Citation: Zhou A, et al. Lancet Oncology. 2025 Sep;26(9):1145–1157.
METHODS: ETER100 was a multicentre, randomised, open-label, phase 3 trial at 37 sites in China. Patients aged 18–80 years with previously untreated, advanced clear-cell RCC and ECOG PS 0–1 were randomised 1:1 to benmelstobart (IV 1200 mg q3w) plus anlotinib (PO 12 mg daily, weeks 1–2 of each 3-week cycle) or sunitinib (PO 50 mg daily, weeks 1–4 of each 6-week cycle). Randomisation used stratified block design by IMDC risk. Primary endpoint was PFS by blinded independent central review (RECIST v1.1) in the full analysis and per-protocol sets. Prespecified interim analysis reported (NCT04523272).
RESULTS: 531 patients were randomised (266 combo; 265 sunitinib); 527 included in full analysis. Median follow-up 22.8 months. In full analysis, median PFS was longer with benmelstobart+anlotinib vs sunitinib: 19.0 months (95% CI 15.3–22.8) vs 9.8 months (8.4–12.4); HR 0.53 (0.42–0.67), p<0.0001. Per-protocol PFS: 19.0 vs 11.0 months; HR 0.55 (0.43–0.70), p<0.0001. Most common grade ≥3 TRAE was hypertension (34% vs 21%). Serious TRAEs: 24% vs 16%. Treatment-related deaths: 1% in combo arm, none with sunitinib.
CONCLUSIONS: Benmelstobart plus anlotinib significantly improved PFS compared with sunitinib in first-line advanced clear-cell RCC, with manageable safety.
Citation: Hah AW, et al. The Oncologist. 2025 Jun 4;30(6):oyaf1383.
METHODS: Phase 1b evaluated batiraxcept (15 or 20 mg/kg) plus cabozantinib 60 mg (N=26) to define RP2D and safety. Phase 2 tested batiraxcept RP2D as monotherapy (N=10), doublet with cabozantinib 60 mg in previously treated patients (N=25), and triplet with cabozantinib 40 mg plus nivolumab 240/480 mg in treatment-naïve patients (N=11). Primary endpoint: ORR.
RESULTS: No dose-limiting TRAEs in phase 1b; batiraxcept 15 mg/kg + cabozantinib 60 mg selected as RP2D. Across all doublet patients (phase 1+2, n=51), ORR 43% with median PFS 9.2 months; grade ≥3 TRAEs in 73%. Common batiraxcept TRAEs: diarrhea (31%), fatigue (31%), infusion reactions (24%). Triplet ORR 54%; monotherapy ORR 0%. No new safety signals. Trial discontinued early due to sponsor decision.
CONCLUSIONS: Batiraxcept showed acceptable tolerability and encouraging activity with cabozantinib, particularly in heavily pretreated ccRCC, though development was halted early.
Citation: Bergmann L, et al. Annals of Oncology. 2025 Jul;36(7):796–806.
BACKGROUND: Preclinical data support CDK4/6 inhibition alone or with HIF-2α inhibitors in ccRCC. Randomised phase 2 studies of palbociclib+belzutifan vs belzutifan are ongoing (NCT05468697), but single-agent CDK4/6 activity in ccRCC has not been established. In a multicenter phase 1b trial (NCT04627064), abemaciclib monotherapy was studied in advanced pretreated RCC.
METHODS: Adults with previously untreated advanced/metastatic nccRCC were randomised 1:1 to nivolumab 3 mg/kg + ipilimumab 1 mg/kg q3w ×4, then nivolumab 240 mg q2w or 480 mg q4w, versus SOC. Stratified by histology and IMDC risk; central pathology review mandatory. Primary endpoint: 12-month OS rate. Secondary endpoints: median OS, ORR, PFS, safety, QoL.
RESULTS: 157 patients received ipi/nivo; 152 SOC. 12-month OS rate 78% (95% CI 71–84) vs 68% (60–75), p=0.026. Median OS 33.2 vs 25.2 months; HR 0.81 (0.61–1.099), p=0.163. PFS similar (HR 0.99). ORR 32.8% vs 19.3%. No major endpoint differences between papillary and non-papillary subtypes. Exploratory OS benefit observed with PD-L1 CPS ≥1 (HR 0.56; 95% CI 0.37–0.86). Discontinuation for toxicity: 17% vs 9%.
CONCLUSIONS: Ipilimumab/nivolumab improved 12-month OS with acceptable toxicity in previously untreated nccRCC, supporting a clinically meaningful benefit over SOC.
Citation: Srinivasan R, et al. New England Journal of Medicine. 2025 Jun 19;392(23):2346–2356.
METHODS: Open-label phase 2 study of bevacizumab (10 mg/kg IV q2w) plus erlotinib (150 mg PO daily) in advanced HLRCC-associated or sporadic papillary RCC. Primary endpoint: overall response. Secondary endpoints: PFS and OS (NCT01130519).
RESULTS: 43 HLRCC-associated and 40 sporadic papillary RCC patients enrolled. Confirmed response in HLRCC cohort: 72% (95% CI 57–83), median PFS 21.1 months (95% CI 15.6–26.6), median OS 44.6 months (95% CI 32.7–not estimable). Sporadic cohort response: 35% (95% CI 22–51), median PFS 8.9 months (95% CI 5.5–18.3), median OS 18.2 months (95% CI 12.6–29.3). Common TRAEs: acneiform rash (93%), diarrhea (89%), proteinuria (78%). Grade ≥3 TRAEs: hypertension (34%), proteinuria (17%).
