Solid Tumor Response Criteria v1.1, the best responses among these 55 participants included 11 participants (20%) with PR and 32 participants (58%) with SD.

[0124] A phase 2, open-label efficacy and safety study in participants with VHL-associated RCC is ongoing. As of September 6, 2019, 61 participants had been enrolled at the 120 mg QD dose. Efficacy data are not yet available. Fatigue was the most common grade 3 or higher toxicity AE (reported by ≥5% of participants).

[0125] Additionally, 20 patients with ccRCC are being evaluated in a phase 2 trial, and 18 healthy adult volunteers are being evaluated in a phase 1 bioavailability trial.

[0126] Based on data from these studies, we will evaluate the combination of 120 mg of MK-6482 and 20 mg of lenvatinib in patients with advanced RCC with a clear cell component (ccRCC) (2L) who have previously experienced disease progression (2L+RCC) on or after receiving systemic treatment for advanced disease with a PD-(L)1 checkpoint inhibitor and a VEGF-TKI.

[0127] The primary efficacy objective of this substudy is to evaluate the antitumor efficacy of velzutifan and lenvatinib in participants with advanced ccRCC. Specifically, this study includes male and female participants aged at least 18 years with advanced RCC (ccRCC) with a clear cell component after 2L+ PD-(L)1 inhibitors / VEGF-TKIs. This substudy will use ORR as the primary efficacy endpoint. ORR is defined as the proportion of participants achieving a confirmed CR or PR by the Solid Tumor Response Criteria 1.1 as assessed by BICR. Responses are based on the Solid Tumor Response Criteria 1.1, modified to track up to 10 target lesions and up to 5 target lesions per organ. ORR is an appropriate endpoint for assessing antitumor activity in the reference and experimental groups. Treatment efficacy measured by ORR can represent direct clinical benefit based on the specific disease, setting of use, magnitude of effect, number of CRs, durability of response, disease setting, tumor location, available treatments, and risk-benefit relationship.

[0128] This substudy will use DOR, PFS, OS, and CBR as secondary efficacy endpoints. DOR is defined as the time from first documented evidence of CR or PR to disease progression or death from any cause, whichever occurs first. DOR by the Solid Tumor Response Evaluation Criteria 1.1, modified to track up to 10 target lesions and up to 5 target lesions per organ, as assessed by BICR, serves as an additional measure of efficacy and is an endpoint commonly accepted by both regulatory authorities and the oncology community.

[0129] PFS is defined as the time from the date of randomization to the first documented progression-free progression (PD) or death from any cause, whichever occurs first, as documented by the BICR according to Solid Tumor Response Criteria 1.1. Images are read by the BICR to minimize bias in response assessment. PFS events can reflect tumor growth and be assessed before the determination of survival benefit, which is not confounded by subsequent treatment. Treatment efficacy measured by PFS can be a surrogate endpoint for direct clinical benefit based on the specific disease, context of use, magnitude of effect, disease setting, location of metastatic sites, available treatments, risk-benefit relationship, and clinical consequences of delaying or preventing progression at key disease sites (e.g., delaying new lesions in the brain or spine) or delaying the administration of more toxic treatments.

[0130] OS is recognized as the gold standard for demonstrating the superiority of new antineoplastic therapies in randomized clinical trials. OS is defined as the time from the date of randomization to the date of death from any cause.

[0131] CBR is a commonly used secondary endpoint in many cancer clinical trials and is defined as the proportion of participants who achieve ≥6 months of SD or CR or PR, as assessed by BICR according to Solid Tumor Response Criteria 1.1.

[0132] Tumor size change is an exploratory efficacy endpoint and a proposed intermediate endpoint that may detect a signal of early antitumor activity, defined as the sum of the longest diameter target lesions and the change (and % change) from baseline at each post-baseline assessment.

[0133] Male / female participants with a histologically confirmed diagnosis of advanced clear cell RCC (with or without sarcomatoid features) who are at least 18 years of age will be enrolled in the study. Participants are eligible to participate in the study if they:

[0134] 1. Must have a histologically confirmed diagnosis of locally advanced / metastatic ccRCC (with or without sarcomatoid features), i.e., stage IV RCC by AJCC. 2. Have experienced disease progression during or after receiving systemic treatment for locally advanced or metastatic RCC with both a PD-(L)1 checkpoint inhibitor and a VEGF-TKI, either sequentially or in combination. Progression on PD-(L)1 checkpoint inhibitor treatment is defined by meeting all of the following criteria: Received at least two doses of anti-PD-(L)1 mAb. · Investigator-proven PD as defined by Response Criteria in Solid Tumors 1.1 during or after anti-PD-(L)1 mAb. PD was documented within 12 weeks of the last dose of anti-PD-(L)1 mAb. Progression of VEGF-TKI treatment will be defined by meeting the following criteria: Investigator-proven progression as defined by Response Criteria in Solid Tumors 1.1 during or after treatment with a VEGF-TKI. 3. Have measurable disease per Solid Tumor Response Criteria 1.1 as assessed by BICR. Lesions located in previously irradiated areas are considered measurable if progression has been documented in such lesions.

[0135] The reference groups for this study are described below.

[0136] [Table 1]

[0137] [Table 2]

[0138] [Table 3]

[0139] [Example 2] A VHL-deficient renal cell carcinoma xenograft tumor model treated with a HIF-2α inhibitor (MK-6482) in combination with a VEGF tyrosine kinase inhibitor (lenvatinib).

[0140] In this example, we provide preclinical data using a human VHL-deficient renal cell carcinoma xenograft tumor model to demonstrate the antitumor benefit of combining a HIF-2α inhibitor (MK-6482) with a VEGF tyrosine kinase inhibitor (lenvatinib).

