This multicenter, single-arm, phase II study (FRONTIER) evaluates the efficacy and safety of fruquintinib combined with serplulimab as first-line treatment in patients with metastatic or unresectable non-clear cell renal cell carcinoma (nccRCC). Given the biological heterogeneity and lack of established standard therapies in nccRCC, this study aims to characterize clinical outcomes and explore potential predictive biomarkers associated with treatment benefit.

This is a prospective, multicenter, single-arm phase II study conducted in patients with metastatic or unresectable nccRCC across participating centers in China.

The study consists of a safety run-in phase followed by a cohort expansion phase. Six patients were initially enrolled in the safety run-in stage. As no dose-limiting toxicities or treatment-related deaths were observed during the predefined observation period, the study proceeded to full enrollment.

A total of 39 patients were enrolled and received fruquintinib (5 mg orally once daily, 2 weeks on/1 week off) in combination with serplulimab (4.5 mg/kg intravenously every 3 weeks) as first-line systemic therapy.

Tumor response was assessed at baseline and every 6 weeks during treatment according to RECIST version 1.1 until disease progression, death, or study discontinuation.

In addition to evaluating clinical efficacy and safety, prespecified exploratory translational analyses are conducted using pretreatment tumor samples. These include multiplex immunofluorescence (mIF) to characterize the tumor immune microenvironment (including CD8+ T-cell infiltration, PD-L1 expression, and macrophage markers), as well as potential RNA-based immune profiling to identify biomarkers associated with response or resistance to therapy.

Inclusion Criteria:

1. Signed informed consent
2. Age ≥18 years
3. Histologically or cytologically confirmed metastatic or unresectable nccRCC
4. At least one measurable lesion per RECIST v1.1
5. No prior systemic therapy for advanced disease
6. ECOG performance status 0-1
7. Adequate organ function
8. Life expectancy ≥3 months

Exclusion Criteria:

1. There is a history of allergy to any component of the drug SLT or the drug Fruquintinib.

2. A history of or concurrent malignancy (excluding skin basal cell carcinoma and cervical carcinoma in situ and papillary carcinoma of thyroid) that has been cured for more than 5 years and has no active cancer）.

3. Uncontrolled clinical symptoms or diseases of the heart, including: a) NYHA class II or above heart failure; b) unstable angina; c) myocardial infarction within 1 year; d) significant atrial or ventricular arrhythmias requiring clinical intervention.

4. Having received any of the following treatments: a) previous treatment with PD-1, PD-L1 antibodies, or CTLA-4 antibodies; b) received any investigational drugs within 4 weeks prior to the first dose of the study drug; c) enrolled in another clinical trial, unless it is an observational (non-interventional) study; d) requiring systemic treatment with corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within 2 weeks prior to the first dose of the study drug, with the exception of using corticosteroids for local inflammation or prevention of allergies, nausea, and vomiting. Other special circumstances should be communicated with the investigator. In the absence of active autoimmune diseases, inhaled or locally applied steroids and adrenal cortex hormones that replace a dosage of >10 mg/day prednisone can be used.

   e) Vaccination with anti-tumor vaccines or receipt of live vaccines within 4 weeks prior to the first dose of the study drug; f) underwent major surgery or had any serious trauma within 4 weeks prior to the first dose of the study drug.

5. Toxicity from previous anti-cancer therapy has not recovered to ≤ CTCAE grade 1 (excluding alopecia and residual neurotoxicity related to previous platinum therapy) or does not meet inclusion/exclusion criteria.

6. Serious infection (CTCAE grade >2) within 4 weeks prior to the first dose of the study drug, including severe pneumonia, sepsis requiring hospitalization, and infection-related complications; baseline chest imaging shows active pulmonary inflammation, symptoms and signs of infection within 4 weeks of first dose, or the need for oral or intravenous antibiotics.

7. Active autoimmune diseases or a history of autoimmune diseases (including but not limited to interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism), except autoimmune-mediated hypothyroidism treated with a stable dose of thyroid replacement hormone and I-type diabetes treated with a stable dose of insulin. Patients with vitiligo or childhood asthma/allergy in remission without any intervention in adulthood are not excluded.

8. A history of immunodeficiency diseases, including HIV-positive, other acquired or congenital immunodeficiency diseases, organ transplantation, or allogeneic bone marrow transplantation.

9. A history of interstitial lung disease (excluding radiation pneumonitis that has not been treated with steroids), and a history of non-infectious pneumonia.

10. Evidence of active tuberculosis infection based on medical history and CT examination, a history of active tuberculosis infection within 1 year prior to screening, or a history of active tuberculosis infection over 1 year ago that has not been properly treated.

11. Patients with active hepatitis B (HBV DNA ≥500 IU/mL or 2500 copies/mL) or hepatitis C (positive HCV antibodies and HCV-RNA higher than the detection limit of the assay) are excluded. Patients with HBsAg-positive and HBV DNA-negative or HBV DNA <500 IU/mL or 2500 copies/mL can receive treatment for antiviral therapy for more than 2 weeks before enrolling in the trial and continue antiviral therapy for 6 months after the end of the last dose of the study drug.

12. A known history of psychotropic substance abuse, alcoholism or drug use;

13. Pregnant or lactating women;

14. At the investigator's discretion, patients with other factors that may force them to withdraw from the study, such as concomitant severe illnesses (including mental illness) requiring treatment, significant laboratory abnormalities, and family or social factors that may hinder patient safety or data collection.

15. Patients with severe active bleeding, active peptic ulcers, unhealed gastrointestinal perforations, or gastrointestinal fistulas.