bluuebunny/crossref_metadata_2025 huggingface dataset:
Repurposing ethacrynic acid for the treatment of bladder cancer.
Authors: Lee Eugene , Reed Greg , Dandawate Prasad , Kaushik Gaurav , Subramaniam Dharmalingam , Holzbeierlein Jeffrey M. , Anant Shrikant , Weir Scott James
Published: February 2018

521

Background: Bladder cancer is a common cancer in the US. Approximately seventy-five percent of new cases present as non-muscle invasive bladder cancer (NMIBC) with a high recurrence rate. Our group has demonstrated in well-characterized human NMIBC cell lines that ethacrynic acid (EA) suppresses growth by inhibiting proliferation, clonogenicity, spheroid formation and inducing apoptosis. Additionally, EA affects markers of stemness and may work through the NOTCH signaling pathway. We present a clinical trial characterizing the safety and urinary tract exposure to EA and metabolites following oral administration in patients undergoing transurethral resection of bladder tumor (TURBT). Methods: Institutional review board approval (#3674) was obtained for a Pilot trial in patients with presumed non-muscle invasive bladder cancer undergoing TURBT. All participants were given a single, 50 mg oral dose of EA in the pre-operative bay. Urine was collected at baseline, upon insertion of cystoscope (30-60 minutes post dose), and post-operatively. Urine concentrations of EA and metabolites were determined using a fully-validated UPLC-MS/MS-based analytical method. Participants were monitored for adverse events. Results: Twelve participants participated in the trial between August 2016 and February 2017. Eleven male and one female patient (median age 70.5 years) were enrolled. Final pathology demonstrated urothelial carcinoma in 5/12 (42%) subjects, three with high grade T1 and two with low-grade Ta tumors. Urine concentrations of EA and conjugates observed 30-60 minutes post-dose were as follows: EA 0.1 ug/mL, EA-glutathione 0.2 ug/mL, EA-cysteine 3 ug/mL, and EA-mercapturate 2 ug/mL. No drug-related adverse events were observed following oral EA administration. Conclusions: Despite EA receiving FDA approval over 40 years ago, our pilot trial describes for the first time, urinary tract exposure of EA and its active metabolites in bladder cancer patients after a single oral dose. These data are guiding ongoing preclinical proof of principle studies evaluating EA alone and in combination with standard of care agents in bladder cancer models. These studies warrant further studies of EA in patients with non-muscle invasive bladder cancer. Clinical trial information: NCT02852564.
P53 as a predictor of clinical outcome in localized prostate cancer.
Authors: Mahon Kate Lynette , Stricker Phillip , Kench James , Grogan Judith , Delprado Warick , Turner Jenny , Horvath Lisa , Quinn David I.
Published: February 2018

57

Background: p53 is one of the most common genetic aberrations in human cancer and is associated with poor outcomes with hormone therapy in advanced prostate cancer (PCa). p53 is a well-established predictor of biochemical relapse in PCa, however, increasing evidence from ICECaP has demonstrated that metastatic relapse (MR) not biochemical relapse (BCR) is a surrogate for prostate-cancer specific mortality (PCSM). Furthermore, there are now a range of novel therapeutic strategies targeting p53 mutations and their downstream effector pathways. This study aimed to assess the association between p53 expression and MR/PCSM in men with localized PCa. Methods: The study consisted of 271 men with localized PCa treated with radical prostatectomy. Surgical cancer specimens were stained for p53 by immunohistochemistry (IHC) and scored as a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x200 power field was deemed “cluster positive”. Results: At a median follow-up of 15.8 years (range 4 months - 24.3 years), 57.5% (156/271) had a biochemical relapse, 18% (49/271) had suffered a metastatic relapse, and 9.5% (25/271) had died of prostate cancer. Increasing percentage of p53 positive nuclei was significantly associated with shorter time to BCR (p < 0.001), MR (p < 0.001) and PCSM (p < 0.001). Half of patients were p53 cluster positive. P53 cluster positivity was significantly associated with all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p < 0.001; MR: HR 4.1, 95%CI 2.02-8.14, p < 0.001; PCSM: HR 12.2, 95%CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables including lymph node status, baseline PSA, Gleason and ISUP grade on multivariable analysis. Conclusions: This study has confirmed the association of p53 in radical prostatectomy tissue with clinically relevant endpoints of metastatic relapse and prostate cancer specific mortality. p53 is a potential stratification factor and may be useful for identifying those who will most benefit from adjuvant therapy. Incorporation of p53 status into ongoing clinical trials is now warranted.
IMmotion151: A Randomized Phase III Study of Atezolizumab Plus Bevacizumab vs Sunitinib in Untreated Metastatic Renal Cell Carcinoma (mRCC)
Authors: Motzer Robert J. , Powles Thomas , Atkins Michael B. , Escudier Bernard , McDermott David F. , Suarez Cristina , Bracarda Sergio , Stadler Walter Michael , Donskov Frede , Lee Jae-Lyun , Hawkins Robert E. , Ravaud Alain , Alekseev Boris Y. , Staehler Michael D. , Uemura Motohide , Donaldson Francis , Li Shi , Huseni Mahrukh A. , Schiff Christina , Rini Brian I.
Published: February 2018

