BACKGROUND:Non-clear cell renal cell carcinoma (nccRCC) represents a heterogeneous group of rare malignancies with limited evidence guiding systemic therapy. The recent introduction of immune checkpoint inhibitors (ICIs) and their combinations with tyrosine kinase inhibitors (TKIs) has shown promising results, but real-world data remain scarce. METHODS:We retrospectively collected clinical and pathological data from patients with metastatic nccRCC included in the Italian Meet-URO-23/I-RARE database and from Vall d'Hebron Institute of Oncology (VHIO). Prognostic factors for overall survival (OS) were analyzed using univariate and multivariate Cox regression. Treatment outcomes were assessed by histology and therapeutic regimen. RESULTS:A total of 156 patients were included: papillary (56.4%), chromophobe (22.4%), translocated (10.9%), and unclassified (10.3%) RCC. Median OS was 17.5 months (95%CI 14.7-27.6) and median progression free survival (PFS) 10.2 months (95%CI 7.6-13.7). Patients treated with ICI-combinations (ICI plus ICI or ICI plus VEGF-TKI) showed significantly improved survival (median OS not reached vs 14.7 months for other regimens, p = 0.0053). The overall objective response rate (ORR) and disease free survival (DFS) for ICI+TKI was 53.3% (16/30 evaluable) and 93.3% (28/30), with ORR of 55.5% (10/18) in papillary and 46.1% (6/13) in chromophobe subtypes. In the overall ICI-combination group, ORR was 48%. In multivariate analysis, International Metastatic RCC Database Consortium (IMDC) score, presence of bone metastases, and type of first-line therapy were independently associated with OS. CONCLUSIONS:In this large international real-world cohort, ICI-based combinations demonstrated superior outcomes compared to other regimens in metastatic nccRCC. These results reinforce the role of immunotherapy combinations as a preferred first-line approach and confirm the IMDC score as a reliable prognostic tool in this population.

The therapeutic landscape for renal cell carcinoma (RCC) and urinary tract cancer (UTC) has transformed dramatically, creating complexity in treatment selection and sequencing. The 2025 Advanced Urologic Cancer Consensus Conference was convened to establish evidence‐based expert consensus recommendations for optimal management. A multidisciplinary panel of 51 experts participated in a modified Delphi process addressing questions developed through iterative consensus‐building covering RCC and UTC management. Voting occurred before and after the conference, and analyses focused on postmeeting responses. Consensus was defined as ≥75% agreement, with strong consensus as >90%. Strong consensus was found on the use of adjuvant pembrolizumab for higher risk RCC (pathologic T2 [pT2], grade 4; pT3–pT4, any grade; pTXN1; or fully resected metastatic disease) and on neoadjuvant therapy before cystectomy for localized UTC. There was strong consensus on the use of enfortumab vedotin plus pembrolizumab as frontline therapy for metastatic UTC and the use of platinum‐based chemotherapy postprogression in biomarker‐negative UTC. For RCC, there was consensus on the role of single‐agent vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy after progression on frontline immune checkpoint inhibitor/vascular endothelial growth factor receptor–tyrosine kinase inhibitor therapy or dual immune checkpoint inhibitor therapy. However, there was a lack of consensus on other critical areas in the management of RCC and UTC. The 2025 Advanced Urologic Cancer Consensus Conference provides evidence‐informed guidance for complex clinical scenarios while identifying critical research priorities. The group recognizes that the lack of consensus across multiple areas highlights the need for improved patient selection and prospective studies enabling optimal combination and sequencing approaches. This iterative annual process will address evolving treatment paradigms to optimize outcomes.

BACKGROUND:Papillary renal cell cancer (pRCC) represents the largest subgroup within non-clear cell (ncc) RCC. Compared with clear cell RCC (ccRCC), pRCC is considered less sensitive to currently available systemic therapies. Here, we report exploratory results from the pRCC subgroup of the SUNNIFORECAST trial comparing ipilimumab/nivolumab with standard of care (SOC) based on central pathological review. METHODS AND PATIENTS:SUNNIFORECAST was a prospective, investigator-initiated, phase II trial evaluating ipilimumab/nivolumab versus SOC in patients with untreated, advanced nccRCC. The primary endpoint was the 12-month overall survival (OS) rate. Secondary endpoints included OS, progression-free survival (PFS), and overall response rate (ORR). PD-L1 expression was assessed exploratory. RESULTS:Of 309 randomized patients, 127 had confirmed papillary histology, in 56/173 cases the local diagnosis of pRCC required revision. Among the 127 patients with pRCC, 64 received ipilimumab/nivolumab and 63 SOC, predominantly TKI monotherapy. In the pRCC subgroup, the 12-month OS rate was 74.77% in the ipilimumab/nivolumab arm and 63.44% in the SOC arm (p = 0.085). Median OS was 24.89 months with ipilimumab/nivolumab versus 18.88 months with SOC. PD-L1 expression was evaluable in 116 of 127 patients. A CPS > 1 was more frequently observed with increasing IMDC risk category. Among patients with CPS < 1, the 12-month OS rate was 75.00% with ipilimumab/nivolumab and 68.36% with SOC (p = 0.963). In patients with CPS > 1, the 12-month OS rate was 82.38% in the ipilimumab/nivolumab arm and 63.33% in the SOC arm. DISCUSSION:This exploratory analysis has several limitations; however, it suggests that patients with pRCC treated with ipilimumab/nivolumab may derive a benefit in terms of 12-month OS rate, median OS, and ORR compared with SOC, particularly among those with CPS > 1. (Funded by Bristol Myers Squibb grant CA209-499; ClinicalTrials.gov, EUDRACT Number: 2016-000706-12; NCT03075423.).

