Citations

755 Background: Patients with High-Risk BCG-Unresponsive Non-Muscle Invasive Bladder Cancer have limited treatment options. The US FDA approved treatments for BCG-UR patients with CIS, but additional bladder-sparing therapies are needed, especially for the BCG-UR papillary-only population. Cretostimogene is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Rb-E2F pathway alterations. This releases tumor-specific antigens, initiating an anti-tumor immune response, further amplified by the GM-CSF transgene. The BOND-003 Cohort P study (NCT04452591) is a single-arm clinical trial assessing the efficacy and safety of intravesical cretostimogene in HR, papillary-only, BCG-UR NMIBC patients. Methods: Eligibility criteria include age ≥18 years, ECOG PS of 0-2, and histologically confirmed BCG-UR HG Ta/T1 papillary disease without CIS within 90 days of study enrollment as verified per central pathology review. Patients had no visible evidence of residual bladder cancer before treatment. Intravesical cretostimogene is instilled for six weekly doses during the induction phase, followed by three weekly maintenance cycles quarterly through Month 12, then every six months through Month 36. Re-induction is permitted at 3 months for patients with HG Ta or CIS. Primary disease assessments include serial cystoscopy, urine cytology, axial imaging, and mandatory biopsy directed at prior tumor locations at Month 12, with centralized review of pathologic samples. Endpoints include HG-RFS, HG-EFS, PFS, and safety. The study has completed enrollment. Results: A total of 56 patients who received treatment with cretostimogene are evaluated based on data from September 1, 2025 cut off. At baseline, 76.7% of patients are 65 years or older, 21.4% are female, 64.3% have HG Ta, and 35.7% have HG T1 papillary NMIBC. Kaplan-Meier estimates of HG-RFS at 6- and 9-months are 84.6% (95% CI 73.1 - 96.1%) and 80.4% (95% CI 66.8-94.0%), respectively. No patients have undergone a radical cystectomy. One patient progressed to metastatic disease despite a clinical complete response in the bladder. Cretostimogene demonstrates a favorable safety profile, with most adverse events localized to low grade bladder symptoms. There are no serious treatment-related adverse events and no discontinuations related to cretostimogene. To date, no patients have required a dose delay or missed a dose due to a related adverse event. There have been no deaths related to study treatment. Further, updated data will be presented. Conclusions: These results demonstrate consistent efficacy and a well-tolerated safety profile. Mature data with longer term follow-up will build upon these promising findings and will inform future treatment approaches with cretostimogene. Clinical trial information: NCT04452591 .

743 Background: Although patients with Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) have several emerging therapeutic options, there remains a clinical unmet need to improve efficacy, durability of response, and tolerability while obviating the need for radical cystectomy. TARA-002 is a lyophilized biological preparation for intravesical instillation containing inactivated cells of Streptococcus pyogenes (Group A, type 3) Su strain. TARA-002 rapidly enters cancer cells, activating TLR2 and NOD2 to trigger the innate immune response, inflammation, and potential immunogenic cell death. Herein we present interim safety and efficacy data of TARA-002 from the BCG-unresponsive cohort of the ongoing ADVANCED-2 study (NCT05951179). Methods: ADVANCED-2 (Cohort B) is a Phase 2, open-label study to evaluate the safety and efficacy of intravesical TARA-002 in BCG-unresponsive adults ≥ 18 years with high-grade NMIBC CIS (± Ta/T1). Key exclusion criteria include penicillin allergy; history of ≥ T2 bladder cancer, nodal, or metastatic disease; or concomitant prostatic or upper tract urothelial involvement. TARA-002 is delivered intravesically for 2 hours and includes induction (6 weekly doses), reinduction (if persistent disease at 3 months), and maintenance (through 24 months). Response is assessed every 3 months for 2 years. Biopsy is mandated at Month 3. Long-term follow-up is conducted up to 60 months. Safety is monitored throughout the study. The primary endpoint is