Inclusion Criteria:

1. Signed and dated written informed consent.

2. Male or female ≥ 18 years of age on the day of signing informed consent.

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

4. Histologically confirmed metastatic clear cell renal cell carcinoma (ccRCC)

5. Patients must have received at least one immune oncology (IO) agent and at least one VEGF-targeted therapy (alone or in combination)

6. Measurable tumor burden which can be followed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST 1.1 as assessed by the local site investigator

7. At least one metastatic lesion that is amenable to percutaneous biopsy

8. Adequate organ and bone marrow function resulted ≤ 28 days prior to first dose of protocol-indicated treatment:

   • Absolute neutrophil count (ANC) ≥ 1500/µL.
   • Platelets ≥ 100,000/µL.
   • Hemoglobin ≥ 10.0 g/dL or ≥ 6.2 mmol/L.
   • Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min (as calculated by the Cockcroft-Gault Formula or calculated/measured by an alternative established institutional standard consistently applied across participants).
   • Total bilirubin ≤ 1.5 times institutional upper limit of normal (ULN), or direct bilirubin ≤ ULN for participants with total bilirubin > 1.5 xULN.
   • AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional upper limit of normal (ULN)

9. Women must not be breastfeeding and further agree to not breastfeed during study treatment; and for at least 7 days after patient's final dose of casdatifan.

10. A woman of childbearing potential (WOCBP) - see Appendix 3 for definition of WOCBP - must have a negative serum or urine pregnancy test during screening within 28 days prior to receiving first dose of protocol-indicated treatment, and must agree to follow instructions for using acceptable contraception (Appendix 3) from the time of signing consent, and until at least 7 days after her final dose of casdatifan.

11. Men must refrain from donating sperm for at least 7 days after patient's final dose of casdatifan.

12. A man able to father children (see Appendix 3 for definition) who is sexually active with a WOCBP must agree to follow instructions for using acceptable contraception (Appendix 3), from the time of signing consent, and until at least 7 days after his final dose of casdatifan.

13. No exercise-induced desaturation on a 6-minute walk test, defined as a blood oxygen saturation by pulse oximetry ≤ 88%.

14. No active pneumonitis at screening as assessed by CT scan.

15. No medical history of severe chronic obstructive pulmonary disease (COPD).

16. If a participant has CNS metastases the participant must meet the following criteria:

    • Participants with previously treated brain metastases may participate provided they are clinically stable and without steroid treatment for at least 14 days prior to the first dose of study treatment. Participants with carcinomatous meningitis are excluded.

Exclusion Criteria:

1. Prior treatment with HIF 2α inhibitors (e.g. belzutifan or related agents)

2. Is currently participating in or within 2 weeks prior to receiving first dose of study treatment in a study of an investigational agent or investigational device.

   • Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 2 weeks after the last dose or last exposure to the previous investigational agent or investigational device.

3. Known severe hypersensitivity (≥ Grade 3) to any of the excipients of casdatifan.

4. History of myocarditis or pericarditis or other known underlying heart disease that is clinically significant by investigator judgment (for example, cardiomyopathy, congestive heart failure with New York Heart Association [NYHA] functional classification III or IV, symptomatic arrhythmia not controlled by medication, unstable angina, history of acute myocardial infarction). History of cerebrovascular accident (including TIA) within the past 6 months (24 weeks) prior to starting study treatment.

5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection/sepsis, interstitial lung disease, recent hospitalizations with unresolved symptoms, poorly controlled hypertension, or psychiatric illness/social situations that would limit compliance with study requirements.

6. Inability to swallow study treatment.

7. Contraindications to biopsy (e.g. bleeding diathesis, uncorrectable coagulopathy)