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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.

e16159 Background: Pivotal trials established atezolizumab-bevacizumab and durvalumab-tremelimumab as first-line therapies for unresectable hepatocellular carcinoma (HCC). Atezolizumab plus bevacizumab demonstrated superior survival outcomes compared to sorafenib for unresectable HCC in the IMbrave150 trial in 2020, while durvalumab plus tremelimumab showed superior survival in the HIMALAYA trial in 2022. However, data on head-to-head comparison of these two combinations as first-line systemic therapy for the patient with decompensated HCC are limited. This study aims to compare survival outcomes between these two treatment regimens in decompensated HCC patients to address a critical gap in the current literature, as decompensated patients have largely been excluded from clinical trials. Methods: This retrospective study utilized electronic health records from 146 U.S. healthcare organizations within the TriNetX Network. Adults aged ≥21 years diagnosed with decompensated HCC receiving atezolizumab/bevacizumab and durvalumab/tremelimumab from 10/21/2022 to 8/20/2024 were included. The comparison group received atezolizumab/bevacizumab, and the control group received durvalumab/tremelimumab. The primary outcome was all-cause mortality. A 1:1 propensity score matching was conducted to balance baseline characteristics (age, gender, race/ethnicity, lab results including liver function tests, platelet counts, INR, gamma glutamyl transferase, alpha-fetoprotein, and underlying liver diseases). Kaplan–Meier survival analysis and Cox regression was used to estimate the mortality risk. Subgroup analysis was stratified by HCC etiology. Results: A total of 302 and 664 patients received durvalumab/tremelimumab, atezolizumab/bevacizumab, respectively. After propensity matching, 253 patients per group were included. Median OS was 283 days with durvalumab/tremelimumab and 391 days with atezolizumab/bevacizumab. The two treatment regimens showed no significant difference in survival (hazard ratio [HR]: 0.875, 95% confidence intervals [CI] 0.696–1.101, p=0.254). Subgroup analyses demonstrated no significant differences in survival between the two groups of patients in MASLD (HR: 0.698, 95% CI: 0.468–1.040), alcohol associated liver disease (HR: 0.821, 95% CI: 0.603–1.118), and chronic viral hepatitis (HR: 0.852, 95% CI: 0.596–1.219). Conclusions: There was no statistically significant difference in survival outcomes between atezolizumab plus bevacizumab and durvalumab plus tremelimumab in patients with decompensated advanced HCC. These results support current real-world practice in which both regimens may be considered viable first-line treatment options in this high-risk population with liver decompensation.

625 Background: I-SPY 2 is a multicenter phase II adaptive platform trial evaluating novel agents for stage II-III high-risk breast cancer using response-predictive subtypes (RPS) and a sequential neoadjuvant treatment design of up to three blocks (A/B/C). Investigational regimens are given in Block A, followed by response-guided escalation to standard-of-care (SOC) therapy (tx) in subsequent blocks or early surgery for responders. Topoisomerase I (TOPO1) inhibition plus PARP inhibition may enhance DNA damage and tumor response. DAN-222 is a tumor-targeted polymeric camptothecin conjugate designed to improve the therapeutic index of TOPO1 inhibition. Based on favorable phase 1 safety and preliminary activity in metastatic breast cancer, DAN-222 plus niraparib was evaluated as Block A tx in HER2− disease. Notably, the neoadjuvant regimen used a higher dose of niraparib (200 mg daily) than the prior phase 1 metastatic study. Methods: Patients (pts) with HER2− breast cancer were randomized to DAN-222 plus niraparib for up to 12 weeks in Block A. Response was assessed by serial MRI and biopsy. Inadequate responders escalated early to SOC tx in Blocks B/C. Primary endpoint was pathologic complete response (pCR). Secondary endpoints included residual cancer burden, safety, early discontinuation, and treatment-strategy performance versus subtype-specific SOC tx controls. Given established PARPi sensitivity in BRCA mut disease, the key objective