bluuebunny/crossref_metadata_2025 huggingface dataset:
Cabazitaxel in patients with locally advanced or metastatic transitional cell carcinoma who developed disease progression within 12 months of platinum based chemotherapy: Results of a phase II trial—CAB-B1.
Authors: Zarkar Anjali , Marshall Andrea , Dunn Janet , Davies Amanda , Ford Daniel , James Nicholas D.
Published: September 2018

4542

Background: There is a paucity of chemotherapy options for the treatment of patients who have relapsed following platinum based chemotherapy (CT). Cabazitaxel is a new taxane that showed in-vivo antiproliferative activity on resistant cell lines. Methods: CAB-B1 was a single centre phase II randomised controlled trial of Cabazitaxel (CAB; 25mg/m2 q3 week for 6 cycles) versus best supportive care (BSC) in patients (pts) with histologically proven transitional cell carcinoma (TCC), locally advanced or metastatic, who had received platinum based treatment and recurred within 12 months of the last cycle of CT. Primary outcome was overall response rate (ORR) using RESIST. Secondary outcomes were Progression Free Survival (PFS), Overall Survival (OS), Quality of Life assessment, safety and tolerability. A total of 96 pts required to detect differences in ORR from 5% to 30%; 80% power; 5% alpha level; 10% dropouts. Stopping rules, using Simon’s two stage optimal design to assess the individual effectiveness of CAB, required at least 1 ORR from 10 pts on CAB during 1st stage (i.e. total of 20 pts randomised) and 4 from 29 CAB pts in 2nd stage (assuming lower ORR limit of 0.05, target ORR of 0.20, 80% power, 5% alpha level). The trial was supported by grant from Sanofi. Results: Between January 2013 and October 2016, 20 pts were randomised (10 on each arm). 75% males; median age 68 years; 65% had recurred within 6 months of previous CT. BSC included paclitaxel CT for 9 pts and radiotherapy for 1 pt. 8 pts completed 6 cycles of CT (3 on CAB; 5 on BSC). 6 pts on each arm were evaluated for response after having 2/3 cycles; 2 pts had an ORR on CAB and 1 pt on BSC. 14 pts have died of disease (8 on CAB; 6 on BSC).Median OS was 5.6 months (95% confidence interval (CI) 0.7-15.2) for CAB pts and 8.2 months (95% CI 1.0-8.8) for BSC pts. Median PFS was 4.4 months (95% CI 0.7-9.4) for CAB pts and 4.1 months (95% CI 1.0-6.8) for BSC pts. Conclusions: It has been hard to recruit these poorly patients within a single centre, but CAB-B1 successfully reached the efficacy target for the 1st stage, showing that there could be a role for CAB in these pts. Clinical trial information: NCT01668459.
The clinical role of purified protein derivative skin test reaction in patients with non-muscle invasive bladder cancer treated with bacillus-Calmette Guerin.
Authors: Kikuchi Eiji , Niwa Naoya , Hayakawa Nozomi , Mizuno Ryuichi , Oya Mototsugu
Published: September 2018

4545

Background: We investigated the association between purified protein derivative (PPD) skin test reaction prior to BCG therapy and clinical outcomes, both oncological outcomes and occurrence of side effects, in BCG-naïve non-muscle invasive bladder cancer (NMIBC) patients. Methods: A total of 288 NMIBC patients who received PPD skin test prior to BCG therapy were included. The PPD skin test reaction was categorized into three groups: positive, slightly positive, and negative. The presence of an induration was positive. If an induration was absent, an erythema 10 mm or more and less than 10 mm corresponds to slightly positive and negative, respectively. Results: Sixty-six (22.9%), 149 (51.7%), and 73 (25.3%) patients had positive, slightly positive, and negative PPD skin test results, respectively. The 5-year recurrence-free survival rate of patients with a positive PPD skin test was 89.4±4.1%, which was significantly higher than that of patients with slightly positive (65.5±4.2%, p = 0.001) and negative (56.4±6.6%, p < 0.001) results. Multivariate Cox regression analysis demonstrated that a positive PPD skin test was independently associated with tumor recurrence (Hazard ratio of 0.213, p < 0.001) but not with stage progression. The occurrence rate of major side effects in patients with a positive BCG skin test (33.3%) was significantly higher than that in patients with slightly positive (26.8%) and negative PPD skin tests (13.7%). The incidence rate of fever persisting beyond 2 days or fever of ≥38°C in patients with a positive PPD skin test (18.2%) was significantly higher than that in patients with slightly positive (8.7%) and negative PPD skin tests (4.1%). Conclusions: NMIBC patients with a positive PPD skin test and who were treated with BCG therapy had a significantly lower tumor recurrence rate and higher incidence of major side effects such as fever persisting beyond 2 days or fever of ≥38°C. Our findings suggest that PPD skin test prior to BCG therapy can predict clinical outcomes following BCG therapy and provide useful information regarding who would experience a strong therapeutic effect for BCG therapy and BCG-related major side effects.
Oncological outcomes of intravesical gemcitabine and docetaxel for select patients with high grade recurrent NMIBC.
Authors: Milbar Niv , Kates Max , Chappidi Meera R. , Schoenberg Mark P. , Bivalacqua Trinity
Published: September 2018

