5012 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by radical cystectomy (RC) is a standard treatment for MIBC. PD-1/L1 inhibitors as single agent induce pathological complete responses (pCR) in this setting. Predictors of response are still ill defined. DUTRENEO trial aimed to prospectively explore the activity of anti-PDL1 + anti-CTLA4 vs CT in pts selected according to a tumor pro-inflammatory IFN-gamma signature (tumor immune score, TIS). Methods: Cisplatin-eligible pts with urothelial MIBC (cT2-T4a, N≤1, M0) candidates to RC were classified as “hot” or “cold” according to a tumor TIS determined by Nanostring technology. Patients with "hot" tumors were randomized to DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles or standard cisplatin-based CT (GEMCIS or MVACdd). Pts in the “cold” arm received standard CT. Primary endpoint was to achieve ≥8 pCR in the DU+TRE arm. PDL1 expression was assessed using immunohistochemistry. Results: 61 pts were recruited in 10 sites between oct-2018 and dec-2019. Pts randomized in the “hot” arms received standard CT (n = 22) or DU+TRE (n = 23) and had a pCR rate of 8/22 pts (36.4%) vs 8/23 pts (34.8%), respectively [OR = 0.923 (0.26 – 3.24)]. In the “cold” arm, 16 pts received CT obtaining a pCR rate of 68.8% (11/16 pts). There were more PDL1 low tumors in the "cold" TIS arm (10/12, 83.3%). pCR rate by PDL1 status is shown in the table. One pt in the DU+TRE arm refused RC. Full treatment was delivered to 81.3% of CT "cold" vs 59.1% of CT "hot" vs 73.9% in the DU+TRE arm pts. Grade 3-4 toxicities were more frequent in the CT arms. Conclusions: The combination of DU+TRE is safe and active in MIBC patients in the neoadjuvant setting. Nevertheless prospective stratification by a pro-inflammatory IFN-gamma signature failed to select patients more likely to benefit from IO vs CT in this context. Further studies are required to guide treatment selection. Clinical trial information: NCT03472274 . [Table: see text]
Introduction: The increasing life expectancy and the proportion of octogenarians make radical cystectomy (RC) more frequent in octogenarian patients with muscle invasive bladder cancer. Objective: To analyze overall survival and complications in our series. Material and Methods: Descriptive analysis of patients older than 80 years undergoing RC between 2000 and 2012. Surgical risk (American Society of Anesthesiologists scale, ASA), hospital stay, complications (Clavien-Dindo classification) and types of urinary diversion were evaluated. Variables were expressed in mean or medians. Overall survival was analyzed using the Kaplan-Meier method. Univariate overall survival analysis was performed using the univariate Cox regression model. The null hypothesis was rejected by a type I error <0.05. Statistical analyses were performed using SPSS 15.0 (SPSS Inc., Chicago, Ill., USA). Results: Thirty-three patients were included. Their mean age was 81.9 ± 1.8 years. There were 24 males (72.7%). The surgical risk was identified as follows: ASA II in 9 patients (27.3%), ASA III in 23 (69.7%) and ASA IV in 1 (3%). Concerning urinary diversion, 19 patients (57.6%) underwent ureteroileostomy and 14 (42.4%) bilateral cutaneous ureterostomy. Average hospital length of stay was 19 days (14-30). TNM stage was T0 in 1 patient (3%), T1 in 4 (12.1%), T2 in 11 (33.3%), T3 in 13 (39.4%), T4 in 4 (12.1%), Nx in 9 (12%), N0 in 13 (39.4%), N1 in 3 (9.1%), and N2 in 5 (15.2%). The most frequent complications were pneumonia in 6 patients (18.2%) and surgical wound infection in 6 (18.2%). Lymphadenectomy did not involve a significant increase in complications. Six patients (18.2%) died in the immediate postoperative period, 5 of whom from respiratory complications. The mean survival of the rest of the series was 24 months (range 15.1-32.8). Conclusions: Overall assessment of the patient is essential and not only the chronological age. RC is a valid option despite chronological age. In the postoperative period, there is a higher risk of complications but not higher mortality due to surgical complications.
