Casdatifan for use in the treatment of cancer

Abstract

Methods of treating cancer in a subject comprising administering to a subject in need of treatment an HIF-2a inhibitor, particularly Compound (I) having the structure: (I) in an amount that is about 2 times above to about five times above, or even above about 2 times above to about ten times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction. Methods of treating cancer in a subject, comprising administering the HIF-2a inhibitor to the subject in need of treatment.

Description

CASDATIFAN FOR USE IN THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 643,481 filed on May 7, 2024; U.S. Provisional Patent Application No. 63 / 710,308 filed on October 22, 2024; U.S. Provisional Patent Application No. 63 / 717,119 filed on November 6, 2024; and U.S. Provisional Patent Application No. 63 / 758,515 filed on February 14, 2025; the entire contents of each of which are incorporated by reference herein.BACKGROUND

[0002] The following discussion is provided to aid one skilled in the art in understanding the disclosure, to satisfy enablement and written description legal requirements, and is not admitted to be prior art.

[0003] Hypoxia inducible factors (HIFs) are a family of transcription factors that modulate the cellular response to hypoxia. HIF is a heterodimer containing an oxygen-regulated alpha subunit (of which there are 3 isoforms: HIF-la, HIF-2a, and HIF-3a) that can heterodimerize with a constitutively expressed beta subunit. Under normal tissue oxygen saturation, HIF-2a protein is continuously degraded. In hypoxic tissue oxygen status, or in the case of VHL mutation or epigenetic silencing (pseudohypoxia), HIF-2a is stabilized and undergoes nuclear translocation. Upon dimerization with HIF-10, HIF-2a mediates transcription of pro- tumorigenic genes associated with proliferation and angiogenesis.

[0004] HIF-2a inhibitors have been described in the literature, and were first approved for the treatment of renal cell carcinoma associated with von-Hippel-Lindau disease, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. While HIF-2a inhibitors are known, their utility is thought to be limited by their ability to penetrate a relevant tissue. Thus, there remains a need for HIF-2a inhibitors with improved properties and other advantages described herein.SUMMARY

[0005] In one aspect, the disclosure describes a method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction. In another aspect, the disclosure describes a HIF-2a inhibitor foruse in a method of treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction. In another aspect, the disclosure describes a use of a HIF -2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction. In another aspect, the disclosure describes a use of a HIF- 2a inhibitor in the manufacture of a medicament for treating cancer, wherein the HIF-2a inhibitor is formulated for administration in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction.

[0006] In another aspect, the disclosure describes a method of treating cancer in a subject comprising administering to a subject in need of treatment a total daily dose of 100 mg of a HIF-2a inhibitor. In another aspect, the disclosure describes a HIF-2a inhibitor for use in a method of treating cancer, comprising administering to a subject in need of treatment a total daily dose of 100 mg of the HIF-2a inhibitor. In another aspect, the disclosure describes a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment a total daily dose of 100 mg of the HIF-2a inhibitor. In another aspect, the disclosure describes a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, wherein the HIF-2a inhibitor is formulated for administration at a total daily dose of 100 mg.

[0007] In still another aspect, the disclosure describes a method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved. In still another aspect, the disclosure describes a HIF-2a inhibitor for use in a method of treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved. In still another aspect, the disclosure describes a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved. In still another aspect, the disclosure describes a use of a HIF-2ainhibitor in the manufacture of a medicament for treating cancer, wherein the HIF-2a inhibitor is formulated for administration in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved.

[0008] In a further aspect, the disclosure describes a method of treating ccRCC in a subject in need thereof, said method comprising administering 100 mg of Compound (I):Compound (I) to the subject daily, wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor. In still another aspect, the disclosure describes Compound (I) for use in a method of treating ccRCC comprising administering to a subject in need of treatment 100 mg of Compound (I) daily, wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor. In still another aspect, the disclosure describes the use of Compound (I) in the manufacture of a medicament for treating ccRCC in a subject, comprising administering 100 mg of Compound (I) daily, wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor. In still another aspect, the disclosure describes the use of Compound (I) in the manufacture of a medicament for treating ccRCC in a subject, wherein the HIF-2a inhibitor is formulated for daily administration in an amount of 100 mg, and wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Fig. 1A, Fig.lB, and Fig. 1C show mean (±standard deviation) EPO percent change from baseline (relative to predose) in placebo and healthy volunteers or patients with ccRCC or other solid tumors. Fig. 1A depicts healthy volunteers in Study ARC-14 dosed once with placebo or Compound (I) at doses of 3 mg, 10 mg, 30 mg or 100 mg. Fig. IB depicts healthy volunteers in Study ARC-14 dosed once daily for 7 days with placebo or Compound (I) at doses of 15 mg, 30 mg, or 50 mg. Fig. 1C depicts patients with ccRCC and other solid tumors in Study ARC-20 dosed with Compound (I) at doses of 20 mg once daily, 50 mg once daily,50 mg twice daily, or 150 mg once daily. Fig. ID and Fig. IE depict percent tumor reduction per patient in Expansion Cohort 1 and Expansion Cohort 2, respectively. Fig. IF and Fig. 1G depict percent EPO change from baseline in patients with ccRCC in Study ARC-20 dosed with Compound (I) at a dose of 50 mg once or twice daily. (Fig. 1G depicts the same data from Fig. IF in one graph.)

[0010] Fig. 2A and Fig. 2B show median (± median absolute derivation) Compound (I) plasma concentration vs time profiles following single (3 mg, 10 mg, 30 mg, or 100 mg) (Fig. 2A) or multiple (15 mg, 30 mg, or 50 mg QD) (Fig. 2B) oral doses of Compound (I) in healthy volunteers (Study ARC- 14).

[0011] Fig. 3A, Fig. 3B, and Fig. 3C show mean (+ standard deviation) Compound (I) plasma concentration vs time profiles following single (Fig. 3A) or multiple (Fig. 3B and Fig. 3C) oral doses of Compound (I) at 20 mg QD, 50 mg QD, 50 mg BID, or 150 mg QD at C1D1 (cycle 1, day 1), C1D15 (cycle 1, day 15), and C2D1 (cycle 2, day 1) in participants with cancer (Study ARC-20).

[0012] Fig. 4A and Fig. 4B show hemoglobin levels for patients receiving 50 mg or 100 mg daily of Compound (I) (Fig. 4A) or for patients receiving 120 mg daily of a Comparator HIF Inhibitor (Fig. 4B). Fig. 4C and Fig. 4D show hemoglobin change from baseline for patients receiving 50 mg or 100 mg daily of Compound (I) (Fig. 4C) or for patients receiving 120 mg daily of a Comparator HIF Inhibitor (Fig. 4D). The data for the Comparator HIF Inhibitor (Fig. 4B and Fig. 4D) was from VHL patients (Nature Medicine, 2021, 385(22), 2036-2048.

[0013] Fig. 5A shows Compound (I) pharmacodynamic (PD) effect at 20 mg versus PD effect of a Comparator HIF-2a Inhibitor at 120 mg. The solid line is the median of simulated Compound (I) concentration. The shaded range is the inter-quartile range of population PK / PD simulated concentrations of Compound (I). The data for the Comparator HIF-2a Inhibitor (belzutifan) was sourced from the NDA-FDA review document for that compound. Fig. 5B shows dose-linear human PK profile of Compound (I) at 20 mg dose and at 100 mg dose.

[0014] Fig. 6 is a box plot depicting maximum EPO reduction for patients having confirmed best overall response of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).

[0015] Fig. 7 is a box plot showing maximal EPO reduction in patients with and without primary disease progression.

[0016] Fig. 8 is a box plot depicting normalized tumor EPO mRNA expression between patients with (Y) and without (N) primary progressionDETAILED DESCRIPTION OF THE DISCLOSURE

[0017] The disclosure is not limited to the particular embodiments set forth herein, and it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.Definitions

[0018] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains.

[0019] The term “about” as used herein has its original meaning of approximately and is to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In general, the term “about” refers to the usual error range for the respective value readily known to the skilled person in this technical field. If the degree of approximation is not otherwise clear from the context, “about” means either within plus or minus 10% of the provided value, or rounded to the nearest significant figure, in all cases inclusive of the provided value. Where ranges are provided, they are inclusive of the boundary values.

[0020] The term “biomarker” as used herein refers to an indicator, e.g., predictive, diagnostic, and / or prognostic, which can be detected in a sample. The biomarker may serve as an indicator of a particular subtype of a disease or disorder characterized by certain, molecular, pathological, histological, and / or clinical features. Biomarkers include, but are not limited to, polypeptides (e.g., proteins), and polynucleotides (e.g., DNA, and / or RNA). Biomarkers can be detected in the periphery (e.g., from a serum or blood sample), or from diseased tissues (e.g., from a tumor biopsy).

[0021] “Expression” generally refers to the process by which information (e.g., gene- encoded) is converted into the structures present and operating in the cell. Therefore, as used herein, “expression” may refer to transcription into a polynucleotide, translation into a polypeptide. Fragments of the transcribed polynucleotide, the translated polypeptide shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of thepolypeptide, e.g., by proteolysis. “Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs). Expression levels may be measured by methods known to one skilled in the art and also disclosed herein. The expression level or amount of a biomarker (e.g., EPO) may be used to identify / characterize a cancer that may be likely to respond to, or benefit from, a particular therapy.

[0022] The terms “patient” or “subject” are used interchangeably to refer to a human.

[0023] The terms “treat”, “treating”, treatment” and the like refer to a course of action that eliminates, reduces, suppresses, mitigates, ameliorates, or prevents the worsening of, either temporarily or permanently, a disease, disorder or condition (e.g., cancer) to which the term applies, or one or more of the symptoms associated therewith. Treatment includes alleviation of symptoms, diminishment of extent of disease, inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease, delaying or slowing of disease progression, improving the quality of life, and / or prolonging survival of a subject as compared to expected survival if not receiving treatment or as compared to a published standard of care therapy for a particular disease. In some embodiments, assessments may include determining disease progression, tumor growth, reduction in primary tumor volume, time to progression, progression free survival, overall response rate, or duration of response.

[0024] The term “in need of treatment” as used herein refers to a judgment made by a physician or similar professional that a subject requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of the physician’s expertise, which may include a positive diagnosis of a disease, disorder or condition. A subject may be in need of treatment because, for example, the subject is exhibiting symptoms of disease, or the subject has evidence from blood tests or evidence from other diagnostic procedures indicating the presence of a disease or a precursor of a disease. A subject may also be in need of treatment if other treatments have been tried and failed, or if the subject is not responding to their current treatment. As used herein, “in need of treatment” also encompasses the concept of administering treatment to a subject “in need thereof’, i.e. the subject is in need of treatment.

[0025] The term “previously treated patient” refers to a cancer patient that has experienced disease progression on or after treatment with an approved therapy for the cancer, for example,a ccRCC patient that has experienced disease progression on or after treatment with an immune checkpoint inhibitor (e.g., an anti-PD-1 or anti-PD-Ll agent), a tyrosine kinase inhibitor (e.g., a VEGF or VEGFR inhibitor), mTOR inhibitor, etc. Similarly, the term “previously treated cancer” refers to a cancer that has progressed while being treated or after being treated with an approved therapy for the cancer (e.g., an immune checkpoint inhibitor, a tyrosine kinase inhibitor, mTOR inhibitor, etc.). As used herein, the terms “previously treated patient” and “patient having received a prior therapy” are used interchangeably.Methods of Treatment, Compounds for Use, and Uses in the Manufacture of a Medicament

[0026] Erythropoietin (EPO) is a hormone produced in the kidney under partial transcriptional control of HIF-2a. Reduction in EPO is an expected pharmacological effect from inhibition of HIF-2a. EPO can be measured in the periphery (e.g., from a blood or serum sample) and used as a peripheral pharmacodynamic (PD) parameter to approximate HIF-2a exposure. Without wishing to be bound by theory, complete inhibition of HIF-2a does not result in a complete loss of peripheral EPO due to compensatory mechanisms. Accordingly, once sufficient HIF-2a inhibitor has been administered to prevent further HIF-2a mediated peripheral EPO production, further administration, as described herein, of a HIF-2a inhibitor will not result in a further decrease in peripheral EPO levels due to EPO production from other mechanisms. In other words, there is a maximum HIF-2a-mediated decrease in EPO. Taking into account patient-by-patient variability, and diurnal variation in serum EPO levels, the maximum HIF-2a mediated peripheral EPO reduction may range from about 70% to about 90%, from about 65% to about 85%, from about 70% to about 80%, each from baseline.

[0027] Anemia can result from reduced levels of EPO and is an expected on-target effect associated with administration of a HIF-2a inhibitor. Hypoxia is another on-target effect associated with HIF-2a inhibition. Surprisingly, while administration of Compound (I) results in a more durable suppression of EPO as compared to a comparator HIF-2a inhibitor (e.g., belzutifan), the rate of the associated on-target effect remains consistent with the rate observed for the comparator HIF-2a inhibitor. Without wishing to be bound by theory, Compound (I) may provide more durable tumor responses through stronger inhibition of HIF-2a without increasing the severity and or incidence of adverse safety signals such as, e.g., anemia and / or hypoxia.

[0028] Compound (I) can be prepared as described in international (PCT) patent publication WO 2021 / 188769 Al, and U.S. Patent No. 12,145,901. Methods of treating cancer with Compound (I), Compound (I) for use in methods of treating cancer, and uses of Compound (I) in the manufacture of a medicament for treating cancer are described herein.

[0029] In one aspect, there is provided a method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a-mediated peripheral EPO reduction. In another aspect, there is provided a HIF-2a inhibitor for use in a method of treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction. In another aspect, the disclosure describes a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction. In another aspect, the disclosure describes a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, wherein the HIF-2a inhibitor is formulated for administration in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction.

[0030] In particular embodiments, the HIF-2a inhibitor is administered to a patient in need of treatment in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved.

[0031] In particular embodiments, the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprises administering a total daily dose of 100 mg of a HIF-2a inhibitor.

[0032] In particular embodiments the HIF-2a inhibitor is Compound (I):

[0033] In particular embodiments, the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprises administering a HIF-2a-inhibitor, particularly Compound (I), wherein the compound achieves an AUCtau that is above 25 h*pg / mL in the subject. In some particular embodiments, the treatment results in a medium time to response that is < 3.5 months, more particularly, the treatment results in a decreased incidence of progression at 6 weeks, or at 12 weeks. Incidence of progression can be determined using, e.g., CT scans, or may be determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

[0034] In particular embodiments of the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, the cancer is a HIF-2a driven cancer, more particularly the cancer is a solid tumor, still more particularly the cancer is kidney cancer, and still more particularly the cancer is clear cell renal cell carcinoma (ccRCC). Without wishing to be bound by theory, a HIF-2a driven cancer may be characterized by high serum and / or tumor EPO expression.

[0035] In particular embodiments of the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer as described, the subject has received no prior lines of therapy. In other particular embodiments, the subject has received one or more prior lines of therapy, particularly wherein the one or more prior lines of therapy comprise treatment with an immune checkpoint inhibitor and / or treatment with a tyrosine kinase inhibitor. In some embodiments, the one or more prior lines of therapy consist of treatment with an immune checkpoint inhibitor and / or treatment with a tyrosine kinase inhibitor. In some embodiments, the subject has experienced progression on or after a prior line of therapy with an immune checkpoint inhibitor (e.g., an inhibitor of PD-1 or PD-L1) and / or treatment with a tyrosine kinase inhibitor (e.g., an inhibitor of VEGF or VEGFR). A prior line of therapy includes adjuvant therapy, neoadjuvant therapy, and subsequent lines of therapy (e.g., a first-line therapy). In some embodiments, a prior line of therapy is an approved treatment for ccRCC.

[0036] In some particular embodiments, the one or more prior lines of therapy comprise an immune checkpoint inhibitor that is an inhibitor of PD-1 or PD-L1. In some embodiments, theone or more prior lines of therapy comprise or consist of an immune checkpoint inhibitor that inhibits or antagonizes PD-1, PD-L1, CTLA-4, or a combination thereof. In some embodiments, the prior line of therapy comprises an anti -PD-1 antibody and an anti-CTLA-4 antibody (e.g., nivolumab or pembrolizumab and ipilimumab). In some embodiments, the prior line of therapy comprises or consists of nivolumab and ipilimumab. In some particular embodiments, the one or more prior lines of therapy comprise or consist of a tyrosine kinase inhibitor that is an inhibitor of VEGF or VEGFR (e.g., cabozantinib, lenvatinib, or axitinib). In some embodiments, the one or more prior lines of therapy comprise or consist of an immune checkpoint inhibitor and a tyrosine kinase inhibitor that inhibitors VEGF or VEGFR. In some embodiments, the prior line of therapy comprises or consists of an anti -PD-1 antibody and an inhibitor of VEGF or VEGFR (e.g., nivolumab or pembrolizumab and cabozantinib, lenvatinib, or axitinib). In some embodiments, the prior line of therapy comprises or consists of nivolumab and cabozantinib. In some embodiments, the prior line of therapy is a course of therapy immediately prior to the methods described herein. In some embodiments, the prior line of therapy occurred no greater than 6 months prior to methods described herein. A prior line of therapy may be a full course of treatment or a course of treatment discontinued prior to completion due to disease progression or intolerability.