578

Background: Atezolizumab (atezo; anti–PD-L1) + bevacizumab (bev; anti-VEGF) showed first-line (1L) anti-tumor activity with a manageable safety profile in PD-L1+ mRCC pts in a Phase II study (McDermott ASCO-GU 2017). Here we describe the first randomized Phase III trial of a PD-L1/PD-1 pathway inhibitor combined with an anti-VEGF agent in 1L mRCC. Methods: IMmotion151 (NCT02420821) enrolled treatment-naïve pts regardless of prognostic risk group randomized 1:1 to receive atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sunitinib (sun) 50 mg PO QD 4 wk on/2 wk off. Pts were stratified by PD-L1 status (< 1% vs ≥ 1% PD-L1 expression on tumor-infiltrating immune cells [IC]; SP142 IHC assay). Coprimary endpoints: progression-free survival (PFS; by investigator per RECIST v1.1) in PD-L1+ pts (≥ 1% IC) and overall survival (OS) in intent-to-treat (ITT) pts. Secondary endpoints included PFS in ITT pts, ORR and DOR. Results: Baseline characteristics were comparable between arms within PD-L1+ (40% of ITT) and ITT pts. Median survival follow-up was 15 mo. PFS HR for atezo + bev vs sun was 0.74 (95% CI 0.57, 0.96) in PD-L1+ pts and 0.83 (95% CI 0.70, 0.97) in ITT pts. OS was immature at first interim analysis. PFS benefit was consistent across analyzed subgroups, including MSKCC risk, liver metastases and sarcomatoid histology. In PD-L1+ pts, ORR was 43% and DOR was not reached for atezo + bev vs 35% and 12.9 mo for sun. 40% of atezo + bev–treated pts and 54% of sun-treated pts had treatment-related Gr 3-4 AEs; 12% and 8% of treatment-related all-Gr AEs led to discontinuation, respectively. Conclusions: The study showed longer PFS for atezo + bev vs sun in PD-L1+ pts. Improved PFS was also observed in ITT pts. Safety was consistent with that of the individual agents. These results support the use of atezo + bev as a 1L treatment option in mRCC. Clinical trial information: NCT02420821. [Table: see text]
Cabozantinib versus sunitinib for previously untreated patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk: Subgroup analysis of progression-free survival (PFS) and objective response rate (ORR) in the Alliance A031203 CABOSUN trial.
Authors: George Daniel J. , Hessel Colin , Halabi Susan , Sanford Ben L. , Michaelson M. Dror , Hahn Olwen Mary , Walsh Meghara K. , Olencki Thomas , Picus Joel , Small Eric Jay , Dakhil Shaker R. , Feldman Darren R. , Mangeshkar Milan , Scheffold Christian , Morris Michael J. , Choueiri Toni K.
Published: February 2018

582

Background: The randomized phase 2 CABOSUN trial (NCT01835158) compared cabozantinib (C) with sunitinib (S) as initial systemic therapy in patients (pts) with RCC of intermediate or poor risk. Compared with S, C improved both PFS and ORR as assessed by independent radiology review committee (IRC). Median PFS per IRC was 8.6 mo for C vs 5.3 mo for S (HR 0.48, 95% CI 0.31-0.74 two-sided p = 0.0008), and ORR per IRC was 20% vs 9%. Methods: 157 patients were randomized 1:1 to receive C (60 mg qd) or S (50 mg qd, 4 weeks on/2 weeks off) stratified by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group and the presence of bone metastases. Subgroup analyses of PFS per IRC and ORR per IRC are presented based on stratification factors, age, sex, baseline ECOG status, and MET tumor expression by immunohistochemistry. The primary endpoint was investigator-assessed PFS. PFS and ORR were evaluated by IRC in a post-hoc analysis. Results: 45% of pts were ≥65 years, 78% were male, 54% were ECOG 1 or 2, 19% were poor risk, and 36% had bone metastases. MET status was determined in 131 pts; of these 47% were MET positive. The HR for PFS per IRC favored C over S across all subgroups analyzed (Table). Subgroups with poor prognostic characteristics (poor risk, ECOG 1 or 2, presence of bone metastases) had shorter median PFS for both C and S. Odds ratios for ORR also favored C over S, with the highest C ORR in the MET positive subgroup (34% C vs 10% S). Conclusions: C was associated with improved PFS and ORR compared with S in previously untreated pts with advanced RCC irrespective of baseline characteristics. Clinical trial information: NCT01835158. [Table: see text]
Self-reported quality of life as a predictor of survival in renal cell carcinoma.
Authors: Alam Ridwan , Patel Hiten , Pierorazio Phillip M.
Published: February 2018

