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.

4510 Background: Although adj atezo did not prolong disease-free survival (DFS) in the IMmotion010 trial, accompanying studies identified post-nephrectomy serum KIM-1 levels to be potentially predictive of benefit with atezo. We investigated whether tissue genomics could complement these findings. Methods: Tumors were obtained from patients pre-treatment and (if additional consent obtained) at disease recurrence. Whole transcriptome profiles were generated using TruSeq RNA Access Technology (Illumina). Previously, non-negative matrix factorization (NMF) was performed in a separate phase 3 study in advanced RCC (IMmotion151), establishing 7 molecular subgroups (NMF 1-7) (Motzer et al Cancer Cell 2020). For each IMmotion010 tumor, we derived signature scores dichotomized at the median as well as NMF1-7 subtype using random forest. Clinical outcome was assessed within these groups alone and with the addition of baseline serum KIM-1 levels, dichotomized into KIM-1 high (KIM-1 H ) and KIM-1 low (KIM-1 L ) using the previously established cutoff of 86 pg/mL. Where possible, we sought to characterize the evolution of molecular profiles at disease recurrence. Results: Baseline tissue was obtained from 754 pts, reflecting 97% of the intention-to-treat population. Tumors from KIM-1 H patients were enriched in myeloid, granulocyte and proliferation gene signatures at baseline. Among 722 pts for whom both serum KIM-1 and NMF subtype could be characterized, pts in cluster 6 (stromal/proliferative) appeared to derive benefit from atezo (n=50) (Table). Across all patients, no difference in outcome was observed among baseline Teff H and Teff L subsets. Within the KIM-1 H population, Teff H tumors were associated with longer DFS with atezo vs pbo. Paired baseline/recurrence tissue was obtained from 80 pts (atezo: 49; pbo: 31). At recurrence, tumors exhibited increased stromal and proliferation gene signatures, regardless of treatment, reflected in an increased proportion in NMF6 (baseline: 6%; progression: 22%). Exploratory analyses also revealed a decreased MHC-I signature after treatment with atezo. Conclusions: This is the first report of tissue genomic profiling in a phase 3 adjuvant immune checkpoint inhibitor study in RCC. While certain molecularly defined subsets may carry predictive value, serum KIM-1 remains the most robust predictor of outcome with atezo. Analyses of progression biopsies highlight an evolution in genomic profile and offer insights into mechanisms of relapse. Clinical trial information: NCT03024996 . Subgroup n DFS HR Serum KIM-1 KIM-1 H 290 0.7* KIM-1 L 443 1.13 T-effector signature Teff H 367 0.87 Teff L 366 0.97 NMF subtype NMF1 82 1.14 NMF2 271 1.04 NMF3 131 0.96 NMF4 62 0.88 NMF5 60 0.77 NMF6 50 0.25* NMF7 66 1.62 T-effector signature in KIM-1 H pts KIM-1 H Teff H 147 0.59* KIM-1 H Teff L 143 0.93 *P<0.05.

PURPOSE:To investigate the feasibility and safety of robot-assisted partial nephrectomy (RAPN) to treat large (T2) cystic renal-cell carcinoma. METHODS:A multinational study was conducted worldwide. Patients with renal tumors larger than 7cm who underwent partial nephrectomy between December 2007 and July 2017 were recruited retrospectively. The patients were divided into solid tumor group (143 cases) and cystic tumor group (28 cases). Baseline parameters, tumor characteristics, perioperative variables, and pathological outcomes were collected. RESULTS:Between cystic and solid tumors, no statistically significant differences were detected in age, gender, BMI, ASA score, clinical tumor size, laterality, or R.E.N.A.L nephrometry score. Operating time, warm ischemic time, estimated blood loss, complications, histology outcomes, and margin status were comparable. Pathology of 6 cystic tumors came back benign (21.4%). In solid tumors, 6 intraoperative bleeding require transfusion, 1 ureteral damage, and 3 postoperative urinary fistulas were observed. In cystic tumors, conversion to radical nephrectomy happened in one case, because of sticky fat and the risk of cyst rupture. In two cases, postoperative bleeding was treated with embolism. The longest follow-up was 113 months. In cystic group, 1 recurrence or metastasis was observed, while in solid group, 14 cases were observed. CONCLUSION:RAPN can be safely performed to treat large (T2) cystic renal-cell carcinoma. Patients with cystic renal-cell carcinoma exhibited favorable renal function recovery after robot-assisted partial nephrectomy (RAPN), which maximally preserved normal renal tissue and its function. Further studies are needed to better understand the role of RAPN for these challenging cases.