4528 Background: In first-line aRCC, C+N significantly improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) vs S in the phase 3 CheckMate 9ER trial (NCT03141177; Motzer et al. Ann Oncol 2026). In an exploratory analysis with median 18.1-mo f-u, C+N improved PFS, OS, and ORR vs S in patients with or without bone metastasis at baseline. We performed an updated exploratory analysis of outcomes by baseline bone metastasis status based on the 5-year update and analyzed subgroups with additional metastatic sites. Methods: 651 patients with clear-cell aRCC were randomized 1:1 to C (40 mg QD) + N (240 mg Q2W) or S (50 mg QD for 4 weeks of 6-week cycles). Median f-u was 67.6 mo. PFS (primary endpoint) and ORR were per RECIST v1.1 by blinded independent central review. Patient subgroups analyzed here include those with or without bone metastasis at baseline and those with liver, lung, lymph node (LN), or adrenal gland metastasis in addition to bone metastasis. Results: 154 patients had bone metastasis at baseline. Baseline characteristics were generally consistent between treatment arms for subgroups with and without bone metastasis. PFS and OS were prolonged with C+N vs S in patients with or without bone metastasis (Table). The ORR was higher and duration of response (DOR) was longer with C+N vs S in both groups. Although outcomes were less favorable in those with vs without bone metastasis, the relative benefit with C+N vs S was consistent across metastatic site subgroups. The safety profile among patients with bone metastasis was generally consistent with the overall population. Conclusions: With additional follow-up, a consistent benefit was maintained for C+N vs S in patients with or without bone metastasis. Among patients with bone metastasis, a consistent benefit was observed regardless of concomitant metastasis in liver, lung, LN, or adrenal gland. Clinical trial information: NCT03141177 . Efficacy by metastatic sites. Subgroup(C+N v S) Bone + Any Site(s) a (n=79 v n=75) No Bone(n=244 v n=253) Bone + Liver(n=15 v n=17) Bone + Lung(n=57 v n=58) Bone + LN(n=33 v n=38) Bone + Adrenal Gland(n=10 v n=8) mPFS, mo 13.8 v 5.3 b 16.6 v 9.5 6.9 v 3.8 10.0 v 4.4 9.0 v 4.1 15.2 v 5.7 PFS HR (95% CI) 0.43 (0.30, 0.64) b 0.60 (0.49, 0.74) 0.77 (0.33, 1.76) 0.45 (0.29, 0.70) 0.50 (0.29, 0.87) 0.62 (0.19, 2.07) mOS, mo 34.8 v 20.7 b 49.5 v 41.0 20.9 v 12.7 31.6 v 22.1 21.3 v 17.5 54.4 v 31.0 OS HR (95% CI) 0.66 (0.45, 0.95) b 0.85 (0.68, 1.06) 0.57 (0.26, 1.24) 0.72 (0.47, 1.10) 0.72 (0.43, 1.20) 0.72 (0.21, 2.50) ORR, % 49 v 9 b 58 v 33 40 v 18 51 v 10 42 v 5 70 v 13 mTTR, mo 2.9 v 7.3 2.8 v 4.3 2.9 v 3.0 2.8 v 5.7 2.9 v 3.4 4.0 v 11.0 mDOR, mo 18.0 v 6.9 22.9 v 15.4 12.6 v 6.4 18.0 v 6.7 16.7 v NC 14.4 v 19.3 a Only 9 patients had bone-only disease (n=7, C+N; n=2, S), precluding meaningful analysis of this subgroup. b Motzer et al. Ann Oncol 2026. m, median; NC, not calculable; TTR, time to response.

TPS4636 Background: For patients (pts) with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have relapsed post anti-PD-1/PD-L1 treatment, second line treatment options remain limited, consisting primarily of tyrosine kinase inhibitors (TKI) monotherapy. Hypoxia-inducible factor 2 alpha (HIF-2α) inhibition represents a promising target as its mechanism of action has been clinically validated in ccRCC and is distinct from that of TKIs without overlapping toxicities. Casdatifan (cas) is an orally bioavailable, selective HIF-2α inhibitor that has a potentially improved pharmacodynamic profile relative to other members of the therapeutic class (Ghasemi 2025). Combining cas with a TKI (cabozantinib [cabo]) that targets VEGFR, MET, and AXL may yield enhanced antitumor activity beyond the individual agents. Preliminary efficacy data from the Phase 2 ARC-20 Study demonstrated promising antitumor activity with the combination (cas + cabo; Choueiri 2025). PEAK-1 is currently the only Phase 3 that examines the efficacy and safety of a HIF-2α inhibitor in combination with a TKI in ccRCC. Methods: PEAK-1 (NCT07011719) is an ongoing Phase 3, randomized, active-control, double-blind, 2-arm, global, multicenter study in adult pts with confirmed advanced or metastatic ccRCC who have experienced progression on or after anti-PD1 or anti-PD-L1 treatment. Approximately 720 pts will be enrolled and randomized 2:1 to treatment with 100 mg QD cas + 60 mg QD cabo (experimental arm) or placebo + 60 mg QD cabo (comparator arm). Crossover is not allowed. Stratification factors include by region (North America vs Western Europe vs rest of world); prior VEGFR-TKI (yes vs no); and International Metastatic RCC Database Consortium risk score (favorable vs intermediate/poor). Key eligibility requirements include adults (≥ 18 years) who have received anti-PD-1 or anti-PD-L1 treatment as part of the most recent regimen (either adjuvant monotherapy or first line in combination with anti-CTLA-4 or VEGFR-TKI), with ≤ 1 prior regimens in the metastatic setting. Pts must have a Karnofsky Performance Status score ≥ 80%, at least 1 target lesion measurable by computed tomography/magnetic resonance imaging per RECIST 1.1, and adequate organ and marrow function. Key exclusion criteria include prior treatment with a HIF-2α inhibitor or cabo, receiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, and uncontrolled or poorly controlled hypertension (sustained blood pressure >140/90 mm Hg on ≥ 3 antihypertensives). The primary endpoint of the study is PFS BICR according to RECIST 1.1. Secondary endpoints include safety, overall survival, overall response rate, duration of response, and disease control rate. Pt reported outcomes using NFKSI-DRS will also be assessed. Enrolment is ongoing as of 1 Oct 2025. Clinical trial information: NCT07011719 .