[0037] In some embodiments, the one or more prior lines of therapy comprise an mTOR inhibitor.

[0038] In some particular embodiments of the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF- 2a inhibitor in the manufacture of a medicament for treating cancer as described, the HIF-2a inhibitor is administered to the subject as one daily dose or two daily doses. In some particular embodiments, the HIF-2a inhibitor is administered by oral administration.

[0039] In one aspect of the disclosure, there is provided a method of treating cancer in a subject in need of treatment, comprising administering a HIF-2a inhibitor to a subject in need of treatment in combination with another therapeutic agent. In another aspect of the disclosure, there is provided a HIF-2a inhibitor for use in a method of treating cancer, comprising administering the HIF-2a inhibitor to a subject in need of treatment in combination with another therapeutic agent. In another aspect of the disclosure, there is provided another therapeutic agent for use in a method of treating cancer, comprising administering the another therapeutic agent to a subject in need of treatment in combination with a HIF-2a inhibitor. Inanother aspect of the disclosure, there is provided a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering the HIF-2a inhibitor to a subject in need of treatment in combination with another therapeutic agent. In another aspect of the disclosure, there is provided a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, wherein the HIF-2a inhibitor is formulated for administration in combination with another therapeutic agent. In another aspect of the disclosure, there is provided a use of another therapeutic agent in the manufacture of a medicament for treating cancer, comprising administering the another therapeutic agent to a subject in need of treatment in combination with a HIF-2a inhibitor. In another aspect of the disclosure, there is provided a use of another therapeutic agent in the manufacture of a medicament for treating cancer, wherein the another therapeutic agent is formulated for administration in combination with a HIF-2a inhibitor. In particular embodiments, the (an)other therapeutic agent is a tyrosine kinase inhibitor; more particularly, the tyrosine kinase inhibitor inhibits the tyrosine kinase activity of MET, VEGFR-1, VEGFR-2, VEGFR-3, AXL, RET, ROS1, TYR03, MER, KIT, TRKB, FLT-3, TIE-2, or any combination thereof.

[0040] In some embodiments, the HIF-2a inhibitor, particularly Compound (I), is administered in an amount that is about 2 times above the amount that achieves maximum HIF- 2a mediated peripheral EPO reduction, or at least about 2 times above, at least about 3 times above, at least about 4 times above, at least about 5 times above, at least about 6 times above, at least about 7 times above, at least about 8 times above, at least about 9 times above, or at least about 10 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction. In some embodiments, the HIF-2a inhibitor, particularly Compound (I), is administered in an amount that is about 2 times to about 10 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction, such as, for example, about 2 times to about 9 times above, about 2 times to about 8 times above, about 2 times to about 7 times above, about 2 times to about 6 times above, about 2 times to about 5 times above, about 2 times to about 4 times above, about 2 times to about 3 times above, about 3 times to about 10 times above, about 3 times to about 9 times above, about 3 times to about 8 times above, about 3 times to about 7 times above, about 3 times to about 6 times above, about 3 times to about 5 times above, about 3 times to about 4 times above, about 4 times to about 10 times above, about 4 times to about 9 times above, about 4 times to about 8 times above, about 4 times to about 7 times above, about 4 times to about 6 times above, about 4 times to about 5 times above, about 5 times to about 10 times above, about 5 times to about 9 times above, about5 times to about 8 times above, about 5 times to about 7 times above, about 5 times to about 6 times above, about 6 times to about 10 times above, about 6 times to about 9 times above, about6 times to about 8 times above, about 6 times to about 7 times above, about 7 times to about 10 times above, about 7 times to about 9 times above, about 7 times to about 8 times above, about 8 times to about 10 times above, about 8 times to about 9 times above, about 9 times to about 10 times above, or about 10 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction. In some embodiments, the HIF-2a inhibitor, particularly Compound (I), is administered in an amount that is about 5 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction. In some embodiments, the HIF-2a inhibitor is administered in an amount that is about 4 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction. In some embodiments, the HIF-2a inhibitor is administered in an amount that is about 3 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction. In some embodiments, the HIF-2a inhibitor is administered in an amount that is about 2 times above the amount that achieves maximum HIF-2a mediated peripheral EPO reduction.

[0041] In some embodiments, Compound (I) is administered, such as orally, at a dosage of from about 10 mg to about 130 mg (total dose per day, e.g., in one dose per day or as multiple smaller doses per day). The dosage of Compound (I) may be, for example, about 50-120 mg, or about 75-120 mg, or about 80-120 mg, or about 85-115 mg, or about 90-110 mg, or about 95-105 mg, or about 98-102 mg (total dose per day, e.g., in one dose per day or as multiple smaller doses per day). In some embodiments, Compound (I) is administered at a total daily dosage of from about 100 mg to about 120 mg (e.g., as one or two daily doses). Compound (I) may be administered, such as orally, at a dosage of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, or any value between about 10 mg and about 130 mg (total dose per day, e.g., in one dose per day or as multiple smaller doses per day) (e.g., between about 15 mg and about 130 mg, between about 20 mg and about 130 mg, between about 25 mg and about 130 mg, between about 30 mg and about 130 mg, between about 35 mg and about 130 mg, between about 40 mg and about 130 mg, between about 45 mg and about 130 mg, between about 50 mg and about 130 mg, between about 55 mg and about 130 mg, between about 60 mg and about 130 mg, between about 65 mg and about 130 mg, between about 70 mg and about 130 mg, between about 75 mg and about 130 mg, between about 80 mg and about 130 mg, between about 85 mg and about 130 mg, betweenabout 90 mg and about 130 mg, between about 95 mg and about 130 mg, or between about 100 mg and about 130 mg, total dose per day; or between about 15 mg and about 125 mg, between about 20 mg and about 125 mg, between about 25 mg and about 125 mg, between about 30 mg and about 125 mg, between about 35 mg and about 125 mg, between about 40 mg and about 125 mg, between about 45 mg and about 125 mg, between about 50 mg and about 125 mg, between about 55 mg and about 125 mg, between about 60 mg and about 125 mg, between about 65 mg and about 125 mg, between about 70 mg and about 125 mg, between about 75 mg and about 125 mg, between about 80 mg and about 125 mg, between about 85 mg and about 125 mg, between about 90 mg and about 125 mg, between about 95 mg and about 125 mg, or between about 100 mg and about 125 mg, total dose per day; or between about 15 mg and about 120 mg, between about 20 mg and about 120 mg, between about 25 mg and about 120 mg, between about 30 mg and about 120 mg, between about 35 mg and about 120 mg, between about 40 mg and about 120 mg, between about 45 mg and about 120 mg, between about 50 mg and about 120 mg, between about 55 mg and about 120 mg, between about 60 mg and about 120 mg, between about 65 mg and about 120 mg, between about 70 mg and about 120 mg, between about 75 mg and about 120 mg, between about 80 mg and about 120 mg, between about 85 mg and about 120 mg, between about 90 mg and about 120 mg, between about 95 mg and about 120 mg, or between about 100 mg and about 120 mg, total dose per day; or between about 15 mg and about 115 mg, between about 20 mg and about 115 mg, between about 25 mg and about 115 mg, between about 30 mg and about 115 mg, between about 35 mg and about 115 mg, between about 40 mg and about 115 mg, between about 45 mg and about 115 mg, between about 50 mg and about 115 mg, between about 55 mg and about 115 mg, between about 60 mg and about 115 mg, between about 65 mg and about 115 mg, between about 70 mg and about 115 mg, between about 75 mg and about 115 mg, between about 80 mg and about 115 mg, between about 85 mg and about 115 mg, between about 90 mg and about 115 mg, between about 95 mg and about 115 mg, or between about 100 mg and about 115 mg, total dose per day; or between about 15 mg and about 110 mg, between about 20 mg and about 110 mg, between about 25 mg and about 110 mg, between about 30 mg and about 110 mg, between about 35 mg and about 110 mg, between about 40 mg and about 110 mg, between about 45 mg and about 110 mg, between about 50 mg and about 110 mg, between about 55 mg and about 110 mg, between about 60 mg and about 110 mg, between about 65 mg and about 110 mg, between about 70 mg and about 110 mg, between about 75 mg and about 110 mg, between about 80 mg and about 110 mg, between about 85 mg and about 110 mg, between about 90 mgand about 110 mg, between about 95 mg and about 110 mg, or between about 100 mg and about 110 mg, total dose per day; or between about 15 mg and about 105 mg, between about 20 mg and about 105 mg, between about 25 mg and about 105 mg, between about 30 mg and about 105 mg, between about 35 mg and about 105 mg, between about 40 mg and about 105 mg, between about 45 mg and about 105 mg, between about 50 mg and about 105 mg, between about 55 mg and about 105 mg, between about 60 mg and about 105 mg, between about 65 mg and about 105 mg, between about 70 mg and about 105 mg, between about 75 mg and about 105 mg, between about 80 mg and about 105 mg, between about 85 mg and about 105 mg, between about 90 mg and about 105 mg, between about 95 mg and about 105 mg, or between about 100 mg and about 105 mg, total dose per day; or between about 15 mg and about 100 mg, between about 20 mg and about 100 mg, between about 25 mg and about 100 mg, between about 30 mg and about 100 mg, between about 35 mg and about 100 mg, between about 40 mg and about 100 mg, between about 45 mg and about 100 mg, between about 50 mg and about 100 mg, between about 55 mg and about 100 mg, between about 60 mg and about 100 mg, between about 65 mg and about 100 mg, between about 70 mg and about 100 mg, between about 75 mg and about 100 mg, between about 80 mg and about 100 mg, between about 85 mg and about 100 mg, between about 90 mg and about 100 mg, or between about 95 mg and about 100 mg, total dose per day).

[0042] In some embodiments, Compound (I) is administered, such as orally, at a dosage of about 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, or any value between about 10 mg and about 60 mg, twice per day (e.g., between about 15 mg and 60 mg, between about 20 mg and 60 mg, between about 25 mg and 60 mg, between about 30 mg and 60 mg, between about 35 mg and 60 mg, between about 40 mg and 60 mg, between about 45 mg and 60 mg, or between about 50 mg and 60 mg, twice per day; or between about 15 mg and 55 mg, between about 20 mg and 55 mg, between about 25 mg and 55 mg, between about 30 mg and 55 mg, between about 35 mg and 55 mg, between about 40 mg and 55 mg, between about 45 mg and 55 mg, or between about 50 mg and 55 mg, twice per day; or between about 15 mg and 50 mg, between about 20 mg and 50 mg, between about 25 mg and 50 mg, between about 30 mg and 50 mg, between about 35 mg and 50 mg, between about 40 mg and 50 mg, or between about 45 mg and 50 mg, twice per day). In some embodiments, Compound (I) is administered at a dosage of about 50 mg twice per day.

[0043] In some embodiments, Compound (I) is administered, such as orally, at a dosage of about 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, or any value between about 20 mg and about 130 mg, or between about 20 mg and about 150 mg once per day (e.g., between about 15 mg and about 150 mg, between about 20 mg and about 150 mg, between about 25 mg and about 150 mg, between about 30 mg and about 150 mg, between about 35 mg and about 150 mg, between about 40 mg and about 150 mg, between about 45 mg and about 150 mg, between about 50 mg and about 150 mg, between about 55 mg and about 150 mg, between about 60 mg and about 150 mg, between about 65 mg and about 150 mg, between about 70 mg and about 150 mg, between about 75 mg and about 150 mg, between about 80 mg and about 150 mg, between about 85 mg and about 150 mg, between about 90 mg and about 150 mg, between about 95 mg and about 150 mg, or between about 100 mg and about 150 mg, once per day; between about 15 mg and about 130 mg, between about 20 mg and about 130 mg, between about 25 mg and about 130 mg, between about 30 mg and about 130 mg, between about 35 mg and about 130 mg, between about 40 mg and about 130 mg, between about 45 mg and about 130 mg, between about 50 mg and about 130 mg, between about 55 mg and about 130 mg, between about 60 mg and about 130 mg, between about 65 mg and about 130 mg, between about 70 mg and about 130 mg, between about 75 mg and about 130 mg, between about 80 mg and about 130 mg, between about 85 mg and about 130 mg, between about 90 mg and about 130 mg, between about 95 mg and about 130 mg, or between about 100 mg and about 130 mg, once per day; or between about 15 mg and about 125 mg, between about 20 mg and about 125 mg, between about 25 mg and about 125 mg, between about 30 mg and about 125 mg, between about 35 mg and about 125 mg, between about 40 mg and about 125 mg, between about 45 mg and about 125 mg, between about 50 mg and about 125 mg, between about 55 mg and about 125 mg, between about 60 mg and about 125 mg, between about 65 mg and about 125 mg, between about 70 mg and about 125 mg, between about 75 mg and about 125 mg, between about 80 mg and about 125 mg, between about 85 mg and about 125 mg, between about 90 mg and about 125 mg, between about 95 mg and about 125 mg, or between about 100 mg and about 125 mg, once per day; or between about 15 mg and about 120 mg, between about 20 mg and about 120 mg, between about 25 mg and about 120 mg, between about 30 mg and about 120 mg, between about 35 mg and about 120 mg, between about 40 mg and about 120 mg, between about 45 mg and about 120 mg, between about 50 mg and about 120 mg, between about 55 mg and about 120 mg, between about 60 mg and about 120 mg, between about 65 mg and about 120 mg, between about 70 mg and about 120 mg, between about 75 mg and about 120 mg, between about 80 mgand about 120 mg, between about 85 mg and about 120 mg, between about 90 mg and about 120 mg, between about 95 mg and about 120 mg, or between about 100 mg and about 120 mg, once per day; or between about 15 mg and about 115 mg, between about 20 mg and about 115 mg, between about 25 mg and about 115 mg, between about 30 mg and about 115 mg, between about 35 mg and about 115 mg, between about 40 mg and about 115 mg, between about 45 mg and about 115 mg, between about 50 mg and about 115 mg, between about 55 mg and about 115 mg, between about 60 mg and about 115 mg, between about 65 mg and about 115 mg, between about 70 mg and about 115 mg, between about 75 mg and about 115 mg, between about 80 mg and about 115 mg, between about 85 mg and about 115 mg, between about 90 mg and about 115 mg, between about 95 mg and about 115 mg, or between about 100 mg and about 115 mg, once per day; or between about 15 mg and about 110 mg, between about 20 mg and about 110 mg, between about 25 mg and about 110 mg, between about 30 mg and about 110 mg, between about 35 mg and about 110 mg, between about 40 mg and about 110 mg, between about 45 mg and about 110 mg, between about 50 mg and about 110 mg, between about 55 mg and about 110 mg, between about 60 mg and about 110 mg, between about 65 mg and about 110 mg, between about 70 mg and about 110 mg, between about 75 mg and about 110 mg, between about 80 mg and about 110 mg, between about 85 mg and about 110 mg, between about 90 mg and about 110 mg, between about 95 mg and about 110 mg, or between about 100 mg and about 110 mg, once per day; or between about 15 mg and about 105 mg, between about 20 mg and about 105 mg, between about 25 mg and about 105 mg, between about 30 mg and about 105 mg, between about 35 mg and about 105 mg, between about 40 mg and about 105 mg, between about 45 mg and about 105 mg, between about 50 mg and about 105 mg, between about 55 mg and about 105 mg, between about 60 mg and about 105 mg, between about 65 mg and about 105 mg, between about 70 mg and about 105 mg, between about 75 mg and about 105 mg, between about 80 mg and about 105 mg, between about 85 mg and about 105 mg, between about 90 mg and about 105 mg, between about 95 mg and about 105 mg, or between about 100 mg and about 105 mg, once per day; or between about 15 mg and about 100 mg, between about 20 mg and about 100 mg, between about 25 mg and about 100 mg, between about 30 mg and about 100 mg, between about 35 mg and about 100 mg, between about 40 mg and about 100 mg, between about 45 mg and about 100 mg, between about 50 mg and about 100 mg, between about 55 mg and about 100 mg, between about 60 mg and about 100 mg, between about 65 mg and about 100 mg, between about 70 mg and about 100 mg, between about 75 mg and about 100 mg, between about 80 mg and about 100 mg,between about 85 mg and about 100 mg, between about 90 mg and about 100 mg, or between about 95 mg and about 100 mg, once per day). In some embodiments, Compound (I) is administered at a dosage of about 150 mg once per day. In some embodiments, Compound (I) is administered at a dosage of about 100 mg once per day. In some embodiments, Compound (I) is administered at a dosage of about 50 mg once per day. In some embodiments, Compound (I) is administered at a dosage of about 25 mg once per day.

[0044] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg per day before optionally being reduced to 50 mg per day. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg per day before optionally being reduced to 50 mg per day and further optionally being subsequently reduced to 25 mg per day.

[0045] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg per day before being reduced to 50 mg per day. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg per day before being reduced to 50 mg per day and further being subsequently reduced to 25 mg per day.

