497 Background: Patients with clear cell renal cell carcinoma (ccRCC) progressing after immune checkpoint inhibitors (ICIs) therapy have limited therapeutic options. The combination of everolimus with VEGFR-TKIs has been recognized as a promising second-line therapeutic strategy. Fruquintinib (Fru, a selective VEGFR inhibitor) has demonstrated promising antitumor activity in patients with treated ccRCC. We conducted a phase II study (NCT06317298) aimed to evaluate the combination of fruquintinib and everolimus (Eve) in ccRCC patients who experienced disease progression following prior ICI-containing therapy. Methods: Pts with histologically confirmed ccRCC who had disease progression after combination therapy with an ICI plus a TKI were eligible. In the dose-establishing phase, based on a standard 3+3 design, pts were treated with Fru (3 mg, 4 mg, 5 mg; starting from 4 mg) once daily (QD) on d1-21 plus Eve 5 mg QD, at 4-week cycles, until intolerable toxicity, disease progression, or patient withdrawal. This analysis was designed to conduct before dose-expansion phase, on which pts would receive the combination of Fru+Eve at the dose regimen established during the dose-establishing phase. The primary endpoints were determination of the MTD and objective response rate (ORR) as assessed by RECIST 1.1 criteria. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), and safety. Results: Nine pts were enrolled in the dose-establishing phase. Median age was 54 (41-71) years and all pts were male and all received at least one line of TKIs and ICI. Seven pts were classified as having intermediate/high-risk disease according to the IMDC criteria. At the data cut-off date (September 30th, 2025), 4 pts remained on study treatment. No DLTs were observed during the evaluation period. All pts experienced at least one treatment-related adverse event (TRAE) of any grade, with hypertension (9/9, 100%), mucositis (4/9, 44.4%) and fatigue (3/9, 33.3%) being the most frequently observed. All TRAEs were grade 1~2 except 1 patient with grade 3 diarrhea. 2 patients temporarily interrupted for reversible grade 2 interstitial lung disease due to Eve. No serious adverse events, TRAEs leading to permanent drug discontinuation, or death were reported. Of all 9 pts, the confirmed ORR was 66.7% (95% CI: 29.9-92.5) and the confirmed DCR was 77.8% (95%CI: 40.0-97.2). At a median follow-up of 12.0 (95% CI: 5.0-not estimable) months, the median PFS was 10.0 (95% CI: 2.0-13.0) months. Conclusions: Preliminary data showed promising antitumor activity of Fru at 5mg QD 3 weeks-on/1 week-off plus Eve 5mgQD in patients with ICI-pretreated ccRCC. The safety profile of fruquintinib combined with everolimus were tolerable and manageable. Clinical trial information: NCT06317298 .
Kw et al. (Sun,) studied this question.