INTRODUCTION:Patients with mRCC who achieve a complete response (CR) to immuno-oncology (IO) combinations have an excellent prognosis and may experience prolonged responses. However, real-world data on CR durability, mortality, and need for subsequent therapy remain limited. PATIENTS AND METHODS:Using the International mRCC Database Consortium (IMDC), we identified patients with mRCC who achieved a documented CR to first-line treatment between 2015 and 2022. We described baseline characteristics, time to next treatment (TTNT), time to second line (TT2L), overall survival (OS), and use of subsequent therapies in patients treated with a vascular endotelial growth factor receptor pathway targeted therapy vascular endotelial growth factor (VEGF), IO plus VEGF (IO-VE), or Ipilimumab plus Nivolumab (IOIO). RESULTS:CR was achieved with IO-VE in 25 of 610 (4.1%) patients, with IO-IO in 82 of 1313 (6.2%), and with VEGF in 46 of 2980 (1.5%) patients. OS in patients with CRs was not significantly different (log-rank P = .42) among the 3 treatment groups. After a median follow-up of 46.7 months, 4-year OS was for IO-VE 100% (95% CI, 100%-100%; HR ref), for IO-IO 92.9% (95% CI, 86.2%-100%; HR 1.89, 95% CI, 0.22-16.4), and for VEGF 94.8% (95% CI 88%-100%; HR 3.18, 95% CI 0.4-25.2). In the IO-VE cohort, 5 (20%) started second-line therapy, and 1 died; in IO-IO, 11 (13.4%) began second-line, and 5 (6.1%) died; and in VEGF, 17 (37%) started second-line, and 9 (19.6%) died. TTNT was not reached for any treatment, and TT2L was in IO-VE 46.8 months (95% CI, 27.5-NR), in IO-IO 30.2 months (95% CI, 21.5-NR), and in VEGF 23 months (95% CI, 14.3-51.7) (P = .66). IO rechallenge occurred in 20% (n = 1) of IO-VE and 63.6% (n = 7) of IO-IO patients receiving second-line, with CR to second-line in 2/8, PR in 4/8, standard deviation in 2/8, and no deaths. DISCUSSION:This real-world study confirms that achieving CR confers an excellent prognosis. However, CR does not guarantee a cure, as a subset of patients do experience a relapse. Retreatment with IO was frequent and effective. These results support the significance of CR but highlight the need for ongoing surveillance and tailored care.

Importance:The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk criteria stratify metastatic renal cell carcinoma (mRCC) into favorable, intermediate, and poor risk groups, but heterogeneity within the favorable risk category remains poorly understood. Objective:To evaluate a proposed very favorable subgroup (tier 1: Karnofsky Performance Status ≥90%; diagnosis to treatment ≥3 years; and no brain, liver, and bone metastases) and characterize its molecular and clinical features. Design, Setting, and Participants:This retrospective cohort study analyzed IMDC data, from January 2015 to September 2024, of patients with favorable risk mRCC (tier 1 and tier 2 [favorable and not tier 1]). Molecular profiling leveraged IMmotion151 (A Study of Atezolizumab in Combination With Bevacizumab Versus Sunitinib in Participants With Untreated Advanced Renal Cell Carcinoma) trial data with whole-exome sequencing, RNA sequencing, and programmed cell death ligand 1 immunohistochemistry. Exposures:Systemic standard of care treatments for mRCC, which include vascular endothelial growth factor receptor targeted therapy (VEGF-TT [sunitinib or pazopanib]), immune-oncology-VEGF (IO-VE [pembrolizumab and axitinib, pembrolizumab and lenvatinib, nivolumab and cabozantinib, or avelumab and axitinib]), and 2 IO (IO-IO [ipilimumab and nivolumab]) regimens. Main Outcomes and Measures:The primary end point of this study was overall survival (OS) at 2 years of the favorable risk group and in the tier 1 and tier 2 subgroups with the different treatment options. Secondary end points included time to next treatment, treatment duration, and overall response rate. Outcomes were compared across treatment types: VEGF-TT, IO-VE, and IO-IO. Results:Among 641 patients with favorable risk mRCC (median [IQR] age, 65 [58-71] years; 475 males [74.1%]), 176 (27.5%) were in tier 1, and 465 (72.5%) were in tier 2. Those in tier 1 met criteria for a very favorable subgroup, characterized by similar age and treatment distribution but lower rates of sarcomatoid features; more patients with only 1 metastatic site; and an absence of brain, bone, and liver metastases compared with patients in tier 2 with favorable risk. Patients in tier 1 showed a median OS of 79.1 (95% CI, 73.7 to not reached) months vs 54.5 (95% CI 45.5-67.7) months in tier 2 (P < .001) and distinct molecular features: high polybromo-1 alterations (64.7%), low BRCA1-associated protein 1 alterations (8.8%), and programmed cell death ligand 1 positivity (21.9%); transcriptomics revealed less immune-infiltrated tumors (8.5% immunogenic clusters) than in the other subgroups. Clinically, IO-IO underperformed in tier 1, with a 2-year OS of 73.1% (95% CI, 49.1%-97.1%) vs 89.1% (95% CI, 79.0%-99.2%) with IO-VE and 92.4% (95% CI, 86.5%-98.3%) for VEGF-TT (IO-IO hazard ratio, 3.64 [95% CI, 1.49-9.06]; P = .005), and a lower overall response rate (26.3% vs 63.3% in IO-VE and 57.0% in VEGF-TT). Conclusions and Relevance:In this cohort study, the very favorable risk subgroup had a less immunogenic molecular profile and superior outcomes from VEGF-containing regimens (VEGF-TT and IO-VE) compared with the favorable risk group. The IO-IO combination showed significantly worse survival in this population, suggesting that VEGF inhibition remains essential for optimal outcomes.