4546

Background: Bacillus Calmette-Guerin (BCG) unresponsive patients with Non-Muscle Invasive Bladder Cancer (NMIBC) who prefer bladder preservation over Radical Cystectomy (RC) or are poor surgical candidates may be offered intravesical therapies. 2nd line intravesical Gemcitabine (GEM) combined with Docetaxel (DOCE) has been offered at Johns Hopkins Hospital (JHH). Our objective was to evaluate JHH experience with GEM/DOCE, and specifically to address appropriate endpoints for 2nd-line therapies in NMIBC. Methods: 33 patients who received full induction courses of GEM/DOCE since 2011, per the protocol adapted from Michael O’Donnell at U. Iowa, were identified in the IRB-approved JHH NMIBC database. Multivariable logistic regression determined factors associated with LG and HG recurrence. Cox proportional hazard models evaluated risk factors for disease free survival (DFS) and HG recurrence-free survival (HG-RFS). Results: Median DFS was 6.5 months with 42% 1-year and 24% 2-year DFS. Median HG-RFS was 17.1 months with 56% 1-year and 42% 2- year HG-RFS. Median HG-RFS among patients who initiated GEM/DOCE with HG pathology was 15.7 months, with 51% 1-year HG-RFS and 34% 2-year HG-RFS. Within initial HG-NMIBC presentation, 46% (13/28) had HG recurrence. 80% (4/5) of patients with initial LgTa had LG recurrence and 20% (1/5) had HG recurrence. There were no significant predictors for HG-RFS or DFS. There were 5 LG recurrences, and 16 HG recurrences, with 6 progressions among these. 7 patients underwent RC at a median of 14.9 months. Conclusions: GEM/DOCE is a well-tolerated alternative to immediate RC for highly selected patients with HG-NMIBC. As anticipated, including LG recurrence as an endpoint made GEM/DOCE appear less efficacious. However, since standard of care for LG recurrence is further intravesical therapy and recurrence does not result in worse cancer outcomes, it may not be an appropriate endpoint. Future studies of 2nd line therapies for NMIBC should identify endpoints based on clinically meaningful outcomes of interest.
Myeloid derived suppressor cells (MDSC) and inflammatory biomarkers in metastatic urothelial carcinoma (mUC).
Authors: Ornstein Moshe Chaim , Diaz-Montero C. Marcela , Rayman Patricia A. , Elson Paul , Haywood Samuel , Kim Jin Sub , Pavicic Paul G , Finke James , Rini Brian I. , Stephenson Andrew J. , Lamenza Marcelo , Dann Priscilla , Schach Kim , Devonshire Sarah , Ko Jennifer S , Fergany Amr Farouk , Ernstoff Marc S. , Hoimes Christopher J. , Garcia Jorge A. , Grivas Petros
Published: September 2018