was to assess clinically meaningful activity of DAN-222 plus niraparib in BRCA wt pts. Accordingly, a prespecified Bayesian interim futility analysis focused on BRCA wt and tested the probability of the true pCR rate after Block A alone exceeded 15% after 50 pts. Results: Fifty pts enrolled from Sep to Dec 2024. In BRCA wt (n=47), estimated Block A pCR was 3%, with posterior probability of 0.02 that that true pCR exceeded 15%, meeting futility criteria and prompting arm closure. Across all blocks, pCR rate was 57% (8/14) for HR-HER2−; 11% (4/36) for HR+ HER2−, largely after SOC tx. 2/3 BRCA mut pts achieved pCR. Treatment strategies initiating with DAN-222 plus niraparib underperformed subtype-specific controls. 68% discontinued Block A early, mainly due to toxicity. Grade ≥3 cytopenias were common: neutropenia (n=25; 50%), anemia (24%), and thrombocytopenia (18%). Cystitis occurred in 36% (1 grade ≥3). Conclusions: Neoadjuvant DAN-222 plus niraparib showed insufficient activity and no treatment-strategy benefit in BRCA wt HER2− breast cancer, underscoring challenges for TOPO1–PARP inhibitor combinations. Although not supported for further development in this setting, these results highlight the strength of I-SPY 2 in rapidly enrolling patients and quickly distinguishing ineffective from promising therapeutic strategies to accelerate progress toward improved outcomes for patients with curable breast cancer. Clinical trial information: NCT01042379 .

5004 Background: Patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated continuously with testosterone suppression (TS) plus an androgen receptor pathway inhibitor (ARPI) can experience cumulative toxicity. We conducted this single-arm phase 2 trial (NCT05241860) to test the hypothesis that pts who achieve favorable response to TS + ARPI can have prolonged treatment-free interval with testosterone recovery after treatment interruption (TI). Here we report on the primary endpoint. Methods: Eligible pts had mHSPC by conventional imaging with prostate-specific antigen (PSA) ≥ 5 ng/ml and testosterone ≥ 150 ng/dl prior to starting TS+ARPI, with PSA < 0.2 ng/ml and testosterone < 50 ng/dl at the time of enrollment after having received TS for 540-750 days and ARPI for ≥ 360 days. Prior local therapy, radiation to metastases and docetaxel were permitted. After enrollment, pts discontinued TS and ARPI and were followed with PSA and testosterone levels every 3 months (mo), CT/MRI and bone scan at least every 6 mo, and FACT-P questionnaire for patient-reported outcomes (PROs) every 6 mo. Treatment was resumed for PSA ≥ 5 ng/ml, radiographic change (progressive disease [PD] per RECIST 1.1 on CT/MRI or unconfirmed PD per PCWG3 on bone scan), or prostate cancer-related symptoms. The primary endpoint was proportion of men remaining treatment-free 18 mo after TI with eugonadal testosterone ( > 150 ng/dl). Target enrollment was 75 pts to differentiate 18-mo treatment-free rates of 0.30 (H 0 ) and 0.45 (H a ). Results: Of 79 pts enrolled between 07/2022 and 03/2024, 78 were eligible and underwent TI. Among these 78, median PSA prior to starting TS+ARPI was 19 (range 5-6759), 27 (35%) had high volume disease, 31 (40%) never received local therapy, and 55 (71%) did not receive radiation to metastases. By 18 mo after TI, 67% (52/78) recovered testosterone and 58% (45/78) remained treatment-free; 41% (32/78) remained treatment-free with testosterone recovery (80% CI 33.5-48.9%, one-sided p 0.0249). At median follow-up of 21.2 mo, 35% (27/78) resumed initial TS+ARPI after meeting re-initiation criteria (of whom 1 required treatment switch for PD 9 mo later); 5% (4/78) resumed prior to meeting criteria; 9% (7/78) pursued alternative therapy instead of resuming TS+ARPI per protocol; 5% (4/78) withdrew; 1 died of myocardial infarction prior to resuming treatment. 4 pts died, 1 of prostate cancer. Conclusions: The primary objective was achieved with 41% of favorable responders to TS+ARPI remaining treatment-free with testosterone recovery at 18 mo after TI. Analyses of biomarkers and PROs are in progress, and pts will be followed for long-term outcomes. Support: U10CA180821, U10CA180882, UG1CA189823, https://acknowledgments.alliancefound.org, Veracyte Inc. Clinical trial information: NCT05241860 .