595

Background: Quality of life (QOL) in cancer patients has gained increasing attention and may provide prognostic value above and beyond traditional demographic and disease parameters. We evaluate the utility of self-reported QOL to predict mortality in patients with renal cell carcinoma (RCC). Methods: The Medicare Health Outcomes Survey was linked to SEER data to identify patients who completed a QOL questionnaire after the diagnosis of RCC from 1998-2014. Mental component summary (MCS) and physical component summary (PCS) scores were classified as high (≥50) or low ( < 50) based on a population mean score of 50 points. Patients were classified into four groups: 1) high MCS, high PCS; 2) high MCS, low PCS; 3) low MCS, high PCS; and 4) low MCS, low PCS. Multivariable Cox proportional hazards regression evaluated associations between QOL and all-cause mortality (ACM). The Harrell’s concordance statistic (C-index) estimated predictive accuracy. Fine and Gray competing risks models adjusted for stage, demographics, and comorbidities evaluated RCC-specific and non-RCC-specific mortality. Results: A total of 1494 patients with a median age of 73.4 years (IQR 68.8-79.3) at survey completion were included. Median follow-up was 5.6 years (IQR 4.0-8.3). There were 747 deaths, of which 139 were due to RCC. Models showed that each additional MCS and PCS point reduced the hazard of ACM by 1.3% (95% CI 0.981-0.993, P< 0.001) and 2.2% (95% CI 0.972-0.985, P< 0.001), respectively. The C-index was 72.1%. In the competing risks model, the subdistribution hazard ratio (SHR) of RCC mortality in Groups 2, 3, and 4 were 2.71 (95% CI 1.18-6.22, P= 0.02), 4.55 (95% CI 1.57-13.18, P= 0.005), and 3.11 (95% CI 1.35-7.16, P= 0.008), respectively, compared to Group 1. The SHR for non-RCC mortality were 1.50 (95% CI 1.16-1.94, P= 0.002), 1.03 (95% CI 0.59-1.78, P= 0.9), and 1.83 (95% CI 1.41-2.38, P< 0.001), respectively, relative to Group 1. Conclusions: Self-reported QOL metrics can be used to predict ACM in RCC patients with good accuracy; lower PCS and MCS scores led to higher rates of ACM, even after accounting for differences in disease, demographics, and comorbidity. Furthermore, non-RCC mortality was associated more with low physical health rather than low mental health.
Antibiotic use and outcomes with systemic therapy in metastatic renal cell carcinoma (mRCC).
Authors: Lalani Aly-Khan A. , Xie Wanling , Lin Xun , Steinharter John A. , Martini Dylan J. , Duquette Audrey , Bosse Dominick , McKay Rana R. , Simantov Ronit , Wei Xiao X. , McGregor Bradley A , Harshman Lauren Christine , Choueiri Toni K.
Published: February 2018

607

Background: Antibiotic (Abx) use is shown to alter commensal gut microbiota, a key regulator of immune homeostasis. We conducted the largest investigation to date on the impact of Abx use on outcomes in mRCC patients treated with systemic agents. Methods: Two cohorts were analyzed: an institutional cohort (DFCI, n = 146) of patients receiving PD-1/PD-L1-based immune checkpoint inhibitors (ICI), and an external cohort from pooled phase II/III clinical trials (Pfizer, n = 4144) of patients treated with interferon (IFN, n = 510), mTOR inhibitors (n = 660), and VEGF inhibitors (n = 2974). Abx use was defined as Abx treatment at any time between 8-weeks pre- and 4-weeks post the start of systemic therapy. We examined the associations of Abx use and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) using Cox/logistic regression models, adjusted for prognostic factors including risk groups. Results: In the DFCI cohort, 15% had non-clear cell histology, 43% had first-line ICI, 45% had combotherapy. Baseline characteristics were balanced between Abx users (n = 31, 21%) and non-users (p > 0.15). Abx users had a lower ORR (12.9 vs 34.8%, p = 0.026) and shorter PFS compared to non-users (Table). In the external cohort, Abx users (n = 709) had lower ORR (19.3 vs 24.2%, p = 0.005). IFN treated patients (current or prior cytokines) had worse OS if they received Abx compared to those who did not. However, there was no OS difference by Abx use in mTOR or VEGF treated patients without prior cytokines. Conclusions: Abx use was independently associated with worse outcomes in mRCC patients receiving contemporary ICI or historic cytokine immunotherapy. We hypothesize that concurrent use of Abx may reduce the efficacy of ICI due to a complex interplay with the host microbiome. [Table: see text]
Impact of hypertension on recurrence and survival of patients with renal cell carcinoma after surgery.
Authors: Suyama Takahito , Kanesaka Manato , Otsuka Kotaro , Fujimoto Ayumi , Hou Kyokushin , Kato Tomonori , Araki Kazuhiro , Masuda Hiroshi , Kojima Satoko , Naya Yukio
Published: February 2018

611

Background: Hypertension (HT) is an established risk factor for developing renal cell carcinoma (RCC), and a relationship between the renin-angiotensin system and RCC has been emphasized. However, information about the impact of HT on treatment outcomes of patients after RCC surgery is limited. The present study aimed to clarify the impact of HT on the recurrence and survival of patients with RCC after surgery. Methods: Relationships between HT and clinical data including treatment outcomes were retrospectively analyzed in 149 patients (male, n = 112; female, n = 37; median age, 63 y; range, 29-86 y at the time of surgery) who underwent surgery between 2010 and 2016 at our hospital. Data were statistically analyzed using JMP version 9.0. Results: During a median follow-up period of 30.9 months, 28 and 16 patients experienced recurrence and died, respectively. Patients (n = 15) with Stage IV RCC were excluded from the analysis of recurrence. Five-year overall (OS) and recurrence-free (RFS) survival rates of the entire cohort were 80.8% and 76.1%, respectively. Kaplan-Meier analysis did not uncover a relationship between HT and OS, but the RFS rate was significantly lower for patients with HT than without HT (P = 0.0468). Tumor stage and the prevalence of proteinuria were significantly higher in the group with HT. The prevalences of vessel invasion (P = 0.0582) and low pre-surgical hemoglobin values (P = 0.0585) tended to be significantly higher for patients with HT. Conclusions: Patients with HT had significantly worse RFS rates, a more advanced stage of disease at the time of surgery, and a tendency towards a higher rate of vessel invasion. Further investigations are warranted to determine how HT promotes cancer progression.
Tivozanib combined with nivolumab: Phase Ib/II study in metastatic renal cell carcinoma (mRCC).
Authors: Escudier Bernard , Barthelemy Philippe , Ravaud Alain , Negrier Sylvie , Needle Michael N. , Albiges Laurence
Published: February 2018