[0046] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg twice daily before optionally being reduced to 50 mg once daily. In some embodiments, Compound (I) is administered, such as orally, ata dosage of 50 mg twice daily before optionally being reduced to 50 mg once daily and further optionally being subsequently reduced to about 25 mg once daily.

[0047] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg twice daily before being reduced to 50 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg twice daily before being reduced to 50 mg once daily and further being subsequently reduced to about 25 mg once daily.

[0048] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily and further optionally being subsequently reduced to 10 mg once daily.

[0049] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily. In some embodiments, Compound(I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily and further being subsequently reduced to 10 mg once daily.

[0050] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 20 mg once daily before optionally being reduced to 10 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 25 mg once daily before optionally being reduced to 10 mg once daily and further optionally subsequent dosing is discontinued.

[0051] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 25 mg once daily before being reduced to 10 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 25 mg once daily before being reduced to 10 mg once daily and further subsequent dosing is discontinued.

[0052] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 200 mg once daily before optionally being reduced to 100 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 200 mg once daily before optionally being reduced to 100 mg once daily and further optionally being subsequently reduced to 50 mg once daily.

[0053] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 200 mg once daily before being reduced to 100 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 200 mg once daily before being reduced to 100 mg once daily and further being subsequently reduced to 50 mg once daily.

[0054] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 150 mg once daily before optionally being reduced to 100 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 150 mg once daily before optionally being reduced to 100 mg once daily and further optionally being subsequently reduced to 50 mg once daily.

[0055] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 150 mg once daily before being reduced to 100 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 150 mg once daily before being reduced to 100 mg once daily and further being subsequently reduced to 50 mg once daily.

[0056] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before optionally being reduced to 50 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg once daily beforeoptionally being reduced to 50 mg once daily and further optionally being reduced to 25 mg once daily.

[0057] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before being reduced to 50 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before being reduced to 50 mg once daily and further being subsequently reduced to 25 mg once daily.

[0058] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily and further optionally subsequent dosing is discontinued.

[0059] In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily. In some embodiments, Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily and further subsequent dosing is discontinued.

[0060] In particular embodiments, the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprises administering a HIF-2a-inhibitor, particularly Compound (I), wherein the administration of the compound achieves an AUCtau that is above 15 h*pg / mL in the subject. In particular embodiments, administration of the compound achieves an AUCtau that is above 16 h*pg / mL in the subject, more particularly an AUCtau that is above 17 h*pg / mL in the subject, more particularly an AUCtau that is above 18 h*pg / mL in the subject, and more particularly an AUCtau that is above 19 h*pg / mL in the subject. In particular embodiments, the administration of the compound achieves an AUCtau that is above 20 h*pg / mL in the subject. In still more particular embodiments, administration of the compound achieves an AUCtau that is above 21 h*pg / mL in the subject, more particularly an AUCtau that is above 22 h*pg / mL in the subject, more particularly an AUCtau that is above 23 h*pg / mL in the subject, and still more particularly an AUCtau that is above 24 h*pg / mL in the subject.

[0061] In particular embodiments, the method of treating cancer in a subject in need of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprises administering a HIF-2a inhibitor, particularly Compound (I), wherein the administration of the compoundachieves an AUC® that is above 15 h*pg / mL in the subject. In particular embodiments, administration of the compound achieves an AUCoo that is above 16 h*pg / mL in the subject, more particularly an AUCoo that is above 17 h*pg / mL in the subject, more particularly an AUCoo that is above 18 h*pg / mL in the subject, and more particularly an AUCoo that is above 19 h*pg / mL in the subject. In particular embodiments, the administration of the compound achieves an AUCoo that is above 20 h*pg / mL in the subject. In still more particular embodiments, administration of the compound achieves an AUCoo that is above 21 h*pg / mL in the subject, more particularly an AUCoo that is above 22 h*pg / mL in the subject, more particularly an AUCoo that is above 23 h*pg / mL in the subject, and still more particularly an AUCoo that is above 24 h*pg / mL in the subject.

[0062] In some particular embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, results in a median time to response that is less than about 4 months, more particularly less than about 3.5 months, and still more particularly less than about3 months.

[0063] In particular embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, results in a decreased incidence of progression during treatment. In some embodiments, treatment results in a decreased incidence of progression for at least about 2 weeks of treatment, such as, for example, about 3 weeks of treatment, or about4 weeks of treatment, or about 5 weeks of treatment, or about 6 weeks of treatment, or about 7 weeks of treatment, or about 8 weeks of treatment, or about 9 weeks of treatment, or about 10 weeks of treatment, or about 11 weeks of treatment, or about 12 weeks of treatment, or at from about 2 weeks to about 12 weeks of treatment. In particular embodiments, incidence of progression is determined by CT scans, or according to RECIST 1.1.

[0064] In some embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, slows or stops disease progression after a certain duration of time on treatment. In some embodiments, disease progression stops or slows after a duration of time on treatment that is less than 15 weeks, or less than 20 weeks, or less than 21 weeks, or less than 22 weeks, or less than 23 weeks, or less than 24 weeks, or less than 25 weeks, or less than 26 weeks, or less than 27 weeks, or less than 28 weeks, or less than 29 weeks, or less than 30weeks. In certain such embodiments, continued administration of the HIF-2a inhibitor after the duration of time results in stable disease or disease reduction. In some embodiments, the methods, compound for use, and use of a compound according to this disclosure results in a time to response of less than about 12 weeks, less than 15 weeks, or less than 20 weeks, or less than 21 weeks, or less than 22 weeks, or less than 23 weeks, or less than 24 weeks, or less than 25 weeks, or less than 26 weeks, or less than 27 weeks, or less than 28 weeks, or less than 29 weeks, or less than 30 weeks.

[0065] In some embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, results in reduced rate of primary disease progression when compared to a suitable control. A suitable control can be, e.g., treatment with a comparator HIF-2a inhibitor (e.g., belzutifan) in the same patient population. In some embodiments, the rate of primary progression is less than about 30%, or less than about 25%, or less than about 20%.

[0066] In some embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, results in extended progression free survival when compared to a suitable control. A suitable control can be, e.g., treatment with a comparator HIF-2a inhibitor (e.g., belzutifan) in the same patient population. In some embodiments, progression free survival is greater than 5 months, or greater than 6 months, or greater than 7 months, or greater than 8 months, or greater than 9 months, or greater than 10 months, or at least 11 months, or at least 12 months.

[0067] In some embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, results in stable disease. In some embodiments, the stable disease is for a duration of time of at least about 5 months, or at least about 6 months, or at least about 7 months, or at least about 8 months, or at least about 9 months, or at least about 10 months, or at least about 11 months, or at least about 12 months. In some embodiments, the stable disease is for a duration of time of at least 5 months, or at least 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months. In some embodiments, the stable disease is for the duration of treatment.

[0068] In some embodiments, the method of treatment, the HIF-2a inhibitor for use in a method of treating cancer, or the use of a HIF-2a inhibitor in the manufacture of a medicamentfor treating cancer, results in tumor size reduction. In some embodiments, the tumor size is reduced by 10% or more, such as by 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[0069] As described herein, an effective dose of Compound (I) may be an amount that, when administered in one or more doses to a subject, produces a desired result relative to a healthy subject. For example, for a subject experiencing a particular disorder, an effective dose may be one that improves a diagnostic parameter, measure, marker and the like of that disorder by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or more than 90% up to 100%, or any value between about 5% and 100%, where 100% is defined as the diagnostic parameter, measure, marker and the like, exhibited by a healthy subject.

[0070] A therapeutically effective dose of Compound (I) may be an amount that provides the specific pharmacological effect for which the compound is administered to a subject in need of such treatment. For treatment, a therapeutically effective dose may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with a disease, delay disease progression, result in stable disease, prolong survival, decrease the dose of other medication(s) required to treat the disease, or a combination thereof. With respect to cancer specifically, a therapeutically effective dose may, for example, result in the killing of cancer cells, reduce cancer cell counts, reduce tumor burden, eliminate tumors or metastasis, or reduce metastatic spread. A therapeutically effective dose may vary based on, for example, one or more of the following: the age and weight of the subject, the subject’s overall health, the stage of the subject’s disease, the route of administration, and prior or concomitant treatments. The therapeutically effective dose may be administered as a single quantity or as multiple, smaller quantities (e.g., as one tablet with “x” amount, as two tablets each with “x / 2” amount, etc.).

[0071] The methods of this disclosure may be associated with limited adverse events. For example, administration of a therapeutically effective amount of Compound (I) may not result in grade 3 or higher adverse events. In some embodiments, administration of a therapeutically effective amount of Compound (I) may not result in grade 4 adverse events. In some embodiments, the methods of this disclosure are not associated with higher incidence of adverse events when compared with a suitable control. A suitable control may be administration of a comparator HIF-2a inhibitor (e.g., belzutifan) in the same patient 1population. The grade of an adverse event is determinable by those skilled in the art. Guidelines for determining adverse event grades include, e.g., the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Exemplary adverse events include, for example, decreased hemoglobin, anemia, dehydration, hypoxia, dizziness, nausea, diarrhea, fatigue, headache, vomiting, musculoskeletal pain, pollakiuria, dyspnea, increased creatine, increased alanine aminotransferase, decreased sodium, increased potassium, increased aspartate aminotransferase, increased glucose, increased gamma-glutamyltransferase, and decrease in lymphocyte counts.

[0072] In some embodiments, the subject may have a mutation in one or more gene(s) encoding a metabolic enzyme, which is associated with the metabolism and excretion of certain drugs. Such subjects may, for example, have a mutation or deletion of the UGT2B17 gene or the gene encoding CYP2C19. Additionally or alternatively, the subject may be a dual UGT2B17 and CYP2C19 poor metabolizer. For some known HIF-2a inhibitors (e.g., belzutifan), such subjects are not ideal for treatment due to potential increases in exposure that may increase the incidence or severity of severe side effects like anemia. Compound (I), on the other hand, is not significantly metabolized by UGT2B17 and CYP2C19, and therefore such subjects are still suitable for treatment with the Compound (I). In some embodiments, the methods of this disclosure result in less incidence of adverse events in certain patient populations when compared to a suitable control. In some embodiments, the patient population includes patients that are poor UGT2B17 and / or CYP2C19 metabolizers. A suitable control may be treatment of a subject in the same patient population with a comparator HIF-2a inhibitor (e.g., belzutifan).

[0073] In some embodiments, a subject treated using the methods described herein is not at an increased risk of anemia. In some embodiments, a subject treated using the methods described herein maintains a hemoglobin level of 8 g / dL or higher.

[0074] In some embodiments, a subject treated using the methods described herein is not at an increased risk of hypoxia. In some embodiments, a subject treated using the methods described herein maintains an oxygen saturation level of 88% or above. In some embodiments, the oxygen saturation level is maintained at rest. In some embodiments, the oxygen saturation level is maintained during exercise.

[0075] In some embodiments the methods described herein may lead to longer time on treatment as compared to a suitable control. In some embodiments, the time on treatment is atleast 6 months, or at least 7 months, or at least 8 months, or at least 9 months, or at least 10 months, or at least 11 months, or at least 12 months, or at least 13 months, or at least 14 months, or at least 15 months, or at least 16 months, or at least 17 months, or at least 18 months, 19 months, or at least 20 months, or at least 21 months, or at least 22 months, or at least 23 months, or at least 24 months. Without wishing to be bound by theory, the half-life of Compound (I) allows for straightforward management of adverse events, allowing for patients to stay on treatment even if brief interruptions are used to manage adverse events. In some embodiments, the methods according to this disclosure may result in fewer treatment disruptions (including fewer dose reductions) and / or fewer treatment discontinuations for a patient group or group of patients, as compared to a suitable control. A suitable control may be, for example, treatment with a comparator HIF-2a inhibitor (e.g., NKT2152, DFF332).

[0076] In some embodiments, a subject may be administered a HIF-2a inhibitor as described herein until a suitable clinical endpoint is reached, for example, disease progression, remission, or other clinical endpoint suitable based on the subject’s cancer or intolerance.

[0077] In some embodiments, a subject administered a HIF-2a inhibitor according to the methods described herein experience suppression of EPO levels compared to baseline while on treatment. In some embodiments, the suppression of EPO is maintained for more than 4 weeks of treatment, such as more than 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, or at least 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or more than 24 months. In some embodiments, EPO levels are suppressed compared to baseline for a duration of time of at least 10 weeks. This includes 10 weeks, 11 weeks, 12 weeks, 13 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, or at least 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, or more than 24 months. In some embodiments, EPO levels are suppressed compared to baseline for a duration of time of at least 13 weeks. In some embodiments, the suppression of EPO is maintained for the duration of treatment. Accordingly, provided herein is a method of treating cancer (e.g., ccRCC) in a subject in need thereof comprising administering a daily dose of a HIF-2a inhibitor, wherein the daily dose is sufficient to suppress serum EPO levels for at least 10 weeks.

[0078] In some embodiments, the serum EPO levels are suppressed by at least 10% from baseline. This includes 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80%, including any value therebetween, from baseline. In some embodiments, the serum EPO levels are suppressed by at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% from baseline. In some embodiments, the serum EPO levels are suppressed by 50% to 80% from baseline. In some embodiments, the serum EPO levels are suppressed by 60% to 80% from baseline.

[0079] In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a median percent decrease in serum EPO levels, or a percent decrease greater than a value within about 30% above or below a median percent decrease in serum EPO levels, derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC), such as greater than a value about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a median percent decrease in serum EPO levels. In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a median percent decrease in serum EPO levels, derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a median percent decrease in serum EPO levels, derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a tertile (i.e., the 33rdor 66thpercentile), or a percent decrease greater than a value within about 30% above or below a tertile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC), such as greater than a value about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a tertile. In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a tertile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a tertile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a quartile (i.e., the 25th, 50th, or 75thpercentile),or a percent decrease greater than a value within about 30% above or below a quartile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC), such as a value greater than about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a quartile. In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a quartile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a quartile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a best cut value or a percent decrease greater than a value within about 30% above or below a best cut value, determined based on the overall survival and / or progression free survival for a group of subjects known to have the same disease (e.g., ccRCC), such as a value greater than about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a best cut value. In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a best cut value determined based on the overall survival and / or progression free survival for a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, the subject’s maximum suppression of serum EPO levels is a percent decrease greater than a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a best cut value determined based on the overall survival and / or progression free survival for a group of subjects known to have the same disease (e.g., ccRCC).Selection of patients

[0080] In various embodiments, the methods according to this disclosure may be used in selected patients.

[0081] The methods according to this disclosure may be used in patients with renal impairment, for example, mild or moderate renal impairment. In some embodiments, methods according to this disclosure may be used in patients with creatine clearance (CLCR) > 40 ml / minute as determined by the Cockcroft-Gault equation. In some embodiments, methods according to this disclosure may be used in patients with a glomerular filtration rate > 30 ml / min / 1.73 m2, > 45 ml / min / 1.73 m2, or > 60 ml / min / 1.73 m2.

[0082] In some embodiments, the methods according to this disclosure may be useful in patients having certain biomarkers. In some embodiments, the patient has increased expression of one or more genes regulated by HIF-2a (e.g., PDGFB, SERPINE1 , EPAS1, ADM, AKAP12, DLL4, GLUT1, GLUT3, SLC2A1, SLC2A3, NDRG1, CXCL8, CCND1, CXCR4, EPO, VEGFA and the like) as compared to a suitable control. A suitable control may be a similar sample from (a) a healthy control, (b) a sample taken from the same subject at an earlier timepoint, or (c) a sample from a subject with another disease, disorder and / or condition not responsive to HIF-2a inhibition. The expression of genes may be assessed using one or more suitable samples (e.g., a tumor biopsy, blood sample, surgical resection sample, etc.). In particular embodiments, the suitable sample is a tumor biopsy.

[0083] Alternatively or in addition, in some embodiments, the methods according to this disclosure may be used in patients identified or previously identified as having a biomarker of hypoxia or pseudohypoxia, microsatellite instability, or high tumor mutational burden as measured in a relevant tissue or sample.

[0084] In some embodiments, the methods according to this disclosure may be useful in patients identified or previously identified as having high baseline tumor EPO expression. Accordingly, provided herein is a method of treating cancer (e.g., ccRCC) in a subject in need thereof comprising administering a therapeutically effective amount of a HIF-2a inhibitor to the subject daily, wherein the subject has a high baseline tumor EPO expression. In some embodiments, baseline tumor expression is measured prior to administration of any therapeutic agent to the patient. In other embodiments, baseline expression may be measured after one or more prior lines of therapy, but prior to receiving treatment with a HIF-2a inhibitor according to this disclosure.