complete response (CR) at any time defined by the absence of any high-grade recurrence. The key secondary endpoint is duration of response. Results: As of 07-October-2025, 32 BCG-unresponsive participants have been enrolled. Majority of participants were White (84.4%, 27 of 32), non-Hispanic (93.8%, 30 of 32), and male (68.8%, 22 of 32). The median age was 74 years (range: 47 to 92). The majority of participants had a baseline diagnosis of CIS only ie, without concomitant Ta/T1 (75.0%, 24 of 32). TARA-002 demonstrated a 68.4% (13 of 19) CR at any time in evaluable participants. The 6-month CR was 75.0% (9 of 12), the 9-month CR was 50.0% (4 of 8), and the 12-month CR was 37.5% (3 of 8). The salvage rate was 75.0% (6 of 8) with reinduction therapy. Most treatment-emergent adverse events (TEAEs) were mild (CTCAE Grades 1-2) and transient; no participants experienced higher than Grade 3 TEAEs. No participants experienced drug-related serious adverse events (SAEs) or drug-related TEAEs leading to withdrawal or death. Conclusions: In participants with BCG-unresponsive high-risk NMIBC with CIS ± Ta/T1, TARA-002 appears to be well tolerated and demonstrated encouraging efficacy, supporting ongoing accrual of the ADVANCED-2 study. Further follow-up will inform durability of response, and data will be updated based on evaluable time points at the time of the presentation. Clinical trial information: NCT05951179 .

741 Background: A significant treatment gap exists for efficacious, well-tolerated bladder-sparing options for patients with HR BCG-UR NMIBC with CIS. Cretostimogene is an oncolytic immunotherapy with dual mechanisms of action. It replicates in and lyses cancer cells with Rb-E2F pathway alterations, while simultaneously amplifying an anti-tumor immune response, further mediated by the GM-CSF transgene. BOND-003 (NCT04452591) is a phase-3 study evaluating the efficacy and safety of cretostimogene in patients with HR BCG-UR NMIBC with CIS +/- HG Ta/T1 (Cohort C) and HG Ta/T1 only (Cohort P). We report data on radical cystectomy performed post-recurrence or progression on Cohort C. Methods: 112 patients were enrolled. Participants had previously received adequate BCG and were considered BCG-UR by the FDA definition. Cretostimogene treatment consisted of a 6 weekly induction course, followed by 3 weekly maintenance cycles every 3 months at year one and every 6 months during years 2-3. Repeat induction was permitted at Month 3, if persistent HG Ta or CIS. Response assessments included serial cystoscopy, urine cytology, and mandatory mapping biopsy at 12 mo, with centralized review of all pathology. The primary endpoint was Complete Response (CR) at any time. Cystectomy-Free Survival (CFS) and Progression-Free Survival (PFS) were key secondary endpoints. Results: As of the June 23, 2025 data cutoff (median follow-up of 25.8 months), the CR rate at any time is 75.5% (83/110) (95% CI 66.3-83.2%). Kaplan-Meier estimates of 12- and 24-month DoR are 64.2% (95% CI 52.5-73.8%) and 60.1% (95% CI 48.2-70.0%), respectively, with a median DoR of 27.9 months (95% CI 14.3-NE%) and ongoing. The 12- and 24- month CR rate is 46.4% (51/110) (95% CI 36.8-56.1%) and 41.8% (46/110) (95% CI 32.5-51.6%), respectively. The 12- and 24-month CFS rates are 89.2 (95% CI 81.3-93.9) and 81.3% (71.8-87.8), respectively, with median CFS not reached. Among 18 patients who underwent radical cystectomy post-disease recurrence or progression; 15 (83.3%) had NMIBC or pT0 on final pathology. At 12- and 24- months, 96.6% are free from ≥T2 progression. Cretostimogene has a well-tolerated safety profile, with no grade ≥3 treatment-related adverse events. Conclusions: Cretostimogene offers distinct advantages with its mechanism of action, efficacy, durability and safety profile for the treatment of HR BCG-UR NMIBC. Furthermore, a significant proportion of patients receiving cretostimogene remained progression-free and avoided radical cystectomy. Most patients who underwent radical cystectomy had NMIBC or pT0 on final pathology maintaining a window of opportunity. Ongoing and future investigations of cretostimogene, as monotherapy and in rational combinations, may address the considerable unmet need for patients with bladder cancer. Clinical trial information: NCT04452591 .