BACKGROUND:Adjuvant pembrolizumab improves disease-free and overall survival among patients with resected clear-cell renal-cell carcinoma. The hypoxia-inducible factor 2α inhibitor belzutifan has activity in advanced disease. Adjuvant pembrolizumab with belzutifan may further improve outcomes in patients with clear-cell renal-cell carcinoma at increased risk for recurrence. METHODS:In this phase 3, double-blind trial, we randomly assigned participants in a 1:1 ratio to receive intravenous pembrolizumab at a dose of 400 mg every 6 weeks (≤9 doses) and either daily oral belzutifan at a dose of 120 mg (pembrolizumab-belzutifan) or placebo (pembrolizumab-placebo) for up to 1 year. The primary end point was disease-free survival as assessed by the investigator; secondary end points included overall survival and safety. RESULTS:A total of 921 participants were assigned to receive pembrolizumab-belzutifan and 920 were assigned to receive pembrolizumab-placebo. The median time from randomization to the data-cutoff date (August 23, 2025) was 28.4 months (range, 15.0 to 40.1). Disease-free survival was significantly higher with pembrolizumab-belzutifan than with pembrolizumab-placebo (hazard ratio for disease recurrence or death, 0.72; 95% confidence interval [CI], 0.59 to 0.87; two-sided P<0.001); the estimated 24-month disease-free survival was 80.7% and 73.7%, respectively. At this interim analysis with 29% of the final-analysis events observed, overall survival did not differ significantly between the groups (hazard ratio for death, 0.78; 95% CI, 0.51 to 1.19; two-sided P = 0.24); the estimated 24-month overall survival was 96.2% with pembrolizumab-belzutifan and 95.7% with pembrolizumab-placebo. Adverse events of grade 3 or higher occurred in 52.1% of the participants who received pembrolizumab-belzutifan and in 30.2% of those who received pembrolizumab-placebo. CONCLUSIONS:Treatment with pembrolizumab-belzutifan led to significantly higher disease-free survival, with a greater risk of grade 3 or higher toxic effects, than treatment with pembrolizumab monotherapy after nephrectomy in participants with clear-cell renal-cell carcinoma at increased risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck [Rahway, NJ]; LITESPARK-022 ClinicalTrials.gov number, NCT05239728.).

Recurrence after nephrectomy in high-risk localized renal cell carcinoma is common, but the genomic and transcriptomic differences between primary and recurrent tumors are not well understood. In the IMmotion010 trial, patients were randomized to receive adjuvant atezolizumab versus placebo. Tumor tissue was collected at pre-treatment baseline (n = 754) and subsequently at the time of recurrence (n = 80). We performed matched transcriptomic (n = 80) and genomic (n = 52) analyses on primary versus recurrent samples. Using previously described transcriptomic classifications, resected primary tumors had a higher proportion of angiogenic and small nucleolar RNA transcriptomic signatures and lower proportion of T-effector/proliferative and stromal/proliferative signatures compared with published metastatic cohorts. Sites of recurrence exhibited upregulation of signatures related to cell proliferation, fatty acid synthesis, and stromal biology, including matrix and fibroblasts. Comparing treatment arms, tumors that recurred in placebo-treated patients demonstrated increased B cell and macrophage signatures, while tumors that recurred despite adjuvant atezolizumab showed downregulation of major histocompatibility complex (MHC)-I. Although requiring further clinical validation, the latter finding may substantiate scientifically a potential rationale for transitioning to vascular endothelial growth factor (VEGF)-inhibition after adjuvant checkpoint inhibition.

LBA4511 Background: RAMPART is evaluating one year of immune checkpoint inhibitor therapy versus active monitoring in patients with renal cell carcinoma (RCC) at intermediate or high risk of recurrence following nephrectomy according to the Leibovich Score (LS) or following complete resection of limited metastatic disease (M1NED). The trial has already shown that durvalumab and tremelimumab improves disease free survival (DFS), largely driven by effect in the higher risk population (LS high and M1NED). Methods: We recruited participants (pts) from 80 sites and randomised them in a 3:2:2 ratio between: Arm A, active monitoring; Arm B, 1 year (13 cycles) of durvalumab (1500mg); or Arm C, 1 year (13 cycles) of durvalumab (1500mg) plus tremelimumab (75mg, cycles 1 and 2 only). Based on the results of the KEYNOTE-564 trial, pembrolizumab became a treatment option for many of the patients who would be eligible for RAMPART, and recruitment was stopped earlier than planned. We revised the RAMPART design without knowledge of the accumulating trial results. In the modified design there is 80% power to detect a hazard ratio (HR) for the primary outcome of DFS of 0.60 for arm B vs. A, and of 0.55 for arm C vs. A. The overall familywise type I error rate remains strongly controlled at 2.5% (1-sided) across all primary analyses. The analysis plan includes a pre-specified, pre-powered analysis by risk of relapse. Results: Between October 2018 and June 2023, we randomised 790 pts (340, 225, and 225 to arms A, B, and C) from the UK (70%), France (21%), Australia (5%) and Spain (4%). Baseline characteristics were balanced across arms. Median age (range) was 60 (22, 83) years, 72% were male, 84% clear cell histology. Treatment with durvalumab (Arm B) was associated with a 26% relative reduction in the hazard of disease recurrence or death; conventional statistical significance was not reached (DFS HR = 0.74; 95% CI 0.53–1.04; 1p=0.041). DFS at 3 years was 78% with Arm B vs 72% Arm A. In the pre-specified DFS analysis by risk of recurrence, no evidence of a treatment-by-subgroup interaction was observed. This contrasts with the results of Arm C vs Arm A. Table 1 summarises results of the two RAMPART primary analyses. Exposure to treatment, safety, quality of life, overall survival and efficacy in non-clear cell subtypes will be presented. Conclusion: In RAMPART, durvalumab plus tremelimumab was associated with a statistically significant improvement in DFS, which was not observed with durvalumab monotherapy. Clinical trial information: NCT03288532 . Primary analysis results. Arm C vs A Arm B vs A All pts N=565; HR=0.65, 95%CI 0.45-0.93 N=565; HR=0.74, 95 CI 0.53–1.04 Higher Risk N=311; HR=0.52, 95%CI 0.34-0.80 N=312, HR=0.77, 95%CI 0.53–1.12 Intermediate Risk N=254, HR= 1.19, 95% CI 0.61-2.32 N=253, HR= 0.64, 95%CI 0.30–1.34 Test for Interaction HR=0.43, 95%CI 0.19-0.95 HR=1.20, 95%CI 0.52-2.74

