Boorjian, Stephen A.

4526 Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) demonstrates a survival benefit in the neoadjuvant setting for patients (pts) with muscle invasive bladder cancer (MIBC). Compared with standard MVAC, AMVAC yielded higher response rates with less toxicity in the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with CrCl >=50 and adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) on day 1, with pegfilgrastim 6 mg day 2 or 3, every 2 weeks. Pts with CrCl < 60 could receive cisplatin split over 2 days. Radical cystectomy (RC) with lymph node dissection was performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month period. Median age 64 (range 45-83). Three withdrew from study early and are not evaluable for response (2 physician discretion, 1 withdrawal of consent). An additional 8 are currently receiving treatment on study with toxicity and response data pending. Of the 33 evaluable pts for whom final data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts received < 3 cycles due to grade 3 fatigue (1), low platelets (1), and disease progression precluding RC (1). 32/33 pts underwent RC, all within 8 weeks of last chemotherapy. Median time from start of chemotherapy to RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI, 22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non muscle invasive disease. For the intent to treat cohort (n=36) 8 pts had grade 3-4 AMVAC related adverse events, the most common being anemia (3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95% CI, 20.4-51.8%). All pts will have completed study treatment by April 2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is well tolerated and preliminary results show a pCR rate similar to that reported for standard 12-week MVAC, suggesting that AMVAC for three cycles (6 weeks) is a safe and efficient alternative.

TPS594 Background: The standard treatment for upper tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU) with bladder cuff resection. Subsequent intravesical recurrence is common and results in patient morbidity and increased healthcare cost. Level 1 evidence has demonstrated reduction of intravesical recurrence with instillation of intravesical Mitomycin C at 10 days following RNU. However, there has been limited adoption of Mitomycin C due to concerns for toxicity and logistics of postoperative drug delivery. Meanwhile, immediate intravesical gemcitabine has been shown to reduce intravesical recurrence following transurethral resection of bladder cancers without increasing toxicity compared to placebo. Moreover, small series have suggested improved efficacy of intraoperative intravesical chemotherapy for RNU. The purpose of the GEMINI trial, therefore, is to prospectively establish the safety and efficacy of intraoperative instillation of intravesical gemcitabine in patients undergoing RNU for UTUC. Methods: GEMINI is a multi-center open-label, single-arm, Phase II study that aims to enroll 90 patients with cTa-T4N0M0 UTUC. Patients receive intraoperative intravesical instillation of gemcitabine at the beginning of RNU, to be held in the bladder for at least 1 hour. The instilled drug will be drained prior to resection of the bladder cuff. Patients will undergo standard of care postoperative surveillance, including cystoscopy at 3, 6, 12, 18, and 24 months. The primary endpoint is 1-year intravesical recurrence-free survival. The historical event rate for no treatment is 30%, and we estimated a 40% relative reduction in event rate with gemcitabine. The study is powered to provide 80% power to detect this difference based on a one-sided exact test of proportions with alpha level 0.05. Secondary endpoints include time to recurrence and stratification of recurrence free survival by tumor grade, tumor stage, neoadjuvant chemotherapy, ureteral tumor location, and history of bladder cancer. Safety and adverse event endpoints will be evaluated. Complete accrual is expected within 3 years.

TPS380 Background: Radical prostatectomy (RP) is the most common surgical treatment for prostate cancer (PC). Yet even with nerve-sparing RP (NS-RP), a significant proportion of men experience transient or permanent erectile dysfunction (ED) partially due to intraoperative neurovascular bundle (NVB) damage from thermal or mechanical trauma. Studies have shown that platelet released growth factors counteract trauma and facilitate healing. We evaluate the use of platelet rich plasma (PRP) to facilitate early nerve healing and decrease ED after NS-RP. Methods: A prospective, open label, 20 subject human trial evaluating intraoperative topical NVB PRP application was approved by the IRB and FDA under an Investigational Device Exemption (IDE 16915) for the investigational use of an approved blood separation device. Men aged 50-60 with newly diagnosed, localized PC and normal preoperative sexual and urinary function, defined as a Sexual Health Inventory for Men (SHIM) score of >19 and an answer of “none” on question 5 of the Expanded Prostate Cancer Index Composite (EPIC) are eligible. Intraoperatively, a 10ml PRP product is created from a 180 mL sample of the patient’s whole blood using the Angel Concentrated Platelet Rich Plasma System (Cytomedix, Inc., Gaithersburg, MD USA). PRP is applied via mechanical transfer to the NVB after completion of the vesicourethral anastomosis. The primary endpoint is the safety and tolerability of PRP on the NVB after NS-RP. Secondary endpoints include feasibility of intraoperative PRP application and longitudinal assessment of erectile function and urinary continence by questionnaire administration at 3, 6, 9, 12 and 18 months after NS-RP. Clinical trial information: NCT02957149.

