The intersection of immunotherapy and circadian biology represents a promising translational frontier in genitourinary (GU) oncology. Immunotherapy has reshaped the treatment landscape and markedly influenced patient outcomes in renal cell carcinoma (RCC) and urothelial carcinoma (UC), yet therapeutic responses remain variable, highlighting the necessity for strategies that can further enhance therapeutic efficacy. Notably, the circadian regulation of immune cell trafficking plays a central role in immune function and tumor biology. Retrospective analyses have suggested that earlier time-of-day administration of immunotherapy improves patient outcomes in RCC and UC. To facilitate the translation of chrono-immunotherapy from a theoretical concept to a clinical standard for patients, the present review assesses the biological rationale behind chronotherapy, summarizes clinical and scientific evidence regarding its therapeutic potential and provides a method for the prospective validation of chronotherapy in GU oncology. The present review also identifies current limitations in chrono-immunotherapy data and proposes potential solutions to validate this data and guide its translation into clinical practice.

INTRODUCTION:To characterize recurrence and survival patterns in pathologically node-positive, nonmetastatic (pN1M0) renal cell carcinoma (RCC) and identify prognostic factors. PATIENTS AND METHODS:Patients with pTanyN1M0 clear cell, papillary, or chromophobe RCC from the Canadian Kidney Cancer Information System who underwent radical or partial nephrectomy with lymph node dissection between 2011 and 2023 were included. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were estimated using Kaplan-Meier methods. Prognostic factors were assessed using univariable and multivariable Cox proportional hazards models. RESULTS:One hundred thirteen patients (69% male) were followed for a median of 3.1 years (IQR 1.2-6.0). Recurrence occurred in 77% (n = 87/113) at a median of 4.8 months (IQR 3.6-7.2), predominantly with distant metastases (n = 59/87). Median CSS was 5.5 years (IQR 3.8-nonestimable) and median OS was 4.4 years (IQR 3.4-6.5). On univariable analysis, pT3/T4 stage (HR 2.14, 95% CI 1.43-3.19, P < .001) and necrosis (HR 0.70, 95% CI 0.54-0.90, P = .006) were associated with RFS. Sarcomatoid differentiation was associated with CSS (HR 2.55, P = .025) and OS (HR 2.73, P = .013). On multivariable analysis, necrosis (adjusted HR 0.61, 95% CI 0.47-0.79, P < .001) and sarcomatoid differentiation (adjusted HR 2.69, 95% CI 1.01-7.21, P = .049) remained independently associated with RFS and CSS, respectively. CONCLUSION:Patients with pN1M0 RCC experience rapid, frequent recurrences predominantly with metastatic disease, with survival outcomes resembling metastatic RCC. Restaging imaging prior to adjuvant immunotherapy initiation is essential to identify patients who may have already progressed.

490 Background: Bone Metastases (BM) occur in approximately 30% of mRCC patients (pts) with evidence suggesting that they portend a worse prognosis. Systemic therapies such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICI) are felt to be active in these pts, with radiation therapy (RT) often employed for BM-directed treatment. The evidence for and use of BPAs, such as bisphosphonates and denosumab, is limited in the current ICI era. We investigated the outcomes of mRCC pts with BM and use of BPA in a contemporary real-world cohort. Methods: We analyzed data collected from the prospectively maintained, multi-institutional Canadian Kidney Cancer Information System (CKCis). Patients with clear cell mRCC treated between January 2011-June 2023 were included. Outcomes were compared between BM+ and BM- pts using Cox proportional hazards models. Kaplan-Meier estimates were used to assess time to treatment failure (TTF) and overall survival (OS) adjusted by IMDC criteria. Results: Of 2,307 patients with clear cell mRCC, 893 (39%) had BM+, of whom 691 (77%) underwent RT, and 139 (16%) received a BPA. Median follow-up was longer for BM- patients (34.6 vs 29.1 mos). Significant differences were noted in Karnofsky performance status (> 80%: 84% vs 78%), IMDC risk group (intermediate/poor: 76% versus 82%) use of RT (35% vs 78%), and use of BPAs (2% vs 16%) between BM- vs BM+ pts (all p < 0.05). In our cohort, first-line treatment in BM+ pts was monotherapy TKI (67%), doublet ICI (20%), and combination TKI+ICI (13%). Median TTF was similar in BM- vs BM+ pts: 9.6 vs 8.6 mos (HR 0.92; 95% CI 0.91-1.02). However, median OS was higher in BM- vs BM+ pts: 57.6 vs 35.8 mos (HR 0.67; 0.58-0.76; p<0.0001); this was consistent irrespective of type of systemic therapy. In BM+ pts, those who did not receive BPAs had a lower TTF (7.9 vs 13.4 mos) and OS (34.0 vs 46.0 mos); however, these were not statistically different when adjusted by IMDC criteria (TTF HR 1.2; 0.95-1.51 and OS HR 1.12; 0.85-1.46). There was no significant difference in TTF (HR 0.89; 0.72-1.10) or OS (HR 0.94; 0.73-1.22) in BM+ pts selected to receive RT. Conclusions: BM remain a poor prognostic factor in mRCC in this contemporary cohort of patients. While BPA use was limited, we observed no improvement in TTF or OS in BM+ pts with their use. These data warrant further investigation of BPA in mRCC including assessment of SREs and potential complications.