4548

Background: MDSC are potent immunosuppressive cells with prognostic implications in many solid tumors. We previously reported significant correlations between MDSC and clinicopathologic features in localized UC. We hypothesized that different MDSC populations may correlate with inflammatory biomarkers and clinicopathologic features in mUC. Methods: Peripheral blood samples were collected from 46 mUC pts. MDSCs were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations & clinicopathologic factors. Results: Of 46 pts:78% men, median age at diagnosis 69 (31-83), 33% never smokers, 76% pure UC, 76% bladder primary, 28% prior intravesical therapy, 35% prior neoadjuvant chemotherapy, 56% prior cystectomy, 83% overweight/obese. G-MDSC was the predominant subset in WB (43%) and PBMC (39%), although M-MDSC were almost equally predominant in PBMC (35%). There was a correlation between the WB and PBMC values of T-, I-, and M- MDSC (p≤0.05). Higher % WB I-MDSC correlated with lower blood neutrophil/lymphocyte ratio (NLR) (p = 0.009), while higher WB G-MDSC and %PBMC G-MDSC were associated with higher NLR (p = 0.03 and p = 0.02, respectively). Higher I-MDSC / G-MDSC ratio was associated with lower NLR (r = -0.35, p = .02) and with various clinicopathologic parameters. Conclusions: HigherI-MDSC / G-MDSC ratio correlates inversely with NLR, which is considered an inflammatory biomarker and had prognostic value in other studies. The mechanism of MDSC interaction with inflammatory response in mUC pts merits evaluation and is being investigated in a larger cohort of UC pts on chemotherapy or immunotherapy (with longer follow up).
Everolimus (EVE) exposure as a predictor of toxicity (Tox) in renal cell cancer (RCC) patients (Pts) in the adjuvant setting: Results of a pharmacokinetic analysis for SWOG S0931 (EVEREST), a phase III study (NCT01120249).
Authors: Synold Timothy W. , Plets Melissa , Tangen Catherine M. , Heath Elisabeth I. , Palapattu Ganesh S. , Mack Philip C. , Stein Mark N. , Meng Maxwell V. , Lara Primo , Vogelzang Nicholas J. , Thompson Ian Murchie , Ryan Christopher W.
Published: September 2018

4566

Background: S0931 is assessing recurrence-free survival in RCC pts randomized to receive EVE versus placebo for one year following nephrectomy. To date, there has been a higher than expected dropout rate due to bothersome tox. Previous reports have shown an association between EVE trough levels and both tox and disease response in RCC pts. Therefore, we have assessed EVE trough levels to evaluate the relationship between measured exposure and probability of tox. This analysis has been approved by the DSMC. Methods: Patients received 10 mg daily EVE or placebo for nine 6-week cycles. Pre-dose whole blood samples collected pre-cycle 2 and pre-cycle 3 were analyzed for EVE. Pts with pre-cycle 2 and/or pre-cycle 3 EVE results were used in the analysis. When both trough levels were available, results were averaged. Pts were segregated into quartiles (Q) based on EVE levels and logistic regression was used to model the following adverse event outcomes using EVE trough as a predictor; any grade 3+ tox, grade 2+ triglycerides, grade 2+ hyperglycemia, grade 2+ oral mucositis, grade 2+ rash, and premature stopping of EVE. Hazard and odds ratios were adjusted for age, BMI and performance status. Results: This study reached its accrual goal and closed on 9/15/2016 with 1545 (775 EVE) randomized patients. A total of 386 pts are included in this preliminary analysis. Median EVE trough was 12.8 ng/mL (range 3.1, 75.6) per 10 mg dose. Event rates for tox were: any grade 3+ tox = 46%, grade 2+ triglycerides = 33%, grade 2+ hyperglycemia = 15%, grade 2+ oral mucositis = 34%, grade 2+ rash = 15%, and premature stopping of EVE = 40%. The risk of grade 2+ triglycerides was increased in Q2 and Q3 vs Q1 (OR = 2.95; p = 0.001 and OR = 3.48; p < 0.001). The risk of grade 2+ rash was increased in Q2 and Q4 vs Q1 (OR = 2.95; p = 0.02 and OR = 3.20; p = 0.01). There was also a trend towards an increased risk of any grade 3+ tox in Q3 vs Q1 (OR = 1.72; p = 0.07). Conclusions: This analysis has identified significant associations between EVE exposure and the probability of tox. EVE analysis is ongoing and the final results will be presented. Clinical trial information: NCT01120249.
Effects of pazopanib (PAZ) and sunitinib (SUN) dose modification on safety and efficacy in patients with metastatic renal cell carcinoma (mRCC) from COMPARZ.
Authors: Bjarnason Georg A. , Kollmannsberger Christian K. , Ahmad Qasim , Dezzani Luca , Elmeliegy Mohamed , Han Jackie , Nathan Paul D.
Published: September 2018