618

Background: Tivozanib is a VEGFR-TKI with high specificity and lower incidence of class effect adverse events. As combinations of vascular endothelial growth factor receptor tyrosine kinase inhibitiors (VEGFR-TKIs) and checkpoint inhibitors have proven to be toxic, alternatives with an improved AE profile are required. We present safety data from a phase Ib/II combination of tivozanib and nivolumab Methods: In this phase Ib/II study, tivozanib was administered orally at two dose levels, 1.0 mg and 1.5 mg, once daily for 21 days every 28 day cycle in combination with nivolumab 240 mg every 14 days intravenously. Results: Eighteen patients have been enrolled. Phase Ib is complete. Safety data is available for 13, 3 at 1.0 mg tivo; 10 at 1.5 mg tivo. The median age was 62; 11 patients were ECOG 0 and 5 ECOG 1; and there were 13 males. 16 had clear cell histology No patient in phase Ib experienced an DLT in cycle 1. Patients in phase II are receiving tivozanib at 1.5 mg. All patients experienced at least one AE. The most common adverse events were hypertension, asthenia, mucositis, diarrhea, hand foot syndrome, arthralgia, and pruritis. Five patients (38%) had grade 3-4 AEs. One patient had both elevated serum lipase and amylase and one patient had an SAE of symptomatic malignant hypertension complicated by a seizure. The other grade 3-4 AEs were pneumonitis, stomatitis, and elevated ALT. Conclusions: As expected from a VEGFR-TKI with high specificity and a preferable toxicity pattern as a single agent, the combination of tivozanib with nivolumab is safe and manageable at full dose of both drugs. Efficacy is pending. This data is based on limited exposure and should be interpreted with caution. Additional patients are being enrolled and treated. This begs the question if tivozanib could be added to a triple combination with ipilimumab and nivolumab. Clinical trial information: NCT03136627. [Table: see text]
Outcomes and patterns of disease progression in metastatic renal cell carcinoma patients treated with nivolumab.
Authors: Zahoor Haris , Barata Pedro C. , Allman Kimberly D , Martin Allison , Ornstein Moshe Chaim , Grivas Petros , Gilligan Timothy D. , Garcia Jorge A. , Rini Brian I.
Published: February 2018

654

Background: Nivolumab (nivo) has been approved for the treatment of refractory metastatic renal cell carcinoma (mRCC). Data regarding the characteristics and outcomes of patients (pts) who progress on nivo are lacking. Methods: A retrospective analysis of pts with clear cell mRCC who received nivo at Cleveland Clinic (2015-2017) was performed. Pts were divided into two groups; 1) PD group; pts with progressive disease (PD) per RECIST v1.1 or clinical PD, and 2) NPD group; pts with non-progressive disease on nivo. Results: Ninety pts (PD group n = 55, NPD group n = 35) with median age of 67 (33-83), 74% men, and 79% ECOG 0-1 were included. Pts had received 1 (44%), 2 (29%), or ≥ 3 (27%) prior systemic treatments, most commonly with sunitinib (71%), axitinib (39%) and pazopanib (33%). Pts in the PD group had a greater incidence of baseline liver metastases (PD, 40% vs. NPD, 14%; p = 0.01), with other baseline characteristics not significantly different. Median follow up was similar in both groups (PD group, 8.0 months (95% CI, 5.5-10.5) and NPD group, 7.1 months (95% CI, 4.9-9.3); p = 0.87). Median duration of treatment for PD group was 8.7 months (95% CI, 7.3-10.1) compared to 16.1 months (95% CI, 8.6-23.6) for NPD group (p = 0.02). In the PD group, 50 (91%) pts developed PD per RECIST v1.1 whereas 5 (9%) pts had clinical PD. New organ sites of metastases were found in 20/55 (36%) pts; brain (8/20; 40%), liver (4/20; 20%), soft tissue (4/20; 20%), and locoregional (4/20; 20%) were the most common new organ sites, whereas lungs, lymph nodes and pancreas were never involved at PD as new organ sites. Twelve pts received treatment beyond progression (TBP) with a median duration of TBP of 2.8 months (95% CI, 0.6-5.0) and 50% of pts had stable disease as their best response. Median overall survival (OS) and progression free survival (PFS) on nivo were 10.1 months (95% CI, 6.6-13.6) and 5.5 months (95% CI, 2.9-8.1), respectively. Conclusions: Pts with PD on nivo have a higher incidence of hepatic metastases at baseline, and one third of these pts develop new sites of metastases at PD, most commonly brain.
Accumulation of tumor infiltrating myeloid-derived suppressor cells associates with changes in the immune landscape of clear cell renal cell carcinoma.
Authors: Lin Lin , Pavicic Paul G , Rayman Patricia A. , Tannenbaum Charles , Rini Brian I. , Hamilton Thomas , Finke James , Diaz-Montero C. Marcela
Published: February 2018

