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 biomarkers associated with treatment benefit.

Study Overview

• Status: Active, not recruiting
• Conditions: Non-clear Cell 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 40 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 assessments were performed at baseline and every 6 weeks during treatment according to RECIST version 1.1 until disease progression, death, or study discontinuation. Investigator assessment is used for the primary progression-free survival endpoint. Objective response rate, disease control rate, and duration of response are assessed by blinded independent central review.

In addition to evaluating clinical efficacy and safety, prespecified exploratory translational analyses are conducted using pretreatment tumor samples. Multiplex immunofluorescence is used to characterize the composition and spatial organization of the pretreatment tumor immune microenvironment.

• Study Type: Interventional
• Enrollment (Actual): 40
• 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 to 85 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. History of allergy to any component of serplulimab or fruquintinib.
2. History of or concurrent malignancy, excluding skin basal cell carcinoma, cervical carcinoma in situ, and papillary thyroid carcinoma, that has not been cured for more than 5 years or has active cancer.
3. Uncontrolled cardiac symptoms or diseases, including NYHA class II or higher heart failure, unstable angina, myocardial infarction within 1 year, or clinically significant atrial or ventricular arrhythmias requiring intervention.
4. Previous treatment with PD-1, PD-L1, or CTLA-4 antibodies; investigational drugs within 4 weeks before the first dose; enrollment in another interventional clinical trial; systemic corticosteroids (>10 mg/day prednisone equivalent) or other immunosuppressive drugs within 2 weeks before the first dose, subject to protocol-specified exceptions; antitumor or live vaccines within 4 weeks; or major surgery or serious trauma within 4 weeks.
5. Toxicity from previous anticancer therapy not recovered to CTCAE grade 1 or lower, excluding alopecia and residual neurotoxicity related to previous platinum therapy, or otherwise not meeting the eligibility criteria.
6. Serious infection (CTCAE grade >2) within 4 weeks before the first dose, including severe pneumonia, sepsis requiring hospitalization, infection-related complications, active pulmonary inflammation on baseline imaging, symptoms or signs of infection, or need for oral or intravenous antibiotics.
7. Active autoimmune disease or history of autoimmune disease, subject to the protocol-specified exceptions for stable thyroid replacement, type 1 diabetes on stable insulin, vitiligo, and childhood asthma or allergy in remission.
8. History of immunodeficiency, including HIV infection, other acquired or congenital immunodeficiency, organ transplantation, or allogeneic bone marrow transplantation.
9. History of interstitial lung disease, excluding radiation pneumonitis not treated with steroids, or history of noninfectious pneumonia.
10. Evidence of active tuberculosis infection, active tuberculosis within 1 year before screening, or inadequately treated tuberculosis more than 1 year before screening.
11. Active hepatitis B or hepatitis C as defined in the protocol; eligible patients with controlled hepatitis B must receive protocol-specified antiviral therapy.
12. Known history of psychotropic substance abuse, alcoholism, or drug use.
13. Pregnant or lactating women.
14. Other factors that, in the investigator's judgment, could require withdrawal or compromise patient safety or data collection, including serious concomitant illness, significant laboratory abnormalities, or family or social factors.
15. 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 receive fruquintinib 5 mg once daily, 2 weeks on/1 week off, combined with serplulimab 4.5 mg/kg by intravenous infusion on day 1 every 3 weeks.	Drug: Fruquintinib combined with Serplulimab; Fruquintinib 5 mg once daily, 2 weeks on/1 week off, and serplulimab 4.5 mg/kg by intravenous infusion on day 1 every 3 weeks.; Other Names: Elunate; HLX10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigator-assessed progression-free survival (PFS)	Time from treatment initiation to the first documentation of disease progression according to RECIST version 1.1, as assessed by the investigator, or death from any cause, whichever occurs first.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Time from treatment initiation to death from any cause	Up to 5 years
Objective response rate (ORR) by blinded independent central review	Proportion of patients achieving complete response (CR) or partial response (PR) according to RECIST version 1.1, as assessed by blinded independent central review	Up to 2 years
Disease control rate (DCR) by blinded independent central review	Proportion of patients achieving CR, PR, or stable disease according to RECIST version 1.1, as assessed by blinded independent central review.	Up to 2 years
Adverse Event	Incidence and severity of adverse events and treatment-related adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pretreatment tumor immune microenvironment analysis	Composition and spatial organization of the pretreatment tumor immune microenvironment assessed using multiplex immunofluorescence.	Up to 2 years
Duration of response (DoR) by blinded independent central review	Time from the first documented CR or PR to radiographic disease progression according to RECIST version 1.1 or death from any cause, whichever occurs first, as assessed by blinded independent central review.	Up to 2 years

Collaborators and Investigators

• Sponsor: RenJi Hospital
• Collaborators: Shanghai Zhongshan Hospital; Sun Yat-Sen University Cancer Center
• Investigators: Principal Investigator: wei xue, Renji Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Estimated): October 22, 2027
• Study Completion (Estimated): October 22, 2030

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): September 16, 2026
• Last Update Submitted That Met QC Criteria: September 13, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: combination therapy; Fruquintinib; first-line; non-clear cell renal cell carcinoma; Serplulimab
• 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