4574

Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS > 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. [Table: see text]
A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma.
Authors: Sheng Xinan , Yan Xieqiao , Tang Bixia , Chi Zhihong , Cui Chuanliang , Si Lu , Mao Li Li , Lian Bin , Li Si Ming , Zhou Li , Wang Xuan , Bai Xue , Kong Yan , Dai Jie , Guo Jun
Published: September 2018

4575

Background: CM082 is an oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination with other therapies. This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM082 in combination with everolimus in patients with metastatic renal cell carcinoma. Methods: A 3+3 dose escalation design with expansion cohort was utilized to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of CM082 plus everolimus at 5 mg PO daily for patients with metastatic clear cell renal cell carcinoma. Eligibility include PS 0-1, age ≥18 y, measurable disease, adequate organ function. Results: 22 patients (M/F: 16/6; median age: 55 y [range 32-69]; 21/22 pts [95.5%] had received prior anti-VEGF treatment (tx); 2/22 pts [9.1%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of CM082 (100 mg [n = 4]; 150 mg [n = 3]; 200 mg [n = 15]) in combination with everolimus 5 mg. One patient in cohort 1 was not evaluable for DLT due to consent withdrawal. DLT were observed in one patient: G4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, but was chosen as the optimal biological dose regimen. Median duration of tx was 24 wk (range 1-57, 7/22 [32%] pts ongoing. The most common tx-related adverse events (AEs), all grades, were proteinuria 96% (G3, 5%); leukopenia 77% (G3, 9%); neutropenia 59%, hypercholesterolemia 64%, anemia 50% (G3, 9%), hypertension 46% (G3, 14%), raised aspartate aminotransferase 41%, fatigue 45%, diarrhea 32%, hypertriglyceridemia 32% (G3, 5%) and thrombocytopenia 20% (G4, 5%). At 200mg, partial response (PR) was observed in 5/14 (36%) patients, durable stable disease (SD) (≥24 week) or PR were achieved in 10/14 (71%) patients. Median PFS was 170 days (5.7 months) at this cohort. Conclusions: CM082 200mg in combination with everolimus 5 mg appeared to be well tolerated when administered to pretreated patients with advanced RCC in this Ph1 study. The preliminary efficacy warrant further evaluationand and the follow-up Ph 2/3 study is underway. Clinical trial information: NCT02577458.
The association of tumor infiltrating CD8+ and Foxp3+ cells with overall response rate (ORR) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose aldesleukin (HD IL-2).
Authors: Pignon Jean-Christophe , Jegede Opeyemi , Novak Jesse , Mahoney Kathleen Margaret , Mier James Walter , Freeman Gordon J. , Atkins Michael B. , Catalano Paul J. , Signoretti Sabina , McDermott David F.
Published: September 2018

4576

Background: In the prospective, biomarker validation HD IL-2 “Select” study, durable remissions and prolonged survival were seen in both proposed “good” and “poor-risk” patients, based on clear-cell histology subclassification and carbonic anhydrase-9 (CA-9) IHC staining. Given the toxicity and limited efficacy of HD IL-2, efforts to improve its therapeutic index are warranted. Since the high-affinity receptor of IL2 is expressed on both T regulatory cells and activated effector T lymphocytes, we explored the association between HD IL-2 response and tumor infiltration of CD8+ T and FoxP3+cells. Methods: Archival tumor tissue was collected for pathologic analysis on 120 mRCC patients enrolled in the HD IL-2 “Select” trial.Density of tumor infiltrating CD8+ T cells and Foxp3+ cells (cell/mm2) were evaluated in the invasive margin (IM) and the tumor center (TC) by IHC and automated image analysis using Aperio algorithms. The association between ORR and immune cell density was assessed using Fisher exact test. Results: Tumor specimens of 89 patients were available for analysis. 24 pts experienced response (R, including 2 CR and 22 PR) and 65 pts did not respond (NR, including 11 SD and 54 PD). Baseline patient characteristics were similar between R and NR groups. A very high density of CD8+ cells in the IM, or a high density of Foxp3+ cells in the TC were significantly associated with ORR. A stronger association with ORR was found for patients having both high density of CD8+ cells in the IM and Foxp3+ cells in the TC. Conclusions: In this prospective, biomarker validation study, response to HD IL-2 was associated with a high density of CD8+ cells in the invasive margin, and a high density of Foxp3+cells in the tumor center. Independent validation is ongoing. To improve the predictive value of Foxp3, characterization of Foxp3 expressing cells (Tregs vs activated effector T cells) in highly infiltrated tumors is underway. [Table: see text]
Outcomes based on age in the phase 3 METEOR trial of cabozantinib (cabo) vs everolimus (eve) in patients with advanced renal cell carcinoma (RCC).
Authors: Donskov Frede , Motzer Robert J. , Voog Eric , Hovey Elizabeth J. , Grüllich Carsten , Nott Louise M. , Cuff Katharine Ellen , Gil Thierry , Jensen Niels Viggo , Chevreau Christine , Negrier Sylvie , Depenbusch Reinhard , Bergmann Lothar , Cornelio Izzy , Champsaur Anne , Escudier Bernard J. , Pal Sumanta K. , Powles Thomas , Choueiri Toni K.
Published: September 2018

