Lenvatinib With Everolimus Versus Cabozantinib for Second-Line or Third-Line Treatment of Metastatic Renal Cell Cancer

Inclusion Criteria

• •1. Patients with histologically or cytologically confirmed metastatic/advanced clear cell RCC, or RCC with a clear cell component, who have received 1 or 2 prior lines of systemic treatment in the advanced or metastatic setting, including a PD-1/PD-L1 checkpoint inhibitor.
• •2. Patients must have previously progressed on or after treatment (at any point after completing prior therapy) with a PD-1/PD-L1-containing regimen. Patients who experienced an immune-mediated adverse event related to their PD-1/PD-L1 containing-regimen and cannot receive additional PD-1/PD-L1 checkpoint inhibitor are permitted, without evidence of progression, if the treating physician intends to change treatment per standard care.
• •3. Patients must have at least one measurable site of disease per RECIST version 1.1. This is defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). For non-lymph node tumor lesions, they must be a minimum size of
• •≥ 10 mm. For malignant lymph node lesions, they must be at least ≥ 15 mm in short axis with conventional techniques or ≥ 10 mm with more sensitive techniques such as MRI or spiral CT scan. If the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation.
• •4. ECOG performance status ≤ 2
• •5. Age ≥ 18 years Patients must have adequate organ and marrow function prior to study entry as defined below: Hemoglobina ≥9 g/dl (treatment allowed) Absolute neutrophil count ≥1,000/µL Platelets ≥75,000/µL Total bilirubinb ≤1.5 mg/dL AST(SGOT) or ALT (SGPT) ≤2.5 X institutional ULN, except in known hepatic metastasis, wherein may be \< 5 x ULN Serum CreatinineC ≤1.5 x ULN (as long as patient does not require dialysis) aMay receive transfusion b For patients with Gilbert's disease, total bilirubin should ≤ 3 mg/dL (≤ 51.3 µmol/L). b If creatinine is not \<1.5×ULN, then calculate by Cockcroft-Gault methods or local institutional standard and CrCl must be ≥30 mL/kg/1.73 m2
• •7\. INR and PT ≤ 1.5 x ULN prior to study entry. Therapeutic anticoagulation is permitted if: on a stable dose of low molecular weight heparin (LMWH) for \> 2 weeks (14 days) at the time of enrollment or on a direct oral anticoagulant (DOAC) for \> 2 weeks at time ofenrollment.
• •8\. Female patients of childbearing potential (not postmenopausal for at least 12 months and not surgically sterile) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) before study entry. Pregnancy test must be repeated if performed \> 14 days before starting study drug. 9. Women must not be breastfeeding. 10. Patients with a history of major psychiatric illness must be judged (by the treating physician) able to fully understand the investigational nature of the study and the risks associated with the therapy. 11. Patients with treated/stable brain metastases are allowed on protocol if they had brain metastases that received CNS-directed therapy, such as surgery or treatment with radiosurgery or Gamma knife, without recurrence for at least 1 month (4 weeks).
• •7. Uncontrolled blood pressure (systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg) in spite of optimized regimen of anti-hypertensive regimens.
• •8. Subjects having \> 1+ proteinuria on urine dipstick testing unless a spot urine protein to creatinine ratio is ≤ 2 mg/mg
• •11. Patients must not have history of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of lenvatinib, everolimus, or cabozantinib or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications.
• •12. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of blood vessels should be considered because of the risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib treatment.
• •13. Any patients who cannot be compliant with the appointments required in this protocol must not be enrolled in this study.
• •14. Severe hypersensitivity (≥ grade 3) to lenvatinib and/or any of its excipients.
• •15. Patients with left ventricular ejection fraction \< 40%