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TPS402 Background: Kidney cancer presenting with synchronous primary tumor and metastases has demonstrated shorter survival outcome, as compared to the patients relapsing later with metastases after nephrectomy. CARMENA trial demonstrated no change in overall survival with addition of nephrectomy to sunitinib therapy. Immune checkpoint based combination therapy has now become the standard of care in frontline setting for RCC. The role of cytoreductive nephrectomy (CN) or primary resection has not been evaluated in the setting of immune checkpoint based systemic therapy. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in advanced RCC within the context of immune checkpoint based combination regimens. The underlying mechanism is that the broader antigen spread and higher neoantigen load enabled by the primary tumor would enhance the efficacy of the immune therapy. CN after initial systemic therapy will potentially enable eradication of the immune resistant clones within the primary. Methods: Eligible patients with primary tumor and metastases are treated with one of the FDA approved ICI based combinations: ipililumab and nivolumab, axitinib and pembrolizumab, or axitinib and avelumab. Cabozantinib + nivolumab and lenvatinib + pembrolizumab combinations are being added into the next amendment. Urology evaluation and response assessment is required. Randomization occurs between 10-14 weeks of therapy; 1:1 to receive CN followed by systemic therapy or to continue on systemic therapy. The primary endpoint is overall survival. We estimate the median survival from time of randomization for the non-surgical arm will be 25 months. The study hypothesis is that CN will result in improvement in OS outcomes in advanced synchronous RCC post-initial systemic immune checkpoint based combination therapy. With a sample size of 302 eligible, randomized participants (151 per arm) and a one-sided alpha = 0.025, the study has 85% power to detect a 47% improvement in median survival (HR = 0.68; 1/0.68 = 1.47) Clinical trial information: NCT04510597.

536 Background: This trial evaluated COXEN, a gene expression model, as a predictive biomarker in muscle-invasive bladder cancer (BC) patients randomized to Gemcitabine-Cisplatin (GC) or dose-dense Methotrexate-Vinblastine-Adriamycin/doxorubicin-Cisplatin (ddMVAC). Primary results correlating COXEN with pathologic response at surgery have been reported. This secondary analysis includes progression-free (PFS) and overall survival (OS). Methods: Eligibility included Stage cT2-T4a N0 M0, urothelial BC (mixed histology allowed), ≥ 5 mm of viable tumor, cisplatin eligible, with plan for cystectomy. 237 patients were randomized between ddMVAC, given every 14 days for 4 cycles, and GC, given every 21 days for 4 cycles. Cox regression was used to evaluate COXEN score or treatment arm association with PFS and OS, adjusting for stratification factors (stage and PS). Results: 167 patients were included in the primary COXEN analysis all having either at least 3 cycles of chemo and surgery within 100 days of last chemo or having progressed while receiving chemo. The COXEN scores were not significantly prognostic for OS or PFS in their respective arms; the COXEN GC score was a significant predictor for OS in pooled arms. OS and PFS data are shown for both scores in the table. In the intent to treat analysis (n=227), there was no significant difference in OS or PFS for ddMVAC versus GC (for OS, HR =0.87, 95% CI 0.54-1.40), p = 0.57); for PFS (HR= 0.76 95% CI 0.58-1.01, p = 0.055). Association of path response with OS will be presented. Conclusions: The COXEN GC score may be prognostic of survival in those receiving platinum-based neoadjuvant treatment. The randomized, prospective design provides estimates of OS and PFS for GC and ddMVAC that appear comparable, but this phase II trial is underpowered for definitive comparisons. The prospective data and correlative samples from S1314 will allow for further assessment of COXEN and other RNA and DNA based predictive and prognostic biomarkers. Clinical trial information: NCT02177695. [Table: see text]

