Pembrolizumab Plus Lenvatinib in REcurrent ccRCC Patients Failing permbroLizUmab aDjuvant trEatment

There is currently no well-recognized treatment paradigm for patients with advanced RCC who have progressed during or after Pembrolizumab in adjuvant setting. In addition, it is critical to understand whether immunotherapy can be used again after progression. The data from this study will provide additional information on the potential efficacy and safety of the combination treatment in participants specifically after receiving Pembrolizumab in adjuvant setting. A single-arm design was chosen, as there is no globally accepted standard-of-care regimen for participants with mRCC previously treated with adjuvant Pembrolizumab and relapsing within 12 months from last dose.

Inclusion criteria

• Male or female
• Age >18 years at the time of signing the informed consent
• Histological confirmation of RCC with a clear-cell component
• Has locally recurrent/metastatic disease (ie, Stage IV per the American Joint Committee on Cancer)
• Patients with RCC with sarcomatoid features are also allowed in this study
• Participants must have progressed on treatment with Pembrolizumab administered as adjuvant treatment. Pembrolizumab treatment progression is defined by meeting all of the following criteria:

• Has received at least 2 doses of Pembrolizumab as adjuvant treatment
• Has demonstrated disease progression after adjuvant Pembrolizumab as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression (as defined in Appendix 4).
• Progressive disease has been documented within 12 months from the last dose of adjuvant Pembrolizumab
• Progressive disease is determined according to iRECIST. This determination is made by the investigator. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.
• Male partecipants: A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose Pembrolizumab and 30 days after last dose of Lenvatinib and agreement to refrain from donating sperm during this period.
• Female partecipants: A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least at least 120 days post pembrolizumab or 30 days post lenvatinib, whichever occurs last, after the last dose of study treatment and agreement to refrain from donating eggs during this period.
• Asymptomatic patients with central nervous system (CNS) metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery. Measurable disease must be present outside the CNS. Before protocol enrollment updated CNS imaging with contrast-enhanced brain CT or brain MRI is required for patients who have received CNS-focal treatment (either by surgery or by RT) ≥ 30 days from initiation of protocol treatment.
• Evaluable International Metastatic RCC Database Consortium (IMDC) risk scores
• Participants who have AEs due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline, unless adverse events are clinically non significant in the opinion of the investigator. Participants with endocrine related AEs who are adequately treated with hormone replacement are eligible.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
• 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
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (KPS >70). Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
• Have adequate organ function as defined in the following table (Table 4). Laboratory tests must be collected within 14 days prior to the start of study intervention
• Has adequately controlled BP with or without antihypertensive medications, defined as BP ≤150/90 mm Hg with no change in antihypertensive medications within 1 week prior to allocation
• Ability to comply with protocol requirements
• The patient or the patient's legal representative has to be able to provide written informed consent. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

Exclusion criteria

• Treatment with any anti-cancer therapy as first line therapy after adjuvant therapy with pembrolizumab
• Adjuvant treatments other than Pembrolizumab
• Patients with non clear cell RCC
• Symptomatic, untreated, or actively progressing CNS metastases (patient has no history of intracranial hemorrhage or spinal cord hemorrhage; patient has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment; no evidence of significant vasogenic edema; patient has no ongoing requirement for corticosteroids as therapy for CNS disease but anticonvulsant therapy at a stable dose is permitted; CNS metastases limited to the cerebellum or the supratentorial region, no metastases to the midbrain, pons, medulla, or spinal cord; no evidence of interim progression between completion of CNS- directed therapy and initiation of study treatment)
• Has known leptomeningeal disease or carcinomatous meningitis
• Uncontrolled tumor-related pain symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement; uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures).
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
• History of malignancy other than renal carcinoma within 5 years prior to screening, with the exception of in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
• Radiotherapy for RCC within 14 days prior to Day 1 of Cycle 1. Patients who are receiving single-fraction radiotherapy given for the indication of pain control are eligible
• Active tuberculosis
• Major surgical procedure within 3 weeks prior to initiation of study treatment. Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility. Minor surgeries (e.g., tumor biopsy, placement of vascular access device) should be performed at least 10 days prior to initiation of study treatment. Patients with clinically relevant ongoing complications from prior surgery are not eligible
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment
• Severe infection within 4 weeks prior to initiation of study treatment
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment. Administration of killed vaccines is allowed. Note: please refer to Section 5.3.2 for information on COVID-19 vaccines
• Treatment with systemic immunostimulatory agents within 4 weeks prior to initiation of study treatment.
• Treatment with systemic immunosuppressive medication (e.g. corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti.TNF-alfa agents) within 2 weeks prior to initiation of study treatment, with the exceptions for patients who received acute or low dose systemic immunosuppressant medication (e.g. >10 mg/day oral prednisone or equivalent), and patients who received corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
• Has a known history of Human Immunodeficiency Virus (HIV) infection. Note: No HIV testing is required unless mandated by local health authority
• Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection or current treatment with anti-viral therapy for HBV or HCV
• Active or history of autoimmune disease or immune deficiency (e.g. myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, vasculitis, or glomerulonephritis, multiple sclerosis, psoriatic arthritis) with the exceptions of patients with a history of autoimmune-related hypothyroidism, patients with controlled Type 1 diabetes mellitus who are on an insulin regimen, patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (are eligible provided all of following conditions are met: rash must cover <10% of body surface area, disease is well-controlled at baseline and requires only low- potency topical corticosteroids, no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet, radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high- potency or oral corticosteroids within the previous 12 months).
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
• Malabsorption syndrome or any other condition that might affect the absorption of lenvatinib.
• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
• Uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
• Tumors invading the GI-tract, active peptic ulcer disease, acute pancreatitis, acute obstruction of the pancreatic or biliary duct, appendicitis, cholangitis, cholecystitis, diverticulitis, gastric outlet obstruction, or inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis).
• Stroke (including transient ischemic attack), myocardial infarction, or other symptomatic ischemic event, or thromboembolic event within 12 months before randomization, subjects with a diagnosis of incidental PE or DVT within 12 months are allowed if asymptomatic and stable at screening treated with low- molecular-weight heparins or the direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before first dose
• Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria. Note: Urine dipstick is the preferred method for testing urinary protein, however, urinalysis may be used if the use of urine dipsticks is not feasible
• 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.
• Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
• History of clinically significant ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities
• History of congenital QT syndrome.
• QT interval corrected with use of Fridericia's formula (QTcF) > 480 ms per ECG within 14 days before randomization
• Significant vascular disease (e.g., aortic aneurysm or arterial dissection requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1 of Cycle 1.
• Evidence of bleeding diathesis or significant coagulopathy.
• Abdominal or tracheoesophageal fistula, bowel obstruction, or gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months before initiation of study treatment. Complete healing of an intra abdominal abscess must be confirmed before initiation of study treatment. Has preexisting ≥ Grade 3 gastrointestinal or non-gastrointestinal fistula
• Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitor dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel)
• Clinical signs or symptoms of GI obstruction or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding
• Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation. NOTE: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
• Clinically significant hematuria, hematemesis, hemoptysis or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before initiation of study treatment.
• Serious active ulcer, or untreated bone fracture
• Prior history of hypertensive crisis or hypertensive encephalopathy
• Known hypersensitivity to any component of the pembrolizumab formulation. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. Has discontinued adjuvant Pembrolizumab due to adverse event
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known allergy or hypersensitivity to any component of the lenvatinib formulation
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.