655

Background: Myeloid-derived suppressor cells (MDSC) are capable of inducing profound immune suppression of anti-tumor T cell responses. Here we examined the ability of intratumoral MDSC accumulation to alter the immune landscape of RCC and to identify the factors involved. Methods: Using flow cytometry, 41 clear cell RCC nephrectomy samples were assessed for their total MDSC infiltrate and the percentage of granulocytic (PMN-MDSC) or monocytic (M-MDSC) subsets. RNA isolated from these tumor samples and 4 non-tumor samples was also evaluated for expression levels of immune-related genes using a Nanostring PanCancer immune panel. A multiple linear regression model was used to identify which immune-related genes might be significantly associated with PMN-MDSC intratumoral accumulation. Log-Rank test was used for comparison of survival curves. Results: Genes encoding cytokines, cancer-testis antigens, interleukins, and T cell function were differentially expressed by clear cell RCC and the non-tumor samples. The transcription of 55 immune-related genes was significantly associated (FDR adjusted p < 0.05) with PMN-MDSC infiltration, including mediators of MDSC recruitment such as CXCL1, CXCL3, CXCL5, CXCR2, IL8, LIF, S100A8, CSF3R, and CCR3, and molecules governing MDSC expansion and function such as IL10, C/EBPB, CD44, COX2, and NFATC3. When a statistically significant 10 gene signature was analyzed in the context of patient survival using the TCGA database of clear cell RCC patients (n = 945), a strong association between the expression of these genes and reduced survival was observed. Moreover, this association seemed to be additive, with expression of 7-10 of these genes correlating with poorer survival when compared to patients expressing 3 or less (p < 0.0001). Conclusions: Consistent with previous studies defining the immunoregulatory role of MDSCs, these results suggest that MDSC accumulation can alter the inflammatory state of the tumor, and indicate that mediators associated with the function of PMN-MDSCs can have a negative impact on outcome. Mechanistic studies aimed at identifying the functionally relevant mediators are ongoing.
Relationship of tumor mutational burden (TMB) to immunotherapy response in metastatic renal cell carcinoma (mRCC).
Authors: Maia Manuel C. , Almeida Lorena , Bergerot Paulo Gustavo , Dizman Nazli , Pal Sumanta K.
Published: February 2018

662

Background: Multiple studies across histologies (e.g., lung cancer, melanoma and bladder cancer) have linked TMB to response to checkpoint inhibition (CPI). However, the association in patients with mRCC remains unclear. Methods: From an institutional database, consecutive patients (pts) with mRCC who had comprehensive genomic profiling (CGP) done in the course of routine clinical care were assessed. Data pertaining to systemic therapy was collected, and for each patient, duration of therapy (DOT) on 1st immunooncology agent (DOT-IO) was computed. Furthermore, best response data (using a RECIST v1.1 defintion) was collected, and patients were characterized as either having clinical benefit (CB; defined as complete/partial response or stable disease) or no clinical benefit (NCB; progressive disease). CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 718X for up to 315 cancer-related genes plus introns from up to 28 genes frequently rearranged in cancer. TMB was estimated using the cumulative number of non-variant of unknown significance (non-VUS) and VUS genomic alterations (GAs). The correlation between TMB and DOT-IO as well as CB rate was assessed. Results: Of 31 patients (26:5 M:F) who received IO, 25 pts and 6 pts had clear cell and non-clear cell (papillary = 4; sarcomatoid = 1; chromophobe = 1) histologies, respectively. The most common 1st IO agent rendered was nivolumab (77%), and this was administered most commonly in the post-2nd-line setting (60%). The median number of GAs in the cohort was 10, with the most frequent GAs encountered being VHL (21%), TERT (10%) and PBRM1 (10%). When segregated in groups by estimate of TMB, DOT-IO was similar in high TMB and low TMB pts (71 days and 70 days, respectively; P = 0.39). The median estimated TMB was similar in pts with CB and NCB (11 and 10, respectively; P = 0.84). Conclusions: While previous studies in other histologies have suggested an association between TMB and IO response, our study fails to confirm these findings in mRCC. Given our limited sample size, this association warrants exploration in larger series.
Phase II trial of pexa-vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, in patients with metastatic, refractory renal cell carcinoma (RCC).
Authors: Kim Seong-Geun , Ha Hong Koo , Lim Sung-nam , De Silva Naomi S. , Pelusio Adina , Mun Jae Hee , Patt Richard H. , Breitbach Caroline J. , Burke James M.
Published: February 2018

671

Background: Pexa-Vec is a vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating anti-tumor immunity, direct oncolysis, and tumor vascular disruption. ( Nat Rev Cancer 2009). Pexa-Vec was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration ( Lancet Oncol 2008; Nature 2011). Methods: RCC patients failing at least 1 prior VEGF/R-targeted therapy received five weekly IV Pexa-Vec infusions. Starting at Week 6, patients with disease control or otherwise clinically benefitting from treatment could continue to receive IV infusions every 3 weeks. The primary study objective was radiographic response based on modified Response Evaluation Criteria (RECIST) 1.0. Secondary objectives included disease control rate, progression free survival and safety. Results: All seventeen patients enrolled received the initial 5 weekly Pexa-Vec infusions. Twelve patients received at least one additional infusion (median Pexa-Vec infusions = 8; range 5-12). The treatment regimen was well-tolerated. Transient influenza-like illness (100%), asthenia (47%), anemia (29%) and nausea (29%) were the most common adverse events. All patients were evaluable radiographically at Week 6. The RECIST disease control rate was 76% at Week 6 including 1 complete response. Conclusions: Pexa-Vec was well-tolerated and associated with one complete RECIST response and 76% disease control at Week 6 in patients with advanced RCC. Further trials of Pexa-Vec in RCC patients are warranted.
Impact of pre-existing diabetes mellitus on survival in stage I renal cell carcinoma.
Authors: Ryan Stephen , Bindayi Ahmet , Bloch Aaron , Nasseri Ryan , Hamilton Zachary , Yim Kendrick , Reddy Madhumitha , Wan Fang , Capitanio Umberto , Larcher Alessandro , Montorsi Francesco , Lane Brian R. , Noyes Sabrina L , Dey Sumi , Uzzo Robert , Joshi Shreyas , Derweesh Ithaar
Published: February 2018

