Makrakis, Dimitrios

e16510 Background: Early-onset RCC may reflect distinct biology and hereditary predisposition, yet data on stage-specific clinical features and outcomes remain limited. We comprehensively evaluated age-stratified, stage-specific clinical features and survival outcomes using the National Cancer Database. Methods: Adults with histologically confirmed RCC diagnosed between 2004 and 2022 were analyzed. Patients were categorized into three groups by age at diagnosis: early-onset ( < 40 years), middle-aged (40–50 years), and late-onset ( > = 50 years). The sociodemographic and clinical characteristics, comorbidities, histology, and treatment patterns were compared using descriptive statistics. Overall survival (OS) was evaluated using Cox proportional hazards models, adjusting for the aforementioned variables. Stage-specific analyses were conducted, including a metastatic disease cohort. Results: Among 742,114 patients, 4.3% were classified as early-onset, 10.9% as middle-aged, and 84.8% as late-onset. Overall, 12.6% presented with metastatic disease. Compared with late-onset, early-onset patients were more likely to be from racial minority populations (non-White: 16.9 % vs. 20.2 % in late-onset), uninsured, and had fewer comorbidities (Charlson–Deyo score 0: 85.2% vs. 65.2%). Early-onset RCC was characterized by a lower proportion of papillary RCC (8.9% vs. 12.5%) and higher proportions of clear cell (54.9% vs. 50.8%) and chromophobe RCC (9.3% vs. 4.5%) than late-onset RCC and more likely to undergo partial nephrectomy (50.4% vs. 30.2%). They also presented with earlier-stage disease, with lower rates of stage III (7.4% vs. 10.2% vs. 13.4%) and stage IV disease (5.4% vs. 8.9% vs. 13.5%) compared with middle-aged and late-onset groups. Among patients with metastatic disease, early-onset RCC demonstrated higher minority representation (30.8% vs. 14.1%) and a higher prevalence of non-clear cell histology (70.6% vs. 58.1%). In multivariable analysis, compared with early-onset RCC, middle-aged (HR 1.44, 95% CI 1.39–1.50; P < 0.001) and late-onset patients (HR 2.83, 95% CI 2.74–2.93; P < 0.001) experienced significantly worse OS. However, among metastatic disease, this survival advantage was attenuated. Early-onset patients had similar OS to middle-aged patients (HR 0.99, 95% CI 0.93–1.05, p = 0.69) and late-onset patients only had a modestly worse OS than the early-onset group (HR 1.09, 95% CI 1.03–1.15 p = 0.003). Conclusions: Early-onset RCC was associated with more favorable baseline characteristics, earlier stage at diagnosis, and higher utilization of nephron-sparing nephrectomy, corresponding to improved OS. However, this survival advantage diminishes in metastatic disease despite better baseline health, highlighting stage-dependent differences in outcomes and suggesting distinct histologic patterns in advanced early-onset RCC.