4578

Background: The incidence of RCC increases with age with the highest incidence at ~75 years of age (Znaor, Eur Urol 2015). The Phase 3 METEOR trial (NCT01865747) showed a significant improvement in progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.74; P < 0.0001), overall survival (OS; HR 0.66, 95% CI 0.53–0.83, P = 0.0003), and objective response rate (ORR; 17% vs 3%; P < 0.0001) for cabo compared with eve in patients with advanced RCC previously treated with VEGFR TKIs (Choueiri, NEJM 2015, Lancet Oncol 2016). Here we present outcomes by 3 categories of age for the METEOR trial. Methods: 658 patients were randomized 1:1 to cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Endpoints included PFS, OS, and ORR. Subgroup analyses by age ( < 65, 65 to 74, and ≥75 years) are presented. Results: At baseline, 60% of patients were < 65 years old, 31% were 65 to 74 years old, and 10% were ≥75 years old. Subgroups by age generally had similar baseline characteristics in both arms. The HRs for PFS favored cabo for all age groups (HR 0.53, 95% CI 0.41–0.68 for < 65 years old; 0.53, 95% CI 0.37–0.77 for 65 to 74 years old; and 0.38, 95% CI 0.18–0.79 for ≥75 years old). ORR per independent radiology committee for cabo vs eve was 15% vs 5% for < 65 years old, 21% vs 2% for 65 to 74 years old, and 19% vs 0% for ≥75 years old. HRs for OS also favored cabo (HR 0.72, 95% CI 0.54–0.95 for < 65 years old; 0.66, 95% CI 0.44–0.99 for 65 to 74 years old; and 0.57, 95% CI 0.28–1.14 for ≥75 years old). Median OS for cabo vs eve was 21.4 mo vs 17.1 mo for < 65 years old, not reached vs 18.0 mo for 65 to 74 years old, and 18.4 mo vs 14.0 mo for ≥75 years old. Older patients more frequently had dose reductions (60% with cabo and 22% with eve for < 65 years old vs 85% with cabo and 36% with eve for ≥75 years old). Grade 3 or 4 adverse events were generally consistent with the safety profiles in the overall population although some events such as fatigue and hypertension occurred at a higher rate in older patients. Conclusions: Treatment with cabo improved PFS, ORR, and OS compared with eve in patients with advanced RCC irrespective of age. Adverse events in older patients were more frequently managed with dose reductions. Clinical trial information: NCT01865747.
Development and clinical validation of circulating tumor cell (CTC) biomarkers in clear cell renal cell carcinoma (ccRCC) for the OMNIVORE clinical trial.
Authors: Arafat Waddah , Desotelle Joshua , Rodems Tamara , McKay Rana R. , Abel Jason , Choueiri Toni K. , Lang Joshua Michael
Published: September 2018

