Khanna, Abhinav

TPS892 Background: Enfortumab Vedotin (EV) plus pembrolizumab (Pembro) is now first-line therapy for advanced urothelial carcinoma (UC), yielding ~30% complete response (CR) rates; nevertheless, most patients (pts) progress within 1 year and median overall survival (OS) remains < 3 years. In muscle invasive bladder cancer, local consolidation after systemic therapy improves outcomes, suggesting that residual, treatment-refractory intravesical disease drives relapse. We hypothesize that cytoreductive cystectomy/nephroureterectomy (CC/U)—with metastasis-directed therapy (MDT) as needed—can consolidate responses to EV/Pembro and extend benefit in regionally advanced or metastatic UC. CAST-AI prospectively evaluates this multimodal strategy and integrates correlative studies of exosomal Nectin-4 and circulating tumor DNA (ctDNA) from blood and urine as predictive/MRD biomarkers. Methods: CAST-AI is a phase II, decentralized single-arm trial enrolling pts with histologically confirmed UC of the bladder or upper urinary tract with ≥N1 and/or M1 disease and ECOG PS 0–2 who are potential surgical candidates (planned n = 75). Treatment: EV 1.25 mg/kg IV D1 & D8 + Pembro 200 mg IV D1 q21d, ≥4 cycles; MDT permitted any time pre-surgery. Response assessments occur q9 weeks (±4) to 18 months, then q12 weeks (±4). Surgical eligibility requires: (A) fitness for surgery; (B) complete or partial response (CR/PR) or, for select low-burden/unmeasurable disease, urologist-adjudicated candidacy; (C) all distant sites addressed; and (D) procedure in pt’s best interest. Post-CC/U maintenance EV/Pembro is encouraged per clinical discretion and guided by definitive surgical pathology results, which provide true pathologic staging often unattainable through imaging after systemic therapy. Primary endpoint: 12-month progression-free survival (PFS). Secondary endpoints: Objective response rate (ORR), CR rate, down-staging at CC/U, PFS, OS, and safety (using CTCAE). Exploratory endpoints: longitudinal exosomal Nectin-4 and ctDNA dynamics as MRD and early relapse indicators; tissue–blood–urine Nectin-4 concordance; pt-reported tolerability (using CIPN20). Key exclusions: > 20% variant histology or disallowed subtypes (e.g., micropapillary, plasmacytoid, sarcomatoid, neuroendocrine); prior chemotherapy for UC; contraindications to surgery/EV/ICI; or active uncontrolled comorbidities/infections. Status: Enrollment is open and ongoing, with 25 of 75 pts enrolled as of September 2025. The trial uses a decentralized model, allowing pts to receive EV/Pembro at their local facility, with central coordination, biospecimen shipping, and surgical evaluation at Mayo Clinic or affiliated sites. ClinicalTrials.gov: NCT06764095. Clinical trial information: NCT06764095 .

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.

454 Background: Immune checkpoint inhibitor (ICI)-based combination therapy has become the standard of care for advanced renal cell carcinoma (RCC). A pathologic complete response (pCR) in the primary tumor may be observed in up to one-third of patients; however, data on the outcomes of these patients remain limited. This study aimed to evaluate the clinical outcomes of patients who achieved a pCR following ICI therapy. Methods: Patients with advanced RCC who underwent nephrectomy following ICI therapy were evaluated across five high-volume U.S. academic centers between 2015 and 2023. Clinical characteristics and outcomes were compared between those with and without a pCR in the primary tumor (ypT0N0/Nx). Multivariable logistic regression models were used to identify factors associated with pCR. Recurrence-free (RFS) and overall survival (OS) rates were estimated using the Kaplan-Meier (KM) method. Results: A total of 182 patients were included (Table 1). Among all patients, downstaging to ≤ypT1N0/Nx was observed in 45 patients (25%), of whom 21 (11%) achieved a pCR. In multivariable analysis, the presence of clinical thrombus was marginally associated with a lower likelihood of achieving pCR (odds ratio [95% CI]: 0.39 [0.15–1.00], p=0.06). During a median follow-up of 25 months, 70 patients (38%) experienced recurrence, including 4 (2%) in the pCR group. Median time to recurrence was 7.5 months. KM analysis demonstrated a higher estimated 5-year RFS in the pCR group compared to those with residual disease; however, the difference was not statistically significant (68% vs. 54%, p=0.2). In addition, OS rates were comparable between the two groups. Conclusions: In our cohort, 11% of patients who underwent nephrectomy following ICI therapy for advanced RCC showed pCR, which correlated with improved oncologic outcomes. Despite the lower recurrence rates observed in the pCR group, sustained long-term surveillance remains necessary due to the continued, albeit reduced, risk of disease recurrence. Clinical characteristics of patients who underwent post-ICI nephrectomy, stratified by their pathologic complete response (pCR). Variable pCR (n=21) No pCR (n=161) p-value Median (IQR) age, year 61 (56 – 70) 64 (56 – 71) 0.46 Gender (male), n (%) 15 (71) 118 (73) 0.8 Tumor advancement, n (%) Locally advanced Metastatic 2 (10)19 (90) 36 (22)125 (78) 0.26 Risk group (for metastatic), n (%) Favorable Intermediate Poor 3 (25)6 (50)3 (25) 38 (34)59 (54)13 (12) 0.42 ICI regimen, n (%) ICI monotherapy ICI+ICI ICI+TKI 4 (19)9 (43)8 (38) 46 (28)64 (40)51 (32) 0.64 Immunotherapy cycles (>4), n (%) 8 (50) 49 (37) 0.42 Median (IQR) clinical tumor size, cm 9.3 (6.7 – 11.9) 8.4 (6.6 – 12) 0.68 Clinical nodal involvement, n (%) 8 (38) 53 (33) 0.63 Clinical thrombus, n (%) 12 (57) 60 (37) 0.1 ICI: immune checkpoint inhibitor; TKI: tyrosine kinase inhibitor.