Chromophobe RCC (chRCC) represents 5-10% of all RCC; however, data regarding outcomes and predictors of recurrence and survival in localized disease are limited. The Canadian Kidney Cancer Information System (CKCis) is a multi-institutional prospective cohort. Patients who had surgical resection for clinically localized chRCC between January 2011 and July 2024 were included. Descriptive statistics were used, and cancer recurrence and time to death were estimated using Kaplan-Meier curves. Associations between baseline and tumour characteristics and recurrence and survival were assessed using Cox proportional hazards models. The study cohort included 790 patients. Median follow-up was 4.9 years, mean age was 57.8 years and 57.5% were male. Partial nephrectomy occurred in 52.7% and radical in 47.3%. Recurrence-free survival was 93.6% at 5 years and 90.2% at 10 years. In the 45 patients who recurred, 40 had metastatic disease, 3 had local recurrences, and 2 had new contralateral disease. Predictors of recurrence included a higher pT stage, sarcomatoid features, positive margins, and tumour necrosis. Overall survival was 94.5% at 5 years and 83.7% at 10 years. Predictors of death included high pT stage, increase in pathological size, and increasing age at diagnosis. In this large Canadian cohort, patients with surgically resected, localized chRCC had favourable 5- and 10-year oncologic outcomes. These favourable outcomes are a reminder that not all RCC patients with non-clear cell histologies should be pooled together as a single entity. There is, however, a subgroup of patients with less favourable outcomes who should be the focus of future research that aims to prevent recurrence and RCC death.

BACKGROUND AND OBJECTIVE:Reported outcomes of partial nephrectomy (PN) for cT2 renal cell carcinoma (RCC) have been variable. We aimed to examine outcomes of PN, compared to radical nephrectomy (RN) for cT2 RCC. METHODS:Patients captured in the Canadian Kidney Cancer information system who underwent surgery for cT2 RCC between 2011 and 2023 were included. Clear cell, papillary, and chromophobe histologies were included. Multifocal tumors, and hereditary RCC syndromes were excluded. Groups were matched up to 1:4 based on tumor size, histology, grade and necrosis. KEY FINDINGS AND LIMITATIONS:Of 1778 cT2 patients, 60 PN patients were matched to 224 RN patients. Positive surgical margins were 8.6% for PN vs. 2.8% for RN (P = 0.06). Postoperative complications were 18.3% for PN vs. 9.8% for RN (P = 0.07). Pathological upstaging to T3 was similar (21.7% PN vs. 22.3% RN, P = 0.73). There were no statistically significant recurrence or survival outcomes, however there were non-significant trends in local recurrence (HR 2.07, 95%CI 0.86-5.0), cancer specific survival (HR 0.65, 95%CI 0.19-2.16), overall survival (HR 0.66, 95%CI 0.28-1.57) for PN vs. RN. PN better preserved eGFR (-15.5 [IQR 27.7] vs. -24.4 [IQR 21.5], P = 0.026). CONCLUSIONS AND CLINICAL IMPLICATIONS:In a cohort of patients with non-metastatic cT2 RCC, PN has better preservation of renal function and may have a higher rate of perioperative complications and local recurrence. Acknowledging the presence of residual confounding, PN for T2 RCC is safe and provides acceptable oncological outcomes in well-selected patients.

PURPOSE:The objective of this study was to determine the incidence of local treatment and incidence of metastasis for patients with a solitary small renal mass (SRM; ≤4 cm) initiating active surveillance (AS). MATERIALS AND METHODS:Patients enrolled in the Canadian Kidney Cancer information system between January 2011 and January 2023 with a solitary renal mass ≤ 4 cm opting for AS were included. The primary outcome was local treatment progression, achieved if the patient received definitive local treatment after initiating AS. The secondary outcomes were growth rate progression (>0.5 cm/y), size progression (>4 cm), composite progression (either size or growth rate progression), and development of metastases. RESULTS:The Canadian Kidney Cancer information system included 1393 patients who initiated AS for an SRM ≤ 4 cm during the study period. At a median follow-up of 4.0 years (95% CI 2.1-6.4), 238 patients received local treatment, and of these, 195 were nephron sparing. Two- and 5-year cumulative incidence of treatment was 8.4% (95% CI 6.9-10) and 21% (95% CI 19-24), respectively. Twenty-nine patients developed metastasis. Two- and 5-year cumulative incidence of metastasis was 0.67% (95% CI 0.32-1.3) and 2.3% (95% CI 1.5-3.5), respectively. Of the 29 patients who developed metastases, 23 had progressed using size or growth rate cutoffs, and 7 had received local treatment with curative intent before the identification of metastases. CONCLUSIONS:Patients choosing surveillance for an SRM have low cumulative incidence of local treatment and metastasis at 5 years, demonstrating AS is a safe initial management approach.