4579

Background: New therapeutic strategies and biomarkers of treatment resistance are needed for metastatic ccRCC patients (pts) progressing on Nivolumab (Nivo). The upcoming OMNIVORE phase II clinical trial will evaluate whether adding Ipilumimab improves rPFS for pts with SD or PD on Nivo alone. We report development and clinical validation of predictive CTC biomarkers that will be evaluated in the OMNIVORE trial. Methods: We tested blood samples from ccRCC pts collected on biomarker trials at Dana Farber and U. of Wisconsin. Carbonic Anhydrase (CA) IX was used to capture CTCs in the VERSA platform to compare protein and gene expression signatures of resistance to Nivo. HLA and PD-L1 expression on CTC was quantified with independent confirmation with multicolor flow cytometry (FC). Results: We identified CTCs in 26/27 pts using RCC-specific CA IX antibody. Staining with CAXII and PAX8 confirmed CTC were of renal origin. The range of captured CK+/CAXII+/CD45- CTCs was 3-279 (median 15) from 18 pts. Multicolor FC found 8/9 pts with triple positive events for renal specific markers CAIX/CAXII/PAX8 [0-14.9%, median 0.32]. PDL1 and HLA staining was validated in cell line and pts samples with high reproducibility. PDL1 was expressed in < 10% of CTCs while HLA expression had high intra- and interpatient heterogeneity. Three pts had CTCs positive for both HLA and PDL1 that correlated with a high frequency of CTCs that were positive for 3 RCC markers (1.3, 5.1 and 14.9% of events) for an R² value of 0.92 (p < 0.0001). In 3 pts with ongoing response to Nivo (9-13 moths) triple positive events were 0, 0.2 and 0.3% (median 0.25%) and absent expression of PDL1/HLA. In 3 pts with early progression on Nivo ( < 5 mo), triple positive CTCs ranged 0.33-14.9% (median 5.05%) with CTCs from 2/3 pts positive for PDL1/HLA. Conclusions: We report the first identification of ccRCC CTCs using CAIX, CAXII and PAX8 as confirmatory markers. CTC frequency and PDL1/HLA expression is lower in Nivo responders versus pts with early progression. High but variable HLA expression suggests variant resistance mechanisms. The utility of theses predictive and pharmacodynamic biomarkers will be tested in the OMNIVORE trial.
Association of circulating tumor DNA (ctDNA) detection in metastatic renal cell carcinoma (mRCC) with tumor burden.
Authors: Maia Manuel Caitano , Bergerot Paulo Gustavo , Dizman Nazli , Hsu JoAnn , Jones Jeremy , Choueiri Toni K. , Sonpavde Guru , Lanman Richard B. , Banks Kimberly , Pal Sumanta K.
Published: September 2018

4582

Background: In a series of 224 pts with advanced RCC, we have previously reported ctDNA detection in 79% of pts (Pal SK et al ASCO GU 2017). Clinical factors associated with detection are unknown. Methods: Data was obtained from pts with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIAA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of Heng risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions. Results: 32 pts were assessed (M:F 19:13) with a median age of 62 (range, 34-84). 25 pts, 4 pts and 3 pts had clear cell, sarcomatoid and papillary histology, respectively. Heng risk was good, intermediate and poor in 13, 18 and 1 pt, respectively. Pts received a median of 2 lines of prior tx. Specifically, 4 pts were not on active therapy (tx), 16 pts were receiving VEGF-directed tx, 6 pts were receiving checkpoint inhibitors (CPIs) and 6 pts were receiving combined VEGF/CPI tx. ctDNA was detected in 16 pts (50%) with a median of 2 genomic alterations (GAs) per pt. No associations were found between Heng risk, histology or tx type and presence/absence of ctDNA. However, pts with detectable ctDNA had a higher SLD compared to pts with no detectable ctDNA (99.6 vs 50.0 mm; P = 0.041). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P = 0.023). TP53 and VHL alterations were the most frequent GAs in this series, each occurring in 25% of the cohort. All 3 pts with brain metastases had ctDNA detected. Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC pts with detectable ctDNA, and increasing SLD may be associated with a higher number of GAs. Further validation of these findings may help identify appropriate pts for ctDNA assessment and maximize yield in clinical practice.
T cell infiltration (TCI) in matched renal biopsy (bx) and nephrectomy (nx) samples in renal cell carcinoma (RCC).
Authors: Zahoor Haris , Pavicic Paul G , Przybycin Christopher , Elson Paul , Diaz-Montero C. Marcela , Finke James , Rayman Patricia A. , Gilligan Timothy D. , Grivas Petros , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I.
Published: September 2018