696 Background: EVP is the preferred 1st-line therapy for patients (pts) with aUC. Upfront EV dose reductions may be utilized to enhance tolerance and minimize treatment-related toxicities when intolerance is anticipated. Prior studies of EV monotherapy suggest that starting dose 1.25 mg/kg resulted in exposure that maximized chance of response. We hypothesize that upfront EV dose reductions would not compromise EVP efficacy. Methods: Pts with aUC treated with EVP in the multi-site UNITE database were analyzed. Upfront dose reduction was defined as starting dose < 1.25 mg/kg. Correlation between clinical features and EV dose reduction were assessed using Fisher’s Exact test. Endpoints include progression-free survival (PFS) and overall survival (OS) from EVP initiation, assessed by Kaplan-Meier analysis and Cox models. Multivariable Cox analysis (MVA) included age (< 75 vs ≥ 75), ECOG performance status (PS) (0-1 vs 2-3), hemoglobin level (< 10 vs ≥ 10), and liver metastases (present vs absent), chosen in accordance with Bellmunt criteria. Correlation with investigator-assessed observed response rate (ORR) was determined using logistic regressions. All tests were 2-sided with p < 0.05 considered significant. Results: A total of 456 pts across 17 sites were included (median age 72; 77% Caucasian; 75% male; 26% upper tract primary; 66% pure UC; 77% ECOG PS 0-1; 17% with liver metastasis; 89% 1 st line EVP). Upfront dose reduction occurred in 96 pts (21%); 76 pts (79%) started at 1.0 mg/kg and 20 pts (21%) at 0.75 mg/kg. Upfront dose reduction was significantly associated with age ≥ 75 (p = 0.002), ECOG PS 2/3 (p = 0.04), and hemoglobin < 10 (p = 0.01) but not with liver metastasis (p = 0.9). Lower starting EV dose correlated with shorter median PFS (5 vs 6 months) and OS (9 vs 10 months), and lower ORR (28% vs. 60%) when compared to full dose (Table). In MVA adjusting for prognostic factors for PFS and OS, these associations were no longer statistically significant. Conclusions: In this real-world analysis, upfront EV dose reductions were most frequently used in pts with factors associated with frailty and poor prognosis, e.g. older age and ECOG PS 2/3, and were associated with lower ORR. When adjusted for these factors, upfront EV dose reductions were not associated with shorter PFS/OS though a trend towards inferior outcomes persisted. These differences in outcomes may reflect baseline risk factors rather than dose intensity; however, prospective investigation is required to validate our hypothesis-generating results. Association of upfront EV dose reduction with outcomes. Outcome (Upfront dose reduction vs no upfront dose reduction) Univariable analysis Multivariable analysis PFS: HR (95% CI), p 1.50 (1.11 – 2.02), 0.008 1.33 (0.95-1.86), 0.09 OS: HR (95% CI), p 1.56 (1.11-2.20), 0.01 1.41 (0.96-2.06), 0.08 ORR: OR (95% CI), p 0.35 (0.21-0.60), 0.0001 0.38 (0.21-0.67), 0.0009

605 Background: Patients with stage I testicular cancer (TCa) have excellent survival, and surveillance after orchiectomy is often preferred. Limited data exist on survivorship outcomes of surveillance versus adjuvant therapy. We compared systemic health outcomes between patients managed with surveillance and those treated with upfront therapy. Methods: Claims data from the OptumLabs Data Warehouse (2007–2022) identified stage I TCa patients managed with surveillance, chemotherapy, or radiation. Adjuvant therapy was defined as chemotherapy or radiation within 4 months of diagnosis with no further therapy. Chemotherapy codes were required within 42 days to ensure multiple cycles were not given. Propensity score–matched cohorts were created using logistic regression. A 3-year analysis evaluated new diagnoses of cardiopulmonary complications, metabolic syndrome, men’s health, psychological, and miscellaneous