e13546 Background: Temple University Hospital-Main Campus (TUH) of TU health system (TUHS) is in North Philadelphia, Pennsylvania (USA) where 40% of residents live below the poverty line. Patients (pts) encounter multiple social determinants of health (SDOH) and face cancer health disparities. Institutional data from Fox Chase Cancer Center (FCCC of TUHS), show that pts with cancer at TUH present with more advanced stage and have worse outcomes. Incidental suspected cancer findings occur during inpatient hospitalizations for unrelated conditions. An approach is needed to avoid delayed workup and missed diagnoses, as oncologic care requires complex diagnostic testing and specialty input. The Multi Visit Patient Cancer Clinic (MVP CAN), led by TUH and in collaboration with FCCC, was created to bridge the gaps and streamline diagnostic workup for suspected cancer findings from the inpatient setting. Methods: MVP CAN model expedites outpatient diagnostic workups for suspicious cancer findings upon inpatient providers placing an electronic order. MVP CAN model includes i) an in-person transitional clinic led by a physician internist for those pts without a PCP or facing health literacy challenges, and/or ii) virtual coordination and an e-consult with the appropriate subspecialist to assess urgency and determine next steps, inclusive of procedural outpatient interventions. MVP CAN includes a navigator who coordinates tests, follow-ups, specialty appointments, and addresses SDOH with a trauma-informed approach. Here, we present results of the pilot implementation. Results: MVP CAN launched in May 2024 with data cutoff Dec 2024. 156 inpatients were referred, with 33% seen in-person and 67% managed virtually. Additionally, 56% had a subspecialty e-consult. Characteristics included: median age 62 yrs; 63% Black, 20% Hispanic, 11% White, 2% Asian; 59% Male, 41% Female; and 12 patients initially uninsured. Of 134 who completed workup: 51% were diagnosed with cancer including 42% referred to Oncology for treatment and 9% to Hospice, while 30% required ongoing surveillance. 13% were lost to follow up and 3% died. The most common cancers ( > 5) were NSCLC, colon, pancreatic, and prostate, with 18% stage III & 69% stage IV. Median time from program entrance to first oncology visit was 22 days (range 3-110). Conclusions: MVP CAN addresses a critical gap in transitioning care from inpatient to outpatient for underserved pts with suspected cancer while concurrently addressing SDOH. Over half of pts referred and completing workup were diagnosed with cancer, with most presenting at advanced stages. This highlights the need for navigation structured programs to enhance timely diagnosis and treatment and address access barriers and SDOH. Ongoing analysis will evaluate time to treatment and survival to assess the impact of MVP CAN on advancing health equity.

Introduction Cystic renal cell carcinoma (cRCC) is a rare subset of renal cell carcinoma (RCC), accounting for approximately 2.5-5% of all RCC cases. While cystic renal masses often carry benign or low-grade malignancies, large cystic lesions with central necrosis can often mask as more indolent biology. Indeed, preoperative differentiation of cRCC from more aggressive variants based on modern imaging remains a clinical challenge. Methods A single institution database of 4,340 kidney lesions treated with either active surveillance or intervention between 2000-2020 was queried for radiographic cystic renal masses ≥ 7 cm. The association between CT radiographic tumor characteristics and high-grade pathology was evaluated. Similarly, we looked at radiographic features and their associations with overall survival (OS) and recurrence free survival (RFS). Radiographic features considered were peripheral thickening, fluid heterogeneity, calcifications, septations, and density mass >20 HU. Results We identified 387 radiographically confirmed cystic lesions in 367 patients. Fifty lesions in 49 patients were noted to be ≥ 7 cm. Of the lesions that underwent intervention (72%, n=36), 33.3% (n=12) were benign and 66.7% (n=24) were malignant. Fluid heterogeneity and cystic density >20 HU were associated with malignancy (P<0.05). High grade pathology was demonstrated in 29.7% (n=11) of malignant lesions and were significantly associated with fluid heterogeneity (P<0.05) (Table 1). Regarding overall survival, 30.6% (n=15) died during the follow up period, with 12.2% (n=6) experiencing cancer-related mortality. Recurrence occurred in 8.2% (n = 4) of the patients, all of which had density > 20 HU. Of the radiographic features examined, density > 20 HU showed a statistically significant difference in terms of OS and RFS (Figure 1). Conclusions Cystic indolent RCC imposters such as solid renal lesions with central necrosis highlight the discordance between radiographic and pathologic characterization. In large cystic lesions (≥ 7 cm), fluid heterogeneity and density > 20HU can serve as a predictor of adverse pathology to appropriately identify patients for intervention. Future work is needed to prevent both over and under treatment of these cystic renal masses.

