A Study of AK104 Monotherapy or AK104 Plus Axitinib in Advanced/Metastatic Renal Cell Carcinoma

Inclusion Criteria:

1. Provide written informed consent/assent for the trial.

2. Be≥18 and ≤ 75 years of age on day of signing informed consent, no matter male orfemale.

3. Have Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior tofirst dosing of AK104.

4. Have estimated life expectancy of at least 3 months.

5. Have histologically or cytologically confirmed diagnosis of RCC withadvanced/metastatic disease (i.e., Stage IV RCC per American Joint Committee onCancer) with clear cell or non-clear cell component (part 1) or solely clear cellcomponent (part 2).

6. Have received no prior systemic therapy for advanced RCC . Note: Priorneoadjuvant/adjuvant therapies are acceptable if disease progression occurred > 12months after last dosage of neoadjuvant/adjuvant treatment.

7. Have measurable disease per RECIST 1.1 as assessed by the investigator /siteradiologist. (brain metastases were excluded).

8. Have provided archival tumor tissue sample or newly obtained core or excisionalbiopsy of a tumor lesion. Formalin-fixed, paraffin embedded (FFPE) tissue blocks arepreferred to slides.

9. Adequate organ function as determined by:

10. Hematology: i. absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L (1,500/mm3); ii.platelets ≥ 100 × 10^9/L (100,000/mm3); iii. hemoglobin ≥ 90 g/L.

11. Renal: i. calculated creatinine clearance * (CrCl) ≥ 50 mL/min; * CrCl will becalculated using the Cockcroft-Gault formula CrCL (mL/min) = {(140-age) × bodyweight (kg) × F }/(SCr (mg/dL) × 72) Where F = 1 for males and F = 0.85 forfemales; SCr = serum creatinine. ii. urine protein < 2 + or 24-hour urineprotein must be < 2.0 g.

12. Hepatic: i. serum total bilirubin (TBil) ≤ 1.5 × ULN; ii. AST and ALT ≤ 2.5 ×ULN, ≤ 3.0 × ULN with liver metastasis; iii. serum albumin (ALB) ≥ 28 g/L.

13. Coagulation function: i. international normalized ratio (INR) and activatedpartial thromboplastin time (APTT) ≤ 1.5 × ULN.

14. Cardiac Function: i. Left ventricular ejection fraction (LVEF) ≥ 50%.

Exclusion Criteria:

1. Has a known additional malignancy that has progressed or has required activetreatment in the last 3 years. Note: Subjects with basal cell carcinoma of the skin,squamous cell carcinoma of the skin that has undergone potentially curative therapyor carcinoma in situ are not excluded.

2. Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an antibodytargeting any other immune-regulatory receptors or mechanisms. Examples of suchantibodies include (but are not limited to) antibodies against IDO, IL-2R,GITR，CTLA-4，CD40, CD137.

3. Has received prior therapy with VEGF/VEGFR or mTOR targeting agents.

4. Has received radiotherapy within 14 days prior to start of study treatment and hasnot recovered adequately from any toxicity and/or complications from priorradiotherapy.

5. Has newly diagnosed brain metastases or known symptomatic brain metastases requiringsteroids. Subjects with previously diagnosed brain metastases are eligible if theyhave completed their treatment and have recovered from the acute effects ofradiation therapy or surgery prior to receiving first dose of trial treatment, havediscontinued corticosteroid treatment for these metastases for at least 3 days andare neurologically stable.

6. Had major surgery 4 weeks or major radiation therapy 2 weeks prior to receivingfirst dose of trial treatment. Prior palliative radiotherapy to metastatic lesion(s)is permitted, provided it has been completed at least 48 hours prior to receivingfirst dose of trial treatment.

7. Has active autoimmune disease that might deteriorate when receiving animmunostimulatory agents. Subjects with diabetes type I, vitiligo, psoriasis,hypo-or hyperthyroid disease not requiring immunosuppressive treatment are eligible.

8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or anyother form of immunosuppressive therapy within 7 days prior to receiving first doseof trial treatment.

9. Has a history of (non-infectious) pneumonitis that required steroids or currentpneumonitis.

10. Has an active tuberculosis and syphilitic infection.

11. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIVantibodies).

12. Has known active Hepatitis B (e.g., Hepatitis B surface antigen [HBsAg] reactive andHBV-DNA>200 IU/ml) or Hepatitis C virus (e.g., HCV RNA [qualitative] is detected).

13. Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg.

14. Has active bleeding disorder or other history of significant bleeding episodeswithin 30 days of screening.

15. Has been pregnant or breastfeeding, or expecting to conceive or father childrenwithin the projected duration of the trial, starting with the screening visitthrough 120 days after the last dose of trial treatment (30 days for axitinib,whichever occurs last).