11064 Background: Local and state paid sick leave (PSL) mandates have been associated with increased use of preventive services, including cancer screening, and reduced emergency care utilization. Little research has examined PSL policies and cancer after diagnosis. This study evaluates associations of PSL policies and timely treatment initiation among women with early-stage breast cancer. Methods: We identified patients aged 18-64 years newly diagnosed with stages 0-II breast cancer from the National Cancer Database in 2004-2023 and linked then to area-level policy implementation, measured as the month and year the state, county, or city required PSL. Primary outcomes were receipt of definitive surgery or neoadjuvant therapy within 30, 60, and 90 days of diagnosis. We compared changes in treatment initiation between patients residing in areas with and without PSL policies during and after the month and year of diagnosis. We used a staggered difference-in-differences design to account for differential timing of implementation, adjusting for patient demographics, clinical, and area-level characteristics. Random errors were clustered at the state level. Supplemental analyses stratified by county-level unemployment rates and individual insurance coverage. Results: The study included 1,891,411 patients, of whom 249,313 (13.2%) resided in an area with PSL policies at diagnosis. Patients in areas with PSL policies were more likely to have Medicaid, reside in higher-income and metropolitan areas. PSL policy implementation was significantly associated with a 3.4 percentage point (PPT) increase in the probability of treatment ≤30 days (95% CI: 1.1-5.7), 3.0 PPT increase ≤60 days (95% CI: 1.6-4.3), 1.3 PPT increase ≤90 days (95% CI: 0.5-2.1) (Table). Improvements in timely treatment were concentrated in low-unemployment areas; no significant improvements were observed in high-unemployment areas. The magnitude of associations between PSL policies and treatment initiation was stronger among patients without private insurance than with private insurance. Conclusions: Local and state PSL mandates were associated with earlier treatment initiation among working-age patients with early-stage breast cancer, especially in areas with low female unemployment rate. Findings suggest that PSL policies play an important role in timely cancer treatment for employed women who may not have PSL through their jobs. Association of paid sick leave policies and breast cancer treatment initiation. Time from diagnosis to surgery/neoadjuvant therapy (days) DID PPT Lower 95% CI Upper 95% CI P-value Overall ≤30 3.4 1.1 5.7 0.004 ≤60 3.0 1.6 4.3 0.000 ≤90 1.3 0.5 2.1 0.001 Low female unemployment ≤30 2.2 -0.7 5.0 0.136 ≤60 3.8 1.8 5.8 0.000 ≤90 1.2 0.3 2.2 0.012 High female unemployment ≤30 1.8 -0.6 4.2 0.145 ≤60 -1.2 -4.5 2.0 0.459 ≤90 -1.4 -3.7 0.9 0.232

1110 Background: CDK4/6 inhibitors with endocrine therapy are widely used for HR+/HER2– metastatic breast cancer (BC). While studies have shown similar progression-free outcomes across agents, overall survival (OS) data are limited. Since OS is a definitive endpoint and BMI may influence outcomes, this study examines BMI-dependent OS differences among CDK4/6 inhibitors. Methods: A retrospective cohort study was conducted using the Mayo Clinic Platform full AMC1 dataset. Postmenopausal women with BC receiving palbociclib/ribociclib/abemaciclib plus aromatase inhibitor (AI) were included. Patients with prior use of fulvestrant, anthracyclines, radiation therapy, GnRH agonists, or history of MACE, heart failure, myocardial infarction, or stroke before BC diagnosis were excluded. Patients were stratified by BMI and CDK4/6 inhibitor. The primary outcome was 5-year OS. Results: Among 1,989 patients (palbociclib: 868; ribociclib: 465; abemaciclib: 656), palbociclib was associated with significantly worse OS compared to ribociclib in BMI <25 (HR 2.91; 95% CI: 1.76–4.79; P < 0.01) and BMI ≥30 (HR 1.91; 95% CI: 1.21–3.01; P < 0.01). Compared to abemaciclib, palbociclib showed worse OS: BMI <25 (HR 