Background: Patients with clear cell renal cell carcinoma (ccRCC) metastases face poor prognoses, even with adjuvant therapies. Tumor-infiltrating T-cells and macrophages are critical in targeting tumor cells within the renal microenvironment. Beyond VHL mutations, loss-of-function mutations in SWI/SNF complex genes, including PBRM1, BAP1, ARID1A, SETD2, SMARCA4 (BRG1), and SMARCA2 (BRM), have been implicated in ccRCC progression. Design: A tissue microarray of 160 ccRCC cases was analyzed via immunohistochemistry (IHC) for SWI/SNF protein expression and CD4 + /CD8 +T-cell infiltration. Clinical and pathologic features were obtained through electronic medical records. Statistical analyses included one-way ANOVA, two-way ANOVA, Pearson's chisquare and t-tests. Results: Loss of SWI/SNF protein expression was observed in PBRM1 (31 %), ARID1A (51 %), SETD2 (14 %), BRG1 (15 %), BRM (38 %), and BAP1 (40 %). T-cell counts varied significantly with stage: CD4 + counts peaked at Stage 3, while CD8 + counts increased through Stage 4 (p G 0.001). Loss of PBRM1 was more frequent in advanced stages (29.4 %, p G 0.001), while BRM and BRG1 losses were more common in earlier stages (p G 0.001, p = 0.006). ARID1A and BRM losses correlated with reduced CD8 + counts (p = 0.016, p = 0.032) and stage-specific CD4 + variations (p G 0.001, p = 0.042). Conclusion: Loss of PBRM1, SMARCA2/BRM, and SMARCA4/BRG1 expression is significantly associated with ccRCC progression, with PBRM1 loss prevalent in advanced stages and SMARCA2/BRM and SMARCA4/BRG1 in earlier stages. ARID1A and SMARCA2/BRM losses correlate with reduced CD8 + counts and stage-specific CD4 + infiltration, highlighting their potential as biomarkers for disease progression and immunotherapeutic response.

BACKGROUND:To determine the utility of creatinine-to-hemoglobin (Cr:Hgb) ratio, as a predictor of survival outcomes in upper tract urothelial carcinoma (UTUC). METHODS:We performed a multi-institutional retrospective analysis of UTUC-patients who underwent robotic radical nephrouretectomy utilizing the ROBUUST (ROBotic surgery for Upper Tract Urothelial Cancer Study) registry. Patients were divided into elevated Cr:Hgb ratio (>0.15, based on upper-limit of normal for creatinine and lower-limit of normal for hemoglobin) vs. non-elevated Cr:Hgb ratio (≤0.15). Primary outcome was all cause mortality (ACM)/overall survival (OS). Secondary outcomes were cancer-specific mortality (CSM) / survival (CSS) and recurrence-free survival (RFS). Cox proportional hazards (MVA) was used to elucidate predictive factors for ACM, CSM, and RFS. Kaplan-Meier analysis (KMA) was performed to analyze 5-year OS, CSS, and RFS. RESULTS:Overall, 829 patients were analyzed (744 non-elevated / 85 elevated Cr:Hgb). Elevated Cr:Hgb patients had more frequently advanced-stage (P=0.016) and high-grade tumors (P<0.001) at time of surgery. MVA demonstrated increasing-age (HR=1.04, P=0.002), elevated Cr:Hgb (HR=2.49, P=0.003), lympho-vascular invasion (HR=4.61, P<0.001), and higher-stage (HR=3.82, P<0.001) to be associated with worsened ACM. Increasing-age (HR=1.04, P=0.030), elevated Cr:Hgb (HR=3.64, P<0.001), and lympho-vascular invasion (HR=4.52, P<0.001) were independently associated with worsened CSM. Elevated Cr:Hgb (HR=1.27, P=0.001) was independently associated with worsened recurrence. For elevated vs. non-elevated Cr:Hgb patients, KMA revealed significantly worse 5-year OS (78% vs. 65%, P=0.002), CSS (86% vs. 74%, P<0.001), and RFS (53% vs. 22%, P=0.004). CONCLUSIONS:Baseline elevated Cr:Hgb predicted worsened survival outcomes in UTUC patients and may serve a pre-operative marker to stratify oncologic risk and guide counseling and management.

OBJECTIVE:To evaluate the efficacy of risk-based, protocol-driven management versus usual management after elective major cancer surgery to reduce 30-day rates of postoperative death or serious complications (DSCs). BACKGROUND:Major cancer surgery is associated with significant perioperative risks, which result in worse long-term outcomes. METHODS:Adults scheduled for elective major cancer surgery were stratified/randomized to risk-based escalating levels of care, monitoring, and comanagement versus usual management. The primary study outcome was a 30-day rate of DSC. Additional outcomes included complications, adverse events, health care utilization, health-related quality of life (HRQOL), and disease-free survival and overall survival. RESULTS:Between August 2014 and June 2020, 1529 patients were enrolled and randomly allocated to the study arms; 738 patients in the intervention arm and 732 patients in the control arm were eligible for analysis. Thirty-day rate of DSC with the intervention was 15.0% (95% CI: 12.5%-17.6%) versus 14.1%, (95% CI: 11.6%-16.6%) with usual management ( P = 0.65). There were no differences in 30-day rates of complications or adverse events (including return to the operating room), postoperative length of stay, rate of discharge to home, or 30, 60, or 90-day HRQOL or rates of hospital readmission or receipt of antineoplastic therapy between the study arms. At a median follow-up of 48 months, overall survival ( P = 0.57) and disease-free survival ( P = 0.91) were similar. CONCLUSIONS:Risk-based, protocol-driven management did not reduce the 30-day rate of DSC after elective major cancer surgery compared with usual management, nor did it improve postoperative health care utilization, HRQOL, or cancer outcomes. Trials are needed to identify cost-effective, tailored perioperative strategies to optimize outcomes after major cancer surgery.