[0141] Prior to the start of the treatment, 7-week-old female SCID Beige mice weighing 18–21 grams were anesthetized and cultured in 0.1 mL of serum-free Dulbecco's modified Eagle's medium (DMEM) containing approximately 95% viable log-phase subconfluent UMRC2 (5.0 × 10 6 A single cell suspension of ) cells was inoculated subcutaneously into the hind flank to initiate tumor development. The mean tumor volume of inoculated animals was approximately 205 mm. 3 Treatment began when tumor size reached 10. Mice were matched into four treatment groups, each consisting of 10 mice. Treatment groups consisted of: 1) 0.5% methylcellulose + 0.5% Tween 80 (vehicle); 2) MK-6482; 3) lenvatinib; and 4) MK-6482 + lenvatinib. Vehicle and MK-6482 were administered by oral gavage at 3 mg / kg body weight twice daily (BID). Lenvatinib was administered orally once daily (QD) at 10 mg / kg body weight. Treatment began on day 0 and was completed on day 34. Tumor and body weight caliper measurements were performed twice weekly. Statistical analysis was performed by one-way ANOVA with Tukey's multiple comparison test at the end of the study on day 34.

[0142] As shown in Figures 1A and 1B, the mean antitumor response of the MK-6482 + lenvatinib combination therapy was greater than that of MK-6482 monotherapy (p<0.0001) or lenvatinib monotherapy (p=0.017). All treatment groups, including MK-6482 monotherapy (p=0.003), lenvatinib monotherapy (p<0.0001), and MK-6482 + lenvatinib (p<0.0001), demonstrated significant antitumor activity compared to the vehicle control group. A summary of tumor growth inhibition (TGI) and partial tumor regression (PR) or complete tumor regression (CR) observations for each treatment group relative to vehicle-treated animals at day 34 is provided in the table below.

[0143] [Table 4]

[0144] A CR was defined as the absence of observable tumor, whereas a PR was a tumor whose volume was smaller than the original tumor size at the start of treatment.No new safety signals were observed in preclinical studies of the lenvatinib + MK-6482 combination, as assessed by weight change or early mortality.

[0145] As shown in the results provided above, treatment with the combination of lenvatinib plus MK-6482 is advantageous over treatment with each agent when administered alone.

Claims

1. 1. A pharmaceutical composition for treating advanced RCC in a human patient in need thereof, comprising: The pharmaceutical composition comprises: (a) a HIF-2α inhibitor; and / or (b) lenvatinib or a pharmaceutically acceptable salt thereof Including, said treatment being carried out using a combination of (a) and (b); The HIF-2α inhibitor is belzutifan: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein the advanced RCC is advanced RCC with a clear cell component (ccRCC).

3. 3. The pharmaceutical composition of claim 2, wherein the human patient has advanced RCC with a clear cell component (ccRCC) who has experienced disease progression (2L+RCC) during or after receiving systemic treatment for advanced disease with a PD-1 checkpoint inhibitor or a PD-L1 checkpoint inhibitor and a VEGF-TKI.

4. (a) a HIF-2α inhibitor; and (b) a kit for treating advanced RCC comprising lenvatinib, or a pharmaceutically acceptable salt thereof, The HIF-2α inhibitor is belzutifan: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

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

6. 1. A pharmaceutical composition for treating advanced RCC in a human patient, comprising a HIF-2α inhibitor, wherein the pharmaceutical composition is administered in combination with lenvatinib or a pharmaceutically acceptable salt thereof; wherein the HIF-2α inhibitor is belzutifan: 【Chemistry 3】 or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising lenvatinib or a pharmaceutically acceptable salt thereof for treating advanced RCC in a human patient, wherein the pharmaceutical composition is administered in combination with a HIF-2α inhibitor; wherein the HIF-2α inhibitor is belzutifan: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of claim 6 or 7, wherein the advanced RCC is advanced RCC with a clear cell component (ccRCC).

9. 9. The pharmaceutical composition of claim 8, wherein the human patient has advanced RCC with a clear cell component (ccRCC) who has experienced disease progression (2L+RCC) during or after receiving systemic treatment for advanced disease with a PD-1 checkpoint inhibitor or a PD-L1 checkpoint inhibitor and a VEGF-TKI.

10. 4. The pharmaceutical composition of claim 1, wherein the HIF-2α inhibitor is belzutifan, and the human patient is administered about 40 mg to about 120 mg of belzutifan, and the belzutifan is administered once daily.

11. 11. The pharmaceutical composition of claim 10, wherein the human patient is administered 40, 80, or 120 mg of belzutifan, and the belzutifan is administered once daily.

12. 12. The pharmaceutical composition of claim 11, wherein the human patient is administered 120 mg of belzutifan.

13. The pharmaceutical composition of any one of claims 10 to 12, wherein the human patient is administered 8, 10, 12, 14, 18, 20, or 24 mg of lenvatinib or a pharmaceutically acceptable salt thereof, wherein lenvatinib or a pharmaceutically acceptable salt thereof is administered once daily.

14. 1. A pharmaceutical composition for treating advanced RCC, comprising: (a) 120 mg of Belzutifan: 【Chemistry 5】 and / or (b) 20 mg of lenvatinib or a pharmaceutically acceptable salt thereof; Including, A pharmaceutical composition wherein said treatment is carried out using a combination of (a) and (b).

15. 15. The pharmaceutical composition of claim 14, wherein (a) and (b) are administered once daily.

16. 16. The pharmaceutical composition of claim 15, wherein (a) and (b) are administered on the same day, and wherein (a) and (b) are administered sequentially or simultaneously.

17. The pharmaceutical composition according to any one of claims 1 to 3, 6 to 7, and 14 to 16, wherein the lenvatinib or a pharmaceutically acceptable salt thereof is lenvatinib mesylate.

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