Nephrectomy Clinical Trials

• Biopsy proven clear cell renal cell carcinoma (ccRCC).

• a. Extra tissue should be submitted if available for correlative analysis. Formalin-fixed paraffinembedded (FFPE) tissue blocks are preferred to slides. Details pertaining to tumor tissue submission can be found in the Lab Procedures Manual.

• Has intermediate-high risk, high risk, or M1 ccRCC as defined by the following pathological tumor-node metastasis and tumor grading:

‣ Intermediate-high risk ccRCC\*

⁃ pT2 (by radiographic/size criteria), Grade 4 or with sarcomatoid/rhabdoid features (on biopsy), N0, M0

⁃ pT3 (presence of tumor thrombus, perinephric and/or sinus fat invastion by imaging), any grade, N0, M0 High-risk ccRCC\*

⁃ pT4, any g.rade, N0, M0

⁃ pT, any stage, any grade, N+, M0 M1 RCC participants who present with the primary kidney tumor, but also solid, isolated, soft tissue metastases that are planned to be completely resected at the time of nephrectomy are eligible (e.g. metastasis to ipsilateral adrenal gland).

∙ NOTE: Fuhrman Tumor Grade and/or WHO/ISUP Tumor Grade are required for all subjects entering the study.

∙ • Evaluated by urology and approved as candidates for nephrectomy.

∙ • Age ≥18 years and consent to participation.

∙ • Performance status of 0-1 per Zubrod/Eastern Cooperative Oncology Group \[ECOG\] scale.

∙ • Absence of distant metastases on imaging of chest, abdomen and pelvis within 42 days of enrollment (by CT, MRI, or PET imaging). Brain imaging is not required unless clinical suspicion per the treating provider.

∙ • Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.

∙ • Screening laboratory criteria include the following: a. ANC ≥1000, PLT ≥ 75, Hgb ≥9 (transfusion allowed if Hgb \< 1.5 or = to upper limit of normal

∙ • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.

∙ • Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (see below) prior to study entry and for the duration of study participation, including for 120 days after the last dose of pembrolizumab and 30 days after the last dose of belzutifan. WOCBP will be required to have a negative pregnancy test prior to cycle 1 day 1 of treatment, ≤24 hours prior to first dose of treatment. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

∙ • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 30 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately

∙ • This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following:

∙ o Postmenopausal (no menses in greater than or equal to 12 consecutive months).

• History of hysterectomy or bilateral salpingo-oophorectomy.

• Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who have received Whole Pelvic Radiation Therapy).

• History of bilateral tubal ligation or another surgical sterilization procedure.

⁃ • Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 days after the last dose of study intervention:

⁃ • 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

⁃ • Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause) as detailed below:

⁃ \- Agree to use a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP 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 participants must also agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex.

⁃ • Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

⁃ • Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of pembrolizumab and 30 days after last belzutifan administration.

‣ Ability to understand and the willingness to sign a written informed consent document.