[0085] In some embodiments, high baseline tumor EPO expression is an expression above a median expression level, or an expression level above a value within about 30% above or below a median expression level, derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC), such an expression level above a value about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a median expression level. In some embodiments, high baseline tumor EPO expression is an expression level above a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a median expression level derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expression is an expressionabove a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a median expression level derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expression is an expression above a tertile (i.e., the 33rdor 66thpercentile), or an expression level above a value within about 30% above or below a tertile, derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC), such as an expression level above a value about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a tertile. In some embodiments, high baseline tumor EPO expression is an expression above a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a tertile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expression is an expression above a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a tertile expression level derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expression is am expression above a quartile (i.e., the 25th, 50th, or 75thpercentile), or an expression above a value within about 30% above or below a quartile, derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC), such as an expression level above a value about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a quartile. In some embodiments, high baseline tumor EPO expression is an expression above a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a quartile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expressionis an expression above a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a quartile derived from samples obtained from a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expression is an expression above a best cut value or an expression above a value within about 30% above or below a best cut value, determined based on the overall survival and / or progression free survival for a group of subjects known to have the same disease (e.g., ccRCC), such as an expression above a value about 25%, or about 20%, or about 15%, or about 10%, or about 5% above or below a best cut value. In some embodiments, high baseline tumor EPO expression is an expression above a value within about 30%, 25%, 20%, 15%, 10%, or 5% above a best cut value determined based on the overall survival and / or progression free survival for a group of subjects known to have the same disease (e.g., ccRCC). In some embodiments, high baseline tumor EPO expression is an expression above a value within about 30%, 25%, 20%, 15%, 10%, or 5% below a best cut valuedetermined based on the overall survival and / or progression free survival for a group of subjects known to have the same disease (e.g., ccRCC).

[0086] The methods according to this disclosure are useful in subjects identified as being responsive to treatment with a HIF-2a inhibitor (e.g., Compound (I)). Subjects responsive to treatment with a HIF-2a inhibitor can be identified by measuring a biomarker (e.g., EPO) from a suitable sample (e.g., a serum, blood or tumor biopsy). In some embodiments, responsiveness is characterized by a high baseline tumor EPO expression as described above. In further embodiments, responsiveness is characterized by a greater maximum suppression of serum EPO measured after treatment with the HIF-2a inhibitor compared to a reference level. The reference level can be based on a median, tertile, quartile, or best cut value as described elsewhere herein. In some embodiments, treatment of a responsive patient using the methods according to this disclosure results in reduction of tumor EPO and / or serum EPO expression. Reduction of EPO expression can be determined by measuring the baseline tumor and / or serum level of EPO in the subject; administering the HIF-2a inhibitor to the subject; and measuring the post-treatment tumor and / or serum level of EPO in the subject. In one or more embodiments, EPO expression predicts subject(s) who are expected to be rapid progressors while undergoing cancer treatment with Compound (I)) according to this disclosure. Rapid progressors are subjects who experience disease progression and are less responsive to cancer treatment compared to other subjects undergoing the same treatment. In one or more embodiments, non-rapid progressors undergoing cancer treatment with Compound (I)) according to this disclosure experience deeper reduction of serum level of EPO and have higher baseline EPO expression than rapid progressors undergoing the same treatment. In one or more embodiments, a subject with higher baseline serum level of EPO is less likely to experience rapid disease progression while undergoing cancer treatment with Compound (I)) according to this disclosure than a subject with a comparatively lower baseline serum level of EPO undergoing the same treatment. In one or more embodiments, treatment with Compound (I) according to this disclosure resulted in a deeper and more sustained reduction of serum level of EPO in a subject compared to treatment with belzutifan.Oncology and Oncology-related Disorders

[0087] In one or more embodiments, a pharmaceutical composition, formulation, or unit dosage form described herein is useful in the treatment and / or prophylaxis of cancer (e.g., carcinomas, sarcomas, leukemias, lymphomas, myelomas, etc.). In certain embodiments, thecancer is HIF-2a mediated cancer. In certain embodiments, the cancer may be locally advanced and / or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or no longer responding to a treatment, such as a standard of care treatment known to one of skill in the art. In some embodiments, a pharmaceutical composition, formulation, or dosage form described herein is useful in the treatment of cancer that has been previously treated (e.g., in the same setting or an earlier setting) with an immune checkpoint inhibitor (e.g., a PD-(L)1 antagonist) and / or a VEGF or VEGFR inhibitor. Exemplary types of cancer contemplated by this disclosure include cancer of the genitourinary tract (e.g., bladder, kidney, renal cell, penile, prostate, testicular, etc.), uterus, cervix, ovary, breast, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestines, colon, or rectum), bone (e.g., chondrosarcoma), bone marrow, skin (e.g., melanoma), head and neck, liver, gall bladder, bile ducts, heart, lung, pancreas, salivary gland, adrenal gland (e.g., pheochromocytoma), thyroid, brain (e.g., gliomas), ganglia, central nervous system (CNS), peripheral nervous system (PNS), the hematopoietic system (i.e., hematological malignancies), and the immune system (e.g., spleen or thymus).

[0088] In some embodiments, Compound (I) is useful in the treatment and / or prophylaxis of hematological malignancies. Exemplary types of cancer affecting the hematopoietic system include, but are not limited to, leukemias, lymphomas and myelomas, including acute myeloid leukemia, adult T-cell leukemia, T-cell large granular lymphocyte leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute monocytic leukemia, Hodgkin’s and Non-Hodgkin’s lymphoma, Diffuse large B Cell lymphoma, and multiple myeloma.

[0089] In another embodiment, Compound (I) is useful in the treatment and / or prophylaxis of solid tumors. The solid tumor may be, for example, ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colon cancer, prostate cancer, cervical cancer, biliary cancer, pancreatic cancer, gastric cancer, esophageal cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), head-and-neck tumors, mesothelioma, melanoma, sarcomas, central nervous system (CNS) hemangioblastomas, and brain tumors (e.g., gliomas, such as astrocytoma, oligodendroglioma and glioblastomas).

[0090] In some embodiments, Compound (I) is useful in the treatment and / or prophylaxis of gastrointestinal cancer, genitourinary cancer, gynecological cancer, lung cancer, or a combination thereof.

[0091] In some embodiments, a pharmaceutical composition, formulation, or unit dosage form according to this disclosure is useful in the treatment of gastrointestinal (GI) cancer. In some embodiments, the GI cancer is colorectal cancer, pancreatic cancer, or liver cancer. In some embodiments, the GI cancer is an upper GI cancer, such as esophageal or gastric cancer. In further embodiments, the upper GI cancer is an adenocarcinoma, a squamous cell carcinoma, or any combination thereof. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as “gastric cancer”) or any combination thereof.

[0092] In some embodiments, Compound (I) is useful in the treatment of pancreatic cancer. In further embodiments, the pancreatic cancer is pancreatic neuroendocrine tumor or pancreatic adenocarcinoma.

[0093] In some embodiments, Compound (I) is useful in the treatment and / or prophylaxis of liver cancer. In further embodiments, the liver cancer is hepatocellular carcinoma. In other embodiments, the liver cancer is liver metastases.

[0094] In some embodiments, Compound (I) is useful in the treatment of genitourinary cancer. In some embodiments, the genitourinary cancer is bladder cancer, kidney cancer or prostate cancer.

[0095] In some embodiments, Compound (I) is useful in the treatment of kidney cancer. In further embodiments, the kidney cancer is renal cell carcinoma (RCC). In further embodiments, the kidney cancer is advanced or metastatic renal cell carcinoma. In still further embodiments, the renal cell carcinoma is clear cell renal cell carcinoma (ccRCC). In still further embodiments, the renal cell carcinoma is advanced or metastatic clear cell renal cell carcinoma (ccRCC). In still further embodiments, the renal cell carcinoma is unresectable locally advanced or metastatic clear cell renal cell carcinoma (ccRCC). In some embodiments, the patient has a favorable International Metastatic RCC Database Consortium (IMDC) risk score. In some embodiments, the patient has an intermediate IMDC risk score. In some embodiments, the patient has a poor IMDC risk score.

[0096] In some embodiments, Compound (I) is useful in the treatment of gynecological cancer. In some embodiments, the gynecological cancer is breast cancer, endometrial cancer, or ovarian cancer. In some embodiments, the gynecological cancer is hormone receptor positive (e.g., ERa-positive cancer, PR-positive cancer, ERa-positive and PR-positive cancer),HER2 positive cancer, HER2 over-expressing cancer, or any combination thereof. In still further embodiments, the cancer is triple negative cancer (e.g., ER, PR and HER2 negative). In further embodiments, the cancer is hormone receptor positive, HER2 negative breast cancer.

[0097] In some embodiments, Compound (I) is useful in the treatment of lung cancer. In further embodiments, the lung cancer is mesothelioma, small cell lung cancer (SCLC) or nonsmall cell lung cancer (NSCLC). In still further embodiments, the lung cancer is NSCLC, optionally lung squamous cell carcinoma or lung adenocarcinoma.

[0098] In some embodiments, Compound (I) is useful in the treatment of a neuroendocrine tumor. In further embodiments, the neuroendocrine tumor is pancreatic neuroendocrine tumor, pheochromocytoma, paraganglioma, or a tumor of the adrenal gland (e.g., neuroblastoma).

[0099] In some embodiments, Compound (I) is useful in the treatment of brain cancer. In further embodiments, the brain cancer is a glioma. In still further embodiments, the glioma is an astrocytoma, an oligodendroglioma, or a glioblastoma (e.g., glioblastoma multiforme).

[0100] In some embodiments, Compound (I) is useful in the treatment and / or prophylaxis of renal cell carcinoma or hepatocellular carcinoma.

[0101] In the aforementioned embodiments, the methods of the present disclosure may be practiced in an adjuvant setting or neoadjuvant setting. In some embodiments, the methods may be practiced in an adjuvant setting as a monotherapy or in combination with one or more immune checkpoint inhibitor(s) (e.g., inhibitors or antagonists of PD-1, PD-L1, and / or TIGIT). In certain such embodiments, the patient may be at intermediate or high risk of recurrence following surgical resection. Alternatively, in some embodiments, the methods may be practiced in a neoadjuvant setting as a monotherapy or in combination with one or more immune checkpoint inhibitor(s) (e.g., inhibitors or antagonists of PD-1, PD-L1, and / or TIGIT).

[0102] Alternatively or in addition, the methods described herein may be indicated as a first line treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In certain embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) as a first line treatment as a monotherapy or in combination with one or more immune checkpoint inhibitor(s) (e.g., an inhibitor or antagonist of PD-1 or PD-L1). Alternatively, Compound (I) is administered (e.g., at an amount of 100 mg daily) in as a first line treatment as a monotherapy or in combination with a tyrosine kinase inhibitor optionally in patients who received an immune checkpoint inhibitor as an adjuvant therapy or as part of a first-lineregimen. In some embodiments, the first-line regimen including an immune checkpoint inhibitor was in a metastatic setting.

[0103] In some embodiments, the methods of the present disclosure (e.g., administration of Compound (I) at an amount of 100 mg daily) are indicated in subjects who have been heavily pre-treated. In some embodiments, the methods described herein may be indicated as a second line, third line, or greater line of treatment, optionally in the treatment of locally advanced, unresectable, or metastatic cancer. In some embodiments, the methods described herein are indicated as a second line of treatment. In some embodiments, the methods described herein are indicated as a third line of treatment. In some embodiments, the methods described herein are indicated as a fourth line of treatment. Second line or greater lines of therapy may be indicated when a prior line of therapy is ineffective, stops working, or has intolerable side effects. When indicated as a second line or greater treatment, in some embodiments an earlier line of therapy included an immune checkpoint inhibitor, a tyrosine kinase inhibitor, and / or a serine / threonine kinase inhibitor. In some embodiments, an earlier line of therapy included an immune checkpoint inhibitor (e.g., an inhibitor or antagonist of PD-1 or PD-L1 and / or an inhibitor or antagonist of CTLA-4). In some embodiments, an earlier line of therapy included an immune checkpoint inhibitor and a tyrosine kinase inhibitor. In further embodiments, an earlier line of therapy included a tyrosine kinase inhibitor. In still further embodiments, an earlier line of therapy included a serine / threonine inhibitor. In some embodiments, an earlier line of therapy included an inhibitor or antagonist of PD-1 or PD-L1 and / or an inhibitor or antagonist of VEGF or VEGFR (e.g., a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti- VEGF antibody, an anti- VEGFR antibody). In some embodiments, the earlier line of therapy included an mTOR inhibitor. In further embodiments, an earlier line of therapy included belzutifan.

[0104] In one or more embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) as a second line or greater line of therapy as a monotherapy or in combination with a tyrosine kinase inhibitor optionally in patients who have not been treated with a tyrosine kinase inhibitor in an earlier line of therapy. In some embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) in a second line or greater line of therapy in combination with a tyrosine kinase inhibitor optionally in patients who have not been treated with a tyrosine kinase inhibitor in an earlier line of therapy.

[0105] In some embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) to a subject having ccRCC as a neoadjuvant therapy. In further embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) in combination with an immune checkpoint as neoadjuvant therapy. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 or anti-PD-Ll antibody. In some embodiments, the immune checkpoint inhibitor is zimberelimab.

[0106] In some embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) as a first line therapy in subjects having ccRCC who are treatment naive with an immunooncology agent (e.g., an immune checkpoint inhibitor). In further embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) in combination with an immune checkpoint inhibitor. In even further embodiments, the immune checkpoint inhibitor inhibits one or more immune checkpoints selected from PD-1, PD-L1, and CTLA-4, or combinations thereof.

[0107] In some embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) as a first line therapy in subjects having ccRCC. In further embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) in combination with an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 or anti-PD- Ll antibody. In some embodiments, the immune checkpoint inhibitor is zimberelimab. Certain benefits may be associated with administering Compound (I) as a first line therapy instead of a tyrosine kinase inhibitor. Tyrosine kinase inhibitors are a standard of care therapy for ccRCC. However, they are associated with adverse events. Accordingly, treatment with Compound (I) in a first line setting allows for tyrosine kinase inhibitor related adverse events to be avoided.

[0108] In some embodiments, Compound (I) is administered as a first line therapy in subjects having favorable-risk ccRCC. In further embodiments, Compound (I) is administered as a monotherapy. Favorable-risk ccRCC can be determined using, for example, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score. Favorable-risk ccRCC subjects are those identified as having no poor prognostic factors. Evaluated prognostic factors include, e.g., Karnofsky Performance Status (KPS), time from diagnosis to treatment, anemia, hypercalcemia, neutrophilia, and thrombocytosis. In one embodiment, Compound (I) is administered in an amount of 100 mg daily to a subject having favorable-risk ccRCC.

[0109] In some embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) as a first line or second line therapy in subjects having ccRCC, wherein the subject hasreceived prior therapy with an immuno-oncology agent (e.g., immune checkpoint inhibitor). In further embodiments, Compound (I) is administered (e.g., at an amount of 100 mg daily) in combination with a tyrosine kinase inhibitor. In still further embodiments, the tyrosine kinase inhibitor is cabozantinib. In some embodiments, cabozantinib is administered at an amount of 60 mg daily.

[0110] In some embodiments, this disclosure provides a method of treating a subject in need thereof, said method comprising administering 100 mg of Compound (I) and 60 mg cabozantinib to the subject daily, wherein the subject has advanced or metastatic ccRCC that has progressed during or after prior treatment with an anti-PD-1 or anti-PD-Ll immune checkpoint inhibitor. In some embodiments, the prior treatment further comprised an anti- CTLA-4 immune checkpoint inhibitor or an inhibitor of VEGF or VEGFR. In some embodiments, the prior treatment was an adjuvant therapy. In some embodiments, the prior treatment was a first line therapy.

[0111] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before optionally being reduced to 50 mg once daily. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before optionally being reduced to 50 mg once daily and further optionally being subsequently reduced to 25 mg once daily.

[0112] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before being reduced to 50 mg once daily. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before being reduced to 50 mg once daily and further being subsequently reduced to 25 mg once daily.

[0113] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily. In some embodiments, Compound (I) is administered in combinationwith a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily and further optionally subsequent dosing is discontinued.

[0114] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily. In some embodiments, and Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily and further subsequent dosing is discontinued.

[0115] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before optionally being reduced to 40 mg once daily. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before optionally being reduced to 40 mg once daily and further optionally being subsequently reduced to 20 mg once daily.

[0116] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before being reduced to 40 mg once daily. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; and cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before being reduced to 40 mg once daily and further being subsequently reduced to 20 mg once daily.

[0117] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before optionally being reduced to 40 mg once daily; and Compound (I) is administered without dosage reduction. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before optionally being reduced to 40 mg once daily and further optionally being subsequently reduced to 20 mg once daily; and Compound (I) is administered without dosage reduction.

[0118] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before being reduced to 40 mg once daily; and Compound (I) is administered without dosage reduction. In some embodiments, cabozantinib is administered, such as orally, at a dosage of 60 mg once daily before being reduced to 40 mg once daily and further being subsequently reduced to 20 mg once daily; and Compound (I) is administered without dosage reduction.

[0119] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before optionally being reduced to 50 mg once daily; and cabozantinib is administered without dosage reduction. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before optionally being reduced to 50 mg once daily and further optionally being subsequently reduced to 25 mg once daily; and cabozantinib is administered without dosage reduction.

[0120] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before being reduced to 50 mg once daily; and cabozantinib is administered without dosage reduction. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 100 mg once daily before being reduced to 50 mg once daily and further being subsequently reduced to 25 mg once daily; and cabozantinib is administered without dosage reduction.

