Fruquintinib plus serplulimab as first-line therapy in metastatic or unresectable non-clear cell renal cell carcinoma (nccRCC): Updated efficacy and safety data from a multicenter, single-arm, phase II trial.

Abstract

422 Background: Despite recent advancements, non-clear cell renal cell carcinoma (nccRCC) remains a significant therapeutic challenge with poor prognosis. Innovative therapeutic strategies are urgently needed. We previously reported promising anti-tumor activity of the combination of fruquintinib (small-molecule VEGFR inhibitor) and serplulimab (anti–PD-1 antibody) as first-line therapy in metastatic or unresectable nccRCC patients (pts). Here, we present the updated efficacy and safety data. Methods: This study was designed to enroll 39 treatment-naïve pts (aged 18–80 years, ECOG performance status 0–1) with metastatic or unresectable nccRCC. All pts received fruquintinib (5 mg QD, orally, 2 weeks on/1 week off) plus serplulimab (4.5 mg/kg, IV, Q3W). The primary endpoint was progression-free survival (PFS) per RECIST 1.1, while secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results: As of September 30th, 2025, 38 pts were enrolled across 3 centers. The median age was 53.5 years (range 19–78), with 68.4% being male; 44.7% had an ECOG performance status of 1. Histological subtypes included papillary (50.0%), unclassified (18.4%), fumarate hydratase-deficient (13.2%), TFE3-rearranged (7.9%), chromophobe (5.3%) and rare variants (5.2%). Sarcomatoid features were observed in 5 pts. The most frequent metastatic sites were lymph nodes (52.6%), lungs (34.2%), peritoneum (34.2%). With a median follow-up of 10 months (95% CI: 9.2–15.9) for PFS, the median PFS was not reached, and the 9-month PFS rate was 87.3%. Among the 36 efficacy evaluable pts, 1 achieved complete response, 18 achieved partial response and 16 had stable disease, yielding an ORR of 52.8% (95% CI: 36.5–69.1) and a DCR of 97.2% (95% CI: 85.5–99.9). Three pts experienced rapid progression (progressing within 4 months in this study), all with sarcomatoid differentiation. 94.7% pts experienced at least one treatment-related adverse event (TRAE) of any grade, with the most common (≥15%) TRAEs were rash (28.9%), proteinuria (26.3%), hypertension (26.3%), hypothyroidism (21.1%), increased ALT or AST (21.1% each), fever (18.4%) and increased blood creatinine (15.8%). The majority of these events were grade 1 or 2, except for one pt who experienced a grade 3 increased AST. No serious adverse events (SAEs) or adverse events leading to permanent discontinuation of medication were observed during the study period, and no TRAEs resulting in death were reported. Conclusions: The combination of fruquintinib and serplulimab showed promising anti-tumor activity with acceptable tolerability as first-line treatment for metastatic or unresectable nccRCC. This novel combination therapy has the potential to become a valuable therapeutic option for this challenging disease. Clinical trial information: NCT05831891 .