471 Background: Papillary renal cell carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) representing up to 15% of RCC. First line (1L) phase II trials have evaluated immunotherapy (IO) in combination with IO or tyrosine kinase inhibitors (TKI) in nccRCC, but these cohorts are heterogeneous, with few comparative results. Therefore, the specific value of IO therapy for pRCC remains unquantified. Methods: We conducted an analysis based on prospectively collected data from the Canadian Kidney Cancer information system (CKCis) database. The objective was to evaluate efficacy of 1L systemic therapy of metastatic pRCC with either IO based or VEGFR-TKI. Baseline characteristics, treatment outcome and safety were collected. Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included overall survival (OS), objective response rate (ORR), adverse events requiring a change in dose/schedule (TRAEs). TTF, OS and ORR were adjusted (adj) for IMDC risk groups. Results: Between 01/2011 to 01/2024,206 pRCC pts were treated: 70 on IO single agent or in combination IO-IO/IO-TKI and 136 with TKI monotherapy. The median follow-up was 20.6 months (mo) (range: 1.6-146.1). There were no significant differences in baseline characteristics between 2 groups, described in table. The median TTF with IO was 9.8 mo (95%CI: 4.5, 15.9) versus (vs) 5.7 mo with TKI (95%CI: 4.6, 8.1) (adj HR: 0.61 [0.42-0.89] p=0.01). The median OS was 36.9 mo with IO (95%CI: 26.5, not reached (NR)) vs 21.6 mo with TKI (95%CI: 18, 27.9) (adj HR: 0.51 [0.3-0.85], p=0.009). Among the 170 evaluable pts, ORR was 37% (95% CI: 24.2-49.9) with IO and 21.5% (95% CI: 14.1-29) with TKI (adj OR: 2.4 [1.0-5.6] p=0.04). The TKI-IO subgroup had better TTF and OS compared to TKI therapy, with 16.9 mo (95%CI: 5.5-22.6) (adj HR: 0.46 [0.26-0.82] p=0.009), and NR (95%CI: 18.9-NR) (adj HR: 0.24 [0.08-0.78] p=0.02) respectively. 28% of pts discontinued treatment. TRAEs of grade 3-5 were noted in 27% in IO group and in 73% in TKI group. Conclusions: This study presents comparative data on 1L treatment metastatic pRCC. It shows an improved TTF and OS in the IO group, particularly in TKI-IO treated pts. Our findings underline the need for further clinical trials evaluating 1L IO in pts with metastatic pRCC. Baseline characteristics. Overall cohortn = 206 IO treatmentn = 70 (34%) TKI treatmentn = 136 (66%) Median age (range) 67 (30-89) 69 67 Sex Male 162 (79%) 51 (73%) 111 (82%) IMDC score Favorable Intermediate Poor Unknown 31 (20%)93 (60%)30 (19.5%)52 15 (29%)30 (58%)7 (13%)18 16 (16%)63 (62%)23 (22%)34 Prior Nephrectomy 164 (80%) 56 (80%) 108 (79%) Sarcomatoid component 12 (8%) 5 (7%) 7 (5%) Therapy Nivolumab + ipilimumab Pembrolizumab + axitinib Pembrolizumab + lenvatinib Pembrolizumab Nivolumab Sunitinib Pazopanib Cabozantinib Crizotinib Savolitinib m-Tor inhibitors 27 (13%)23 (11%)7 (3.5%)11 (5%)2 (1%) 88 (43%)20 (10%)8 (4%)3 (1.5%)7 (3.5%)9 (4.5%)

OBJECTIVE:To compare the outcomes of metastatic renal cell carcinoma (mRCC) patients, with or without sarcomatoid features, who underwent cytoreductive nephrectomy (CN) before or after systemic therapies (ST). METHODS:Synchronous metastatic RCC patients of IMDC intermediate- and high-risk diagnosed between January 2011 to December 2022, treated with CN before or after ST, and with histological documentation of the presence or absence of sarcomatoid features in nephrectomy specimens were identified using the Canadian Kidney Cancer information system (CKCis). Patients were classified by treatment sequence received: (1) CN after ST (2) CN before ST. Inverse probability of treatment weighting using propensity scores was used to balance for covariates. Cox proportional hazards models were used to assess the impact of initial treatment received on overall survival (OS). RESULTS:Of 709 eligible patients, 105 were treated with CN after ST and 604 with CN before ST. 75% were male, and the majority (70%) received targeted therapies (TT) used alone. In nonsarcomatoid patients (80 CN after ST and 454 CN before ST), treatment with CN after ST was associated with an improvement in OS, that was not statistically significant, compared to CN before ST (median of 60 vs. 48 months, HR 0.84, 95% CI 0.64-1.11). In sarcomatoid patients (25 CN after ST and 150 CN before ST), CN after ST was also not associated with better survival (median of 24 vs. 36 months, HR 1.10, 95% CI 0.70-1.73). CONCLUSION:In conclusion, this study demonstrated that, no matter the sarcomatoid status, there is no statistical difference between receiving CN after ST or CN before ST. The timing of CN could potentially be linked more so to clinical assessments than the knowledge of sarcomatoid status.

Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) compared to sunitinib in the pivotal Checkmate 214 trial of metastatic renal cell carcinoma (mRCC) with International Metastatic RCC Database Consortium (IMDC) intermediate/poor risk disease. We evaluated the efficacy and toxicity of ipi/nivo in older and frailer populations in a real-world mRCC cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N = 551) treated with first-line ipi/nivo from the Canadian Kidney Cancer information system (CKCis) database from January 2014 to December 2021. A comparison was made between outcomes and toxicity in patients 1. <70 versus (vs.) ≥70 yo, 2. <75 vs. ≥75 yo, and 3. KPS ≥70 vs. <70 yo. OS, progression-free survival (PFS), and time to treatment failure (TTF) were calculated by Kaplan–Meier analysis. Log-rank tests were used for comparison between groups. Results: Ipi/nivo treatment had no impact on survival outcomes or toxicity for patients >70 yo and >75 yo when controlled for IMDC. However, when comparing patients with KPS > 70 vs. KPS < 70, patients with a poor performance status had decreased median OS at 54.5 m vs. 10.8 m (p-value < 0.0001) and PFS at 11.6 vs. 3.1 m (p-value < 0.0001). Conclusions: The use of ipi/nivo in mRCC demonstrated similar survival outcomes and toxicity in an older patient population. In patients with a poor performance status, it was associated with inferior OS and PFS. We believe that ipi/nivo is a reasonable treatment option for these patient populations, particularly in older patients.

Intracranial metastatic disease (IMD) is a serious complication of renal cell carcinoma (RCC). However, large-scale data on its clinical characteristics, survival outcomes, and treatment strategies are limited, especially at the population level. To examine the clinical features, survival outcomes, and treatment patterns of RCC patients with IMD in Ontario, Canada, and provide insights to optimize patient management. This population-based retrospective cohort study included RCC patients diagnosed between 2010 and 2019 in Ontario. Demographics, treatments, and survival data were obtained from provincial healthcare records. Kaplan-Meier and Cox regression analyses assessed overall survival (OS). Propensity score matching (PSM) was used to compare survival outcomes between treatment groups. Among 13,353 RCC patients (mean age: 62 years), 4.6% developed IMD (71% metachronous, 29% synchronous), with a median time to IMD of 8.3 months [Interquartile Range: 1.3, 25.6]. Median OS was significantly shorter for patients with IMD (20.9 months) versus those without IMD (125.4 months; p < 0.001). Synchronous IMD (HR: 2.58) was linked to worse OS. Those without metastases at diagnosis had the longest OS (127.0 months), compared to patients with extracranial metastases alone (13.6 months; HR: 6.89) or synchronous IMD (4.8 months; HR: 14.71). Patients with stage 4 disease at diagnosis who developed metachronous IMD had better OS than those who never developed IMD (17.7 vs. 12.0 months). In patients with IMD, systemic therapy was associated with improved survival (HR: 0.47). Stereotactic radiosurgery (SRS) and/or neurosurgery was associated with improved survival, compared to whole-brain radiotherapy (WBRT) or no IMD-directed treatment (HR: 0.47). Propensity-matched analyses showed that receipt of SRS/neurosurgery was associated with improved OS, compared to WBRT or no IMD-directed treatment (25.9 vs. 13.1 months; HR: 0.55). This study provides large-scale, population-based insights into the impact of IMD in RCC. Our findings show that SRS/neurosurgery is protective in all subgroups of RCC patients with IMD, informing clinical decision-making and offering valuable guidance for optimizing patient outcomes and resource allocation. Additionally, these findings highlight the need for routine brain imaging in RCC to enable early detection and improve management strategies. Madison Sherman, Karim Hafazalla, Arjun Sahgal, Georg Bjarnason, Sunit Das. Real-world outcomes of renal cell carcinoma and intracranial metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5967.