systemic conditions. Outcomes were stratified by treatment group. Chi-square tests and Cox regression analyses compared survivorship outcomes between adjuvant therapy and surveillance. Results: Eight-hundred forty-two patients had 3 years of coverage: 531 surveillance, 159 chemotherapy, and 152 radiation. No significant differences were found in cardiopulmonary, metabolic, psychological, or other systemic outcomes between therapy and surveillance (Table 1). Men’s health diagnoses were more frequent with chemotherapy (35.2% vs 23.9%, p=0.027) compared to surveillance. However, Cox regression showed no significant time-to-event differences on time-to-event analysis between groups. Conclusions: Adjuvant chemotherapy may be associated with higher rates of men’s health complications (infertility, erectile dysfunction, hypogonadism), but over time the risk is not significantly different than surveillance. Propensity-score matched survivorship outcomes: A) surveillance vs chemotherapy; B) surveillance vs radiation. A) Surveillance (N=159) Chemotherapy (N=159) p value Cardiopulmonary Complications 0.157 Yes 14 (8.8%) 22 (13.8%) No 145 (91.2%) 137 (86.2%) Men’s Health Complications 0.027 Yes 38 (23.9%) 56 (35.2%) No 121 (76.1%) 103 (64.8%) Metabolic Syndrome Complications 0.631 Yes 53 (33.3%) 49 (30.8%) No 106 (66.7%) 110 (69.2%) Miscellaneous Systemic Disorders 0.879 Yes 25 (15.7%) 26 (16.4%) No 134 (84.3%) 133 (83.6%) Psychological Diagnoses 0.401 Yes 29 (18.2%) 35 (22.0%) No 130 (81.8%) 124 (78.0%) B) Surveillance (N=152) Radiation (N=152) p value Cardiopulmonary Complications 0.682 Yes 12 (7.9%) 14 (9.2%) No 140 (92.1%) 138 (90.8%) Men’s Health Complications 0.630 Yes 51 (33.6%) 55 (36.2%) No 101 (66.4%) 97 (63.8%) Metabolic Syndrome Complications 0.086 Yes 42 (27.6%) 56 (36.8%) No 110 (72.4%) 96 (63.2%) Miscellaneous Systemic Disorders 0.650 Yes 25 (16.4%) 28 (18.4%) No 127 (83.6%) 124 (81.6%) Psychological Diagnoses 0.650 Yes 28 (18.4%) 25 (16.4%) No 124 (81.6%) 127 (83.6%)

514 Background: Poly(ADP-ribose) polymerase 1 (PARP1) senses single strand DNA damage and catalyzes repair mechanisms. PARP inhibitor (PARPi) suppresses PARP1 activity and promotes cell death in BRCA1 or BRCA2 mutated cancers that are homologous recombination repair deficient (HRD) via a phenomenon known as “synthetic lethality”. Utility of PARPi in HRD-negative (HRDn) cancers remain uncertain, although in a preclinical study overexpression—but not endogenous levels—of BRCA2 in mouse hybridoma cells led to HRD and increased sensitivity to DNA crosslinking agents, suggesting potential sensitization to PARPi. In renal cell carcinoma (RCC), HRD mutations are rare and the role of PARPi remains investigational. In this study, PARP1 and BRCA1/2 expression and overall survival (OS) in high risk of recurrence localized clear cell-type renal carcinoma (hrr-ccRCC) were explored. Methods: Batch-corrected bulk mRNA profile (RNA Seq V2 RSEM) and clinical data of HRDn stages II grade 4-only (n = 4) and III (n = 100) ccRCC from The Cancer Genome Atlas Pan-Cancer project were reviewed. Gene expression was classified “high” if mRNA level is higher than median, otherwise it was classified “low”. Survival analyses were Log-rank Kaplan-Meier. Group comparisons were two-tailed Mann-Whitney test. Results: In HRDn hrr-ccRCC (n = 104), BRCA1 and BRCA2 were upregulated by median fold change (mFC) of 1.6 and 3.7, respectively, whereas PARP1 was downregulated by mFC 0.8 compared to normal control (n = 72, all p < 0.0001). BRCA1 and BRCA2 levels were positively correlated (R 2 = 0.71). Median duration of follow-up for OS was 36.5 months (IQR 20.9-60.0). High BRCA2 (n = 54) was associated with superior OS compared to low BRCA2 (n = 50) with hazard ratio (HR) for death at 0.34 (95% CI 0.19-0.63, p = 0.0008). When high BRCA2 group