BackgroundNew biomarkers are needed to improve treatment selection in patients with metastatic clear cell renal cell carcinoma (CCRCC). This study aims to identify predictive biomarkers through the investigation of serum proteins related to angiogenesis and tumor immune escape, alongside metabolic patterns associated with clinical outcomes.MethodsWe conducted a prospective, multicenter study in patients with locally advanced or metastatic CCRCC receiving first-line sunitinib. Serum protein levels, including those related to angiogenesis and immune escape, were measured. Additionally, untargeted lipidomic and targeted metabolic analyses focused on tryptophan metabolism and amino acid profiles were performed. Routine blood test results were recorded, and correlations among all parameters were analyzed.ResultsThirty-eight patients from ten Spanish hospitals were included. Median progression-free survival (PFS) was 9.87 months, and median overall survival (OS) was 21.10 months. Multivariate analysis identified higher interleukin-6 (IL-6), arginase-1, and S100 calcium binding protein A9 (S100A9) concentrations as significant predictors of shorter OS. We defined three distinct risk groups based on the combined levels of S100A9 and IL-6: high levels of both proteins, high levels of either one protein, or low levels of both proteins confer a poor, intermediate and favorable prognosis, respectively. Metabolomic analysis revealed significant differences in the tryptophan-kynurenine pathway between patients with extreme PFS and OS phenotypes. Elevated levels of tryptophan metabolites were associated with poorer PFS, while alterations in amino acids and tryptophan metabolites correlated with OS extremes. Notably, significant correlations were observed between IL-6 levels and increased tryptophan metabolism.ConclusionsThis study underscores the prognostic value of specific proteins and metabolites in metastatic CCRCC, proposing potential biomarkers for patient stratification and treatment response prediction.

Abstract Background For patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have relapsed after anti-programmed death protein 1 (anti–PD-1) or anti-programmed death ligand-1 (anti–PD-L1) treatment, second-line treatment options remain limited, consisting primarily of tyrosine kinase inhibitor (TKI) monotherapy. Hypoxia-inducible factor 2 alpha (HIF-2α) inhibition represents a promising target as its mechanism of action has been clinically validated in ccRCC and is distinct from that of TKI without overlapping toxicities. Casdatifan is an orally bioavailable, potent, and selective HIF-2α inhibitor that has a potentially improved pharmacodynamic profile relative to other members of the therapeutic class (Ghasemi 2025). Combining casdatifan with cabozantinib, a second-generation TKI which targets VEGF, MET, and AXL, may enhance antitumor activity beyond the individual agents. Preliminary data from the phase 1 ARC-20 study showed promising antitumor activity with the casdatifan plus cabozantinib combination (Choueiri 2025). PEAK-1 is a phase 3 study evaluating the efficacy and safety of casdatifan in combination with cabozantinib for the treatment of patients with ccRCC. Methods PEAK-1 (NCT07011719) is an ongoing, global, randomized, double-blind, phase 3 study in adults with confirmed advanced or metastatic ccRCC who have experienced progression on or after anti–PD-1 or anti–PD-L1 therapy. Approximately 720 patients will be randomly assigned (2:1) to casdatifan 100 mg plus cabozantinib 60 mg once daily or placebo plus cabozantinib 60 mg once daily; crossover is not permitted. Stratification factors include region (North America vs Western Europe vs rest of world), prior VEGFR-TKI use (yes vs no), International Metastatic RCC Database Consortium risk score category (favorable vs intermediate/poor). Eligible patients are adults (aged ≥ 18 years) with a most recent regimen that includes anti–PD-(L)1 therapy (adjuvant or first-line in combination with anti–CTLA-4 or VEGFR-TKI), ≤ 1 prior regimen in the metastatic setting, a Karnofsky Performance Status score ≥ 80%, ≥ 1 target lesion measurable by CT/MRI per RECIST v1.1, and adequate organ and marrow function. Key exclusion criteria include prior use of an HIF-2α inhibitor or cabozantinib, ongoing concomitant use of moderate or strong CYP3A4 inducers, and uncontrolled or poorly controlled hypertension (sustained blood pressure > 150 mmHg systolic or > 90 mmHg diastolic). The primary endpoint of the study is progression-free survival assessed by blinded independent central review per RECIST v1.1. Secondary endpoints include safety, overall survival, objective response rate, disease control rate, and duration of response. Patient-reported outcomes will also be assessed using the disease-related symptoms subscale of the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–Kidney Symptom Index. Results Enrollment is ongoing. Targeting HIF-2α with casdatifan in combination with the TKI cabozantinib may offer a complementary strategy to overcome resistance after prior immunotherapy. The casdatifan plus cabozantinib combination is a novel treatment approach for patients with ccRCC in the post–first-line setting. Conclusions N/A