1.73; P < 0.01), BMI 25–30 (HR 1.56; P < 0.01), and BMI ≥30 (HR 1.82; P < 0.01). No significant OS differences were observed between ribociclib and abemaciclib. Palbociclib patients were older, particularly in BMI <25 (Cohen's D = 0.39 vs. ribociclib; 0.27 vs. abemaciclib) and BMI ≥30 (0.28 vs. ribociclib; 0.23 vs. abemaciclib). In the BMI 25–30 group, palbociclib group was also older than ribociclib group (Cohen's D = 0.26). Conclusions: In postmenopausal BC patients on AIs and CDK4/6 inhibitors, palbociclib was associated with worse OS in BMI < 25 and BMI ≥ 30 groups, while ribociclib and abemaciclib showed similar outcomes across BMI groups. Palbociclib patients were older than those on other drugs, which may partially confound results; however, in the BMI 25–30 group, despite similar age differences, no survival difference was observed between palbociclib and ribociclib, suggesting age alone may have limited impact. These findings indicate a potential interaction between BMI and drug choice, and highlight the need for prospective studies to confirm and adjust for these variables. Limitations include the observational design and inability to perform multivariable regression analyses to adjust for confounders. Overall survival comparisons by CDK4/6 inhibitor and BMI subgroup. Comparison BMI Group Hazard Ratio (95% CI) P-value Palbociclib vs Ribociclib <25 2.91 (1.76 – 4.79) < 0.01 25 – 30 1.34 (0.87 – 2.071) 0.17 ≥30 1.91 (1.21 – 3.01) < 0.01 Palbociclib vs Abemaciclib <25 1.73 (1.29 – 2.32) < 0.01 25 – 30 1.56 (1.09 – 2.23) < 0.01 ≥30 1.82 (1.15 – 2.88) < 0.01 Ribociclib vs Abemaciclib <25 1.27 (0.81 – 1.99) 0.29 25 – 30 0.87 (0.54 – 1.43) 0.59 ≥30 1.05 (0.63 – 1.75) 0.85

Abstract Rationale Lymphangioleiomyomatosis (LAM) is a rare, progressive, cystic lung disease affecting women. Sirolimus has been shown to stabilize lung function in women with LAM, but real-world data on long-term safety and efficacy are limited. Methods The NIH Multicenter Safety and Durability of Sirolimus for LAM (MIDAS, NCT02432560) observational registry was launched in 2015. All adult (≥18 years) women with LAM (treated or untreated) were eligible to enroll at any of the 20 U.S. sites and followed longitudinally with serial assessments of lung function, health-related quality of life, and treatment related adverse event (TRAEs). Baseline cohort characteristics and TRAEs are summarized using descriptive analyses. Marginal structural models (MSMs) with inverse probability of treatment weighting estimated the causal effect of sirolimus on annualized forced expiratory volume in one-second (FEV1) decline, adjusting for age at LAM diagnosis, prior treatment with sirolimus, menopausal status, race, presence of angiomyolipomas, supplemental oxygen use; time-varying covariates included diffusing capacity for carbon monoxide (DLCO) and serum vascular endothelial growth factor-D (VEGF-D) levels. Results Longitudinal data was available in 350 LAM patients, most of whom (246, 70.3%) had sporadic LAM. The median age at the baseline pulmonary function test (PFT) measurement was 46 years (range: 19 - 74) and the median (IQR) number of serial PFTs obtained per patient was 3 (1 - 5). The average follow-up duration per patient was 2.8 years. Over half of the patients (196, 56%) were treated with sirolimus during the MIDAS observation period for a median (IQR) treatment duration of 4.9 (2.4 - 7.5) years. MSM analysis demonstrated that sirolimus treatment was durably effective and reduced FEV₁ decline by 74.36 mL/year (95% CI: 15.87 - 132.85) compared with no treatment (-85.31 mL/year for the untreated group vs. -10.95 mL/year for the treated group, p = 0.01). Sirolimus was generally well tolerated; treatment interruption ≥3 months was observed in 38 (19.4%) of the 196 sirolimus treated patients. Logistic regression analysis showed that higher levels of FEV1 (odds ratio: OR = 3.12 [1.45 - 7.11], p = 0.005), VEGF-D (OR = 1.0007 [1.0004 - 1.001], p &lt; 0.001), and DLCO (OR = 1.023 [1.0053 - 1.0413, p = 0.01]), were associated with treatment interruption. Conclusions In the MIDAS cohort, sirolimus treatment resulted in durable stabilization of lung function with a favorable safety profile over a 5-year period. These real-world data support sirolimus as a chronic suppressive therapy for LAM, demonstrating durable efficacy in slowing lung disease progression and tolerability with long-term use. This abstract is funded by: National Institutes of Health