was further stratified by PARP1 level, those with concomitant low PARP1 (n = 16) trended towards a superior OS compared to those with high PARP1 (n = 38) with HR 0.19 (95% CI 0.06-0.60, p = 0.067). Similarly, high BRCA1 (n = 53) was associated with superior OS compared to low BRCA1 (n = 51) with HR 0.53 (95% CI 0.29-0.96, p = 0.04). However, no differential OS was seen when high BRCA1 group was stratified by PARP1 level. No differential OS was seen when low BRCA1 or low BRCA2 groups were stratified by PARP1 level. Conclusions: In this retrospective analysis of HRDn hrr-ccRCC, high BRCA2 was associated with superior OS which was more pronounced with concomitant low PARP1 . High BRCA1 was also associated with superior OS, but PARP1 levels had no influence. The findings of this study may imply a potential therapeutic value of PARP1 suppression with PARPi by mimicking low PARP1 expression in treating HRDn hrr-ccRCC with BRCA2 overexpression. Further investigation is warranted.

498 Background: Radiotherapy-based metastasis-directed therapy (MDT) has emerged as a viable treatment paradigm for oligometastatic clear cell renal cell carcinoma (ccRCC). However, the optimal integration of MDT with frontline immune checkpoint inhibition (ICI) is unclear, especially in light of the M1 NED subgroup analysis of KEYNOTE-564 suggestive of a larger benefit from adjuvant pembrolizumab. Here, we sought to compare the effects of MDT with or without pembrolizumab on clinical and translational outcomes among patients with oligometastatic ccRCC enrolled on two prospective phase II trials. Methods: We undertook an exploratory cohort study of two prospective, single-arm, investigator-initiated phase II trials. The RAPPORT trial (NCT02855203) assigned 30 patients to radiotherapy-based MDT followed by pembrolizumab 200 mg Q3W for eight cycles (MDT+ICI cohort). The MD Anderson trial (NCT03575611) assigned 121 patients to serial MDT (which was almost exclusively radiotherapy-based) without systemic therapy (MDT cohort). For both trials, eligibility criteria consisted of 1 to 5 ccRCC metastatic lesions amenable to MDT. For the present analysis, the primary endpoint was progression-free survival (PFS), prospectively defined by RECIST v1.1 and analyzed using Cox regression. Peripheral blood flow cytometry obtained at baseline, end of MDT in both cohorts (after 1 cycle of ICI in the MDT+ICI cohort), and after completion of all treatment in both cohorts (3 months in the MDT alone cohort and 12 months in the MDT+ICI cohort) was compared using adjusted linear mixed effect models. Results: A total of 150 patients were included for analysis (MDT+ICI: 30; MDT: 120). Median follow-up time was 34 months (MDT+ICI: 28; MDT: 36). At enrollment, the MDT+ICI cohort had a larger number of metastases (median 3 vs 1). Adjusted for prognostic factors, median PFS was 28 months after MDT+ICI and 17 months after MDT (HR, 0.57; 95% CI: 0.31 to 0.998; P = 0.049). Induction of activated systemic CD8 + T cells (ICOS + ) was observed in both cohorts following MDT; however, this increase was greater in the MDT+ICI cohort. Moreover, there was evidence of decreased systemic CD8 + T cell immunosuppression (CD73 + ) following treatment cessation in the MDT+ICI group. Conclusions: To our knowledge, this is the largest prospective analysis of MDT for ccRCC in the ICI era. The addition of maintenance ICI to MDT may improve clinical outcomes in patients with oligometastatic ccRCC. Greater immunomodulatory signals were observed with MDT+ICI, providing a mechanistic link to the clinical benefits. The ASTROs trial (NCT06004336) randomizing patients with oligometastatic ccRCC to MDT with or without pembrolizumab has been initiated to test the hypotheses generated by the present study. Clinical trial information: NCT02855203 and NCT03575611 .