[0121] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily; and cabozantinib is administered without dosage reduction. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before optionally being reduced to 25 mg once daily and further optionally subsequent dosing is discontinued; and cabozantinib is administered without dosage reduction.31

[0122] In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily; and cabozantinib is administered without dosage reduction. In some embodiments, Compound (I) is administered in combination with a tyrosine kinase inhibitor; the tyrosine kinase inhibitor is cabozantinib; Compound (I) is administered, such as orally, at a dosage of 50 mg once daily before being reduced to 25 mg once daily and further subsequent dosing is discontinued; and cabozantinib is administered without dosage reduction.

[0123] In some embodiments, Compound (I) is administered as a second line or greater line of therapy in subject having ccRCC. In further embodiments, Compound (I) is administered as a monotherapy.

[0124] The present disclosure also provides methods of treating or preventing other cancer- related diseases, disorders or conditions, HIF-2a inhibitors for use in a method of treating or preventing other cancer-related diseases, disorders or conditions, and uses of a HIF-2a inhibitor in the manufacture of a medicament for treating or preventing other cancer-related diseases, disorders or conditions. The use of the term(s) cancer-related diseases, disorders and conditions is meant to refer broadly to conditions that are associated, directly or indirectly, with cancer and non-cancerous proliferative disease, and includes, e.g., angiogenesis, precancerous conditions such as dysplasia, and non-cancerous proliferative diseases disorders or conditions, such as benign proliferative breast disease and papillomas. For clarity, the term(s) cancer- related disease, disorder and condition do not include cancer per se.

[0125] In general, the disclosed methods for treating or preventing cancer, or a cancer- related disease, disorder or condition, in a subject in need thereof; HIF-2a inhibitors for use in a method of treating or preventing cancer, or other cancer-related diseases, disorders or conditions; and uses of a HIF-2a inhibitor in the manufacture of a medicament for treating or preventing cancer, or other cancer-related diseases, disorders or conditions; comprise administering to the subject a pharmaceutical composition, formulation, or dosage form disclosed here. In some embodiments, the present disclosure provides methods for treating or preventing cancer, or a cancer-related disease, disorder or condition; HIF-2a inhibitors for use in a method of treating or preventing cancer, or a cancer-related disease, disorder or condition; and uses of a HIF-2a inhibitor in the manufacture of a medicament for treating or preventing cancer, or a cancer-related disease, disorder or condition; with a pharmaceutical composition,formulation, or dosage form disclosed herein and one or more additional therapies, examples of which are set forth elsewhere herein.Von-Hippel-Lindau Disease

[0126] In one or more embodiments, a pharmaceutical composition, formulation, or unit dosage form described herein, particularly containing Compound (I), is useful in the treatment and / or prophylaxis of von Hippel-Lindau (VHL) disease or VHL disease associated tumors. In some embodiments, the disease, disorder, and / or condition is VHL disease associated with renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, pancreatic neuroendocrine tumors (pNET), or solid tumors.Metabolic and Inflammatory-related Disorders

[0127] In one or more embodiments, Compound (I) is useful in the treatment and / or prophylaxis of metabolic or inflammatory -related diseases, disorders and conditions. A nonlimiting list of metabolic diseases, disorders and conditions which may be treated or prevented with Compound (I) include insulin resistance, diabetes, obesity, nonalcoholic fatty liver disease (NAFLD) (e.g., fatty liver disease and metabolic dysfunction-associated steatohepatitis (MASH) also known as nonalcoholic steatohepatitis (NASH), and the like. A non-limiting list of inflammatory-related diseases, disorders and conditions which may be treated or prevented with the compounds, such as Compound (I), and compositions of the present disclosure include allergic diseases, disorders, and conditions; cardiovascular disease, disorders and conditions (aortic valve stenosis, asthma, arteriosclerosis, atherosclerosis, cardiac ischemia, cardiac fibrosis, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), congestive heart failure, pulmonary fibrosis, pulmonary arterial hypertension (PAH), stroke, etc.); chronic kidney disease or kidney failure; colitis; inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis); anemia; inflammatory neurological diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis, etc.); musculoskeletal diseases (e.g., arthritis, rheumatoid arthritis, systemic sclerosis, asthma; fibrosis; fibromyalgia; lupus; pancreatitis; psoriasis; surgical complications (e.g., where inflammatory cytokines prevent healing); infections; allergic contact dermatitis and other eczemas, transplantation, and osteoporosis.Combination Therapy

[0128] In one or more embodiments, the methods according to this disclosure comprise administering Compound (I) in combination with one or more additional therapeutic agents. Inembodiments comprising one or more additional treatment modality, Compound (I) can be administered before, after or during treatment with the additional treatment modality. In embodiments comprising one or more additional therapeutic agent, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. If administered separately, each therapeutic agent in the combination can be given at or around the same time, or at different times. Furthermore, the therapeutic agents are administered “in combination” even if they have different forms of administration (e.g., oral capsule and intravenous), they are given at different dosing intervals, one therapeutic agent is given at a constant dosing regimen while another is titrated up, titrated down or discontinued, or each therapeutic agent in the combination is independently titrated up, titrated down, increased or decreased in dosage, or discontinued and / or resumed during a patient’s course of therapy. If the combination is formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0129] In some embodiments, one or more of the additional therapeutic agents is chemotherapy. The chemotherapy can be a chemotherapeutic agent or a combination of chemotherapeutic agents. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, pomalidomide, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites, such as methotrexate and 5 -fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine,carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher, such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g., paclitaxel, nab paclitaxel, and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes (i.e., “platinum-containing chemotherapeutic agent”), such as cisplatin, carboplatin and oxaliplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11 ; proteasome inhibitors, such as bortezomib, carfilzomib and ixazomib; topoisomerase inhibitors such as irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine; anthracyclines and pharmaceutically acceptable salts, acids or derivatives of any of the above. In certain embodiments, combination therapy comprises chemotherapy (e.g., a chemotherapy regimen) that includes one or more chemotherapeutic agents. In one embodiment, combination therapy comprises chemotherapy comprising one or more of a taxoid (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), a fluoropyrimidine- containing chemotherapeutic agent (e.g., fluorouracil, capecitabine, floxuridine), a platinum- containing chemotherapeutic agent, and / or gemcitabine. In some embodiments, the chemotherapy is FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (e.g., folinic acid, fluorouracil, and irinotecan), FOLFIRINOX (e.g., fluorouracil, leucovorin, irinotecan, and oxaliplatin), CAPOX (capecitabine and oxaliplatin), or NALIRIFOX (fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin).

[0130] In some embodiments, one or more of the additional therapeutic agents are immune checkpoint inhibitors. As used herein, the term “immune checkpoint inhibitor” refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms “immune checkpoint inhibitor”, “checkpoint inhibitor” and “CPI” may be used herein interchangeably.Immune checkpoint inhibitors may antagonize an inhibitory or co-inhibitory immune checkpoint by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated in various types of cancer cells, that can be antagonized include, but are not limited to, PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuator); CTLA-4 (cytotoxic T-lymphocyte associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoreceptor with Ig and ITIM domains); CD276 (B7-H3), PD-L2, Galectin 9, CEACAM-1, CD69, Galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, and Killer Inhibitory Receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs), and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Also contemplated are other less well-defined immune checkpoints that have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands such B7-H3 (also known as CD276) and B7- H4 (also known as B7-S1, B7x and VCTN1)).

[0131] In some embodiments, the methods described herein comprise administering to the subject, in addition to Compound (I), a therapeutically effective amount of a PD-1 inhibitor or a PD-L1 inhibitor (i.e., a PD-(L)1 inhibitor). In some embodiments, the methods described herein further comprise administering to the subject a therapeutically effective amount of a PD- 1 inhibitor. In some embodiments, the methods described herein further comprise administering to the subject a therapeutically effective amount of a PD-L1 inhibitor.

[0132] In some embodiments, the PD-1 inhibitor or PD-L1 inhibitor comprises one or more agents selected from avelumab, atezolizumab, balstilimab, budigalimab, camrelizumab, cemiplimab, cosibelimab, dostarlimab, durvalumab, envafolimab, ezabenlimab, nivolumab, pembrolizumab, penpulimab, pidilizumab, pimivalimab, retifanlimab, sasanlimab, serplulimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimberelimab.

[0133] In some embodiments, the PD-L1 inhibitor is avelumab. In some embodiments, the PD-L1 inhibitor is atezolizumab. In some embodiments, the PD-L1 inhibitor is durvalumab. In some embodiments, the PD-L1 inhibitor is envafolimab.

[0134] In some embodiments, the PD-1 inhibitor is nivolumab. In some embodiments, the PD-1 inhibitor is balstilimab. In some embodiments, the PD-1 inhibitor is budigalimab. Insome embodiments, the PD-1 inhibitor is camrelizumab. In some embodiments, the PD-1 inhibitor is cemiplimab. In some embodiments, the PD-1 inhibitor is cosibelimab. In some embodiments, the PD-1 inhibitor is dostarlimab. In some embodiments, the PD-1 inhibitor is ezabenlimab. In some embodiments, the PD-1 inhibitor is pembrolizumab. In some embodiments, the PD-1 inhibitor is pidilizumab. In some embodiments, the PD-1 inhibitor is pimivalimab. In some embodiments, the PD-1 inhibitor is retifanlimab. In some embodiments, the PD-1 inhibitor is sasanlimab. In some embodiments, the PD-1 inhibitor is spartalizumab. In some embodiments, the PD-1 inhibitor is sintilimab. In some embodiments, the PD-1 inhibitor is tislelizumab. In some embodiments, the PD-1 inhibitor is toripalimab. In some embodiments, the PD-1 inhibitor is zimberelimab.

[0135] In some embodiments, Compound (I) is administered in combination with zimberelimab. In some embodiments, zimberelimab is administered at a dose of about 100 mg to about 600 mg or about 200 mg to about 600 mg, about 600 mg to about 800 mg. In some embodiments, zimberelimab is administered at a dose of about 100 mg, 150 mg, 200 mg, 220 mg, 240 mg, 260 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, or 460 mg. Doses of zimberelimab may be administered once a week, or less frequently (e.g., once every two, three, four, five, six weeks, or more). In some embodiments, a dosing cycle comprises administering zimberelimab at a dose of about 360 mg once every three weeks or at a dose of about 480 mg once every four weeks.

[0136] In some embodiments, the PD-1 inhibitor is administered once every two weeks, once every three weeks, or once every four weeks to the subject. In some embodiments, the PD-1 inhibitor is administered once every two weeks. In some embodiments, the PD-1 inhibitor is administered once every three weeks. In some embodiments, the PD-1 inhibitor is administered once every four weeks to the subject.

[0137] In some embodiments, the PD-L1 inhibitor is administered once every two weeks, once every three weeks, or once every four weeks to the subject. In some embodiments, the PD-L1 inhibitor is administered once every two weeks. In some embodiments, the PD-L1 inhibitor is administered once every three weeks. In some embodiments, the PD-L1 inhibitor is administered once every four weeks to the subject.

[0138] In some embodiments, Compound (I) is administered in combination with an immune checkpoint inhibitor that is a TIGIT antagonist. In further embodiments, the TIGIT antagonist can be an antagonistic TIGIT antibody. Suitable antagonistic anti-TIGIT antibodiesinclude, but are not limited to, monospecific antibodies such as AGEN1327, AB308 (WO2021247591), BMS 986207, COM902, domvanalimab, belrestotug, etigilimab, IBI-929, JS006, dargistotug, ociperlimab, SEA-TGT, tiragolumab, vibostolimab; as well as bi-specific antibodies such as AGEN1777 and AZD2936. In certain embodiments, an immune checkpoint inhibitor is an antagonistic anti-TIGIT antibody disclosed in WO2017152088 or WO2021247591. In certain embodiments, an immune checkpoint inhibitor is domvanalimab or AB308.

[0139] In some embodiments, Compound (I) is administered in combination with a VEGF inhibitor or a VEGFR inhibitor. In some embodiment, the VEGF or VEGFR inhibitor is a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti- VEGF antibody, or an anti-VEGFR antibody. In some embodiments, Compound (I) is administered in combination with axitinib, bevacizumab, cabozantinib, lenvatinib, pazopanib, ramucirumab, regorafenib, sunitinib, sorafenib, tivozanib, or zanzalintinib. In some embodiments, Compound (I) is administered in combination with axitinib, cabozantinib, lenvatinib, pazopanib, regorafenib, sunitinib, sorafenib, or tivozanib. In some embodiments, combining Compound (I) with a VEGF or VEGFR inhibitor can allow for dose reductions of the VEGF or VEGFR inhibitor without losing efficacy associated with the VEGF or VEGF inhibitor. Such dose reductions may also result in fewer side effects associated with the VEGF or VEGFR inhibitor.

[0140] In some embodiments, Compound (I) is administered in combination with cabozantinib. In certain such embodiments, the methods of this disclosure are associated with a reduced risk for cardiac related adverse events (e.g., myocardial infarction, and heart failure). In some embodiments, the methods of this disclosure may be indicated in subjects identified as being at higher risk for cardiac related adverse events. Without wishing to be bound by theory, cardiac related adverse events may be associated with QT prolongation effect. In some embodiments, administration of Compound (I) does not result in QT prolongation.

[0141] In some embodiments, Compound (I) is administered in combination with an additional treatment modality. Exemplary treatment modalities include, but are not limited to, surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy.

[0142] In some embodiments, the methods described herein are for treating kidney cancer, optionally clear cell renal cell carcinoma, by administering Compound (I) in combination with:(a) an mTOR inhibitor; or (b) a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody; or (c) an mTOR inhibitor and an additional therapy selected from a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, and an anti-VEGFR antibody; (d) a checkpoint inhibitor; or (e) a checkpoint inhibitor and an additional therapy selected from a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, and an anti-VEGFR antibody. The checkpoint inhibitor may be a CTLA-4 antagonist, a PD-L1 antagonist, a PD-1 antagonist, or a TIGIT antagonist. In some embodiments, the checkpoint inhibitor may be a CTLA-4 antagonist, a PD-L1 antagonist, or a PD-1 antagonist. In some embodiments, the kidney cancer is a von-Hippel-Lindau (VHL) disease-associated cancer.

[0143] In some embodiments, the present disclosure contemplates the use of Compound (I) in the treatment of liver cancer, optionally hepatocellular carcinoma, in combination with: (a) a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, or an anti-VEGFR antibody; or (b) a checkpoint inhibitor; or (d) a checkpoint inhibitor and an additional therapy selected from a small molecule VEGFR inhibitor, a small molecule VEGF kinase inhibitor, an anti-VEGF antibody, and an anti-VEGFR antibody. The checkpoint inhibitor may be a CTLA-4 antagonist, a PD-L1 antagonist, or PD-1 antagonist, or a TIGIT antagonist. In some embodiments, the checkpoint inhibitor may be a CTLA-4 antagonist, a PD-L1 antagonist, or a PD-1 antagonist. In some embodiments, the kidney cancer is a von-Hippel-Lindau (VHL) disease-associated cancer. In some embodiments, the liver cancer is inoperable, has extensive liver tumor burden, locally advanced or metastatic.

[0144] In one aspect of the disclosure there is provided a method of treating cancer in a subject in need of treatment, comprising administering a HIF-2a inhibitor, particularly Compound (I), to a subject in need of treatment in combination with another therapeutic agent. In another aspect of the disclosure, there is provided a HIF-2a inhibitor for use in a method of treating cancer, comprising administering the HIF-2a inhibitor, particularly Compound (I), to a subject in need of treatment in combination with another therapeutic agent. In another aspect of the disclosure, there is provided a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering the HIF-2a inhibitor, particularly Compound (I), to a subject in need of treatment in combination with another therapeutic agent. In another aspect of the disclosure, there is provided a use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, wherein the HIF-2a inhibitor, particularly Compound (I), is formulated for administration in combination with another therapeutic agent.In particular embodiments, the other therapeutic agent is a tyrosine kinase inhibitor; more particularly, the tyrosine kinase inhibitor inhibits the tyrosine kinase activity of MET, VEGFR- 1, VEGFR-2, VEGFR-2, AXL, RET, ROS1, TYR03, MER, KIT, TRKB, FLT-3, TIE-2, or any combination thereof.

[0145] In another aspect, the present disclosure contemplates the use of Compound (I) in combination with one or more additional therapeutic agents useful in the treatment of metabolic and / or inflammatory-related diseases, disorders or conditions.

[0146] In some embodiments, one or more additional therapeutic agents comprise nonsteroidal anti-inflammatory drugs (NS AID), acyclooxygenase-2 (COX-2) inhibitors, or steroids.

[0147] In some embodiments, one or more additional therapeutic agents comprise JAK inhibitors.

[0148] In some embodiments, one or more additional therapeutic agents comprise immune checkpoint inhibitors. Suitable immune checkpoint inhibitors are described above.

[0149] In some embodiments, one or more additional therapeutic agents comprise cytokine suppressive anti-inflammatory drugs (CSAIDs); antibodies to, or antagonists of, other human cytokines or growth factors, for example, TNF, LT, IL-10, IL-2, IL-6, IL-7, IL-8, IL-15, IL- 16, IL-18, EMAP-II, GM-CSF, FGF, or PDGF.