477 Background: Multiple phase 3 trials have established either dual immunotherapy with ipilimumab and nivolumab (IPI-NIVO) or immunotherapy with a VEGFR inhibitor (IO-VE) as standard-of-care first-line therapy for metastatic clear cell renal cell carcinoma (mRCC). We focused this analysis on patients with IMDC intermediate or poor risk where either IPI-NIVO or IO-VE would be standard. Methods: Using the IMDC database, we performed a retrospective analysis of patients with intermediate or poor risk disease (1 or more IMDC risk factors) who received first-line therapy with IPI-NIVO or an approved IO-VE combination (avelumab-axitinib, nivolumab-cabozantinib, pembrolizumab-axitinib, or pembrolizumab-lenvatinib). Baseline characteristics, objective response rates (ORR), time to next therapy (TTNT), and overall survival (OS) were compared between IPI-NIVO and IO-VE regimens by Cox regression analyses. Results: A total of 1,523 patients were identified of whom 72.9% received IPI-NIVO and 28.2% received IO-VE. Baseline characteristics of our cohort are summarized in the table. Median follow-up was 24 months. The ORR was lower with IPI-NIVO compared with IO-VE (39.1% vs 48.0%; p = 0.004). Median TTNT was shorter in IPI-NIVO than IO-VE (10.4 months, 95% CI 9.4-11.7 vs 18.6 months, 95% CI 16.3-24.6; p <0.0001). Median OS was similar between groups at 35.4 months (95% CI: 31.4-41.9) and 35.6 months (95% CI: 28.9-44.1) for IPI-NIVO and IO-VE respectively (p = 0.277), and there were no significant differences when intermediate and poor risk groups were analyzed separately. Median OS in IO-VE vs IPI-NIVO was not significantly different when adjusted by IMDC criteria, brain, bone and liver metastases (HR 0.87, 95% CI 0.71-1.06; p=0.165). Conclusions: In a real-world setting amongst patients with IMDC intermediate-poor risk disease, IPI-NIVO and IO-VE strategies show similar survival outcomes although longer follow-up will be necessary to assess the tails of these survival curves. IO-VE is associated with a greater response rate compared with IPI-NIVO. Baseline characteristics. IPI-NIVON = 1110 IO-VEN = 413 p-value Male 808 (72.8) 303 (73.4) 0.823 IMDC Intermediate/Poor Risk 730/280 (65.8/34.2) 274/139 (66.3/33.7) 0.832 Pre-existing autoimmune condition 16 (2.6) 12 (4.6) 0.133 Non-clear cell histology 139 (15.9) 57 (16.4) 0.844 Sarcomatoid 147 (21.3) 50 (17.2) 0.1437 Nephrectomy 613 (55.3) 239 (57.9) 0.374 Brain metastasis 90 (8.4) 23 (5.7) 0.084 Bone metastasis 373 (34.3) 173 (42.5) 0.003 Liver metastasis 218 (20.2) 65 (16.0) 0.063

567 Background: The International Metastatic RCC Database Consortium (IMDC) criteria are widely used for risk stratification in metastatic renal cell carcinoma (RCC), but their role in non-metastatic RCC is less defined, especially as a biomarker of recurrence. This study seeks to evaluate (1) the prevalence of IMDC abnormalities in non-metastatic RCC patients (nmRCCC), (2) the impact of nephrectomy on the normalization of these criteria, and (3) the association between post-operative IMDC abnormalities and oncological outcomes. Methods: Data from the Canadian Kidney Cancer Information System (CKCis) were analyzed to identify non-metastatic RCC patients diagnosed between January 2011 and April 2024 who underwent nephrectomy after diagnosis. Laboratory tests were evaluated preoperatively (within 6 months before surgery) and postoperatively (between 2 and 15 months). Univariable and multivariable analyses were performed to assess the association with overall survival, recurrence-free survival, and cancer-specific survival. Results: A total of 1,804 patients were analyzed, with 65.7% male and mean age was 62.5y. Tumors pathological characteristics were: pT1 (69.2%), pT2 (5.6%), pT3 (1.8%), pT4 (0.28%); tumors necrosis (21.8%); mean tumor size (4.7cm) and clear cell carcinoma (73.1%). Preoperative hemoglobin (Hb), neutrophils, platelets (Plt), and corrected calcium (Ca 2+ ) IMDC criteria abnormalities were identified in 19.4, 9.6, 4.3, and 3.2% of patients, respectively. After surgery, 45.4, 79.8, 80.4, and 76.9% of these abnormal cases normalized, respectively. Among patients with normal preoperative Hb, neutrophils, Plt, and Ca 2+ , 9.65, 4.4, 1.0, and 1.6% developed postoperative IMDC criteria abnormalities, respectively. In multivariate analysis, patients with normal Hb, neutrophils, and Ca 2+ , both pre- and postoperatively, had an increase in overall survival (OS) compared to those with abnormal postoperative values. Hazard ratios (HR[95%CI]) for increased OS were 3.6[2.8-4.7], 2.1[1.7-2.7] and 3.5[1.5-43.1], respectively, compared to those with abnormal postoperative values. Furthermore, those with normal Hb, neutrophils, Plt, and Ca 2+ , both pre- and postoperatively, had an increase in cancer-specific survival (CSS) with HR of 3.3, 4.3, 8.0 and 5.7 (p<0.05),indicating a significantly higher CSS probability than patients with abnormal postoperative values. Conclusions: Abnormal IMDC laboratory criteria are frequently found in nmRCC, especially anemia, and most normalize after surgery. Finding abnormal IMDC laboratory criteria post-surgery is associated with decreased CSS and OS. This knowledge may be useful in stratifying patients for intensified monitoring or for future adjuvant therapy clinical trials.