Abstract Background The randomized, double-blind, phase 3 LITESPARK-022 study (NCT05239728) showed significant disease-free survival benefit with the addition of belzutifan to adjuvant pembrolizumab in participants with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence following surgery. We present patient-reported outcome (PRO) findings for LITESPARK-022. Methods Adults with ccRCC stage M0 and intermediate-high or high risk of recurrence after nephrectomy or stage M1 with no evidence of disease after surgery were randomly assigned 1:1 to receive pembrolizumab with either belzutifan or placebo. PROs were evaluated in all randomly assigned participants with ≥1 dose study treatment and ≥1 completed assessment. The Functional Assessment of Cancer Therapy–Kidney Symptom Index—Disease-Related Symptoms (FKSI-DRS), European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), and Functional Assessment of Cancer Therapy–General item 5 (FACT-GP5) were done on day 1 at cycles 1-3, 5, 7, and 9 and during the efficacy follow-up after treatment discontinuation or completion. Assessments continued for 3 years from randomization until recurrence or new therapy. Prespecified secondary end points included least square mean change from baseline to week 84 in symptom scores measured by FKSI-DRS and health-related quality of life (HRQoL) by QLQ-C30 global health status/quality of life (GHS/QoL), physical functioning (PF), and role functioning (RF) scores. The analysis time point was week 84 (last time point where completion and compliance rates of ≥ 60% and ≥80%, respectively, were observed). PRO analyses were descriptive and not formally statistically tested. Results Median follow-up was 28.4 months (range, 15.0-40.1). Of 1841 randomized participants, 907 in the pembrolizumab plus belzutifan group and 912 in the pembrolizumab plus placebo group completed ≥1 PRO assessment and were included in the PRO analysis set. Completion and compliance rates for FKSI-DRS and EORTC QLQ-C30 were >90% at baseline for both instruments and were >60% and >80%, respectively, at week 84. Least square mean change from baseline to week 84 was −0.67 with pembrolizumab plus belzutifan versus −0.76 with pembrolizumab plus placebo (difference 0.10 [95% CI, −0.28 to 0.47]) in FKSI-DRS score; −2.18 with pembrolizumab plus belzutifan versus −1.95 with pembrolizumab plus placebo (difference −0.23 [95% CI, −1.95 to 1.49]) in QLQ-C30 GHS/QoL score; −1.67 with pembrolizumab plus belzutifan versus −2.38 with pembrolizumab plus placebo (difference 0.71 [95% CI, −0.66 to 2.09]) in QLQ-C30 PF score; and −1.14 with pembrolizumab plus belzutifan versus −1.86 with pembrolizumab plus placebo (difference 0.72 [95% CI, −1.27 to 2.71]) in QLQ-C30 RF score. According to FACT-GP5, most participants in both groups (≥80%) reported being affected either “not at all” or “a little bit” by side effects of treatment across all time points. Conclusions No clinically meaningful changes in PROs from baseline to week 84 were observed with either adjuvant pembrolizumab plus belzutifan or adjuvant pembrolizumab plus placebo, and PRO findings were similar between the 2 groups. The totality of efficacy, safety, and PRO results support the potential use of adjuvant pembrolizumab plus belzutifan in patients with RCC at increased risk of recurrence after surgery.

4547 Background: The optimal first-line treatment for favorable-risk metastatic renal cell carcinoma (mRCC) remains debated in the immune checkpoint inhibitor (ICI) era. Real-world data assessing prognostic subgroups treated with VEGFR-TKI monotherapy are limited. Methods: TIVOREAL-SOGUG is a retrospective multicenter study including patients with clear-cell mRCC treated with first-line tivozanib between 2017 and 2024 across 14 Spanish centers. Favorable-risk was defined by IMDC criteria (0 risk factors). A very favorable-risk (VFAV) subgroup was identified according to Zarba et al. criteria (time from diagnosis to systemic therapy >3 years, Karnofsky performance status 90–100%, and absence of brain, liver, or bone metastases). The primary endpoint was time to treatment failure (TTF); secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), subsequent therapies, and safety. Results: Among 198 evaluable patients, 84 (42.4%) had favorable-risk disease, including 23 (27.4%) classified as VFAV. In the overall favorable-risk cohort, ORR was 48.8%, including 7.1% complete responses. Median PFS and TTF were 23.7 and 14.7 months, respectively. Median OS was not reached, with 2- and 5-year OS rates of 85.4% and 67.8%. VFAV-risk patients showed higher ORR (65.2%), prolonged PFS (32.2 months) and TTF (31.1 months), and low primary progression. Treatment discontinuation due to toxicity occurred in 9.5% of patients. Most frequent adverse events were grade 1–2 fatigue, diarrhea, mucositis, dysphonia and hypertension, with grade ≥3 events being infrequent and mainly limited to hypertension. After progression, most favorable-risk patients received ICIs, whereas VFAV-risk patients required subsequent therapy less frequently, reflecting more durable disease control. Conclusions: In routine clinical practice, first-line tivozanib provides durable disease control and long-term survival in IMDC favorable-risk mRCC, and particularly in VFAV-risk patients. ICI and cabozantinib remain effective salvage options in this setting upon disease progression. Key clinical outcomes by prognostic subgroup. Outcome Favorable-risk (n=84) Very favorable-risk (n=23) Median TTF, months (95% CI) 14.7 (9.2–20.1) 31.1 (8.0–54.1) Median PFS, months (95% CI) 23.7 (14.1–33.3) 32.2 (21.1–43.4) ORR, % (CR %) 48.8 (7.1) 65.2 (13.0) Primary progressive disease, % 14.3 4.3 2-year OS, % (95% CI) 85.4 (77.2–92.8) 95.7 (88.1–100) Discontinuation due to toxicity, % 9.5 8.7 TTF and PFS were estimated using Kaplan–Meier methodology; tumor response was assessed according to RECIST 1.1.