725 Background: The impact of surgical resection of renal tumors on peripheral immune related cells is not well characterized, and has potential implications as biomarkers for systemic immune therapy are being developed. We sought to assess the effect of surgical resection on circulating cytotoxic T-cells (CTLs) for patients with renal tumors. Methods: We prospectively enrolled 40 patients undergoing partial, radical, or cytoreductive nephrectomy (PN, RN, CN) for unilateral primary renal tumors between 2016 and 2018. Blood draws were performed pre-op, 1 day post-op, and 3 months post-op. Flow cytometry was performed on peripheral blood mononuclear cells (PBMCs). The % of PBMCs expressing CD11a/CD8 (CTLs) were assessed. The % of CTLs expressing PD-1, Bim (a downstream PD-1 pathway pro-apoptotic mediator), CX3CR1/GZMB (an effector memory T-cell phenotype), and Ki67 (a proliferation marker) were assessed. Median changes in % of CTLs were evaluated with the Wilcoxon signed rank test. Comparisons between aggressive (pT3-4, N1, M1, or aggressive histology (high-grade, coagulative necrosis, sarcomatoid dedifferentiation, or specific RCC-variant histologies)) versus indolent tumors were assessed using the Wilcoxon rank sum test. Results: Twenty, 12, and 8 patients underwent RN, PN, and CN, respectively. Thirty, 7, and 3 patients had clear-cell RCC, non-clear cell RCC, and oncocytoma, respectively. Twenty-three and 17 patients had aggressive and indolent tumors, respectively. While there was no significant change at 1 day, by 3 months there were significantly increased CTLs among PBMCs (+1.3%; p=0.004). There was significant decrease in CX3CR1+GZMB+ CTLs (-2.9%; p<0.001) and significant increase in Bim+ CTLs (+3.0%; p=0.03) at 1 day but not 3 months. Interestingly, Ki67+ CTLs increased at day 1 (+0.6%; p<0.001) but decreased by 3 months (-0.6%; p=0.001). There were no significant changes in PD-1+ CTLs at either time point. There were no significant changes in any CTL characteristics at 1 day or 3 months between aggressive and indolent tumors. Conclusions: These findings characterize changing CTL profiles over time with surgical resection of renal tumors which may help guide biomarker development.

610 Background: Personalized treatment for clinical T1 renal cortical masses (RCMs) should account for competing risks related to tumor and patient characteristics. Using a contemporary multi-institutional cohort, we developed treatment-specific prediction models for cancer-specific mortality (CSM), other-cause mortality (OCM), and 90-day complication rates for patients managed with surgery, thermal ablation (TA), and active surveillance (AS). Methods: Preoperative clinical and radiological features were collected for eligible patients aged 18-91 years treated at four academic centers from 2000-2016. Prediction models used competing risks regressions for CSM and OCM and logistic regressions for 90-day Clavien >3 complications, adjusting for tumor size as well as patient age, sex, ECOG performance status (PS), and Charlson comorbidity index (CCI). Predictions accounted for missing data using multiple imputation. Results: After excluding 25 patients with no follow-up, the cohort included 4995 patients treated with radical nephrectomy (RN, n=1270), partial nephrectomy (PN, n=2842), thermal ablation (n=479), or active surveillance (n=404). Median follow-up was 5.1 years (IQR 2.5-8.5). Predictions from the fitted model are shown in an online calculator ( https://rgulati.shinyapps.io/rcc-risk-calculator ). To illustrate the use of this calculator for a specific patient, a 70-year-old female with a 5.5 cm RCM, PS of 2, and CCI of 3 has a predicted 5-year CSM of 4-7% across treatments, 5-year OCM of 34-49%, and 90-day risk of Clavien ≥3 complications of 4%, 10%, and 6% for RN, PN, and TA respectively. Conclusions: Personalized treatment selection for cT1 RCM is challenging. We present a competing risk calculator that incorporates pretreatment features to quantify competing causes of mortality and treatment-associated complications. Pending validation, this tool may be used in clinical practice to provide patients with estimated individualized treatment-specific probabilities of competing causes of death and complication risks to facilitate shared decision-making.