676

Background: AUA guidelines recommend consideration of nephron sparing surgery in patients with comorbidities that are likely to impact renal function, such as diabetes mellitus (DM). We compared the impact of partial nephrectomy (PN) and radical nephrectomy (RN) on overall survival (OS) in patients with pre-existing DM and Stage I Renal Cell Carcinoma (RCC). Methods: Multicenter retrospective analysis of surgically treated Stage I RCC from 2005-16 with or without DM. Primary outcome was OS analyzed by DM+ or DM- and surgical approach (PN or RN) for AJCC Stage I. Logistic (OR) and Cox (HR) regression were utilized for OS. Results: 2173 patients were analyzed (1223 RN, 1819 PN, 555 DM+, 2487 DM-) with mean follow-up of 49.1 months. Increasing Age (OR 1.028, p = .009), RN (OR 2.446, p = .001), and most recent eGFR < 45 (OR 2.306 p = .002) remained significant on multivariate analysis for OS (Table 1). In the PN subgroup, DM+ or DM- was not associated with decreased OS (HR 1.48 p = 0.19). DM+ was associated with decreased OS in the RN subgroup (HR 1.97 p = 0.005). Conclusions: In Stage I RCC, DM and RN negatively impacted OS, while only RN remained significant on MVA. Subgroup analysis of PN showed that OS was similar in DM- and DM+ patients, but diagnosis of DM had a profound impact on OS in the RN group. This supports the guideline statements and offers evidence that urologists should prioritize nephron sparing surgery in patients with DM and Stage I Renal Cell Carcinoma.[Table: see text]
Characterization of the benefit-risk profile of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-naïve advanced renal cell carcinoma (aRCC; CheckMate 214).
Authors: Tannir Nizar M. , Hammers Hans J. , Amin Asim , Grimm Marc-Oliver , Rini Brian I. , Mekan Sabeen , McHenry M. Brent , Kollmannsberger Christian K.
Published: February 2018

686

Background: The phase 3 CheckMate 214 study demonstrated superior efficacy for N+I v S in intermediate/poor-risk aRCC patients (pts), with manageable safety (Escudier, ESMO 2017). Here we report additional data to define benefit-risk. Methods: Pts with clear-cell aRCC were randomized 1:1 to N 3 mg/kg + I 1 mg/kg every 3 wk for 4 doses followed by N 3 mg/kg every 2 wk, or S 50 mg daily orally for 4 wk (6-wk cycles). Primary endpoints were efficacy parameters in intermediate/poor-risk pts. Secondary endpoints included adverse event (AE) incidence in all treated pts. Select AEs were defined as AEs pooled by organ category that may differ from AEs caused by non-immunotherapies, may require immunosuppression, and whose early recognition may mitigate severe toxicity. Results: 1096 pts were randomized (pts treated: N+I: n = 547; S: n = 535). N+I showed statistically significant OS benefit, significantly higher ORR, numerically longer PFS, and better symptom control v S. 79% of N+I pts received all 4 I doses. Drug-related grade 3-5 AEs occurred in 46% with N+I v 63% with S; drug-related AEs leading to discontinuation occurred in 22% v 12%. Drug-related select AEs resolved in 72%-92% of N+I pts, except endocrinopathies (43%; Table). An analysis of the relationship between safety and efficacy will be presented. Conclusions: Drug-related select AEs with N+I were manageable, with the vast majority resolving except endocrinopathies. These additional data further support the favorable benefit-risk profile of N+I v S in CheckMate 214. Clinical trial information: NCT02231749. [Table: see text]
Identification and characterization of circulating tumor cells in post prostatectomy patients with localized high risk prostate cancer.
Authors: Friedlander Terence W. , Welty Christopher J. , Anantharaman Archana , Hough Jeffrey , Edwards Matthew , Stromlund Alise , Simko Jeff , Graf Ryon , Rodriquez Angel , Wang Yipeng , Carroll Peter , Cooperberg Matthew R. , Dittamore Ryan Vance , Paris Pamela
Published: February 2018

69

Background: Over 15% of men with newly diagnosed prostate cancer (PCa) have high-risk features that raise the recurrence risk. Better biomarkers could allow for even earlier detection of biochemical recurrence (BCR) and inform adjuvant treatment decisions. Circulating tumor cells (CTCs) may represent the earliest form of metastases, however their role as biomarkers in men with localized PCa is not well defined. Here, we aim to enumerate and molecularly and genomically analyze CTCs using an enrichment-free, unbiased CTC identification technology from men with high-risk, localized PCa after radical prostatectomy (RP) and correlate the analysis with clinical outcomes. Methods: Blood samples from 37 patients with high-risk, localized PCa were obtained 2-5 mos post RP and shipped to Epic. All nucleated cells were subjected to immunofluorescent staining for cytokeratin (CK), CD45, and AR. CTCs were identified using algorithmic analysis. CK+ CTCs were enumerated and subsequently analyzed for AR expression and individually sequenced for copy number alterations (CNA). Patients were followed for BCR, defined as detectable PSA > 0.2ng/dL. Progression free survival (PFS) was calculated using Kaplan-Meier and Cox proportional hazards. Results: CTCs were detected in 81.1%(30/37) of patients with an average of 5.2 CTCs/ml (range: 0 – 22.9) detected per patient. AR expression was detected in 18.9% (7/37) of patients. Ninety nine CTCs from 14 patients were picked and sequenced. CNAs were identified in CTCs in commonly mutated genes in PCa, including MYC amplification and CHD1 deletions. Patients with higher traditional CTC (CK+) burdens exhibited a trend towards shorter PFS (hazard ratio: 1.65; 95% confidence interval: 0.7-3.86; p = 0.13). Conclusions: There was a high incidence of CTC detection after RP in patients with high-risk, localized PCa. A trend toward shorter PFS was seen in those with higher CTC burden. Genomic alterations were detectable in CTCs and consistent with established CNAs in PCa. With further testing in appropriately powered cohorts early CTC detection after primary therapy could represent an informative biomarker to stratify patients with high risk PCa.
External beam radiotherapy (EBRT) and high dose rate (HDR) brachytherapy for intermediate and high-risk prostate cancer: Whole pelvis or prostate-only EBRT?
Authors: Tharmalingam Hannah , Tsang Yatman , Choudhury Ananya , Hoskin Peter ,   The UK National HDR Prostate Brachytherapy Database Group
Published: February 2018

