Neoadjuvant Lenvatinib and Pembrolizumab for IVC Tumor Thrombus

Inclusion Criteria: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent 2. Have histologically confirmed cT3-4,N0-1,M0-1 (clinical stage III-IV) diagnosis of renal cell carcinoma (any subtype) with level II-IV inferior vena cava tumor thrombus as per the Mayo classification of macroscopic venous invasion in renal cell carcinoma: 1. Level 1 tumor thrombus is either at the entry of renal vein or within the IVC \< 2 cm from the confluence of renal vein and IVC 2. Level II tumor thrombus extends within the IVC \> 2 cm above the confluence of renal vein and IVC, but still remains below the hepatic veins. 3. Level III tumor Thrombus involves the intrahepatic IVC. 4. Level IV tumor thrombus extends above diaphragm or into the right atrium. 3. The primary tumor and thrombus may be assessed to be resectable or unresectable at the time of enrollment. 4. Male participants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the 120 day neoadjuvant treatment period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period. Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) OR b. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 30 days after the last dose of study treatment. 5. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. 6. Have measurable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. 7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 14 days prior to the first dose of study intervention. 8. Criteria for known Hepatitis B and C positive subjects: Hepatitis B and C screening tests are not required unless: • Known history of HBV or HCV infection • As mandated by local health authority Hepatitis B positive subjects: • Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. • Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention. Hepatitis C positive subjects: • Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening. 9. Participants must have completed curative anti-viral therapy at least 4 weeks prior to randomization 10. HIV-positive participants may be enrolled. 11. HIV-infected participants must have well-controlled HIV on ART, defined as: 1\. Participants on ART must have a CD4+ T-cell count ≥350 cells/mm3 at the time of screening 2. Participants on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening 3. It is advised that participants must not have had any AIDS-defining opportunistic infections within the past 12 months. 4\. Participants on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study 5. The combination ART regimen must not contain any antiretroviral medications that interact with CYP3A4 inhibitors/inducers/substrates (https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers) 12\. Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 14 days prior to the start of study intervention. Absolute neutrophil count (ANC) ≥1500/µL Platelets ≥100 000/µL Hemoglobin ≥9.0 g/dL At the investigator's discretion, patients presenting with microhematuria and an Hb ≥8 who are asymptomatic may be considered as eligible for the trial and such patients will receive appropriate treatment for their anemia to ensure an Hb≥9 prior to starting treatment. Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases) International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants Exclusion Criteria: 1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to allocation (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 3. Has received prior systemic anti-cancer therapy including investigational agents prior to allocation. 4. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 week