[0150] Particular combinations of additional therapeutic agents may interfere at different points in the autoimmune and subsequent inflammatory cascade, and include, but are not limited to, TNF antagonists such as chimeric, humanized or human TNF antibodies, infliximab, adalimumab, anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75 TNF receptors, derivatives thereof, p75TNFRIgG (entanercept) or p55TNFRlgG (lenercept), soluble IL-13 receptor (sIL-13), and also TNFa-converting enzyme (TACE) inhibitors; similarly, IL-1 inhibitors (e.g., Interleukin- 1 -converting enzyme inhibitors) may be effective. Other combinations include Interleukin 11, anti-P7s and p-selectin glycoprotein ligand (PSGL). Other examples of agents useful in combination with a pharmaceutical composition, formulation, or unit dosage form of Compound (I), as described herein include, but are not limited to, interferon 0-la; interferon-|3-lb, glatiramer acetate; hyperbaric oxygen; intravenous immunoglobulin; clabribine; and antibodies to, or antagonists of, other human cytokines or growth factors (e.g., antibodies to CD40 ligand and CD80).

[0151] In some embodiments, one or more additional therapeutic agents comprise diuretics, including, but not limited to furosemide, bumetanide, and spironolactone.

[0152] In some embodiments, one or more additional therapeutic agents comprise cardiac glycosides, e.g., digoxin.

[0153] In some embodiments, one or more additional therapeutic agents comprise anticoagulants (e.g., warfarin).

[0154] In some embodiments, one or more additional therapeutic agents comprise agonists of THR-P (e.g., resmetirom).

[0155] In another aspect, this disclosure provides the use of Compound (I) in combination with one or more additional treatment modalities. Exemplary additional treatment modalities include vitamin supplements (e.g., vitamin E), exercise, weight loss, low fat diet, and oxygen therapy.Treatment Modification

[0156] The methods according to this disclosure may be modified in order to manage adverse events. In some embodiments, the methods according to this disclosure comprise managing adverse events by modifying the administration of Compound (I). Modifying administration of Compound (I) includes reducing the dose of Compound (I) administered to the subject (e.g., dose reduced from 100 mg once daily to 50 mg or 25 mg once daily; or dose reduced from 50 mg once daily to 25 mg once daily), or discontinuing administration of Compound (I) to the subject for a period of time (e.g., discontinue until the severity of the adverse event is reduced, or permanently). In some embodiments modifications further comprise providing supportive care to the subject (e.g., diet modification, administering an additional agent to treat the symptoms of an adverse event, or another treatment modality (e.g., a blood transfusion)). In further embodiments comprising administration of an additional therapeutic agent to the subject (e.g., cabozantinib), administration of the additional therapeutic agent is modified, e.g., the dose of the additional therapeutic agent is reduced (e.g., cabozantinib dose reduced from 60 mg once daily to 40 mg or 20 mg once daily; or cabozantinib dose reduced from 40 mg once daily to 20 mg once daily), or administration of the additional therapeutic agent is discontinued for a period of time (e.g., discontinued until the severity of the adverse event is reduced, or permanently). In some embodiments modifications further comprise providing supportive care to the subject (e.g., diet modification, administering an additional agent to treat the symptoms of an adverse event, or another treatment modality(e.g., blood transfusion)). In embodiments comprising administration of Compound (I) and an additional therapeutic agent, administration of Compound (I) is modified (e.g., by dose reductions or discontinuations), administration of the additional therapeutic agent is modified (e.g., by dose reductions or discontinuation), or the administration of Compound (I) and the additional therapeutic agent are independently modified (e.g., each agent is independently dose reduced or discontinued). In some embodiments modifications further comprise providing supportive care to the subject (e.g., diet modification, administering an additional agent to treat the symptoms of an adverse event, or another treatment modality (e.g., blood transfusion)). The decision to modify treatment to manage adverse events can be made by a physician or similar professional. In some embodiments, adverse events of any grade are managed using dose reductions, discontinuations, and / or supportive care. In some embodiments, adverse events of grade 2 or higher are managed using dose reductions, discontinuations, and / or supportive care. In some embodiments, adverse events of grade 3 or higher are managed using dose reductions, discontinuations, and / or supportive care. In some embodiments, the adverse event is anemia, hypoxia, or fatigue.

[0157] In another aspect, this disclosure provides a method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):Compound (I) at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for anemia; and continuing to administer Compound (I) and cabozantinib to the subject in the absence of adverse reaction in the subject or if the subject has been determined to have Grade 1 severity of anemia; or if the subject has been determined to have Grade 2 severity of anemia, (1) continuing to administer Compound (I) to the subject; and (2) optionally administering an erythropoiesis-stimulating agent or providing a blood transfusion; and (3) optionally conducting an anemia work-up and administering iron therapy / supplementation based on the anemia work-up; orif the subject has been determined to have Grade 3 severity of anemia, (1) withholding Compound (I) until the subject has been determined to have a hemoglobin level greater than or equal to 9 g / dL and (2) resuming administration of Compound (I) at 100 mg once daily or at 50 mg once daily; or if the subject has been determined to have Grade 4 severity of anemia, (1) withholding Compound (I) until the subject has been determined to have a hemoglobin level greater than or equal to 9 g / dL and (2) resuming administration of Compound (I) at 25 mg once daily or permanently discontinuing Compound (I) administration.

[0158] In another aspect, this disclosure provides a method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):Compound (I) at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for hypoxia; and continuing to administer Compound (I) and cabozantinib to the subject in the absence of adverse reaction in the subject or if the subject has been determined to have Grade 1 severity of hypoxia; or if the subject has been determined to have Grade 2 severity of hypoxia, (1) withholding Compound (I) until the subject has been determined to have resolution of or reduction in severity of hypoxia, and resuming administration of Compound (I) at 100 mg once daily or at 50 mg once daily; or (2) administering supplemental oxygen while continuing to administer Compound (I) at a dosage of 100 mg once daily or at 50 mg once daily, provided that severity of hypoxia does not worsen; or if the subject has been determined to have Grade 3 severity of hypoxia, (1) withholding Compound (I) until hypoxia is resolved or reduces in severity; and (2) resuming administration of Compound (I) at 25 mg once daily or discontinuing Compound (I) administration; orif the subject has been determined to have Grade 4 severity of hypoxia, permanently discontinuing Compound (I) administration.

[0159] In another aspect, this disclosure provides a method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):Compound (I) at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for fatigue unrelated to anemia, deconditioning, depression, anxiety, poor nutrition, dehydration, sleep disturbance, or thyroid disorder(s); and continuing to administer Compound (I) and cabozantinib to the subject in the absence of adverse reaction in the subject or if the subject has been determined to have Grade 1 or Grade 2 severity of fatigue; or if the subject has been determined to have Grade 3 severity of fatigue, (1) withholding Compound (I) while the subject has been determined to have no reduction in fatigue; and (2) resuming administration of Compound (I) at 100 mg once daily or 50 mg once daily if the subject has been determined to have reduction in fatigue to Grade 2 or less in severity.

[0160] In another aspect, this disclosure provides a method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):Compound (I) at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily;monitoring the subject for adverse reaction other than (i) anemia, (ii) hypoxia, or (iii) fatigue unrelated to anemia, deconditioning, depression, anxiety, poor nutrition, dehydration, sleep disturbance, or thyroid disorder(s); and continuing to administer Compound (I) and cabozantinib to the subject in the absence of the adverse reaction in the subject or if the subject has been determined to have Grade 1 or Grade 2 severity of the adverse reaction; or if the subject has been determined to have Grade 3 severity of the adverse reaction, (1) withholding Compound (I) until the subject has been determined to have resolution of or reduction in severity of the adverse reaction; (2) resuming administration of Compound (I) at 100 mg once daily or at 50 mg once daily; and (3) discontinuing Compound (I) administration upon recurrence to Grade 3 severity; or if the subject has been determined to have Grade 4 severity of the adverse reaction, permanently discontinuing Compound (I) administration.EXAMPLESExample 1: Reduction in EPO Levels in Healthy Volunteers

[0161] The reduction in erythropoietin (EPO) concentrations is an on target pharmacological effect from HIF-2a inhibition. Therefore, changes in EPO were assessed as a PD marker.

[0162] Study ARC- 14 evaluated the safety and tolerability, pharmacokinetic, and pharmacodynamic profile, and drug-drug interaction (DDI) of Compound (I) in healthy participants. From this study, PD data on EPO reduction are available for 42 healthy volunteers who received a single dose of Compound (I) at 3, 10, 30, or 100 mg (SAD cohorts), or multiple oral doses of Compound (I) at 15, 30, or 50 mg once daily (QD) for 7 days (MAD cohorts).

[0163] Following single oral dosing of Compound (I) (3, 10, 30, or 100 mg) in Study ARC- 14, PD effects were seen at the 10, 30, and 100 mg dose levels with the maximal EPO reduction of 41%, 80%, and 85%, respectively, observed at 24-hours post dose (Fig. 1A). Following a single dose of 10 to 100 mg of Compound (I), the EPO levels gradually rebounded within 96 hours.

[0164] Following multiple oral doses of Compound (I) (15, 30, or 50 mg QD) in Study ARC-14, PD effects were seen at all dose cohorts with the maximal reduction of 70%, 72%, and 83%, respectively, observed at 24 hours after the seventh dose (Fig. IB). Reduction in EPOrelative to pre-dose was sustained throughout the 7-day dosing period. EPO in Compound (I)- treated participants rebounded after the end of Compound (I) dosing.Example 2: Compound (I) DDI in Healthy Volunteers

[0165] The DDI portion of ARC- 14 was performed in 1 cohort of 12 healthy female participants. Midazolam was administered after an overnight fast of at least 10 hours which continued for 4 hours post-dose on Day 1 when administered alone and on Day 8 when coadministered with Compound (I). Compound (I) was administered at least 4 hours before and after meal and fluid on Days 2 and 7 and at least 2 hours before or after meal and fluid on Days 3-6.

[0166] Plasma samples were obtained at both periods when midazolam was administered alone and with Compound (I) to characterize the PK profile of midazolam. The analysis of midazolam and T-hydroxymidazolam (a metabolite of midazolam produced by CYP3A4) in plasma samples was performed at ICON Bioanalytical Laboratories using validated liquid chromatography-mass spectrometry / mass spectrometry methods. The lower limit of quantification (LLOQ) was 0.05 ng / mL for midazolam and I '-hydroxymidazolam.

[0167] The effect of Compound (I) on the natural log -transformed Cmax, AUCo-iast, and AUCo-inf of midazolam and l '-hydroxymidazolam were assessed with a linear mixed effects model. Treatment (combined Compound (I) + midazolam as test treatment versus single midazolam treatment as reference treatment) was used as fixed effect and subject was used as a random effect. The back-transformed (i.e., exponentiated) least-squares means (LS Means) for each treatment and their ratio along with its 90% CI were estimated in this model.

[0168] Midazolam median plasma PK profile was lower following coadministration of midazolam with Compound (I) compared with administration of midazolam alone, coadministration of midazolam and Compound (I) resulted in approximately 23%, 38%, and 38% decrease in geometric mean value for midazolam Cmax, AUCo-iast, and AUCo-inf, as compared to midazolam alone, respectively (Table 1). Furthermore, the geometric mean of l'-hydroxymidazolam Cmax, AUCo-iast, and AUCo-inf increased by approximately 66%, 38%, and 36% when midazolam was co-administered with Compound (I) as compared with administration of midazolam alone.

[0169] While coadministration of Compound (I) with midazolam, a sensitive CYP3A4 substrate, reduced midazolam exposure, the magnitude of the reduction was consistent with aweak CYP3 A4 inducer at the tested dose. Accordingly, dose adjustments for coadministration of Compound (I) with therapeutic agents that are CYP3 A4 substrates are likely not required.Table 1: Summary Statistics (Geometric Mean [Range]) and LS Geometric MeanRatios (90% CI) of Midazolam Plasma Pharmacokinetic ParametersANOVA=analysis of variance; CI=confidence interval; LS=least-squares; DDI=dmg-dmg interaction;N=number of subjects per treatment; PK=pharmacokinetic; QD=once dailyFor tmax, the median (range) is presented instead of geometric mean (range).aNote, DDI was assessed in an ANOVA model with treatment as fixed effect and subject as random effect.Example 3: Compound (I) in the treatment of patients with advanced solid tumor malignancies and in patients with ccRCC

[0170] Study ARC-20 is a Phase 1, open-label, dose escalation and dose expansion study evaluating the safety, tolerability, PK profile, preliminary clinical activity, PD, and biomarkers of Compound (I) as a monotherapy in patients with advanced solid tumor malignancies (dose escalation) and as a monotherapy and in combination with cabozantinib in patients with ccRCC (dose expansion).Dose Escalation

[0171] During the dose-escalation phase of the study, increasing dose levels of Compound (I) (20 mg QD, 50 mg QD, 50 mg twice daily [BID], 150 mg QD) were evaluated orally (PO) in 21 -day cycles as monotherapy. No dose-limiting toxicities, maximum tolerated dose (MTD), or clinically significant safety findings for Compound (I) were reported during dose escalation. Overall, the safety profile was consistent with the historical safety data observed for aComparator HIF-2a inhibitor (belzutifan) as a monotherapy in patients with advanced solid tumors or previously treated advanced ccRCC. Each dose was evaluated by a dose escalation committee prior to proceeding to the subsequent dose and / or expanding at a dose level. Compound (I) exhibited durability in dose escalation study, with time on treatment ranging from 8.5+ to 14.5+ months.

[0172] Patients in the study showed significant decline in EPO levels relative to predose levels, with mean maximum reduction from baseline up to around 80% (Fig. 1C).Dose Expansion

[0173] The dose-expansion phase consists of 4 cohorts described below (Expansion Cohorts 1 , 2, 3, and 4). Compound (I) was administered orally (PO) as either a capsule or tablet QD or BID as monotherapy (Cohorts 1-3) or in combination with cabozantinib (Cohort 4). Combination safety data were obtained to support the proposed dosing administration for a Phase 3 study.• Expansion Cohort 1 consisted of patients who received Compound (I) 50 mg BID (as capsules) as monotherapy as a 2L+ treatment for ccRCC.• Expansion Cohort 2 consisted of patients who received Compound (I) 50 mg QD (as capsules) as monotherapy as a 2L+ treatment for ccRCC.• Expansion Cohort 3 consisted of patients who received Compound (I) 150 mg QD (as tablets) as monotherapy as a 2L+ treatment for ccRCC.• Expansion Cohort 4 consisted of patients who received Compound (I) 100 mg QD (as tablets) in combination with cabozantinib 60 mg QD (as tablets) as a 2L+ treatment for ccRCC. This cohort was added by protocol amendment to further evaluate the safety and efficacy of this regimen.

[0174] Data from Expansion Cohort 1 (Compound (I) 50 mg BID) and Expansion Cohort 2 (Compound (I) 50 mg QD) were evaluated during an interim analysis. The demographics of the patients enrolled in those cohorts are summarized in Table 2. The results are summarized in Table 3. Two unconfirmed responders in the 50 mg BID and one in the 50 mg QD cohorts remain on study with the potential to achieve a confirmed response. Only one unconfirmed response (in the 50 mg BID cohort) does not have the potential to be confirmed.Table 2: Patient demographics of Expansion Cohort 1 and Expansion Cohort 2Table 3: Summary of interim analysis results from Expansion Cohort 1 and ExpansionCohort 2*Includes one patient in the 50 mg BID cohort who had a new response after data cut-off

[0175] Majority of patients in Expansion Cohort 1 (Compound (I) 50 mg BID) and Expansion Cohort 2 (Compound (I) 50 mg QD) experienced tumor reduction (Fig. ID and IE). Five patients in Expansion Cohort 1 (Compound (I) 50 mg BID) and eleven patients in Expansion Cohort 2 (Compound (I) 50 mg QD) with stable disease remain on treatment and could respond with longer follow-up. One patient in Expansion Cohort 1 (Compound (I) 50 mg BID) with best response of PD achieved 100% tumor reduction in their primary lesion. Deep responses seen regardless of number of prior lines of therapy, including in patients with more than three prior lines of therapy. Durable disease control was observed in both Expansion Cohorts 1 and 2. Ten of eleven and seven of seven responders remain on study in Expansion Cohort 1 and Expansion Cohort 2, respectively. In Expansion Cohort 1 , sixteen patients remain on treatment, ten with partial responses. In Expansion Cohort 2, twenty patients remain on treatment, seven with partial responses.