86

Background: In high-risk prostate cancer, the risk of occult lymph node metastases in the pelvic lymph nodes can be as high as 40%. However, the use of whole pelvis radiotherapy (WPRT) in high-risk patients remains controversial with mixed retrospective evidence and two negative prospective trials. Data from a national UK database of patients treated with external-beam radiotherapy (EBRT) and high-dose rate (HDR) brachytherapy was reviewed to evaluate the benefit of pelvic treatment. Methods: From 2009 to 2013, 755 patients with intermediate- and high-risk prostate cancer (clinical stage ≥T2c, Gleason score ≥7 or presenting prostate-specific antigen (pPSA) ≥10) were treated with EBRT and HDR brachytherapy. The pelvic nodes to the level of the common iliac chain were treated in 370 patients with a dose of 46Gy in 23 fractions. The remaining 385 patients received radiotherapy to the prostate only (PORT) at a dose of 37.5Gy in 15 fractions. A single dose of 15Gy was delivered with HDR brachytherapy in each case. Corresponding biologic effective doses to the prostate were 107Gy and 100Gy respectively (α/β = 1.5). 96.5% of patients received ADT with a median duration of 24 months. Biochemical failure was defined as a PSA rise of ≥2ng/ml above nadir. Analysis used log-rank and Cox univariate and multivariate tests. Results: Median follow-up was 4.5 years; 5-year biochemical progression-free survival rates for the WPRT versus the PORT arms were 88% vs 80% (p < 0.05) for all patients and 89% vs 76% (p < 0.05) for high-risk patients. Differences in bPFS remained significant (p < 0.05) after accounting for Gleason score, pPSA, T stage and ADT duration as co-variates. There was no difference in overall survival. Conclusions: Whole pelvis EBRT with HDR brachytherapy appears to significantly improves 5-year biochemical progression-free survival in intermediate- and high-risk prostate cancer compared to prostate-only EBRT and HDR brachytherapy which persists after allowing for covariates including presenting tumour parameters and ADT use. The PIVOTAL boost trial in the UK will assess this further in a prospective randomised study.
Neoadjuvant enzalutamide and androgen deprivation therapy for high-risk prostate cancer: Early results from a feasibility trial.
Authors: VanderWeele David James , Turkbey Baris , Karzai Fatima , Harmon Stephanie , Sowalsky Adam G. , Ye Huihui , Wilkinson Scott , Chun Guinevere , Gold Samuel , Pinto Peter A. , Choyke Peter L. , Dahut William L.
Published: February 2018

94

Background: Intensive androgen-targeted therapy improves survival for patients with androgen naive metastatic prostate cancer. Neoadjuvant androgen deprivation therapy (nADT) with abiraterone for localized disease leads to complete responses (pCR) rates of up to 10%. In this study we tested the efficacy of nADT with enzalutamide for patients with high risk, localized disease and the ability of post-treatment multiparametric MRI (mpMRI) to evaluate response. Methods: A single institution trial (NCT02430480) evaluated nADT and enzalutamide 160 mg daily in patients with high risk non-metastatic prostate cancer. Patients underwent MRI-TRUS-guided fusion biopsy at screening and repeat mpMRI followed by radical prostatectomy (RP) after completing six months of therapy. Results: Twenty patients have completed therapy and undergone radical prostatectomy. Clinical characteristics were typical of those with high risk disease: median PSA 8.96 ng/ml (range 2.07-985.9) and clinical stage by mpMRI cT2 (one patient), cT3 (17 patients), or cT4 (2 patients); 7 patients had enlarged pelvic lymph nodes. Following 6 months of therapy, median pre-RP PSA was < 0.02 ng/ml (range < 0.02 – 0.35). On final pathology, 0 patients were upstaged, 5 (25%) were unchanged, and 15 (75%) were downstaged, including 3 (16%) pCR. Four patients were downstaged from N1 to N0. There was little correlation between post-treatment mpMRI tumor volume and pathologic tumor volume. Two patients had radiographic complete responses, one of whom had extensive residual disease. Conclusions: Six months of nADT with enzalutamide has activity in high risk, localized prostate cancer, with a small number of patients having exceptional responses. Standard analysis of mpMRI does not reliably characterize depth of response. Evaluation of molecular characteristics that predict exceptional response or intrinsic resistance is on-going. Patients are being followed for recurrence. Clinical trial information: NCT02430480.
The PACE trial: International randomised study of laparoscopic prostatectomy vs. stereotactic body radiotherapy (SBRT) and standard radiotherapy vs. SBRT for early stage organ-confined prostate cancer.
Authors: Morrison Kirsty , Tree Alison , Khoo Vincent , Van As Nicholas John ,   On Behalf of the PACE TMG
Published: February 2018

