Neoadjuvant Pembrolizumab and Axitinib in Renal Cell Carcinoma With Inferior Vena Cava Tumor Thrombus

Inclusion Criteria:

• Provision to sign and date the consent form.

• Stated willingness to comply with all study procedures and be available for theduration of the study.

• Participant self-identified gender ages >/= 18 years old is acceptable andappropriate if they meet other inclusion criteria.

• Histologically proven clear cell component RCC.

• An upfront candidate for definitive surgery per treating Urologist.

• Suitable for and willing to undergo nephrectomy (either cytoreductive or withcurative intent) per treating urologist.

• T Stage of any of the following: cT3b, cT3c, cT4

• N stage of any of the following: cN0 or cN1

• M stage of any of the following: cM0 or cM1

• ECOG performance status 0 - 2.

• Urinalysis <2+ protein. If dipstick is ≥2+ then a 24-hour urine collection should beperformed, and the patient may enter the trial if urinary protein is <2g per 24hours.

• All participants who have reproductive potential must have a negative serum or urinepregnancy test within a maximum of 14 days prior to starting trial treatment.

Reproductive potential is defined as the following:

• Women will be considered post-menopausal if they have been amenorrheic for 12 monthswithout an alternative medical cause. The following age-specific requirements apply:

• Women <50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of exogenous hormonaltreatments and if they have luteinizing hormone and follicle-stimulatinghormone levels in the post-menopausal range for the institution or underwentsurgical sterilization (bilateral oophorectomy or hysterectomy)

• Women ≥50 years of age would be considered post-menopausal if they have beenamenorrheic for 12 months or more following cessation of all exogenous hormonaltreatments, had radiation-induced menopause with last menses >1 year ago, hadchemotherapy-induced menopause with last menses >1 year ago, or underwentsurgical sterilization (bilateral oophorectomy, bilateral salpingectomy orhysterectomy

• For males with reproductive potential, use effective birth control duringtreatment with Axitinib and Pembrolizumab is recommended.

Exclusion Criteria:

• Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to enrollment.

• Has had major surgery within 4 weeks or received radiation therapy within 1 weekprior to enrollment to the study.

• Has had prior treatment with any anti-programmed cell death (anti-PD-1) orprogrammed cell death ligand 1 (PD-L1), or an antibody targeting any otherimmune-regulatory receptors or mechanisms.

• Has received prior systemic anti-cancer therapy for RCC with vascular endothelialgrowth factor (VEGF)/VEGF receptors (VEGFR).

• Has a history of severe hypersensitivity reaction (e.g., generalized rash/erythema,hypotension, bronchospasm, angioedema, or anaphylaxis) to Axitinib.

• Has a diagnosis of immunodeficiency OR is receiving a systemic steroid therapygreater than Prednisone 10 mg daily or a steroid equivalent, or any other form ofimmunosuppressive therapy within 7 days prior to enrollment to the study except inthe case of central nervous system (CNS) metastases.

• Has an active autoimmune disease requiring systemic treatment within the past 2years OR a documented history of clinically severe autoimmune disease. Note:Participants with vitiligo, Sjogren's syndrome, Type 1 diabetes, resolved childhoodasthma/atopy, hypothyroidism or adrenal or pituitary insufficiency who are stable onhormone replacement are not excluded.

• Has a known additional malignancy that has progressed or has required activetreatment in the last 3 years. Note: Basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, superficial bladder cancer, or carcinoma in situ such asbreast cancer in situ, thyroid cancer (papillary, hurthle cell or follicular), orlocalized prostate cancer are acceptable if they have undergone potentially curativetherapy.

• Has known active CNS metastases and/or carcinomatous meningitis.

• Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

• ALT or AST above 3 times the upper limit of normal

• Has received a live virus vaccine within 30 days of enrollment to the study.

• Active GI bleeding, as evidenced by hematemesis, hematochezia, or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy.

• Intraluminal metastatic lesion with suspected bleeding, inflammatory bowel disease,ulcerative colitis or other GI condition associated with increased risk ofperforation.

• Has QT interval corrected for heart rate (QTc) ≥480 msec.

• Has a history of any of the following cardiovascular conditions within 12 months ofenrollment to the study:

• Myocardial infarction

• Unstable angina pectoris

• Cardiac angioplasty or stenting

• Coronary/peripheral artery bypass graft

• Class III or IV congestive heart failure per New York Heart Association

• Cerebrovascular accident or transient ischemic attack

• Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥150 mmHg and/or diastolic blood pressure (DBP) ≥90 mm Hg on 3 or more dose optimized anti-hypertensive medication.

• Has evidence of inadequate wound healing per treating physician discretion.

• Has active bleeding disorder or other history of significant bleeding episodeswithin 30 days of enrollment to the study.

• Has current use (within 7 days of enrollment) or anticipated need for treatment withdrugs or foods that are known to be strong cytochrome P450 (CYP3A4/5) inhibitors.

• Has current use (within 7 days of enrollment) or anticipated need for treatment withdrugs that are known strong CYP3A4/5 inducers, including but not limited tocarbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort;or drugs that are known with proarrhythmic potential.

• Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the study by subject self-report.

• Has had a prior solid organ transplant.

• Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the study, starting with the screening visit through 120 daysafter the last dose of study drug.