500 Background: PPI are widely used in pts with cancer. PPI are associated with anti-inflammatory properties and direct effects on neutrophils and monocytes that might prevent inflammation. We investigate the role of PPI on outcomes of pt receiving ICI in mUC. Methods: Medical records from pts with mUC treated with ICI from May 2013 to May 2019 using a multi-institutional database was evaluated. Use of PPI was defined: 30 days prior, during the treatment and 30 days after the last dose of ICI. ORR were assessed according to RECIST v1.1. The X2 test was used to determine differences in rates. PFS and OS were estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: Overall, 115 pts received therapy with ICI. Of these pts, 20 were not included due to the absence of information about PPI. Thus, 95 pts were included for the analysis. 50 (52.6%) pts received PPI. Median age was 68 years, 79 pts (83.2%) were male, 78 pts (82.1%) had ECOG PS 0-1, 20 pts (21.1%) had liver metastasis and 36 pts (37.9%) received ICI treatment as frontline therapy. ICI prescribed were atezolizumab (58.9%), pembrolizumab (17.9%), durvalumab (12.6%), nivolumab (6.3%) and durvalumab/tremelimumab (4.2%). Pts with no PPIs use had higher ORR (CR [8.9%] +PR [14.4%]) compared to those pt who use PPIs (CR [4.4%] + PR [8.9%]) (P=0.197). Median PFS was 10.05 mo (95% CI: 3.86-16.27) for non PPI users and 3.87 mo (95% CI:1.84-5.91) for PPI users (P=0.04). Median OS was 19.71 mo (95% IC:8.93-30.49) for non PPI users and 7.9 mo (4.4-11.45) for PPI users (P=0.072). Conclusions: We have observed shorter PFS and trend toward lower OS and ORR for PPI users. The real impact of PPI should be confirmed in prospective studies.
TPS4588 Background: Cisplatin-based neoadjuvant chemotherapy (CT) followed by cystectomy improves overall survival in patients (pts) with MIBC. Immune checkpoint inhibitors as single agents are approved in pts with advanced UC. Combination of both programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) checkpoints might be synergistic. Durvalumab (DU) is a selective, engineered, human IgG1 monoclonal antibody (mAb) that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab (TRE) is an anti-CTLA-4 mAb of the lgG2 isotype. Pembrolizumab and atezolizumab, have shown a promising activity (including significant pathologic complete responses (pT0)) in MIBC pts candidate to cistectomy, with better results in those pts with PD-L1 overexpression. It is expected that the dual targeting of the immune system with an anti-PDL1 + antiCTLA4 such as DU and TRE in the neoadjuvant setting may improve these outcomes. In addition, the most precise selection of pts according to a molecular INF-gamma signature is intended to increase the efficacy. Methods: This is a prospective and randomized phase II, open-label study conducted in urothelial MIBC pts diagnosed of T2-T4 and/or N+ candidates to cystectomy, ECOG 0-1 and adequate organ function. Pts will be treated according to the score of a pro-inflammatory signature (PIS) determined with Nanostring technology. Pts with a low PIS will receive standard cisplatin-based neoadjuvant therapy (22 pt). Pts with a high PIS will be randomized 1:1 to receive cisplatin-based neoadjuvant therapy (22 pt) or DU 1500 mg + TRE 75 mg every 4 weeks x 3 cycles (22 pt). If more than 8 responses (pT0) are observed in first 22 pts included in DU+TRE arm, 24 additional pts will be recruited in this arm. Primary objective is to assess the antitumor activity of DU+TRE measured as pT0 rate in pts with a positive PIS. Disease free survival and safety profile will be also evaluated. Tissue, plasma and urine samples will be collected for translational studies. Clinical trial information: NCT03472274.
496 Background: There is a growing interest in local treatment for metastatic solid tumors. Recently, retrospective studies have reported the potential benefit of RLT to primary bladder cancer in pts with metastatic disease. We tested the impact of previous RLT in pts with mUC treated with ICI. Methods: Data from pts with mUC treated with ICI collected between May 2013 and May 2019 using a multi-institutional database was evaluated. Stratification was made according to previous RLT with ICI versus no RLT with ICI. We defined RLT as radical surgery (RS) or ≥50 Gy of radiotherapy (RT) delivered to the bladder. The X2 test was used to determine differences in rates. Overall survival (OS) between previous RLT plus ICI (group A) versus no RLT plus ICI (group B) generated using Kaplan-Meier method was compared by log-rank test. OS was calculated from the date of initiation of ICI to the date of death. Analyses were performed using SPSS v21. Results: A total of 115 pts with mUC were treated with ICI, 62 (53.9%) previously were treated with RS, 7(6.1%) RT and 46 (40%) no received RLT. ICI prescribed were atezolizumab (55.7%), pembrolizumab (16.5%), durvalumab (11.3%), durvalumab/tremelimumab (7.8%), nivolumab (5.2%) and avelumab (3.5%). The disease control rate (CR [6.9%] +PR [9.6%] +SD [14.1%]) was higher for pts with previous RLT compared to those pts who did not receive RLT (CR [3.2%] + PR [5.8%] + SD [6.4%](P=0.325). Median OS was 11.23 mo (95% CI; 6.02-16.44) and 7.95 mo (95%IC; 5.15-10.75) for group A and group B, respectively (P=0.481). Conclusions: This multicenter cohort suggests that previous RLT might play an impact for control disease in pts with mUC treated with ICI. Although this is hypothesis generating, the true value of this approach remains to be demonstrated in prospective studies.
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