496 Background: Approximately 10% of patients with renal cell carcinoma (RCC) have an associated venous tumor thrombus (VTT), the presence of which impacts surgical management and increases perioperative risk. Historical systemic therapy regimens had limited success in downsizing VTT; however, the impact of immune checkpoint inhibitors (ICIs) on VTT shrinkage is unknown. Our primary objective is to assess VTT shrinkage comparing responses to ICI versus non-ICI regimens. Methods: This multicenter retrospective cohort study included patients with RCC and VTT from 2006-2024 who received upfront systemic therapy. Patients were evaluated at tertiary referral centers across Mayo Clinic Rochester, Florida, and Arizona. Systemic therapies were categorized as ICI versus non-ICI regimens. VTT length was quantified by distance relative to the superior border of the renal vein ostium. The primary outcome was change in VTT length on serial imaging as measured by absolute length reduction (cm), RECIST version 1.1 criteria, and Mayo VTT level reclassification. Linear mixed-effect models (LMMs) identified associations with VTT shrinkage and clinicopathologic features. Results: A total of 108 patients with median age 65 years (IQR 57-71) were included, of whom 49 (45%) received ICI regimens. ICI regimens were associated with greater VTT shrinkage (1cm vs 0.1 cm, p=0.025), increased RECIST responses (51% vs 32%, p=0.046), and a higher rate downstaging per Mayo VTT level (33% vs 12%, p=0.008) compared to non-ICI regimens. On multivariable LMM analysis, ICI regimens remained more likely to result in VTT shrinkage compared to non-ICI regimens (-0.12 cm/month, 95% CI –0.24-0.00, p=0.046). Absence of abdominal lymphadenopathy was also associated with VTT shrinkage (-0.18cm/month, 95% CI -0.06- -0.30, p=0.004). Initial Mayo VTT level, IMDC risk, and number of metastatic sites were not associated with VTT shrinkage. Conclusions: Treatment with ICI-regimens resulted in VTT shrinkage and Mayo VTT level reduction. This is a particularly important area of exploration as radical nephrectomy and tumor thrombectomy carry up to a 40% risk of peri-operative major complications. These data support using ICI regimens for patients with RCC with VTT who are not candidates for upfront surgery and prioritizing ICI regimens in neoadjuvant clinical trials.

484 Background: Renal cell carcinoma (RCC) is the most common type of urogenital cancer. Lifestyle and metabolic risk factors seem to play an important role in this rising incidence. Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity. Emerging evidence suggests that these agents may have potential anti-tumor activity as GLP-1 signaling may influence pathways involved in cell proliferation and inflammation. Our study aims to evaluate the impact of GLP-1 receptor agonists on outcomes among patients with RCC and comorbid obesity. Methods: A retrospective cohort study was conducted using the US Collaborative Network TriNetX, covering January 2000 to December 2023, encompassing data from 105 global healthcare organizations. Adult patients aged 18 and above with RCC and comorbid obesity were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, race, and common comorbidities. We followed these patients for 5 years to assess outcomes, including overall mortality, myocardial infarction, heart failure, ischemic stroke, chronic kidney disease (CKD), metabolic dysfunction-associated steatotic liver disease (MASLD), and need for hemodialysis. Results: We identified 2232 patients with RCC and obesity who received GLP-1 receptor agonists, and 13090 patients with RCC and obesity who did not receive GLP-1 therapy. After propensity matching, each cohort consisted of 2231 patients with similar baseline characteristics. Our analysis found that over 5 years, patients with RCC and obesity who received GLP-1 receptor agonists had a significantly lower risk of overall mortality (Hazard Ratio (HR): 0.493, 95% CI: 0.427 to 0.57, p-value < 0.001), myocardial infarction (Risk Difference: -2.239%, 95% CI: -3.836 to -0.642, p-value = 0.006), heart failure (Risk Difference: -4.213%, 95% CI: -6.876 to -1.551, p-value = 0.002), ischemic stroke (ischemic stroke: -2.111%, 95% CI: -3.44 to -0.781, p-value = 0.002), and CKD (Risk Difference: -8.526%, 95% CI: -11.441 to -5.611, p-value < 0.001). There was no statistically significant difference in the risk for MASLD and need for hemodialysis between the two subgroups. Conclusions: Our study revealed that patients with RCC and obesity who received GLP-1 receptor agonists had a significantly lower risk of mortality, myocardial infarction, heart failure, CKD and ischemic stroke. Further longitudinal cohort studies are imperative to better understand these associations and guide evidence-based clinical practice in this population.