4549 Background: Immune checkpoint inhibitor (ICI)-based regimens, including ICI + ICI and ICI+VEGF-targeted therapy (VEGF-TT), represent the current standard of care for first line (1L) in mRCC. A subset of patients (pts) experiences primary refractory disease, defined as progressive disease (PD) as best response. The aim of this study is to investigate the clinical characteristics and determinants of pts with primary refractory mRCC. Methods: Pts with mRCC treated with 1L ICI-based regimens from the IMDC were included. Pts were categorized as primary refractory (PD as best response evaluated per RECIST 1.1 criteria) and non-primary refractory (stable disease or partial/complete response as best response). Baseline characteristics were compared using a Chi-Square test. Independent factors associated with primary refractory mRCC were identified using a logistic regression. Results: In total, 2001 pts were included, of which 1301 (65%) were treated with dual ICI, and 701 (35%) with ICI+VEGF-TT. Of 2001 pts, 494 (24%) experienced PD at first restaging. Primary refractory and non-primary refractory groups did not differ by age or gender. The primary refractory group had more pts treated with dual ICI (76 vs. 62%), more pts with poor IMDC risk (29 vs. 19%), and more pts with non-clear cell RCC (27 vs. 19%; all p < 0.001). The primary refractory group had shorter diagnosis to treatment interval (mean: 1.6 vs. 2.3 years), lower KPS (median: 80 vs. 90), higher rate of anemia (65% vs. 52%), neutrophilia (11% vs. 9%), and thrombocytosis (30 vs 22%; all p < 0.001). The primary refractory group had more liver (24 vs. 17%; p < 0.001), bone (39 vs 32%; p < 0.001) and lymph nodes metastasis (52 vs. 47%; p = 0.03) at the start of 1L therapy. On multivariable analysis, independent factors associated with primary refractory RCC were low KPS, and the presence of liver metastasis or bone metastasis (Table). Dual ICI regimen was associated with a 1.8-fold increase of primary refractory RCC. Conclusions: In pts with mRCC, low KPS and the presence of liver or bone metastasis are independent risk factors for the development of primary refractory disease. Primary refractory disease is more commonly observed in pts receiving dual ICI compared to those on ICI+VEGF-TT regimen. Multivariable analysis for independent factors associated with primary refractory RCC. OR Lower 95% CI Upper 95% CI p-value Diagnosis to treatment interval < 1 year (yes vs. no) 1.2 0.9 1.6 0.2 Anemia (yes vs. no) 1.37 1.1 1.8 0.03 Low KPS(<80: yes vs. no) 1.9 1.4 2.5 <0.001 Neutrophilia (yes vs. no) 1.3 1 1.8 0.09 Thrombocytosis (yes vs. no) 0.9 0.7 1.3 0.6 Liver metastasis (yes vs. no) 1.7 1.3 2.3 <0.001 Lymph Nodes metastasis (yes vs. no) 1.3 1 1.6 0.07 Bone metastasis (yes vs. no) 1.3 1.03 1.7 0.03 Dual ICI (vs. ICI+VEGF-TT) 1.8 1.37 2.4 <0.001 Non-clear cell RCC (vs. clear cell) 1.3 1 1.8 0.06 Nephrectomy (yes vs. no) 0.9 0.7 1.2 0.6

Immunotherapy-based systemic treatment (ST) is the standard of care for most patients diagnosed with metastatic renal cell carcinoma (mRCC). Cytoreductive nephrectomy (CN) has historically shown benefit for select patients with mRCC, but its role and timing are not well understood in the era of immunotherapy. The primary objective of this study is to assess outcomes in patients who received ST only, CN followed by ST (CN-ST), and ST followed by CN (ST-CN). The Canadian Kidney Cancer information system (CKCis) database was queried to identify patients with de novo mRCC who received immunotherapy-based ST between January 2014 and June 2023. These patients were classified into three categories as described above. Cox proportional hazards models were used to assess the impact of the timing of ST and CN on overall survival (OS) and progression-free survival (PFS), after adjusting for the International Metastatic RCC Database Consortium (IMDC) risk group, age, and comorbidities. Best overall response and complications of ST and CN for these cohorts were collected. A total of 588 patients were included in this study: 331 patients received ST only, 215 patients received CN-ST, and 42 patients received ST-CN. Patient and disease characteristics including age, gender, performance status, IMDC risk category, comorbidity, histology, type of ST, and metastatic sites are reported. OS analysis favored patients who received ST-CN (hazard ratio [HR] 0.30, 95% confidence interval [CI] 0.13–0.68) and CN-ST (HR 0.68, CI 0.47–0.97) over patients who received ST only. PFS analysis showed a similar trend for ST-CN (HR 0.45, CI 0.26–0.77) and CN-ST (HR 0.9, CI 0.68–1.17). This study examined baseline features and outcomes associated with the use and timing of CN and ST using real-world data via a large Canadian real-world cohort. Patients selected to receive CN after ST demonstrated improved outcomes. There were no appreciable differences in perioperative complications across groups. Limitations include the small number of patients in the ST-CN group and residual confounding and selection biases that may influence the outcomes in patients undergoing CN.

