Efficacy of fruquintinib (F) plus sintilimab (S) versus axitinib (A) or everolimus (E) by scores of IMDC risk factors and PD-L1 expression at baseline in previously treated advanced renal cell carcinoma (RCC): A subgroup analysis of the FRUSICA-2 study.

4531 Background: FRUSICA-2 (NCT05522231), a randomized, open-label, controlled phase 2/3 study, demonstrated a significant efficacy of F plus S vs A or E in previously treated advanced RCC (BIRC-assessed mPFS 22.21 vs 6.90 mo; HR 0.373, p<0.0001; ORR 60.5% vs 24.3%, OR 4.622, p<0.0001; D Ye, et al; 2025 ESMO). Given the IMDC classification as the most common prognostic model and PD-L1 expression has demonstrated prognostic value across various cancer types, we conducted this exploratory subgroup analysis to evaluate clinical outcomes by baseline scores of IMDC risk factors and PD-L1 expression. Methods: Patients (pts) with histologically confirmed advanced RCC previously treated with VEGFR-TKI were randomized 1:1 to receive either F (5 mg QD, 2 weeks on/1 week off) plus S (200 mg iv, every 3 weeks), or investigator's choice of A (5 mg twice daily) or E (10 mg once daily). Efficacy was analyzed by IMDC risk factor scores (0, 1, 2, and ≥3) and PD-L1 combined positive score (CPS≥1, <1, or unknown). Data cutoff was February 17, 2025. Results: Among 234 patients in the phase 3 part, IMDC risk scores and PD-L1 CPS distributions are detailed in table. With a median follow-up of 16.56 mo, BIRC-assessed mPFS for F+S vs A/E across IMDC subgroups were: score 0, not estimable(NE) vs 8.31 mo (stratified HR 0.270, p=0.0009); score 1, 24.87 vs 8.25 mo (HR 0.289, p<0.0001); score 2, 13.8 vs 6.9 mo (HR 0.436, p=0.0164); and score ≥3, 9.69 vs 4.21 mo (HR 0.591, p=0.3267). Across PD-L1 expression subgroups, BIRC-assessed mPFS for F+S vs A/E were: CPS ≥1, 22.21 vs 3.22 mo (stratified HR 0.232, p=0.0004); CPS <1, NE vs 8.28 mo (HR 0.350, p<0.0001). An additional 82 patients had unknown PD-L1 CPS status (F+S: n=40; A/E: n=42) and were not included in PD-L1 subgroup analysis. ORR analyses consistently favored F+S over A/E across all subgroups defined by IMDC risk factors and PD-L1 expression, with detailed results presented in table. Conclusions: In the exploratory analyses, these findings suggest that the efficacy benefit of F+S vs A/E is maintained across different IMDC risk scores and PD-L1 CPS in previously treated advanced RCC patients, supporting its broad application. Clinical trial information: NCT05522231 . Efficacy results by IMDC risk scores and PD-L1 expression. F+S v A/E IMDC score 0(33 v 32) IMDC score 1(43 v 41) IMDC score 2(30 v 31) IMDC score ≥3(13 v 11) PD-L1 CPS≥1(23 v 20) PD-L1 CPS<1(56 v 53) mPFS mo NE v 8.31 24.87 v 8.25 13.80 v 6.90 9.69 v 4.21 22.21 v 3.22 NE v 8.28 HR (95%CI) 0.27 (0.12, 0.62) 0.29 (0.15, 0.55) 0.44 (0.22, 0.88) 0.59 (0.20, 1.72) 0.23 (0.10, 0.56) 0.35 (0.20, 0.61) Unstratified Log-rank p 0.0009 < 0.0001 0.0164 0.3267 0.0004 < 0.0001 ORR, % 63.6 v 25.0 62.8 v 26.8 60.0 v 19.4 46.2 v 27.3 78.3 v 10.0 64.3 v 35.8 Odds Ratio (95%CI) 5.25(1.61, 17.71) 4.60(1.66, 12.98) 6.25(1.75, 23.80) 2.29(0.32, 19.10) 32.40(4.67, 338.60) 3.22(1.37, 7.61)