483 Background: Sarcomatoid dedifferentiation (sRCC) in metastatic clear-cell renal cell carcinoma (mccRCC) confers aggressive disease and poor prognosis. We maintain a living meta-analysis of first-line immune checkpoint inhibitor (ICI)–based combinations in mccRCC (Riaz et al., Eur Urol Oncol 2021), which demonstrated improved survival with ICI-based regimens over sunitinib. Here, we present an updated synthesis focused on the comparative efficacy of ICI combinations in the sarcomatoid subset. Methods: A systematic search of MEDLINE, EMBASE, and CENTRAL through October 2025 was performed as part of our living meta-analysis of first-line mccRCC therapy. Eligible phase III RCTs compared ICI combinations (IO/IO or IO/TKI) versus sunitinib, including CheckMate 214, CheckMate 9ER, KEYNOTE-426, CLEAR/KEYNOTE-581, JAVELIN Renal 101, and IMmotion151. Extracted outcomes included overall (OS) and progression-free survival (PFS), and objective (ORR), complete (CR), and partial (PR) response rates. Random-effects meta-analyses generated pooled hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for response rates with 95% confidence intervals. Subgroup interaction analyses compared sarcomatoid versus non-sarcomatoid subgroups, with p < 0.1 considered significant. Results: Six phase III RCTs (n = 5,121; 624 sarcomatoid) were included. Across all ICI-based combinations, ICI therapy improved outcomes versus sunitinib in both sarcomatoid and non-sarcomatoid disease. In the pooled analysis, the OS interaction favored sRCC meeting the prespecified significance threshold for subgroup analyses (HR 0.53 vs 0.68; p-interaction = 0.06 < 0.10), while no significant interaction was seen for PFS. Response outcomes showed the strongest differential benefit, particularly with IO/TKI regimens. IO/IO results were directionally consistent but limited by smaller non-sarcomatoid samples. Conclusions: ICI-based combinations significantly improve survival and response outcomes versus sunitinib in mccRCC. Using a prespecified α = 0.10 for interaction testing, the pooled analysis showed a significant OS interaction and higher response rates in sRCC, indicating enhanced ICI sensitivity. These updated meta-analysis data support ICI regimens as the preferred first-line therapy for mRCC with sarcomatoid de-differentiation. Endpoint Regimen Subgroup (S = sarcomatoid; NS = non-sarcomatoid) Effect (95% CI) p-interaction PFS IO/IO S 0.51 (0.40–0.65) – IO/TKI S vs NS 0.48 (0.36–0.64) vs 0.46 (0.39–0.52) 0.81 OS IO/IO S 0.54 (0.07–4.42) – IO/TKI S vs NS 0.51 (0.17–1.48) vs 0.68 (0.30–1.58) 0.24 ORR IO/IO S 2.93 (0.49–17.37) – IO/TKI S vs NS 2.43 (1.84–3.21) vs 1.95 (1.67–2.28) 0.03 CR IO/IO S 3.81 (0.82–17.71) – IO/TKI S vs NS 5.93 (4.73–7.42) vs 2.85 (0.10–83.73) 0.007 PR IO/IO S 3.48 (1.70–7.11) – IO/TKI S vs NS 2.10 (1.78–2.47) vs 1.75 (1.18–2.61) <0.001