Abstract Rationale Mismatch of airway to lung size has been implicated in chronic obstructive pulmonary disease (COPD) pathophysiology, whether arising from disproportioned growth or from acquired pathologies over the life course. Lower airway-to-lung ratio (ALR), assessed reproducibly via computed tomography (CT) as the mean airway lumen diameters (trachea-to-subsegments) divided by the cubed root of lung volume, is associated with COPD risk and mortality (all-cause, respiratory, cardiovascular, lung cancer). We sought to characterize the airway biology associated with lower ALR by profiling bronchial gene expression across current and former smokers. Methods We leveraged clinical, radiologic, and bronchial epithelial RNA sequencing data from the SPIROMICS (SubPopulations and Intermediate Outcomes Measures in COPD Study) Phase 1 Bronchoscopy Sub-study (n = 161). To analyze transcriptional differential expression (DE) between participants based on CT-assessed ALR, we utilized DESeq2 and then identified impacted pathways by Ingenuity Pathway Analysis (IPA). Generating cell-type transcriptional signatures from lung and blood single cell sequencing atlases, we also assessed association of ALR with differences in airway cellular composition. Results Across all ever-smokers, after adjustment for age, sex, height, COPD status, smoking status, and pack-years, n = 1,324 genes from airway epithelial samples exhibited DE at a false discovery rate (FDR) &lt;0.2. Per IPA, enriched pathways associated with lower ALR included neutrophilic degranulation and macrophage activity. In cell type analysis, lower ALR was associated with higher signatures of macrophages, neutrophils, dendritic cells, and B cells, and lower ciliated and club cell signatures. When we repeated DE analysis using the same covariate adjustments plus an interaction term for ALR and smoking, n = 713 DE genes were identified at FDR &lt;0.2; the association of DE with lower ALR was overwhelmingly in current rather than former smokers (3699 vs. 2 genes). By pathway and cell type analyses, the association between lower ALR and heightened inflammation (greater macrophage and neutrophil signaling) and epithelial dysregulation (downregulated ciliated and club cell function) was primarily restricted to current smokers. Conclusions In adult ever-smokers, lower ALR is associated with transcriptomic evidence of heightened neutrophil- and macrophage-driven airway inflammation and reduced ciliated and club cell expression, associations that were most evident among current smokers. Whether these cross-sectional patterns, which suggest impaired mucociliary defense and a diminished capacity to clear inhaled particulates, are the result of pre-existing reduced ALR, its cause, or both, will require further investigation. This abstract is funded by: SPIROMICS was supported by contracts from the NIH/NHLBI (HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C, HHSN268200900020C, 75N92024D00012), grants from the NIH/NHLBI (U01HL137880, U24HL141762, R01HL182622, R01HL144718, and R01HL093081), and supplemented by contributions made through the Foundation for the NIH and the COPD Foundation from Amgen; AstraZeneca/MedImmune; Bayer; Bellerophon Therapeutics; Boehringer-Ingelheim Pharmaceuticals, Inc.; Bristol Myers Squibb; Chiesi Farmaceutici S.p.A.; Forest Research Institute, Inc.; Genentech; GlaxoSmithKline; Grifols Therapeutics, Inc.; Ikaria, Inc.; MGC Diagnostics; Novartis Pharmaceuticals Corporation; Nycomed GmbH; Polarean; ProterixBio; Regeneron Pharmaceuticals, Inc.; Sanofi; Sunovion; Takeda Pharmaceutical Company; Theravance Biopharma; Verona; and Mylan/Viatris.