483 Background: We evaluate the impact of salvage intravesical therapy on survival in patients with NMIBC previously treated with BCG who ultimately underwent radical cystectomy (RC). Methods: We retrospectively identified patients with NMIBC who received at least 1 complete induction course of BCG and subsequently underwent RC for bladder cancer between 2000-2018. Patients were stratified by receipt of salvage intravesical therapy following BCG prior to RC. Oncologic outcomes were compared using Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: We identified 371 patients who underwent RC after receiving BCG, of whom 55 (15%) received salvage intravesical therapy, most commonly Mitomycin C (n = 26), Valrubicin (n = 8), Gemcitabine (n = 7), and CG0070 (n = 6). Median follow-up among survivors was 1.1 (IQR 0-4.3) years. Patients who received salvage intravesical therapy were more likely to initially present with CIS (27% vs 17%) and less likely to present with T1 disease (33% vs 50%, both p < 0.05). Receipt of salvage intravesical therapy was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (33% vs 41%, p = 0.27). Furthermore, on Kaplan-Meier analysis, receipt of salvage intravesical therapy was not associated with cancer-specific or overall survival. On multivariable Cox proportional hazards regression, clinical stage prior to RC, but not receipt of salvage intravesical therapy, was associated with inferior cancer-specific survival and overall survival. Conclusions: Our results suggest that RC following carefully managed salvage intravesical therapy after BCG is not associated with inferior oncologic outcomes, which can improve patient counseling. [Table: see text]

442 Background: Patients (pts) with BCG-unresponsive NMIBC are at significant risk for disease recurrence and progression. While cystectomy can be curative, many such pts are unwilling or unable given the attendant morbidity of surgery. To date, effective salvage intravesical therapies in this setting remain lacking. Nadofaragene firadenovec is a novel intravesical gene-mediated therapy that delivers the human IFNα2b gene resulting in IFNα2b expression that provided durable responses in a previous Phase 2 trial. Herein, we report the results from a follow-up Phase III trial of this agent for pts with BCG unresponsive NMIBC. Methods: This multicenter, open-label Phase 3 study investigated nadofaragene for high-grade NMIBC (CIS ± Ta/T1, or Ta/T1 alone) unresponsive to BCG. Nadofaragene (3X1011 vp/mL [75 mL]) was administered once every 3 months for up 4 doses in the initial 12 months, with additional dosing at the investigator’s discretion. The primary endpoint was complete response (CR) at any time in pts with carcinoma in situ (CIS). Results: A total of 157 pts (safety population, n=157; efficacy population, n=151) were enrolled. Among pts with CIS (n=103), 55 (53.4%) (95% CI, 43.3-63.3) achieved CR, all by month 3 after treatment. Of these 55 CIS CR pts, 25 (45.5%) remained free of high-grade recurrence at month 12, confirmed on protocol-mandated biopsy. For pts with HG Ta/T1 alone, 35 (72.9%) and 21 (43.8%) were free from recurrence at 3 and 12mos, respectively. Most treatment-emergent adverse events (TEAEs) were transient in nature: instillation site discharge 33.1%; fatigue 23.6%; bladder spasm 19.7%; micturition urgency 17.8%; hematuria 16.6%. There were 2 Gr4 TEAEs (sepsis and anaphylactic reaction, neither related to study drug) and no Gr5 TEAEs. Conclusions: Nadofaragene achieved CR in 53.4% of pts with BCG-unresponsive CIS, and was well tolerated. Responses were noted early and remained durable to one year. These data represent a potentially significant management advancement for a historically difficult to treat disease state. Clinical trial information: NCT02773849.