448 Background: Sarcomatoid renal cell carcinoma (sRCC) is aggressive with poor outcomes. Dual checkpoint blockade (nivolumab–ipilimumab; NIVO-IPI) and immune–VEGF combinations (IO-VEGF) are standard therapies, but real-world data are limited. Methods: We retrospectively analyzed IMDC sRCC treated first-line with NIVO-IPI or IO-VEGF between 2000–2025. Favorable-risk patients were excluded to focus on a clinically homogeneous intermediate/poor-risk cohort. Objective response rate (ORR; proportion achieving complete or partial response) was assessed per investigator evaluation. Additional outcomes included treatment duration (time from therapy start to discontinuation for any reason including toxicity or response), time to next treatment (TTNT), and overall survival (OS). Kaplan–Meier estimates and log-rank tests compared survival distributions, while multivariable Cox regression adjusted for key prognostic variables and metastatic sites. Results: A total of 337 intermediate/poor-risk patients were included, of whom 87 received IO-VEGF and 250 received NIVO-IPI. Baseline characteristics (Table 1) showed no significant between-group differences. The ORR was nearly identical between regimens at 49.3% with IO-VEGF and 49.1% with NIVO-IPI (p = 0.95). Among evaluable patients (IO-VEGF n=73; NIVO-IPI n=226), complete response rate was 5.5% vs 11.5% (p=0.136) and primary progressive disease rate was 26.0% vs 25.7% (p=0.951) for IO-VEGF and NIVO-IPI respectively. Median treatment duration was longer with IO-VEGF (12.6 vs 5.0 months; log-rank p = 0.026). Median time to next treatment (TTNT) was 32.2 months for IO-VEGF and 27.6 months for NIVO-IPI (unadjusted log-rank p = 0.28; adjusted HR 1.24, 95% CI 0.81–1.96, p = 0.35). Bone metastases independently predicted shorter TTNT (HR 2.05, p < 0.001). Median overall survival (OS) was 24.0 months with IO-VEGF and 30.2 months with NIVO-IPI (unadjusted log-rank p = 0.65; adjusted HR 0.85, 95% CI 0.58–1.25, p = 0.40). Worse OS was associated with Karnofsky Performance Status < 80% (HR 1.70, p = 0.02) and the presence of bone metastases (HR 2.03, p < 0.001). Conclusions: In IMDC intermediate/poor-risk sRCC, NIVO-IPI and IO-VEGF regimens did not demonstrate statistically significant differences in ORR, TTNT, or OS. Bone metastases and reduced performance status consistently predicted poorer outcomes, highlighting the importance of accounting for disease burden and functional status when selecting first-line therapy and designing future studies. Baseline characteristics. Characteristic IO-VEGFN = 87 NIVO-IPIN = 250 p-value Intermediate risk, N (%) 55 (63.2%) 142 (56.8%) 0.36 Poor risk, N (%) 32 (36.8%) 108 (43.2%) Median Age 62.5 62.1 0.82 Bone Metastases, N (%) 28 (32.6%) 81 (32.5%) 0.99

BACKGROUND:Simlukafusp alfa (FAP-IL2v) was engineered to preferentially activate CD8+ T and natural killer (NK) cells in tumor microenvironments overexpressing fibroblast activation protein (FAP). Checkpoint inhibitors combined with antiangiogenic agents are standard therapy for metastatic renal cell carcinoma (mRCC), which overexpresses FAP. Here, we explored the efficacy, safety, and pharmacodynamic effects of FAP-IL2v in combination with atezolizumab with or without bevacizumab in patients with mRCC. METHODS:Patients with treatment-naïve or pretreated clear cell and/or sarcomatoid mRCC were eligible. Dose escalation explored FAP-IL2v every 2 weeks (Q2W) with atezolizumab Q2W (doublet, arm A), and with atezolizumab and bevacizumab Q2W (triplet, arm B) in patients treated with up to one prior systemic therapy. Dose extension explored in untreated patients the recommended FAP-IL2v dose administered Q2W (doublet, arm A; and triplet, arm B) or 3-weekly (doublet, arm C; and triplet, arm D). Primary objectives were the recommended FAP-IL2v dose and antitumor activity. Secondary objectives included safety, pharmacodynamics, and exploratory biomarkers in peripheral blood and paired biopsies. RESULTS:By the data cut-off date (31 August, 2021), 66 patients were enrolled. The median duration of treatment was 11.0 months. Objective response rates (ORRs) were 25% for the doublet and 47% for the triplet, and median progression-free survival was 6.3 and 18.3 months, respectively. Safety profiles were consistent with the individual drugs, including expected interleukin-2 (IL-2) class-specific adverse events (AEs). Two deaths were recorded caused by AEs related to study treatment (acute kidney injury, n=1; pancytopenia, n=1). Expansion and activation of NK and T cells, but not regulatory T cells, was observed in peripheral blood, leading to increased tumor infiltration and inflammation in paired biopsies. The addition of bevacizumab led to a reduced angiogenesis signature score and reduced vessel density. CONCLUSION:The combination of FAP-IL2v plus atezolizumab with or without bevacizumab was consistent with the known safety profile of the individual drugs. The maximum tolerated dose was not reached, with a recommended FAP-IL2v dose of 10 mg. ORR was higher among patients receiving the triplet therapy compared with the doublet. Pharmacodynamic results were consistent with the mechanism of action of IL-2, supporting further research in this field.