367 Background: Ipilimumab and nivolumab (ipi/nivo) improved overall survival (OS) and response rates compared to sunitinib in the pivotal Checkmate 214 trial of intermediate/poor risk mRCC. A subgroup analysis showed no significant difference in OS for ipi/nivo in pts 65 to 75 years old (yo), as well as pts >75 yo. In another subgroup analysis, Karnofsky performance status (KPS) <70 was associated with worse median OS compared with pts with KPS ≥ 70. We evaluated efficacy and toxicity of ipi/nivo in an older and frailer population in a real-world cohort. Methods: Analysis was conducted on a real-world cohort with mRCC (N=378) treated with ipi/nivo as first line treatment from the Canadian Kidney Cancer Information System (CKCis) database from January 2011 to March 2022. Median follow-up was 14.3 m (range 0 to 87.6). A comparison was made between outcomes and toxicity in pts ≥ versus (vs) <70 yo, ≥ vs <75 yo, KPS < vs ≥70, and ≥70 yo with KPS <70 vs <70 yo with KPS >70. Toxicity was graded as per CTCAE v4.03 or any toxicity that resulted in a dose/schedule change. OS, progression free survival (PFS) and time to treatment failure (TTF) were calculated by Kaplan-Meier analysis. Log rank tests were used for comparison between groups. Multivariate analysis was done including IMDC for all outcomes. Results: Median OS was worse in older patients at 30.0 m in pts ≥ 70 yo vs 45.4 m in pts < 70 yo (p=0.060), and 19.0 m in the pts ≥ 75 yo vs 45.5 m in pts < 75 yo (p=0.003) despite similar disease control rates and toxicity. Median PFS was similar in younger and older pts: < vs ≥ 70 yo (p=0.560) and < vs ≥ 75 yo (p=0.296). Median TTF was comparable in < 70 yo and ≥ 70 yo (p=0.106) and < 75 and ≥ 75 yo groups (p-value=0.733). Median OS, PFS and TTF were comparable in pts KPS < 70 vs pts KPS ≥ 70 and in pts ≥70 yo with KPS < 70 vs pts < 70 yo with KPS >70. Adjusted and unadjusted analysis showed no difference in OS and PFS between groups. Conclusions: Use of ipi/nivo in mRCC in older patients was associated with inferior OS, while decreased performance status had equivalent OS. Both groups had equivalent TTF and PD without higher toxicity. We believe that ipi/nivo is a reasonable treatment option for older and low performance status patients. [Table: see text]

393 Background: First-line treatment for mRCC includes I/N and A/P. These two regimens have not been compared in a randomized clinical trial as both CM-214 and KN-426 used single-agent tyrosine kinase inhibitors (TKIs) as the comparator. Meta-analyses suggest improved efficacy outcomes with A/P, but increased likelihood of complete response with I/N. We compared these treatments in the real-world. Methods: Data of consented mRCC patients with clear cell histology from the Canadian Kidney Cancer information system (CKCis) was obtained from January 2013 to December 2021. Treatment outcomes adjusting for age including overall survival (OS), progression free survival (PFS), and response rate (RR) for all patients and intermediate-poor risk patients were completed. Chi-square tests compared the frequency of side effects. Results: Among 547 patients, 360 received I/N and 187 received A/P. Median follow-up was 30.0 (0.1-112.1) months. Median duration of treatment was 6.9 (0.0-68.4) months for I/N and 20.2 (0.1-72.4) months for A/P. Intermediate-poor risk patients were higher in the I/N compared to A/P cohort (91.9% vs. 66.2%; p<0.0001). Cox regression for OS showed no difference between I/N compared to A/P (aHR 1.1, 95% CI [0.77-1.58], p=0.61). PFS showed no statistical difference but a trend for worse with I/N at 12.1 months compared to 22.3 months for A/P (aHR=1.2, 95% CI [0.95-1.62], p=0.11). RR was 40.9% with I/N compared to 56.0% in A/P (aOR 0.52, 95%CI [0.33-0.83], p=0.005). Subgroup analyses for the intermediate-poor risk mRCC patients showed no differences in OS (aHR 0.95, 95%CI [0.65-1.38], p=0.79) and PFS (aHR 1.21, 95%CI [0.90-1.62], p=0.21) between treatment groups but improved RR (aOR 0.58, 95%CI [0.35-0.96], p=0.06) with A/P. 61.7% of I/N patients compared to 79.1% of A/P suffered adverse events that led to a dose or schedule change (p<0.001). Most common toxicities for both groups include diarrhea, fatigue, transaminitis, rash, and anorexia. Conclusions: There was no difference in OS between mRCC patients treated with I/N compared to A/P. A/P demonstrates improved RR and a trend towards longer PFS at the expense of increased frequency of side effects. Despite a median follow-up of 30 months, the data is limited by a high amount of censoring.[Table: see text]