[0176] Additionally, EPO levels from patients in Expansion Cohort 1 (Compound (I) 50 mg BID) and Expansion Cohort 2 (Compound (I) 50 mg QD) were monitored. Data from the interim analysis of the ongoing trial demonstrate long-term EPO suppression during treatment (Fig. IF and Fig. 1G). This long-term suppression contrasts observations from patients undergoing administration with belzutifan, a comparator HIF-2a inhibitor. Those subjects experienced EPO rebound after 13 weeks of treatment (Marathe, D.D., Jauslin, P.M., Jan Kleijn, H., De Miranda Silva, C., Chain, A., Abraham, A.K., Kauh, E.A., Liu, Y., Perini, R.F., Alwis, D.P.d. and Jain, L. (2024), Exposure-Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling. J Clin Pharm, 64: 1246-1258. https: / / d0i.0rg / l 0.1002 / jcph.2459). Surprisingly, while treatment with Compound (I) results in more durable EPO suppression compared to the comparator HIF-2a inhibitor, the rate of treatment emergent adverse events (TEAEs) is comparable between the two treatments (Choueiri, T.K et al, (2024) Belzutifan versus Everolimus for Advanced Renal-CellCarcinoma; N. Engl. J. Med.; 391 :710-21; DOI: 10.1056 / NEJMoa2313906). A summary of TEAEs from Expansion Cohort 1 (Compound (I) 50 mg BID) and Expansion Cohort 2 (Compound (I) 50 mg QD) is presented in Table 4 below.Table 4: TEAEs from Expansion Cohort 1 (Compound (I) 50 mg BID) and Expansion Cohort 2 (Compound (I) 50 mg QD)Belzutifan anemia rates: *all grade = 83%; **Grade 3 related = 33%Belzutifan hypoxia rates: ***all grade = 15%; ****Grade 3 related = 11%Table 4.1 Patient Demographics Cohort 4Table 4.2 Treatment with Cas+Cabo in Patients with > 2 ScansaAll eligible patients who received any study treatment and have at least 2 post-baseline efficacy assessment or discontinued study treatment due to progressive disease or death.bOne patient had confirmed partial response after data cutoffGrade 3 treatment related AEs were also assessed at the same timepoint. There were no grade 4 or 5 casdatifan related AEs. AEs leading to dose reduction were also assessed.Table 4.3 Cohort 4 AEs Leading to Dose ReductionaSafety population included patients who received any amount of study drug.bTreatment-emergent adverse events (any grade) leading to dose reduction in casdatifan, cabozantinib, or any study drug reported in > 3% of patients in any treatment armExample 4: General Pharmacology and Pharmacokinetic Characteristics of Compound(I)

[0177] Compound (I) PK data were available for participants, including healthy participants in Studies ARC-14 and ARC-28 and patients with histologically or cytologically confirmed ccRCC and other solid tumors in Study ARC-20. The available PK and PD data were collected following single oral doses of Compound (I) ranging from 3 mg to 100 mg in healthy participants, and multiple oral doses of Compound (I) ranging from 15 mg to 150 mg once daily (QD) in healthy participants and cancer patients. Serial PK, EPO, and hemoglobin (Hb) data were gathered in all study participants pre-dose till end of treatment. The population PKPD model was developed using mixed effects methodology with NONMEM software to relate dose, PK, and PD (EPO and Hb) data.

[0178] Following single (3 to 100 mg) or multiple (15 to 150 mg QD) oral dosing of Compound (I), plasma concentrations increased rapidly with a median time to reach maximum concentration (Tmax) at Day 1 of 1 to 4 hours and at steady state of 1 to 2 hours, followed by biphasic decline in plasma concentrations (Figs. 2A, 2B, 3A, 3B, and 3C). Mean apparent terminal half-life was approximately 18 to 24 hours, supporting QD dosing (Table 5). Compound (I) exposure (AUC and Cmax) increased approximately dose proportionally over the single-dose range of 3 to 100 mg (Fig. 2A) and over the multiple daily dose range of 15 to 150 mg (Figs. 2B, 3A, 3B, and 3C, and Table 6) across all studies and formulations tested. After multiple daily dosing, Compound (I) reached steady state around Day 4, and the mean AUC accumulation ratio ranges from 1.5 to 2.0, indicating lack of time-dependent PK (Fig. 2B and Table 5). Compound (I) renal clearance ranged from 13.4 to 15.8 mL / min at dose levels of 15- 150 mg and was comparable across all dose levels, accounting for approximately 30% of total systemic clearance of Compound (I).Table 5: Summary Plasma Pharmacokinetic Parameters of Compound (I) following Single orMultiple Oral Doses of Compound (I) in Healthy Volunteers (Studies ARC-14 and ARC- 28) and in Patients with Cancer (Study ARC-20)%CV = coefficient of variation; AUG’ , = area under plasma concentration-time curve from time zero extrapolated to infinity; AUCtau= AUC from one dosing interval (0-24 h for QD dosing and 0-12 hforBID dosing); BID = twice daily; Cap = Capsule; Cm,ix= maximum plasma concentration; DDI = drug-drug interaction; Fed = high-fat meal condition; PK = pharmacokinetic; Tab = Tablet; Tmax= time to reach maximum plasma concentration; ti / 2 = apparent terminal elimination half-life.Notes: Mean (%CV) for Cmax, AUCI(III. AUG’ , . ti / 2. Median (range) for Tmax. For groups with n < 3, individual values (instead of %C V or range) are listed. The PK parameters were calculated using noncompartmental analysis based on nominal time of sample collection. The PK parameters of ARC-14 at 50 mg QD at steady state are based on 6 participants. Steady State in ARC-14 refers to the seventh dose for MAD cohorts at 15, 30, 50 mg QD and sixth dose for the DDI cohort at 50 mg QD. Steady State in ARC -20 refers to Cycle 1 Day 15. For the calculation of AUCtau at steady state (Cycle 1 Day 15) in ARC-20, the Grou h (Cycle 1 Day 16 predose) sample was not collected per protocol and Chough was assumed to be equal to the corresponding predose concentration, assuming steady state was reached prior to Cycle 1 Day 15. PK parameters following BID dosing were characterized based on PK profiles for the dose administration in the morning up to 8 hours postdose. AUCI(IIIfor BID dosing on Cycle 1 Day 1 is not calculated due to the absence of PK sampling at 12 hours postdose unless terminal phase is well characterized for the extrapolations of AUCtau.Table 6: Exploratory Analysis of Dose Proportionality for Compound (I) Over the Dose Range of3 mg to 100 mg Compound (I) Based on ARC-14, ARC-28, and ARC-20 StudiesAUCmf = area under plasma concentration-time curve from time zero extrapolated to infinity; AUCo-24h,ss = AUC from 0-24 h at steady state in multiple dosing; CI = confidence interval; Cmax,frst dose = maximum plasma concentration after the first dose; Cm,ix ss= maximum plasma concentration at steady state; DF = degrees of freedom; PK = pharmacokinetic; SD = standard deviationNote: Dose proportionality was explored using the power model on natural log-transformed PK parameters. Model: ln(PK) = ln(P0) + p 1 •In(dose) + e, where PK is the PK parameter tested (eg, Cm,ixor AUC), ln(P0) is the y intercept, pi is the slope (a pi value of 1 indicates linearity), and e is an error term.A point estimate and 95% CI were produced for the slope. A slope of 1 (ie, a 95% CI containing 1) means that no evidence of a deviation from dose proportionality was found.Example 5: Hemoglobin Changes After Compound (I) Administration

[0179] Compound (I) was administered to patients with ccRCC orally at 50 mg (N=15) and 100 mg (N=32) and hemoglobin levels were measured over time, up to 126 days, (see Fig. 4A) and compared to change from baseline (see Fig. 4C). These data for hemoglobin levels were compared to hemoglobin levels observed in patients with VHL who were administered 120 mg orally of a Comparator HIF-2a inhibitor (N=29 male; 19 female) over 147 days (Fig. 4B) and compared to change from baseline for the same patients (Fig. 4D).Example 6

[0180] Compound (I) at 20 mg dosage was evaluated in subjects from the dose escalation study described in Example 2 for its ability to suppress HIF-2a -dependent EPO. As seen in Fig. 5A, the percent EPO change from baseline at a dose of 20 mg of Compound (I) is about 65%, which is the percent EPO change from baseline observed for 120 mg of a Comparator HIF-2a inhibitor. For Compound (I), the percent EPO change from baseline gradually increases to about 75% at increasing doses up to 100 mg. Compound (I) was also evaluated for PK profile at 20 mg and 100 mg in subjects from the dose expansion study described in Example 2. Those data are shown in Fig. 5B. The data shows serum concentration of Compound (I) in subjects at various timepoints post administration up to 24 hours and show a dosage linear profile for Compound (I) at the two doses evaluated. Specifically, a 100 mg dose of Compound (I) achieves 5 times the exposure (AUCtau) of a 20 mg dose. Furthermore, a PK analysis of the Comparator HIF-2a inhibitor demonstrates that at doses above 120 mg, increase in PK exposure is not linear. Specifically, a dose of 240 mg of the Comparator HIF-2a inhibitor achieves 1.3 times the exposure (AUCtau) of the 120 mg dose. As seen in Fig. 5A, 20 mg of Compound (I) achieves near-complete suppression of HIF-2a-dependent EPO (peripheral PD marker), whereas a 120 mg dose of the Comparator HIF-2a Inhibitor is required for this level of EPO suppression.Example 7: Impact of EPO Reduction Depth on Treatment Benefit

[0181] As indicated in Example 3, decreases in serum EPO levels are indicative of HIF-2a suppression by Compound (I). Deep EPO reduction is sustained up to Cycle 12 Day 1 or study week 34. The depth of percent EPO reduction from baseline are associated and RECIST vl.l confirmed best overall response (CBOR) status. The biomarker evaluable population is defined as a total of 35 ccRCC subjects from 50 mg BID (4 Escalation + 31 Expansion) cohorts and a total of 28 ccRCC subjects from 50 mg QD (1 Escalation + 27 Expansion) cohorts with EPObaseline and on-treatment data and with CBOR status of complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD). Serum EPO was measured at pre-treatment, 4 hours and 8 hours after first dose, pre-treatment of Cycle 1 Day 8, Cycle 1 Day 15 and pre-treatment of every following cycle until a year of treatment. The maximum EPO reduction is minimum % change of EPO from baseline among all on-treatment timepoints per subject and is used to represent best depth of EPO reduction on treatment of Compound (I). Wilcoxon ranked-sum test is used to evaluate the significance of difference between each two groups of CBOR.

[0182] Deeper maximum EPO reduction is observed in CR and PR patients followed by SD then PD patients (Fig. 6, box plot of CBOR). There is a significant difference between PR and PD (P<0.005), between PR and SD (P=0.036). The P values are derived from Wilcoxon ranked-sum tests.

[0183] Patients with above-median EPO reduction (deep) have much higher objective response rate (ORR) of 45.2% and confirmed ORR (cORR) of 38.7% than patients with below- median EPO reduction (shallow) (18.8% and 15.6% for ORR and cORR, respectively) (Table 7). The 95% confidence intervals were calculated with Clopper-Pearson method.Table 7: ORR Comparison between deep and shallow EPO reduction groups

[0184] The association between maximum % EPO reduction and primary disease progression is evaluated in a biomarker evaluable patient (BEP) subset of 124 ccRCC efficacy evaluable patients in monotherapy cohorts of 50 mg and above daily dose of Compound (I) (Escalation cohort 2 - 50 mg QD, n=l; Escalation cohort 3 - 50 mg BID, n=4; Escalation cohort 4 - 150 mg QD, n=3; Escalation cohort 5 - 200 mg QD, n=4; Expansion cohort 1 - 50 mg BID, n=31; Expansion cohort 2 - 50 mg QD, n=27; Expansion cohort 3 - 150 mg QD, n=29; Expansion cohort 5 - 100 mg QD, n=25). The maximum % EPO reductions from 20 patients with and 104 patients without primary disease progression are compared usingunpaired t-test (Fig. 7). There is a significantly deeper (P=0.002) % best EPO reduction in patients who have no primary progression (No) than those who have it (Yes).Example 8: Tumor mRNA Expression of EPO as Predictor of Treatment Response

[0185] Given the regulation of EPO by HIF-2a, it was investigated whether EPO mRNA expression within the tumor can be used as a potential indicator of HIF-2a driven tumor status.

[0186] The transcriptome of formalin-fixed, paraffin embedded (FFPE) human tissue was measured using RNA sequencing (RNA-seq). Briefly, serial 4-5 micron sections were mounted on positive charged glass slides and the first slide was stained with hematoxylin and eosin (H&E). The subsequent slides were macrodissected where possible to enrich for greater than 70% tumor content. RNA and DNA were extracted using the MagMAX™ FFPE DNA / RNA Ultra Kit (ThermoFisher).

[0187] RNA-seq was performed using TruSeq RNA Exome (Illumina). Gene expression was calculated from sequencing reads using a custom RNA-seq Nextflow pipeline. Briefly, reads were aligned using STAR aligner, gene counts were estimated using salmon, and resulting estimated values were transformed using TMM-voom normalization.

[0188] Using mRNA data from 46 tumor biopsies taken prior to treatment with Compound (I) monotherapy (doses ranging from 50mg QD - 200mg QD) from the ARC-20 study, the normalized expression of EPO mRNA transcripts from patients experiencing primary progression to those staying on treatment beyond their 1stevaluation was compared. Notably, patients without primary progression (N) had significantly higher levels of tumor EPO expression compared to those who progressed by 1stevaluation (Y) (Fig. 8; Wilcoxon ranked-sum test, p = 0.042).

[0189] Similarly, when dividing the cohort of mRNA profiled patients into high and low tumor EPO groups based on median tumor EPO mRNA expression, the EPO low group has a higher proportion of individuals experiencing primary progression (Table 8). Although this approach also enriched for metastatic tumors in the EPO low group, examination of EPO groups stratified by primary biopsy or metastatic site show comparable trends in primary progression to that observed in the aggregate data.Table 8: Stratified proportions of primary progression between patients with tumors expressing high and low levels of EPO mRNAExample 9

[0190] PEAK-1 is a Phase 3, randomized, placebo-controlled, double blind, 2-arm, global, multicenter study to evaluate the progression-free survival of Compound (I) versus placebo when each is given in combination with cabozantinib in patients with confirmed advanced or metastatic ccRCC following progression on prior anti-PD-1 or anti-PD-Ll immunotherapy. Approximately 720 patients will be enrolled and randomized 2:1 to Arm A or Arm B (detailed below). Other measures of clinical activity (e.g., overall survival, objective response rate, duration of response, disease control rate) will also be assessedArm A

[0191] Doses and administration of Compound (I) and cabozantinib will be administered on empty stomach (i.e., 1 hour before or 2 hours after eating), using a 28-day cycle. Compound (I) administered orally at 100 mg once daily (QD) of each cycle. Cabozantinib administered orally at 60 mg QD of each cycle.Arm B

[0192] Doses and administration of placebo and cabozantinib will be administered on empty stomach (i.e., 1 hour before or 2 hours after eating), using a 28-day cycle. Placebo administered orally QD of each cycle. Cabozantinib administered orally at 60 mg QD of each cycle.

[0193] Individual patient safety data will be assessed at regular intervals throughout the duration of treatment and during the 90-day safety follow up period. Tumor assessments for clinical activity will be conducted every 8 weeks for the first 2 years and every 16 weeks thereafter according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Tumor assessments will also be conducted according to RECIST 1.1.Inclusion Criteria

[0194] Patients are eligible for study inclusion if the following criteria apply:• Age > 18 years (or age > regionally approved age of consent for participation in investigational clinical studies) at the time of signing the informed consent form (ICF)• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.• Unresectable locally advanced or metastatic renal cell carcinoma with a primary clear cell component.• Must have received anti-PD-1 or anti-PD-Ll therapy as part of the most recent regimen (either adjuvant monotherapy or first-line in combination with anti-CTLA-4 or VEGFR-TKI), with no more than 1 prior regimen in the metastatic setting. o Patients must have received at least 2 cycles of anti-PD-1 or anti-PD-Ll therapy. o For patients who received anti-PD-1 in adjuvant setting, radiographic PD must have occurred on or within 12 months of last dose.• A Karnofsky Performance Score (KPS) > 80%.Exclusion Criteria

[0195] Patients are excluded from the study if any of the following criteria apply:• Unwilling or unable to comply with study procedures and / or study visits, including subsequent treatment data collection for the progression-free survival-2 (PFS-2) endpoint, safety follow-up, and long-term follow-up for survival.• Received prior treatment with a HIF-2a inhibitor.• Received prior treatment with cabozantinibReceiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, or moderate or strong CYP3A4 inhibitors.Receiving ongoing concomitant treatment with sensitive substrates of CYP3A4, CYP2C8, CYP2C9, or CYP2C19 with narrow therapeutic indices.

[0196] Other protocol defined Inclusion / Exclusion criteria may apply.