TPS591 Background: Neoadjuvant cisplatin-based combination chemotherapy improves survival in cisplatin-eligible patients (pts) with muscle invasive bladder cancer (MIBC). An unmet need exists in cisplatin-ineligible pts with MIUC who are offered upfront surgery. Neoadjuvant immune checkpoint inhibitors (ICIs) have been demonstrated to be safe and active although the benefit may not extend to the majority of pts. The combination of GCa and an ICI has been demonstrated to be safe and active in cisplatin-ineligible metastatic urothelial carcinoma. In the neoadjuvant setting, combination GCa and an ICI may improve outcomes across a broad group of MIUC by delivering early systemic therapy to pts with cisplatin-ineligible MIUC. We hypothesized that the combination of GCa and avelumab, a PD-L1 inhibitor, may improve pathologic complete remissions (pCR) and long-term outcomes compared to upfront surgery for MIUC (S2011, NCT04871529). Methods: This multicenter, randomized (1:1), open-label phase II trial is comparing the combination of GCa and avelumab (Arm A) as neoadjuvant therapy vs. upfront surgery (Arm B) for pts with cisplatin-ineligible MIUC including MIBC and high-risk upper tract urothelial carcinoma (UTUC). Adjuvant therapy following radical cystectomy, nephroureterectomy or ureterectomy is deferred to investigator discretion in both arms. Eligible pts include those with MIBC or high-grade UTUC with a predominant urothelial component who are cisplatin-ineligible (≥1 of: Zubrod performance status [PS] = 2, creatinine clearance [CrCl] 30 to < 60 ml/min, neuropathy > grade 1, hearing loss > grade 1, congestive heart failure > grade 2). The primary objective is pCR. The stratification factors include clinical stage (cT2N0M0 vs cT3-4aN0M0), Zubrod-PS (0-1 vs 2), CrCl (30 to < 60 vs ≥ 60 ml/min). With 178 evaluable pts, the trial will have a power of 90% (using a 1-sided alpha 0.05) to detect pCR rate improvement from 15% to 35%. The secondary objectives are toxicities, resectability rates, surgical complications, event-free survival (EFS) and overall survival (OS). Correlative studies include tumor molecular profiling, blood immune studies, circulating tumor-DNA profiling and radiomics. Arm A receives gemcitabine 1000 mg/m2 IV days 1, 8 every 3 weeks x 4 cycles, carboplatin AUC 4.5 (escalated to AUC 5 from cycle 2 if tolerated in cycle 1) IV day 1 every 3 weeks x 4 cycles and avelumab 800 mg IV day 1 every 2 weeks x 6 cycles. Surgery is performed 4-8 weeks after the last neoadjuvant administration. The trial is funded by NIH/NCI grants U10CA180888, U10CA180819, U10CA180821, U10CA180820, U10CA180868, and in part by EMD Serono, as part of an alliance between the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Clinical trial information: NCT04871529.

4541 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. This trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report the 18 month results for all eligible patients who received at least one protocol treatment. The co-primary endpoints were pathological complete response (CR) rate at 6 months in patients with CIS (reported at ASCO 2020), and event-free survival (EFS) in all patients at 18 months using Kaplan-Meier methods (KM), conditional on a positive CIS response rate. A sample size of 135 evaluable patients provided 93% statistical power for detecting a 30% 18-month EFS rate versus 20% using a one-sided alpha = 0.05. EFS in the subset with Ta/T1 disease and duration of response in CIS patients were secondary endpoints. Results: 172 patients were enrolled, 166 received at least one dose of atezolizumab and are included in the safety analysis, and, of those, 128 were eligible and included in the efficacy analysis. As previously reported, 20 (27%) out of 74 patients with CIS attained a pathologic CR at 6 months. The KM estimate of 12 month (actual 11.9 mo) duration of response after 6 month CR for CIS patients was 54% (95% CI 30%, 78%) and the median duration of response was 16.5 months. The KM EFS rate at 18 months in 74 patients with CIS was 17% (90% CI 9%, 25%). The 18 month KM EFS rate in the overall population of 128 patients with Ta, T1 and CIS was 29% (90% CI 22%, 36%). The 18 month actuarial EFS rate in 54 patients with Ta/T1 disease was 45% (90% CI 34, 57%). Any possibly or probably treatment-related adverse event (TRAE) was observed in 142 out of 166 (86%) patients who received any atezolizumab regardless of eligibilty. The most frequent TRAEs were fatigue 72 (43%), diarrhea 34 (20%), and anemia 38 (23%). Grade 3-5 TRAEs occurred in 28 (17%) patients, including rash in 4 (2%), hyponatremia in 4 (2%), hypertension in 3 (2%) and elevated liver function tests in 3 (2%). There were two treatment-related deaths (sepsis and respiratory failure due to myasthenia gravis). Conclusions: The observed response of atezolizumab at 6 and 18 months in patients with BCG-unresponsive CIS suggests that this could be a valuable treatment to address a critical unmet need in this patient population. The 18 month EFS in patients with Ta/T1 disease suggests activity in this patient subset. This trial provided no new safety concerns. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, CA180863 and in part by Genentech. Clinical trial information: NCT02844816.

TPS4591 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. Results: If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Conclusion:Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial information: NCT02844816.