CONCLUSIONS: Bevacizumab+erlotinib demonstrated substantial activity in HLRCC-associated and meaningful activity in sporadic papillary RCC with expected toxicities.
Citation: Menzies AM, et al. Cancer. 2025 Jul 15;131(14):e35962.
METHODS: CheckMate 742 (phase 3b melanoma): nivolumab 1 mg/kg + ipilimumab 3 mg/kg concurrently as fixed-ratio combination (FRC) or sequentially as alternative schedule (ASI) q3w. CheckMate 800 (phase 2 RCC): nivolumab 3 mg/kg + ipilimumab 1 mg/kg as FRC or ASI q3w. Primary endpoint: incidence of anaphylactic-reaction SMQ AEs within 2 days of dosing. Secondary: Narrow-Scope SMQ AEs.
RESULTS: No clinically relevant safety differences between FRC and ASI; odds ratio (95% CI) 0.87 (0.30–2.49) for CheckMate 742 and 1.0 (0.30–3.39) for CheckMate 800. No Narrow-Scope SMQ AEs. One toxicity-related death in CheckMate 742.
CONCLUSIONS: Concurrent fixed-ratio and sequential infusion schedules showed comparable and manageable safety profiles.
Citation: Calvo E, et al. Journal for ImmunoTherapy of Cancer. 2025 Aug 4;13(8):e010777.
METHODS: ARTISTRY-1 part B enrolled adults with advanced melanoma or RCC after prior therapies including ICIs. Nemvaleukin IV daily on days 1–5 of a 21-day cycle at 6 μg/kg/day (RP2D). Primary endpoints: ORR and safety. Secondary endpoints: PK/PD.
RESULTS: 74 patients treated (melanoma n=47; RCC n=27). ORR: melanoma 9% (95% CI 2–21) and RCC 14% (95% CI 3–35). Disease control rate 50% in both cohorts; stable disease ≥6 months in 7% (melanoma) and 9% (RCC). Grade 3–4 nemvaleukin-related TEAEs mainly neutropenia (57% melanoma; 33% RCC). No grade ≥3 cytokine release syndrome or infusion reactions; no capillary leak syndrome TEAEs. PD showed increased peripheral CD8+ T cells and NK cells with minimal Treg change.
CONCLUSIONS: Nemvaleukin demonstrated proof-of-mechanism, modest single-agent activity, and manageable safety in advanced melanoma and RCC.
Citation: Cella D, et al. ESMO Open. 2025 Jun;10(6):105115.
METHODS: Post hoc CheckMate 9ER analysis using FKSI-19 patient-reported outcomes to evaluate HRQoL. Cox models assessed association between early FKSI-19 changes and clinical outcomes; latent class analysis (LCA) identified symptom profiles.
RESULTS: Symptom types similar at baseline and week 13 between CaboNivo and sunitinib, but frequency differed by arm. Early worsening of bone pain (HR 1.45, p=0.010) and sleep quality (HR 1.45, p=0.007) associated with higher mortality risk. LCA identified three symptom-burden subgroups. Limited-symptoms class at week 13 more often received CaboNivo, had longer treatment duration, and lower progression likelihood vs other classes.
CONCLUSIONS: Early HRQoL dynamics correlate with efficacy, underscoring the need to balance outcomes, tolerability, and HRQoL in first-line RCC decisions.
Citation: Kotecha RR, et al. European Urology Oncology. 2025 Aug;8(4):866–870.
ABSTRACT / METHODS: Phase 1b/2 trial of axitinib with escalating talazoparib in refractory ccRCC using 3+3 design, followed by expansion. Primary endpoints: RP2D and ORR (NCT04337970).
RESULTS: 23 patients enrolled (15 escalation; 8 expansion). RP2D: talazoparib 1 mg daily + axitinib 5 mg BID. At RP2D, 13/14 discontinued for progression. Median PFS 6.1 months (95% CI 3.5–8.4). Grade ≥3 TEAEs in 56%; treatment-related grade ≥3 AEs in 39% (diarrhea, nausea, anemia most common).
CONCLUSIONS: VEGFR TKI + PARP inhibition was feasible but did not reach prespecified efficacy for continued development in refractory ccRCC.
Citation: McGregor BA, et al. Clinical Genitourinary Cancer. 2025 Jun;23(3):102318.
ABSTRACT / METHODS: Adults with metastatic RCC with a clear-cell component, ECOG ≤2, progressing after ≥1 prior regimen including immunotherapy and VEGFR TKI, received abemaciclib 200 mg BID in 4-week cycles until progression. Primary objective: ORR; secondary: safety.
RESULTS: 11 patients enrolled (median age 62; 73% IMDC intermediate risk; median 4 prior lines). ORR 0% (8 PD, 1 SD stopping for clinical progression, 2 not evaluable). Grade ≥3 TRAEs in 27% (diarrhea, nausea, neutropenia).
CONCLUSIONS: Abemaciclib monotherapy showed no meaningful activity in heavily pretreated RCC without unexpected toxicity; informs interpretation of ongoing combination trials.
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