Neoadjuvant Belzutifan Plus Pembrolizumab in High-Risk, Locally Advanced Clear Cell Renal Cell Carcinoma

Inclusion Criteria:

1\. Patient has provided written informed consent using the NEBULA Main PICF. 2. Adults aged 18 years or older at the time of written informed consent.

3\. Histologically or cytologically confirmed diagnosis of RCC with clear cell component per American Joint Committee on Cancer (8th edition), with or without sarcomatoid features.

4\. Patients who in the opinion of the treating surgeon require nephrectomy. 5. Patient has high risk ccRCC as defined by the following pathological tumour-node metastasis and tumour grading: • cT2b, Nany, Gany • cT3-cT4, N0, Gany • cTany, cN1, Gany 6. Patient has evaluable primary tumour disease according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST1.1).

7\. Patients has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 10 days prior to randomisation.

8\. Patient has a Karnofsky performance score of at least 70% within 10 days prior to randomisation.

9\. Patients must have adequate bone marrow, hepatic and renal function documented within 10 days prior to randomisation, defined as: • Haemoglobin (Hgb) ≥ 100 g/L. Criteria must be met without erythropoietin dependency and without peripheral red blood cell transfusion within 4 weeks before the haematology screening assessment. • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L. • Platelets ≥ 100 x 109/L. • Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 30 mL/min calculated using the Cockcroft-Gault equation (Appendix 1) or 24-hour urine collection. • Total bilirubin ≤ 1.5 x ULN ≤ 1.5 × ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 × ULN. • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (≤ 5 × ULN for patients with liver metastases). • International normalisation ratio (INR) or prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy as long as INR/PT or aPTT is within therapeutic range of intended use of anticoagulants.

10\. Women of childbearing potential (WCBP) must agree to use a highly effective contraceptive method (with a failure rate of \< 1%) as outlined in Section 9.10.1 during study treatment and for 30 days after the last dose of belzutifan or 120 days after the last dose of pembrolizumab, whichever occurs last and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period.

11\. A WCBP must have a negative highly sensitive urine or serum pregnancy (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to randomisation.

12\. Male patients are eligible to participate if they agree to the following during the treatment period and for at least 7 days after the last dose of belzutifan: • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WCBP who is not currently pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile-vaginal penetration. • Male patients must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.

13\. Patient is willing and able to comply with the protocol for the duration of the study including undergoing surgery, treatment, scheduled visits, and examinations.

Exclusion Criteria:

1. Presence of extensive tumour thrombus that necessitates early surgical intervention as per primary treating urologist.
2. cT1 or cT2a Gany.
3. Metastatic disease, or resected M1 disease.
4. Has received prior systemic therapy for ccRCC.
5. Has received prior radiotherapy for ccRCC.
6. Has any of the following: • Pulse oximeter reading \< 92% at rest. • Requires intermittent supplemental oxygen. • Requires chronic supplemental oxygen.
7. Has clinically significant cardiovascular disease within 6 months prior to randomisation, including NYHA III or IV congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, undergone coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, or cardiac arrhythmia. Note: Medically controlled arrhythmia stable on medication is permitted.
8. Has other clinically significant disorders such as: • Serious active nonhealing wound/ulcer/bone fracture. • Requirement for haemodialysis or peritoneal dialysis.
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy exceeding 10 mg daily dose of prednisone or equivalent or any other form of immunosuppressive therapy within 7 days prior to randomisation.
10. Has an active autoimmune disease that has required systemic treatment in the last 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
11. Has a known additional malignancy that is progressing or has required active treatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ, such as breast cancer in situ, that has undergone potentially curative therapy are not excluded.
12. Has known active central nervous system metastases and/or carcinomatous meningitis.
13. Has received colony-stimulating factors (e.g., G-CSF, GM-CSF) or recombinant erythropoietin or transfusion within 28 days prior to randomisation. 14. Is unable to swallow orally administered medication or has a history or current evidence of a gastrointestinal condition (e.g., inflammatory bowel disease, Crohn's disease, ulcerative colitis) or impaired liver function or diseases that in the opinion of the investigator may significantly alter the absorption or metabolism of oral study intervention.

15\. Has a severe hypersensitivity (Grade ≥ 3) reaction to belzutifan or pembrolizumab and/or any of their excipients.

16\. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.

17\. Has an active infection, requiring systemic therapy. 18. Has a known history of human immunodeficiency virus (HIV) infection. 19. Has known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C (defined as Hepatitis C virus \[HCV\] RNA \[qualitative\] is detected) infection.

20\. Has received a live virus vaccine or live-attenuated vaccine within 30 days prior to randomisation. Note: Administration of killed vaccines is allowed.

21\. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the patient's participation for the full duration of the study, such that it is not in the best interest of the patient to participate, in the opinion of the treating investigator.

22\. Has a known psychiatric or substance abuse disorder that would interfere with the patient's ability to cooperate with the requirements of the study.

23\. Has had a prior solid organ transplant. 24. Is breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through to 30 days after the last dose of belzutifan or 120 days after the last dose of pembrolizumab, whichever occurs last.

25\. Any contraindications for surgery.