Efficacy with fruquintinib plus sintilimab versus axitinib or everolimus in advanced renal cell carcinoma: A post-hoc analysis from FRUSICA-2 trial by baseline tumor burden.

4533 Background: The multicenter randomized phase 2/3 FRUSICA-2 trial (NCT05522231) demonstrated that fruquintinib plus sintilimab (F+S) significantly improved progression-free survival (PFS) (22.2 months vs 6.9 months) and objective response rate (ORR) (60.5% vs 24.3%) by blinded independent central review (BIRC) assessment compared to axitinib or everolimus (A/E) in Chinese patients (pts) with advanced renal cell carcinoma (aRCC) who had failed prior tyrosine kinase inhibitor therapy (Ye D, et al; 2025 ESMO). Considering that baseline tumor burden may correlate with efficacy outcome, we present the results of a relevant post-hoc subgroup analysis. Methods: Overall, 234 eligible pts were 1:1 randomized to receive either F+S or A/E. The primary efficacy endpoint was PFS assessed by BIRC per RECIST 1.1; secondary endpoints included investigator-assessed PFS, ORR, disease control rate, duration of response, time to response, and overall survival. This subgroup analysis evaluated BIRC-assessed PFS and ORR across subgroups defined by the number of target lesions (TLs) and metastatic sites (METs) at baseline. Results: At baseline, 79, 79, 32 and 44 pts had 1, 2, 3 and ≥4 TL(s), respectively. Metastatic disease was present in 117 (98.3%) pts in F+S arm and 110 (95.7%) pts in A/E arm, with a higher proportion of pts in F+S arm (88, 73.9%) having ≥3 METs than in A/E arm (67, 58.3%). By the data cut-off date of Feb 17, 2025, median follow-up for PFS was 16.6 months. As summarized in the table, F+S demonstrated superior PFS versus A/E across all subgroups, with unstratified hazard ratios (HRs) ranged from 0.28 to 0.50, as well as consistently longer median PFS. Similarly, improvements in ORR were observed across subgroups with odds ratios (ORs) ranged 2.46~7.22. Notably, in F+ S arm, fewer baseline TLs and METs appeared to correlate with longer median PFS, though such trend was not observed for ORR. Conclusions: Consistent with the primary analysis, F+S showed superior efficacy compared to A/E in terms of PFS and ORR in the second-line treatment of aRCC, regardless of the amount of baseline TLs or METs. Clinical trial information: NCT05522231 . Subgroup(F+S v A/E) 1 TL(38 v 41) 2 TLs(38 v 41) 3 TLs(16 v 16) ≥4 TLs(27 v 17) 1 MET(29 v 43) 2 METs(39 v 28) ≥3 METs(49 v 39) PFS, HR (95% CI) a 0.39 (0.20, 0.76) 0.33 (0.17, 0.66) 0.43 (0.17, 1.10) 0.28 (0.12, 0.62) 0.28 (0.13, 0.60) 0.50 (0.24, 1.04) 0.31 (0.18, 0.545) Median PFS, months b 24.9 vs 8.3 22.2 vs 6.9 15.3 vs 4.2 13.8 vs 6.9 24.9 vs 8.3 22.2 vs 8.3 NE vs 4.2 ORR, OR (95% CI) c 3.95 (1.35, 11.91) 4.65 (1.63, 13.43) 7.22 (1.17, 52.78) 5.53 (1.21, 28.76) 7.18 (2.22, 23.84) 2.46 (0.81, 7.76) 6.12 (2.13, 18.44) ORR, % 52.6 vs 22.0 65.8 vs 29.3 62.5 vs 18.8 63.0 vs 23.5 65.5 vs 20.9 53.8 vs 32.1 61.2 vs 20.5 NE, not estimable. a Based on an unstratified Cox proportional risk model. b Estimated using Kaplan-Meier method. c Exact 95% CI for OR was calculated using Cochran-Mantel-Haenszel method.