4587

Background: TCI in tumors has been investigated as a biomarker of response to checkpoint inhibitors. A neo-adjuvant trial of checkpoint inhibition in locally-advanced RCC is ongoing at Cleveland Clinic, where TCI in pre-treatment renal mass bx will be compared to post-treatment nx specimens. However, there are no data regarding the association of TCI in matched bx and nx samples without intervening treatment. Understanding this association will enable further study of this potential biomarker in future studies. Methods: Matched bx and nx samples (without intervening systemic therapy) were identified from patients with non-metastatic RCC. Selected tissue sections from bx and nx samples were reviewed, and marked for intra-tumoral lymphocytes by the Pathologist. Immunohistochemistry (IHC) was utilized to stain these selected tissue sections for T cell markers (CD3, CD4 and CD8), and additional immune markers including PD-1, PDL-1 and CD11b. Intra-tumoral staining was then quantified in the pre-marked tissue sections as counts per total tumor area surveyed. Spearman correlation (ρ) was used to measure the strength of association. Results: 30 matched pairs were investigated. The median interval between bx and nx was 2.8 (0.2-87.7) months. Clear cell was the most common histology (29/30; 97%). There was a positive correlation between the frequency of CD8+T cells between matched bx and nx samples (ρ= 0.39; p=0.03). CD3, CD4 and CD11b did not show significant correlation. (Table) PD-1 (bx 4/29, nx 16/29) and PDL-1 (bx 5/28, nx 10/28) expression was positive in the minority of samples. Conclusions: Bx material can potentially be used to assess the degree of CD8+ TCI in RCC nx samples. However the utility of bx evaluation for CD4+TCI and expression of PD-1, PDL-1 and CD11b requires further study. [Table: see text]
Impact of perioperative chemotherapy and radiation for locally advanced penile squamous cell carcinoma (PSCC).
Authors: Hathaway Amanda Redden , Morgan Charity , Yang Eddy Shih-Hsin , Diorio Gregory , Spiess Philippe E. , Sonpavde Guru
Published: September 2018

4589

Background: While neoadjuvant chemotherapy preceding radical surgery (S) for PSCC appears to provide the most optimal outcomes, there are no randomized studies. The impact of triple-modality S plus perioperative chemotherapy (C) plus radiation (XRT) for PSCC is unclear. The differential outcomes provided by perioperative XRT vs. perioperative C are also unclear. Given the absence of prospective trials, we retrospectively analyzed the U.S. National Cancer Database (NCDB) to study this issue. Methods: Data from the NCDB was obtained for pts with locally advanced PSCC from 1998-2011. Patients who underwent S for PSCC pathologic stage ≥1 with data for receipt of perioperative C and/or XRT and follow-up were eligible for analysis. The following variables were evaluated: pathologic stage, age, Charlson Comorbidity Index (CCI), race, overall survival (OS), socioeconomic status based on median income of area of residence and therapy (S+C, S+XRT, S+C+XRT). Treatment patterns were described. Multivariate analyses (MVA) were conducted to determine the impact of factors on OS with P < 0.05 considered significant. Results: A total of 418 pts were evaluable including 132 in the S+XRT group, 166 in the S+C group and 120 in the S+C+XRT group. The number of pts with stages 1, 2, 3, 4 and unknown were 26, 78, 146, 137 and 31, respectively. In the MVA, stage was independently significantly prognostic (p = 0.002), while age (p = 0.056) and CCI (p = 0.057) were trending significant. S+C+XRT was not statistically better than S+XRT (HR 1.37 [95% CI: 0.935 - 2.007]) or S+C (HR 0.834 [95% CI: 0.589 - 1.180]). Additionally, S+C was not associated with significantly different OS compared to S+XRT (HR 1.142 [95% CI: 0.790 - 1.652]). Limitations of a retrospective analysis apply. Conclusions: This is the largest retrospective study of perioperative therapy for locally advanced PSCC. Triple modality therapy (S+C+XRT) did not extend OS compared to dual modality therapy (S+C or S+XRT). Additionally, the analysis did not identify whether C or XRT should be preferred in pts receiving dual modality therapy. The phase II International Penile Cancer Adjuvant Trial (InPACT) will investigate these conundrums for this orphan malignancy.
Post hoc analysis of a phase III study to test the association between circulating methylated glutathione s transferase (mGSTP1) DNA levels and response to docetaxel (DTX) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Mahon Kate Lynette , Qu Wenjia , Lin Hui-Ming , Spielman Calan , Cain Daniel , Jacobs Cindy , Chi Kim N. , De Bono Johann S. , Higano Celestia S. , Clark Susan J. , Horvath Lisa
Published: September 2018