LBA417 Background: There is no globally accepted standard of care (SOC) for advanced RCC after IO therapy. VEGFR-TKIs are often leveraged in this setting, but were primarily tested in phase 3 studies prior to PD-(L)1 inhibitors becoming SOC in earlier lines of therapy. The phase 3 LITESPARK-011 study (NCT04586231) investigates bel + lenva vs cabo in pts with advanced RCC progressing after anti–PD-(L)1 therapy in the 1L, 2L or adjuvant setting. Methods: Eligible pts were ≥18 yrs old with advanced clear cell RCC (ccRCC) that progressed on or after 1L or 2L anti–PD-(L)1 therapy or ≤6 mo of last dose of adjuvant anti–PD-(L)1 therapy. Pts were randomized 1:1 to bel 120 mg + lenva 20 mg QD vs cabo 60 mg QD. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints included objective response rate (ORR, key) and duration of response (DOR) by BICR per RECIST 1.1, and safety. Results are reported for the first (IA1; data cutoff Jun 26, 2024) and second (IA2; data cutoff Apr 9, 2025) interim analysis. Results: 747 pts were randomized to bel + lenva (n = 371) or cabo (n = 376). Median (range) follow-up was 19.6 mo (9.9–39.8) at IA1, and 29.0 mo (19.3–49.2) at IA2. Bel + lenva showed statistically significant improvement in PFS (IA1, IA2) and ORR (IA1) vs cabo (Table). OS results did not reach statistical significance (Table); additional follow-up for OS is ongoing. Median (range) DOR was 23.0 mo (2.0–44.3+) with bel + lenva vs 12.3 mo (1.8+–35.9+) with cabo at IA2. Grade ≥3 TEAEs occurred in 84.1% of pts with bel + lenva and 82.7% with cabo; TEAEs led to death in 5.4% of pts (2 were treatment-related: 1 each thrombotic microangiopathy and pneumonitis) and 3.2% of pts (1 was treatment-related: hemoptysis), respectively. Conclusions: Bel + lenva demonstrated superior PFS and ORR vs cabo in pts with advanced ccRCC following anti–PD-(L)1 therapy. OS favored bel + lenva but did not reach statistical significance and will be tested further at final analysis. The safety profile of bel + lenva was consistent with the profiles of the individual drugs. LITESPARK-011 is the first phase 3 study of a HIF-2α inhibitor combined with a VEGFR-TKI, and the first phase 3 study in RCC to show improved outcomes vs a contemporary VEGFR-TKI. Clinical trial information: NCT04586231 . IA1 IA2 Bel + Lenva, N = 371 Cabo, N = 376 Bel + Lenva, N = 371 Cabo, N = 376 Median PFS (95% CI), mo 14.6 (11.1–16.6) 10.6 (9.2–11.1) 14.8 (11.2–16.6) 10.7 (9.2–11.1) HR (95% CI) 0.74 (0.61–0.89) 0.70 (0.59–0.84) P value (1-sided) .00095* .00007* Median OS (95% CI), mo NR (26.5–NR) 27.4 (23.6–31.4) 34.9 (27.5–NR) 27.6 (24.0–31.4) HR (95% CI) 0.90 (0.70–1.15) 0.85 (0.68–1.05) P value (1-sided) .19322 .06075 ORR, % (95% CI) 52.6 (47.3–57.7) 39.6 (34.6–44.8) 52.6 (47.3–57.7) 40.2 (35.2–45.3) P value (1-sided) .0002* NA NA, not applicable. *Denotes statistical significance.

LBA418 Background: Adjuvant pembrolizumab is a standard of care for patients with ccRCC at increased risk of recurrence following nephrectomy based on the phase 3 KEYNOTE-564 study (N Engl J Med 385:683; N Engl J Med 390:1359). Combination strategies may further improve outcomes in this setting. We present results from the phase 3, double-blind LITESPARK-022 study (NCT05239728) of pembrolizumab + belzutifan vs pembrolizumab + placebo in pts with ccRCC at increased risk of recurrence post nephrectomy. Methods: Pts had ccRCC stage M0 and intermediate-high (pT2 Gr 4 or sarcomatoid, or pT3 any Gr, N0) or high (pT4 any Gr, N0, or any pT and Gr, N+) risk of recurrence after nephrectomy, or ccRCC stage M1 with no evidence of disease (M1 NED) after surgery. Pts were randomized 1:1 to receive 9 doses of IV pembrolizumab 400 mg Q6W (~1 year) with either oral belzutifan 120 mg QD or placebo. The primary endpoint was DFS by investigator. Secondary endpoints included OS (key) and safety. Results are presented from the first interim analysis (IA1; after 87% of DFS events occurred with a minimum of 15 mo of follow-up). Results: Overall, 1841 pts were randomized (921 to pembrolizumab + belzutifan and 920 to pembrolizumab + placebo). As of Aug 23, 2025, median follow-up was 28.4 mo (range, 15.0–40.1). Pembrolizumab + belzutifan significantly improved DFS vs pembrolizumab + placebo (HR 0.72, 95% CI 0.59–0.87; P = 0.0003). Median DFS was not reached in both arms; estimated 24-mo DFS rate was 80.7% (95% CI, 77.7–83.2) vs 73.7% (95% CI, 70.6–76.6), respectively. OS was immature at IA1 with a total of 87 OS events (38 in the pembrolizumab + belzutifan arm vs 49 in the pembrolizumab + placebo arm) and did not reach statistical significance (HR 0.78, 95% CI 0.51–1.19; P = 0.1220) at 29% of the events needed for final OS analysis. 70% of the pembrolizumab + belzutifan arm and 71% of the pembrolizumab + placebo arm completed the assigned treatment. Among treated pts, grade ≥3 treatment-emergent AEs occurred in 52.1% of pts who received pembrolizumab + belzutifan and 30.2% who received pembrolizumab + placebo, most commonly anemia (12.1% vs 0.4%), increased ALT (6.4% vs 2.0%), and hypoxia (4.6% vs 0%). Grade 5 treatment-emergent (1.1% vs 1.2%, respectively) and treatment-related (0.3% vs 0.3%) AEs were similar between arms. No new safety signals were seen. Conclusions: Adjuvant pembrolizumab plus belzutifan demonstrated a statistically significant and clinically meaningful improvement in DFS vs pembrolizumab plus placebo in pts with ccRCC at increased risk of recurrence post nephrectomy, with a safety profile consistent with the known profiles of each drug. These results support adjuvant pembrolizumab plus belzutifan as a potential new standard of care in RCC at increased risk of recurrence. Clinical trial information: NCT05239728 .