[0197] Embodiments are set out in the following clauses:(1) A method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction.(2) A method of treating cancer in a subject comprising administering to a subject in need of treatment a total daily dose of 100 mg of a HIF-2a inhibitor.(3) A method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved.(4) A HIF-2a inhibitor for use in a method of treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction.(5) A HIF-2a inhibitor for use in a method of treating cancer, comprising administering to a subject in need of treatment a total daily dose of 100 mg of the HIF-2a inhibitor.(6) A HIF-2a inhibitor for use in a method of treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved.(7) Use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment the HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF- 2a mediated peripheral EPO reduction.(8) Use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment a total daily dose of 100 mg of the HIF-2a inhibitor.(9) Use of a HIF-2a inhibitor in the manufacture of a medicament for treating cancer, comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved.(10) The method of clause (1) or clause (3), the HIF-2a inhibitor for use of clause (4) or clause (6), or the use of clause (7) or clause (9), wherein the amount of the HIF-2a inhibitor is from about 10-130 mg per day, about 50-120 mg per day, about 75-120 mg per day, about 80-120 mg per day, about 85-115 mg per day, about 90-110 mg per day, about 95-105 mg per day, or about 98-102 mg per day.(11) The method of clause (10), the HIF-2a inhibitor for use of clause (10), or the use of clause (10), wherein the amount of the HIF-2a inhibitor is about 100 mg per day.(12) The method of any one of clauses (1 )-(3), (10) or (11), the HIF-2a inhibitor for use of any one of clauses (4)-(6), (10) or (11), or the use of any one of clauses (7)-( 11), wherein the HIF-2a inhibitor is Compound (I):(13) The method of any one of clauses (1 )-(3) or (10)-(12), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(12), or the use of any one of clauses (7)-(12), wherein administering the HIF-2a inhibitor to the subject achieves an AUCtau that is above 25 h*pg / mL in the subject.(14) The method of any one of clauses (1 )-(3) or (10)-(l 3), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(13), or the use of any one of clauses (7)-(l 3), wherein the treatment results in a medium time to response that is < 3.5 months.(15) The method of any one of clauses (1 )-(3) or (10)-(14), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(14), or the use of any one of clauses (7)-(14), wherein the treatment results in a decreased incidence of progression by 6 weeks, or by 12 weeks, as determined by CT scans.(16) The method of any one of clauses (l)-(3) or (10)-(l 5), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(l 5), or the use of any one of clauses (7)-(15), wherein the cancer is an HIF-2a driven cancer.(17) The method of any one of clauses (l)-(3) or (10)-(16), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(16), or the use of any one of clauses (7)-(16), wherein the cancer is a solid tumor.(18) The method of clause (17), the HIF-2a inhibitor for use of clause (17), or the use of clause(17), wherein the cancer is kidney cancer.(19) The method of clause (18), the HIF-2a inhibitor for use of clause (18), or the use of clause(18), wherein the cancer is clear cell renal cell carcinoma (ccRCC).(20) The method of any one of clauses (l)-(3) or (10)-(19), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(19), or the use of any one of clauses (7)-(19), wherein the subject has received no prior lines of therapy.(21) The method of any one of clauses (1 )-(3) or (10)-(l 9), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(19), or the use of any one of clauses (7)-(l 9), wherein the subject has received one or more prior lines of therapy.(22) The method of clause (21), the HIF-2a inhibitor for use of clause (21), or the use of clause(21), wherein the one or more prior lines of therapy comprise treatment with an immune checkpoint inhibitor and / or treatment with a tyrosine kinase inhibitor.(23) The method of clause (22), the HIF-2a inhibitor for use of clause (22), or the use of clause(22), wherein the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-L1.(24) The method of clause (22), the HIF-2a inhibitor for use of clause (22), or the use of clause (22), wherein the tyrosine kinase inhibitor is a VEGF or VEGFR inhibitor.(25) The method of any one of clauses (1 )-(3) or (10)-(24), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(24), or the use of any one of clauses (7)-(24), wherein the HIF-2a inhibitor is administered to the subject as one daily dose or two daily doses.(26) The method of any one of clauses (1 )-(3) or (10)-(25), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(25), or the use of any one of clauses (7)-(25), wherein the HIF-2a inhibitor is administered by oral administration.(27) The method of method of any one of clauses (1 )-(3) or (10)-(26), the HIF-2a inhibitor for use of any one of clauses (4)-(6) or (10)-(26), or the use of any one of clauses (7)-(26), wherein the HIF-2a inhibitor is administered in combination with another therapeutic agent.(28) The method of clause (27), the HIF-2a inhibitor for use of clause (27), or the use of clause(27), wherein the other therapeutic agent is a tyrosine kinase inhibitor.(29) The method of clause (28), the HIF-2a inhibitor for use of clause (28), or the use of clause(28), wherein the tyrosine kinase inhibitor inhibits the tyrosine kinase activity of MET, VEGFR-1, VEGFR-2, VEGFR-2, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT- 3, TIE-2, or any combination thereof.(30) The method of clause (28), the HIF-2a inhibitor for use of clause (28), or the use of clause (28), wherein the tyrosine kinase inhibitor is cabozantinib.(31) Compound (I) for use in a method of treating ccRCC, comprising administering to a subject in need of treatment 100 mg of Compound (I) to the subject daily, wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor.(32) Use of Compound (I) in the manufacture of a medicament for treating ccRCC, comprising administering to a subject in need of treatment 100 mg of Compound (I) daily, wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor.(33) The Compound (I) for use of clause (31) or the use of clause (32), wherein the subject has received two prior lines of therapy.(34) The Compound (I) for use of clause (31) or the use of clause (32), wherein the subject has received three prior lines of therapy.(35) The Compound (I) for use of clause (31) or the use of clause (32), wherein the subject has received four prior lines of therapy.(36) The Compound (I) for use of any one of clauses (31) or (33)-(35), or the use of any one of clauses (32)-(35), wherein the prior line(s) of therapy comprise an immune checkpoint inhibitor that inhibits or antagonizes, PD-1, PD-L1, CTLA-4, or a combination thereof.(37) The Compound (I) for use of any one of clauses (31 ) or (33 )-(36), or the use of any one of clauses (32)-(36), wherein the prior line(s) of therapy comprise a tyrosine kinase inhibitor that inhibits or antagonizes VEGF or VEGFR.(38) The Compound (I) for use of any one of clauses (31) or (33)-(37), or the use of any one of clauses (32)-(37), further comprising concurrently administering 60 mg of cabozantinib to the subject daily.

Claims

CLAIMSWhat is claimed is:

1. A method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount that is at least about 2 times above the amount effective to achieve maximum HIF-2a mediated peripheral EPO reduction.

2. A method of treating cancer in a subject comprising administering to a subject in need of treatment a total daily dose of 100 mg of a HIF-2a inhibitor.

3. A method of treating cancer in a subject comprising administering to a subject in need of treatment a HIF-2a inhibitor in an amount effective to achieve a blood concentration that is at least about 2 times above the amount measured when maximum HIF-2a mediated peripheral EPO reduction is achieved.

4. The method of any one of claims 1-3, wherein the HIF-2a inhibitor is Compound (I):

5. The method of any one of claims 1-4, wherein administering the HIF-2a inhibitor to the subject achieves an AUCtau that is above 25 h*pg / mL in the subject.

6. The method of any one of claims 1-5, wherein the treatment results in a medium time to response that is < 3.5 months.

7. The method of any one of claims 1 -6, wherein the treatment results in a decreased incidence of progression by 6 weeks, or by 12 weeks, as determined by CT scans.

8. The method of any one of claims 1-7, wherein the cancer is an HIF-2a driven cancer.

9. The method of any one of claims 1-8, wherein the cancer is a solid tumor.

10. The method of claim 9, wherein the cancer is kidney cancer.

11. The method of claim 10, wherein the cancer is clear cell renal cell carcinoma (ccRCC).

12. The method of any one of claims 1-11, wherein the subject has received no prior lines of therapy.

13. The method of any one of claims 1-11, wherein the subject has received one or more prior lines of therapy.

14. The method of claim 13, wherein the one or more prior lines of therapy comprise treatment with an immune checkpoint inhibitor and / or treatment with a tyrosine kinase inhibitor.

15. The method of claim 14, wherein the immune checkpoint inhibitor is an inhibitor of PD-1 or PD-Ll .

16. The method of claim 14, wherein the tyrosine kinase inhibitor is a VEGF or VEGFR inhibitor.

17. The method of any one of claims 1-16, wherein the HIF-2a inhibitor is administered to the subject as one daily dose or two daily doses.

18. The method of any one of claims 1-17, wherein the HIF-2a inhibitor is administered by oral administration.

19. The method of any one of claims 1-18, wherein the HIF-2a inhibitor is administered in combination with another therapeutic agent.

20. The method of claim 19, wherein the other therapeutic agent is a tyrosine kinase inhibitor.

21. The method of claim 20, wherein the tyrosine kinase inhibitor inhibits the tyrosine kinase activity of MET, VEGFR- 1, VEGFR-2, VEGFR-3, AXL, RET, ROS1, TYRO3, MER, KIT, TRKB, FLT-3, TIE-2, or any combination thereof.

22. The method of claim 20, wherein the tyrosine kinase inhibitor is cabozantinib.

23. The method of claim 19, wherein the other therapeutic agent is an immune checkpoint inhibitor.

24. The method of claim 23, wherein the immune checkpoint inhibitor is an anti-PD-1 or anti- PD-L1 antibody.

25. The method of claim 23, wherein the immune checkpoint inhibitor is zimberelimab.

26. A method of treating ccRCC in a subject in need thereof, said method comprising administering 100 mg of Compound (I):Compound (I) to the subject daily, wherein the subject has received one or more prior lines of therapy comprising an immune checkpoint inhibitor and / or a tyrosine kinase inhibitor.

27. The method of claim 26, wherein the subject has received one prior line of therapy.

28. The method of claim 26, wherein the subject has received two prior lines of therapy.

29. The method of claim 26, wherein the subject has received three prior lines of therapy.

30. The method of claim 26, wherein the subject has received four prior lines of therapy.

31. The method of any one of claims 26-30, wherein the prior line(s) of therapy comprise an immune checkpoint inhibitor that inhibits or antagonizes, PD-1, PD-L1, CTLA-4, or a combination thereof.

32. The method of any one of claims 26-31, wherein the prior line(s) of therapy comprise a tyrosine kinase inhibitor that inhibits or antagonizes VEGF or VEGFR.

33. The method of any one of claims 26-32, further comprising concurrently administering 60 mg of cabozantinib to the subject daily.

34. A method of treating ccRCC in a subject in need thereof comprising administering a therapeutically effective amount of a HIF-2a inhibitor to the subject daily, wherein the subject has high baseline tumor EPO expression.

35. The method of claim 34, wherein high baseline tumor EPO expression is: a. an expression above a median expression level, or an expression within about 30% above or below a median expression level, derived from samples obtained from a group of ccRCC subjects;b. an expression above a tertile (i.e., the 33rd or 66th percentile), or an expression within about 30% above or below a tertile, derived from samples obtained from a group of ccRCC subjects; c. an expression above a quartile (i.e., the 25th, 50th, or 75th percentile), or an expression within about 30% above or below a quartile, derived from samples obtained from a group of ccRCC subjects; or d. an expression above a best cut value determined based on progression free survival and / or overall survival for a group of ccRCC subjects.

36. The method of claim 35 or 36, wherein the therapeutically effective amount of Compound (I) is an amount sufficient to suppress serum EPO levels from baseline for a duration of time.

37. The method of claim 36, wherein the duration of time is at least 10 weeks.

38. The method of claim 36 or 37, wherein the duration of time is at least 13 weeks.

39. The method of any one of claims 36-38, wherein the duration of time is the duration of treatment.

40. The method of any one of claims 34-39, wherein the HIF-2a inhibitor is Compound (I).

41. The method of any one of claims 34-40, wherein the therapeutically effective amount of the HIF-2a inhibitor is about 50 mg to about 150 mg.

42. The method of claim 41, wherein the therapeutically effective amount of the HIF-2a inhibitor is about 100 mg.

43. A method of treating ccRCC in a subject in need thereof, comprising administering to the subject a daily dose of a HIF-2a inhibitor, wherein the daily dose is sufficient to suppress serum EPO levels from baseline for at least 10 weeks.

44. The method of claim 43, wherein the serum EPO levels are suppressed by at least 10% from baseline.

45. The method of claim 43 or 44, wherein the serum EPO levels are suppressed by at least 25% from baseline.

46. The method of any one of claims 43-45, wherein the serum EPO levels are suppressed by at least 50% from baseline.

47. The method of any one of claims 43-46, wherein the HIF-2a inhibitor is Compound (I).

48. The method of any one of claims 43-47, wherein the duration of time is at least 13 weeks.

49. The method of any one of claims 43-48, wherein the duration of time is the duration of treatment.

50. The method of any one of claims 43-49, wherein the subject has a high baseline expression of tumor EPO.

51. The method of any one of claims 43-50, wherein the daily dose is about 50 mg to about 150 mg.

52. The method of claim 51, wherein the daily dose is about 100 mg.

53. The method of any one of claims 43-52, wherein the subject’s maximum suppression of serum EPO levels is: a. a percent decrease greater than a median percent decrease in serum EPO levels, or a percent decrease within about 30% above or below a median percent decrease in serum EPO levels, derived from samples obtained from a group of ccRCC subjects; b. a percent decrease greater than a tertile (i.e., the 33rd or 66th percentile), or a percent decrease within about 30% above or below a tertile, derived from samples obtained from a group of ccRCC subjects; c. a percent decrease greater than a quartile (i.e., the 25th, 50th, or 75th percentile), or a percent decrease within about 30% above or below a quartile, derived from samples obtained from a group of ccRCC subjects; or d. a percent decrease greater than a best cut value determined based on progression free survival and / or overall survival for a group of ccRCC subjects.

54. A method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for anemia; and continuing to administer Compound (I) and cabozantinib to the subject in the absence of adverse reaction in the subject or if the subject has been determined to have Grade 1 severity of anemia; or if the subject has been determined to have Grade 2 severity of anemia, (1) continuing to administer Compound (I) to the subject; and (2) optionally administering an erythropoiesis-stimulating agent or providing a blood transfusion; and (3) optionally conducting an anemia work-up and administering iron therapy / supplementation based on the anemia work-up; or if the subject has been determined to have Grade 3 severity of anemia, (1) withholding Compound (I) until the subject has been determined to have a hemoglobin level greater than or equal to 9 g / dL and (2) resuming administration of Compound (I) at 100 mg once daily or at 50 mg once daily; or if the subject has been determined to have Grade 4 severity of anemia, (1) withholding Compound (I) until the subject has been determined to have a hemoglobin level greater than or equal to 9 g / dL and (2) resuming administration of Compound (I) at 25 mg once daily or permanently discontinuing Compound (I) administration.

55. A method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):Compound (I) at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for hypoxia; andcontinuing to administer Compound (I) and cabozantinib to the subject in the absence of adverse reaction in the subject or if the subject has been determined to have Grade 1 severity of hypoxia; or if the subject has been determined to have Grade 2 severity of hypoxia, (1) withholding Compound (I) until the subject has been determined to have resolution of or reduction in severity of hypoxia, and resuming administration of Compound (I) at 100 mg once daily or at 50 mg once daily; or (2) administering supplemental oxygen while continuing to administer Compound (I) at a dosage of 100 mg once daily or at 50 mg once daily, provided that severity of hypoxia does not worsen; or if the subject has been determined to have Grade 3 severity of hypoxia, (1) withholding Compound (I) until hypoxia is resolved or reduces in severity; and (2) resuming administration of Compound (I) at 25 mg once daily or discontinuing Compound (I) administration; or if the subject has been determined to have Grade 4 severity of hypoxia, permanently discontinuing Compound (I) administration.

56. A method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):Compound (I) at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for fatigue unrelated to anemia, deconditioning, depression, anxiety, poor nutrition, dehydration, sleep disturbance, or thyroid disorder(s); and continuing to administer Compound (I) and cabozantinib to the subject in the absence of adverse reaction in the subject or if the subject has been determined to have Grade 1 or Grade 2 severity of fatigue; or if the subject has been determined to have Grade 3 severity of fatigue, (1) withholding Compound (I) while the subject has been determined to have no reduction in fatigue; and (2) resuming administration of Compound (I) at 100 mg once daily or 50 mg oncedaily if the subject has been determined to have reduction in fatigue to Grade 2 or less in severity.

57. A method of treating ccRCC in a subject in need thereof comprising: initiating administration of Compound (I):at a dosage of 100 mg once daily to the subject in combination with administration of cabozantinib at a dosage of 60 mg once daily; monitoring the subject for adverse reaction other than (i) anemia, (ii) hypoxia, or (iii) fatigue unrelated to anemia, deconditioning, depression, anxiety, poor nutrition, dehydration, sleep disturbance, or thyroid disorder(s); and continuing to administer Compound (I) and cabozantinib to the subject in the absence of the adverse reaction in the subject or if the subject has been determined to have Grade 1 or Grade 2 severity of the adverse reaction; or if the subject has been determined to have Grade 3 severity of the adverse reaction, (1) withholding Compound (I) until the subject has been determined to have resolution of or reduction in severity of the adverse reaction; (2) resuming administration of Compound (I) at 100 mg once daily or at 50 mg once daily; and (3) discontinuing Compound (I) administration upon recurrence to Grade 3 severity; or if the subject has been determined to have Grade 4 severity of the adverse reaction, permanently discontinuing Compound (I) administration.

58. A method of treating ccRCC in a subject in need thereof, said method comprising administering 100 mg of Compound (I):Compound (I) to the subject daily.

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