Evaluating the Immunological Effects of Neoadjuvant Pembrolizumab with or without Lenvatinib in Patients with Kidney Cancer Scheduled for Nephrectomy

Inclusion Criteria

• Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of renal cell carcinoma will be enrolled in this study
• 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 lenvatinib: * 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 woman of child-bearing potential (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. ** Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed. * Please note that 7 days after lenvatinib is stopped, if the participant is on pembrolizumab only, no male contraception measures are needed
• A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a WOCBP OR * 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), as described during the intervention period and for at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last. The investigator should evaluate the potential for contraceptive method failure (i.e., noncompliance, recently initiated) in relationship to the first dose of study intervention *A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention (Arm A) or within 72 hours before the first dose of study intervention (Arm B). * If a urine test cannot be confirmed as negative (eg, 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. * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
• Histologically or cytologically confirmed diagnosis of renal cell carcinoma based on newly obtained renal mass core biopsy performed during study screening procedures
• Renal cell carcinoma with clinical stage cT2 to cT4 based on screening CT or MRI imaging assessment and eligible for surgical resection. * Note: Patients with regional nodal involvement (cN+) may be included irrespective of clinical T stage, provided disease is deemed “resectable” per treating urologic surgeon
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 1. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention
• Have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP =< 150/90 mmHg with no change in antihypertensive medications within 1 week prior to randomization
• Absolute neutrophil count (ANC) >= 1500/uL (collected within 10 days prior to the start of study intervention)
• Platelets >= 100,000/uL (collected within 10 days prior to the start of study intervention)
• Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (collected within 10 days prior to the start of study intervention) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
• Creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (collected within 10 days prior to the start of study intervention) * Creatinine clearance (CrCl) should be calculated per institutional standard
• Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (collected within 10 days prior to the start of study intervention)
• Alanine aminotransferase (AST) (serum glutamic pyruvic transaminase [SGOT]) and aspartate aminotransferase (ALT) (serum glutamic oxaloacetic transaminase [SGPT]) =< 2.5 x ULN (=< 5 x ULN for participants with liver metastases) (collected within 10 days prior to the start of study intervention)
• International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (collected within 10 days prior to the start of study intervention)
• Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (collected within 10 days prior to the start of study intervention)

Exclusion Criteria

• A WOCBP who has a positive urine pregnancy test within 24 hours prior to first dose of lenvatinib (Arm A only) or within 72 hours prior to first dose of pembrolizumab (Arms A and B). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• 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)
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization
• Has had major surgery within 3 weeks prior to first dose of study interventions. * Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility
• Has evidence of distant metastatic disease on CT/MRI scans * Note: Regional nodal metastases and/or ipsilateral adrenal metastasis are acceptable, if deemed resectable per primary urologic surgeon
• Has a need for urgent surgical resection per treating investigator
• Has preexisting >= grade 3 gastrointestinal or non-gastrointestinal fistula
• Has a left ventricular ejection fraction (LVEF) =< 40%, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
• Subjects having > 1+ proteinuria on urine dipstick testing, unless a 25-hour urine collection for quantitative assessment indicates that the urine protein is < 1 g/24 hours
• Prolongation of corrected QT (QTc) interval (calculated using Fridericia’s formula) to > 480 ms. * Note: If the QTcF is prolonged to > 480 ms in the presence of a pacemaker, contact the Medical Monitor to determine eligibility
• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia\ associated with hemodynamic instability * Note: Medically controlled arrhythmia would be permitted
• Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib per investigator discretion
• Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, non-invasive urothelial carcinoma, low- or intermediate-risk prostate cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
• Has severe hypersensitivity (>= grade 3) to pembrolizumab or lenvatinib and/or any of their excipients
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed
• Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
• Has an active infection requiring systemic therapy
• Has a known history of Human Immunodeficiency Virus (HIV) infection. * Note: No HIV testing is required during study screening
• Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. * Note: No testing for Hepatitis B and Hepatitis C is required during study screening
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant’s participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• Has had an allogenic tissue/solid organ transplant