Cadonilimab (AK104) Plus Lenvatinib in Previously Immunotherapy-Treated Advanced/Metastatic Clear Cell Renal Cell Carcinoma

A Multicenter, Single-Arm, Phase II Study of Cadonilimab (AK104) Plus Lenvatinib in Patients With Advanced/Metastatic Clear Cell Renal Cell Carcinoma Previously Treated With Immunotherapy-Based Combination Therapy

This is a phase II, open-label, multicenter, single-arm study evaluating the efficacy and safety of cadonilimab (AK104) in combination with lenvatinib in patients with unresectable advanced or metastatic clear cell renal cell carcinoma (ccRCC) who experienced disease progression during or after prior first-line immunotherapy-based combination therapy. Patients receive cadonilimab plus lenvatinib until radiographic disease progression, unacceptable toxicity, withdrawal of consent, death, or investigator decision. The primary endpoint is objective response rate (ORR) according to RECIST version 1.1 as assessed by investigators.

This is a multicenter, open-label, single-arm phase II clinical trial with a planned enrollment of 28 patients with unresectable advanced or metastatic clear cell renal cell carcinoma (ccRCC). Participating centers include Renji Hospital and Ruijin Hospital in Shanghai, China.

Patients receive oral lenvatinib at a starting dose of:

8 mg once daily for body weight <60 kg 12 mg once daily for body weight ≥60 kg Cadonilimab (AK104) is administered intravenously at 10 mg/kg every 3 weeks. Treatment continues until radiographic disease progression, unacceptable toxicity, withdrawal of informed consent, initiation of new anticancer therapy, death, loss to follow-up, or investigator decision.

Tumor assessments are performed at baseline, every 6 weeks (±7 days) during treatment, and at the end-of-treatment visit.

This study uses Simon's optimal two-stage phase II design. In stage 1, 12 evaluable patients are enrolled for futility assessment. If 2 or fewer confirmed objective responses are observed, the study may be terminated early for futility. Otherwise, enrollment proceeds to a total of 28 evaluable patients.

The study is designed to assess whether cadonilimab plus lenvatinib demonstrates sufficient antitumor activity to warrant further clinical investigation in patients with advanced ccRCC previously treated with immunotherapy-based therapy.

Criteria: Inclusion Criteria:

1. Written informed consent provided prior to study procedures.
2. Age ≥18 and ≤80 years at the time of consent.
3. Histologically or cytologically confirmed renal cell carcinoma with clear cell component.
4. Unresectable locally advanced or metastatic disease.
5. Radiographic disease progression during or after prior first-line immunotherapy-based combination therapy for advanced RCC.
6. At least one measurable lesion according to RECIST v1.1.
7. ECOG performance status of 0 or 1.
8. Estimated life expectancy of at least 3 months.
9. Adequate organ function, including hematologic, renal, hepatic, and coagulation parameters, as defined in the protocol.

Exclusion Criteria:

1. History of hypersensitivity to monoclonal antibodies or any component of cadonilimab or lenvatinib.

2. Known additional malignancy that is progressing or has required active treatment. Exceptions include adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ.

3. Prior treatment with dual immune checkpoint blockade, defined as anti-PD-1/PD-L1 combined with anti-CTLA-4 therapy.

4. Uncontrolled clinically significant cardiovascular disease or symptoms.

5. Diagnosis of immunodeficiency or receipt of systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive therapy within 14 days prior to first dose.

6. Active autoimmune disease or history of autoimmune disease that may worsen with immunostimulatory therapy. Subjects with type 1 diabetes mellitus, vitiligo, psoriasis, or hypo-/hyperthyroidism not requiring immunosuppressive treatment are eligible.

7. History of non-infectious pneumonitis requiring steroids or current pneumonitis/interstitial lung disease.

8. Active tuberculosis or active syphilitic infection.

9. Known history of human immunodeficiency virus (HIV) infection.

10. Active hepatitis B infection (HBsAg positive with HBV DNA >500 IU/mL) or active hepatitis C infection (detectable HCV RNA).

11. Clinically significant toxicities from prior anticancer therapy not recovered to Grade ≤1 (except alopecia or stable endocrinopathies).

12. Active bleeding disorder or history of clinically significant bleeding episodes.

13. Drug abuse, psychiatric illness, or medical/social conditions that may interfere with study participation or evaluation of results.

14. Pregnant or breastfeeding women, or participants planning conception during the study treatment period.

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