Involving changes to the primary endpoint, it is difficult to unify the evaluation criteria for subjects' endpoints before and after the change.

The PLUTO-trial is a single-center, open-label, phase II trial investigating Toripalimab plus Lenvatinib in patients with multi-stage clear-cell renal cell carcinoma. In this trial, patients will be enrolled in one of three cohorts according to the stage of their clear-cell renal-cell carcinoma: localized, locally advanced and metastatic RCC. Patients in all cohorts will receive four to five cycles of preoperative Toripalimab (240mg Q3W IV) plus Lenvatinib (20mg QD PO) and will undergo nephrectomy within four weeks after the last cycle. Patients in cohort 1 who are considered to be at high risk according to pathology results of surgery specimen, and all the patients in cohort 2 are supposed to receive postoperative doses of Toripalimab (240mg Q3W IV) for at most 17 doses. Patients in cohort 3 are supposed to continue Toripalimab plus Lenvatinib after surgery.

The primary clinical endpoint of the study is immune-related pathological response to tumorigenesis, defined as the extent of tumor cell reduction in the tumor bed. Simon's two-stage design is used in this study. An initial cohort of 12 patients per cohort will be recruited, followed by an interim analysis. Recruitment to each cohort will be closed if a qualifying immune-related pathological response is not observed in any patient at an interim analysis. If qualifying immune-related pathological response is observed in at least one patient, additional 9 patients will be recruited in the cohort to 21 patients. Considering potential 10% dropout rate in the trial, an anticipation of 69 patients will be recruited for this study.

Inclusion Criteria:

• Have fully understood and voluntarily signed the informed consent Form (ICF);

• Age: 18-80 years old (at the time of signing the informed consent); Both male and female; ECOG PS score: 0-1;

• RCC with clear cell component confirmed by histology or cytopathology, including locally advanced RCC with clear cell component;

• ECOG 0-1 points

• T1b-T2bN0M0, T3a-4N0M0, TanyN1M0 or M1RCC diagnosed by imaging at initial diagnosis:

  1. Cohort 1: T1b-T2bN0M0 RCC;
  2. Cohort 2: T3a-4N0M0 or TanyN1M0 RCC;
  3. Cohort 3: M1 RCC undergoing cytoreductive nephrectomy.

• Radical nephrectomy or partial nephrectomy or renal tumor enucleation was decided after the clinician made the treatment plan and communicated with the patient;

• Willingness and ability to comply with planned visits, therapeutic laboratory testing, and other procedures.

Exclusion Criteria:

• Signs of tumor metastasis involving the central nervous system;

• History of malignant tumors other than the study disease within the previous 5 years, with the exception of malignant tumors that can be expected to be cured with treatment (including but not limited to adequately treated thyroid cancer, carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated with radical surgery);

• Prior to participating in the study, patients had received other systemic treatment drugs, including targeted drugs, immunotherapy drugs and their combination regimens, or local anti-tumor therapy, or received investigational drugs or device therapy;

• Underwent major surgery (judged by the investigator) within 4 weeks before the first trial dose, were recovering, or were unable to undergo baseline puncture;

• History of severe drug allergy, including but not limited to antibody drugs;

• patients with contraindications to immunotherapy restart, including but not limited to:

  1. Grade 2-4 immune myocarditis;
  2. Severe grade 4 proteinuria;
  3. Severe or life-threatening grade 4 immune hepatitis;
  4. Severe grade 3-4 immune pneumonitis;
  5. Severe inflammatory arthritis that significantly affects daily life or quality of life;
  6. Severe neurological toxicity:
  7. Myasthenia gravis grade 2-4;
  8. Guillain-Barre syndrome (GBS) or transverse myelitis of any grade;
  9. Grade 2-4 encephalitis;
  10. Severe or life-threatening grade 3-4 pancreatitis;
  11. Severe or life-threatening bullous disease (grade 3-4);
  12. Severe grade 3-4 uveitis or episcleritis;

• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation or long-term corticosteroid therapy. Patients with thyroid, suprarenal or hypopituitarism that could be controlled only with hormone replacement therapy, type 1 diabetes mellitus, psoriasis or vitiligo without systemic treatment, etc., were eligible to participate in the study.

• Non-resolution of toxicity after previous antineoplastic therapy, i.e., resolution to baseline, NCI-CTCAE 5.0 grade 0-1 (excluding alopecia), or inclusion/exclusion criteria. Irreversible toxicities (e.g., hearing loss) that would not reasonably be expected to be exacerbated by the study drug can be included in the study;

• Known history of clinically significant liver disease, including active viral hepatitis (hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HbcAb) positive, HBV DNA>10000 copies /mL or >2000 IU/mL; Hepatitis C virus (HCV) antibody positive and HCV RNA positive], or other active hepatitis, clinically significant moderate to severe cirrhosis;

• Patients with uncontrolled third space effusion requiring repeated drainage, such as pleural effusion, ascites, pericardial effusion, etc. (Patients who do not need drainage of effusion or stop drainage for 3 days without significant increase in effusion can be enrolled);

• Receiving a systemic corticosteroid (prednisone > 10mg/ day or equivalent) or other immunosuppressive medication within 14 days before the first study medication;

• Patients with any severe and/or uncontrolled disease, including:

  1. Hypertension that is not well controlled by antihypertensive medication (systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg);
  2. Unstable angina pectoris or myocardial infarction, coronary artery bypass grafting or stent implantation within 6 months before study medication;
  3. Grade I or above myocardial ischemia or myocardial infarction, arrhythmia (including QTc≥480ms) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification); Degree Ⅱ or above heart block; Left ventricular ejection fraction (LVEF) < 50%;
  4. Poorly controlled diabetes (fasting blood glucose > 10 mmol/L);
  5. Patients with urinary protein ≥++ and confirmed 24-hour urinary protein > 1.0g;
  6. Severe active or uncontrolled infection;

• Patients with or suspected to have active autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, etc.;

• Renal failure requiring hemodialysis or peritoneal dialysis;

• Patients with a history of immunodeficiency, including HIV positive patients, other acquired immunodeficiency diseases, congenital immunodeficiency diseases, or organ transplantation history;

• History of live attenuated vaccine inoculation within 4 weeks before the first study drug or the expected vaccination during the study period;

• History of psychiatric drug abuse and can not quit or have a history of mental disorders;

• The presence of any other severe, acute or chronic medical disease or mental illness or laboratory abnormality, as judged by the investigator, that may increase the risk associated with participation in the study or that may interfere with the interpretation of the results of the study.