Fruquintinib Plus Serplulimab as First-Line Therapy for Metastatic Non-Clear Cell Renal Cell Carcinoma

A Multicenter, Single-Arm, Phase II Study Evaluating 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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-clear Renal Cell Carcinoma
• Intervention / Treatment: Drug: Fruquintinib combined with Serplulimab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 200123
      • Renji hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Fruquintinib combine with Serplulimab; Patients will receive Fruquintinib 5mg, qd, 2w on/1w off, combined with Serplulimab 4.5mg/kg, IV drip, d1, q3w.	Drug: Fruquintinib combined with Serplulimab; Fruquintinib 5mg, qd, 2w on/1w off and Serplulimab 4.5mg/kg, IV drip, d1, q3w; Other Names: Elunate; HLX10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Defined as the time from treatment initiation to the first documentation of disease progression per RECIST v1.1 or death from any cause, whichever occurs first.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	Proportion of patients achieving complete response (CR) or partial response (PR) per RECIST v1.1	Up to 2 years
Disease control rate (DCR)	Proportion achieving CR, PR, or stable disease.	Up to 2 years
Adverse Event	Incidence and severity of treatment-related adverse events assessed by CTCAE v5.0	Up to 2 years
Overall Survival (OS)	Time from treatment initiation to death from any cause	Up to 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor Immune Microenvironment Analysis	Immune features assessed by multiplex immunofluorescence	Up to 2 years
RNA-Based Immune Profiling	Identification of immune-related gene expression signatures associated with treatment response or resistance	Up to 2 years

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Shanghai Zhongshan Hospital; Peking University Third Hospital; Sun Yat-Sen University Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: April 16, 2023
• First Submitted That Met QC Criteria: April 16, 2023
• First Posted (Actual): April 26, 2023

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: combination therapy; Fruquintinib; first-line; Serplulimab; non-clear renal cell carcinoma
• Additional Relevant MeSH Terms: Urogenital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Urologic Neoplasms; Kidney Neoplasms; Carcinoma; Carcinoma, Renal Cell
• Other Study ID Numbers: FRONTIER

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No