TPS153

Background: The development of Stereotactic Body Radiotherapy (SBRT) has provided a further treatment option for early stage prostate cancer. In addition to the benefits of an overall treatment time reduction, profound hypofractionation could result in therapeutic gain given the radiobiology of prostate cancer. Evidence suggests SBRT to be safe and effective; however randomised data is lacking comparing outcomes with standard treatment options. Aim: To assess whether SBRT offers therapeutic benefit in comparison to prostatectomy or standard radiotherapy. Methods: The PACE trial is an international multicentre phase III trial, comprising two parallel randomisation processes. Within PACE A, potential surgical candidates are randomised between radical prostatectomy and SBRT (36.25 Gy in 5 fractions). In PACE B, randomisation is between standard radiotherapy (78Gy in 39 fractions or 62Gy in 20 fractions) and SBRT (36.35Gy in 5 fractions). SBRT can be delivered using Cyberknife or gantry based techniques. Patients with low or intermediate risk prostate cancer are eligible for the trial, and are treated without the use androgen deprivation therapy. Follow up is for a period of 10 years. The aim is to recruit 234 patients to PACE A (117 in each arm) and 858 patients to PACE B (429 patients in each arm). Primary Objectives: PACE A: To determine whether there is improved quality of life after SBRT compared with surgery at 2 years post treatment, using EPIC score to measure urinary incontinence and bowel bother. PACE B: to determine whether SBRT is non-inferior to surgery in terms of freedom from biochemical/clinical failure at 5 years from randomisation. Progress: PACE A has been slower to recruit than anticipated due to the difficulties of a surgery versus radiotherapy randomisation. However, it is expected to reach target accrual, having recruited 57 patients from 3 centres. In contrast, PACE B is recruiting exceptionally well, open in 40 centres, and as of October 2017 recruited 762 patients. Accrual target is expected to be reached by the end of 2017. Clinical trial information: NCT01584258.
A phase 1b/2 study of CPI-1205, a small molecule inhibitor of EZH2, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Taplin Mary-Ellen , Hussain Arif , Shore Neal D. , Bradley Bill , Trojer Patrick , Lebedinsky Claudia , Senderowicz Adrian Mario , Antonarakis Emmanuel S.
Published: February 2018

TPS398

Background: EZH2 is frequently mutated and overexpressed in human cancer. High levels of expression are correlated with disease stage, aggressiveness, and poor outcome in patients with prostate cancer (Varambally, 2002). EZH2 inhibition restores androgen receptor expression and sensitivity to antiandrogen therapy in preclinical models of advanced prostate cancer, suggesting epigenetic reprogramming as an approach to overcome resistance to antiandrogen therapy (Ku, 2017). CPI-1205 is a potent, selective and cofactor-competitive EZH2 inhibitor, that inhibits both wild-type and mutant EZH2 catalytic activity in a reversible manner. Preclinical studies have shown profound anti-proliferative effects of CPI-1205 in treating both lymphoma and prostate cancer cell models. Antitumor activity of EZH2 methyltransferase inhibitors has been observed in patients with non-Hodgkin’s lymphoma. These observations support the clinical evaluation of CPI-1205 with standard doses of A/P or E in mCRPC. Methods: We present a Phase 1b/2 study to explore the safety and efficacy of two regimens of CPI-1205 in combination with either E or A/P. Key eligibility criteria include progressive mCRPC in patients previously treated with a second generation androgen inhibitor, ECOG 0-1 and measurable or non- measurable disease. Key exclusion criteria include > 1 second generation androgen inhibitor. During the phase 1b, sequentially enrolled cohorts will receive CPI-1205 at continuous – 28-day cycles combined with either standard dose of E (160mg PO once daily) or A/P (1000mg PO once daily/ 5 mg BID). The primary objective is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of each regimen. Secondary objectives include safety, pharmacokinetic, pharmacodynamics profiles and activity (PSA, circulating tumor cells, imaging) in mCRPC. Once RP2D is established, we will start a Phase 2 trial of a 2nd generation androgen inhibitor combined with CPI-1205.
Phase I dose-escalation study of 225Ac-J591 for progressive metastatic castration resistant prostate cancer (mCRPC).
Authors: Tagawa Scott T. , Vallabhajosula Shankar , Jhanwar Yuliya , Ballman Karla V. , Hackett Amy , Emmerich Lauren , Babich John , Sartor A. Oliver , Harshman Lauren Christine , Beltran Himisha , Molina Ana M. , Nanus David M. , Bander Neil Harrison
Published: February 2018

TPS399

Background: PC is a radiosensitive disease. PSMA is overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of beta-emitting radiolabeled anti-PSMA monoclonal antibody (mAb) J591 have demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable, reversible dose-limiting myelosuppression. Alpha emitters are significantly more potent with a shorter range than beta emitters. Though there is no direct tumor-targeting, the bone-targeting alpha emitter Ra223 is approved. Anecdotal reports of PSMA small molecule targeted alpha emitters have hinted at efficacy but are limited by xerostomia and in mouse models may lead to long-term renal damage. Intact mAb J591 has comparatively no to minimal distribution in salivary glands and kidneys. Preclinical studies demonstrated purity, immunoreactivity, and stability with efficacy in a xenograft model [AACR 2017]. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies (excluding beta-emitting bone-targeted radioisotopes) provided adequate organ function will undergo imaging with 68Ga-PSMA-11 PET/CT followed by a single dose of 225Ac-J591. Single-subject cohorts will be enrolled until grade > 1 attributable toxicity, then transition to 3+3 design. Cohort 1 = 13.3 KBq/kg with planned escalation up to 93.3 KBq/kg of 225Ac with fixed 20 mg J591. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS, and patient reported outcomes (FACT-P and BPI-SF). Correlatives include baseline/follow up PSMA imaging, CTC count (CellSearch) changes, tissue and circulating genomic assessment, and immune studies. Enrollment began in October, 2017. Clinical trial information: NCT03276572.