316 Background: Cabozantinib (cabo) is an oral multi-targeted tyrosine kinase inhibitor (TKI) with activity in mRCC. TKI toxicity, an indicator of adequate drug exposure, has been associated with clinical effectiveness for sunitinib, pazopanib, and axitinib. We explored whether cabo dose reductions (a surrogate for toxicity) were associated with improved clinical outcomes in mRCC. Methods: Using the CKCis database, we performed an analysis of patients treated with cabo in the second-line or later between 2011-2021. We divided the cohort into those needing a dose reduction (DR, defined as less than the starting dose at time of treatment discontinuation) and those who did not (no-DR). We compared outcomes by dose reduction status, including objective response rate (ORR), time to treatment failure (TTF), and overall survival (OS). Results: We identified 260 patients who received cabo, of which 103 (41.0%) needed a DR. Across all lines, the ORR was similar between the DR and non-DR groups: 19.6% vs. 18.9% (p = 0.903) respectively. The median TTF was 12.75 months (95% CI 10.38 – 17.64) in the DR group vs. 6.44 months (95% CI 5.49 – 8.67) in the no-DR group. After adjusting for IMDC risk, the hazard ratio (HR) for TTF comparing DR vs. no-DR was 0.69 (95% CI 0.50 - 0.97, p-value = 0.03). The median OS was 29.6 months (95% CI 19.58 – 42.64) in the DR group vs. 15.28 (95% CI 11.04 – 22.64) in the no-DR group. After adjusting for IMDC risk, the HR for OS comparing DR vs. no-DR was 0.65 (95% CI 0.43 - 0.98, p = 0.04). Conclusions: Cabozantinib dose reductions, a surrogate for toxicity and adequate drug exposure, appear to be associated with improved TTF and OS in mRCC. Toxicity driven/individualized dosing strategies for cabo alone and in combination with immunotherapy, warrant further investigation.[Table: see text]

382 Background: The landscape of management of advanced renal cell carcinoma (aRCC) in the first line setting has changed dramatically over the past decade. Axitinib with Pembrolizumab (AP) is one of the combinations which demonstrated improved outcomes in the KEYNOTE 426 study. We report real-world outcomes and safety with this combination. Methods: The Canadian Kidney Cancer information system (CKCis) is a multi-institutional prospective RCC cohort. Patients ≥18 years with aRCC and clear cell histology who received AP as first-line therapy from January 1, 2017 to June 30, 2022 were included. Descriptive and actuarial statistics were reported for the following: progression free survival (PFS), overall survival (OS) and adverse events. Results: The cohort includes 222 patients.165 (74.3%) were male with a median age of 64.5 (37.0-87.7) years. Sixty-three (28.3%) patients were IMDC favourable-risk, 69 (31.0%) intermediate-risk, 45 (20.3%) poor-risk and 45 (20.2%) unknown. Median follow-up was 26.6 (range: 0.1 – 77.2) months. Of 222 patients, 119 discontinued treatment (53.6%) due to disease progression in 45.4% or toxicity in 29.4%. Median duration of treatment was 18.5 (range 0.1 to 72.4) months. PFS probability at 12 and 24 m was 63.8% and 49.9% respectively with a median PFS of 22.6 months (95% CI: 15.9-30.1). Survival probability at 12 and 24 m was 89.1% and 80.2% respectively with a median OS of 51.5 months (95% CI 38.0-NR). By IMDC criteria, intermediate risk median OS was 44.8 m (95% CI 41.5-61.6) and poor risk 33.6 m (18.5-NR). Most patients experienced toxicity requiring dose interruption/delay or discontinuation (n=180; 81.4%) The most common toxicities were diarrhea (73.3%), fatigue (54.4%), hepatotoxicity (50.0%), anorexia (26.1%), mucositis (22.2%), nausea (21.1%), palmar plantar erythrodysesthesia (15.6%), hypertension (13.3%), weight loss (13.3%) and proteinuria (11.7%). Others included pneumonitis (8.9%), thyroid dysfunction (6.7%) and colitis (4.4%). Conclusions: The real-world experience of patients with aRCC receiving AP in Canada is similar to the KEYNOTE-426 study in both outcomes and safety. These data continue to support its position as a standard of care in the first line setting for aRCC. Longer follow up and characterization of these patients is warranted.