4580 Background: ICIs are used for UC in different settings. Most cases have pure urothelial carcinoma (PUC) but about a third have UC mixed with SH. We examined pts with UC treated with ICI and hypothesized that outcomes would not differ between PUC and mixed with SH. Methods: We retrospectively included pts with PUC and any SH component treated with ICI as adjuvant, 1st line [1L] upfront, maintenance avelumab [mAV], ≥2nd line [2+L] therapy; pts were divided by SH type. Pts with multiple SH were included as separate group. We excluded pts with pure non-UC histology and pts treated with neoadjuvant ICI. We calculated overall response rate (ORR), median overall, progression-free and disease-free survival [mOS, mPFS, mDFS] using KM method from ICI start. Analysis was stratified by therapy line; multivariable models were adjusted by Khaki factors for 1L/upfront, mAV and Bellmunt factors for 2+L; reference group was PUC. We used descriptive statistics for small subsets. Results: We included 1525 pts from 26 sites; n=752 1L, n=609 2+L; 76% men, 80% White, 69% smoking history, 80% lower urinary tract primary, 28% SH. Median f/u time from 1L ICI start 24 months (mo): mPFS was 3 (95%CI 2.8-3.2) mo for PUC (n=340), 3 (95%CI 2-4) mo for squamous (n=60) (HR=1, [95%CI 0.7-1.4]), 2 (95%CI 1.4-3.2) mo for micropapillary (n=36) (HR=1.3 [95% 0.9-2]) and 4 (3.5-4.5) mo for ≥2 SH (n=20) (HR=0.9 [95%CI 0.6-1.5]). Median f/u time from 2+L ICI start 26 mo: mPFS was 3 (95%CI 2.4-3.2) mo for PUC (n=264), 4 (95%CI 2-5) mo for squamous (n=33) (HR=0.8, [95%CI 0.6-1.2]), 3 (95%CI 1.6-3.7) mo for micropapillary (n=17) (HR=0.9 [95% 0.6-1.7]) and 3 (2.5-3.1) mo for ≥2 SH (n=10) (HR=1.2 [95%CI 0.6-2.2]); Table shows ORR/OS data. Data on adjuvant and mAV settings will also be presented. Conclusions: We found no significant survival difference between PUC and SH. ORR was numerically higher with sarcomatoid SH and ≥2 SH in the 1L upfront setting. Limitations: retrospective design, small sample size in a few subsets, lack of randomization and central scan/path (% SH) review, selection bias, unmeasured confounders. [Table: see text]

654 Background: MSI and TMB correlate with ICI efficacy. We assessed the association between TMB and MSI with outcomes in pts with aUC treated with anti-PD1/L1 in a ‘real-world’ cohort. We hypothesize that pts with high TMB and MSI-high (H) have better outcomes with ICI. Methods: In this retrospective study we included pts from 13 sites treated with ICI for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using KM method from ICI start. TMB and MSI were assessed by NGS. TMB was analyzed as dichotomous (≥10 vs <10 mut/Mb) and continuous variable. The analysis was stratified by therapy line (1L/upfront, 2+L). Multivariable models were adjusted by Khaki factors for 1L/upfront and Bellmunt factors for 2+L. We separately analyzed pts on maintenance avelumab (mAV). MSI is reported with descriptive statistics only. Results: 342 pts were treated with ICI 1L/upfront or 2+L (69% pure UC, median age at ICI start 69, 77% men, 90% White, 16% upper tract primary, 12% liver metastases [mets], 78% ECOG PS 0-1). Median f/u from ICI start was 34 months (mo). ORR was 36% (95%CI 26-46%) in pts with TMB≥10 vs 30% (95%CI 23-36%) with TMB<10 (OR=1.4 [95%CI 0.8-2.5] p=0.3). ORR was 75% (6/8) in pts with MSI-H and 30% (60/200) with MSI stable (MSI-S). mPFS was similar between TMB≥10 and <10 groups (6 vs 4 mo; HR=0.88 [95%CI 0.61-1.26] p=0.48) and between MSI-H and MSI-S (5 mo). mOS was numerically longer (not significant) in pts with TMB≥10 vs TMB<10: 25 vs 21 mo; (HR=0.7 [95%CI 0.50-1.09] p=0.12) and with MSI-H and MSI-S (NR and 20 mo). A significant association was found between TMB (continuous variable) and OS (HR=0.97 [95%CI 0.95-0.99] p=0.01). TMB analyses by therapy line are shown in Table. In the 1L/upfront setting (N=144), ORR 71% (5/7) vs 33% (45/135), mPFS 5 and 4 mo, mOS NR and 22 mo for MSI-H and MSI-S, respectively. Pts on mAV (n=77) were 77% men, 92% White, 16% upper primary, 13% liver mets, 84% ECOG PS 0-1 with median f/u 15 mo from avelumab start; mOS was NR for MSI-H and 24 mo for MSI-S; mPFS was 4 mo for both groups. Of 3 pts on mAV with MSI-H: 1 CR, 2 SD; of 58 pts with MSI-S: 4CR, 4PR, 24 SD, 21 PD, 5 unknown. Conclusions: MSI-H had numerically higher ORR and higher TMB was associated with longer OS with ICI, but further validation is needed. Limitations: retrospective design, small sample size for MSI-H cases, lack of randomization and central scan review, selection/confounding. [Table: see text]