5014

Background: GSTP1 inactivation is associated with CpG island hypermethylation in > 99% prostate cancers. Detection of circulating mGSTP1 DNA predicts response to DTX and overall survival (OS) in phase I/II mCRPC cohorts. This post hoc analysis of a phase III study aims to test the association between circulating mGSTP1 DNA levels and outcomes. Methods: The phase III SYNERGY study tested DTX +/- custirsen as 1st line chemotherapy in mCRPC (n = 1022) with no OS benefit in the experimental arm. Serum samples were taken at baseline (BL) and preC3 of DTX +/- custirsen from 600 patients (pts) enrolled on the SYNERGY study. mGSTP1levels in free DNA were measured using a sensitive methylation specific PCR assay and correlated with PSA response, time to PSA progression (TTP) and OS. Results: On interim analysis of 300 pts, serum mGSTP1 was detectable at BL in 80% and preC3 in 44%. Undetectable preC3 mGSTP1 correlated with a ≥30% fall in PSA within 3m of starting DTX (p < 0.001). Detectable BL and preC3 mGSTP1 predicted shorter TTP after DTX (BL; HR 1.6 95%CI 1.1-2.3; p = 0.01 and preC3 HR 2.2 95%CI 1.6-2.9; p < 0.001). Detectable mGSTP1 at both time points predicted shorter OS (BL; median OS 18.4 vs 33.1m, HR 2.4 95%CI 1.6-3.7; p < 0.001 and preC3; median OS 13.9 vs 29m, HR 2.7 95%CI 2.0-3.6; p < 0.001). In those with detectable BL mGSTP1, 50% had undetectable preC3 mGSTP1 predicting > 30% fall in PSA within 3m (p < 0.001), improved TTP (HR 0.40 95%CI 0.29-0.57; p < 0.001) and improved OS (25.2 vs 13.9 m HR 0.38 95%CI 0.28-0.51; p < 0.001). On multivariable analysis including Hb, Karnofsky PS, LDH, PSA and visceral metastases, detectable preC3 mGSTP1 independently predicted shorter TTP (HR 1.9 95%CI 1.4-2.6; p < 0.001). Detectable mGSTP1at both time points independently predicted OS (BL; HR1.8 95%CI 1.2-2.8; p = 0.006 and preC3; HR 2.2 95%CI 1.6-3.0; p < 0.001). Results from the full cohort of 600 pts will be available for presentation at the meeting. Conclusions: This study should validate circulating mGSTP1 DNA as a marker of therapeutic benefit and prognosis in men with mCRPC receiving DTX and could be utilized for clinical management.
Development and validation of a prognostic model for overall survival in chemotherapy-naive men with metastatic castration-resistant prostate cancer (mCRPC) from the phase 3 prevail clinical trial.
Authors: Armstrong Andrew J. , Lin Ping , Higano Celestia S. , Sternberg Cora N. , Sonpavde Guru , Tombal Bertrand F. , Templeton Arnoud J. , Fizazi Karim , Phung De , Wong Elaine K , Krivoshik Andrew , Beer Tomasz M.
Published: September 2018

5022

Background: Prognostic models require updating to reflect contemporary medical practice. In a post hoc analysis of the phase 3 PREVAIL trial (enzalutamide vs placebo), we identified prognostic factors for overall survival (OS) in chemotherapy-naive men with mCRPC. Methods: Patients were randomly divided 2:1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined candidate prognostic factors (including treatment) were analyzed in a multivariable Cox model with stepwise procedures and in a penalized Cox proportional hazards model using the adaptive least absolute shrinkage and selection operator (LASSO) penalty (data cutoff June 1, 2014). A multivariable model predicting OS was developed using the training set; the predictive accuracy was assessed in the testing set using time-dependent area under the curve (tAUC). The testing set was stratified based on risk score tertiles (low, intermediate, high), and OS was analyzed using Kaplan-Meier methodology. Results: Demographics, disease characteristics, and OS were balanced between the training and testing sets; median OS was 32.7 months for both datasets. There were no enzalutamide treatment-prognostic factor interactions (predictors). The final multivariable model included 11 prognostic factors: prostate-specific antigen, treatment, hemoglobin, neutrophil-lymphocyte ratio, liver metastases, time from diagnosis to randomization, lactate dehydrogenase, ≥ 10 bone metastases, pain, albumin, and alkaline phosphatase. The tAUC was 0.74 in the testing set. Median (95% confidence interval [CI]) OS for the low-, intermediate-, and high-risk groups (testing set) were not yet reached (NYR) (NYR–NYR), 34.2 months (31.5–NYR), and 21.1 months (17.5–25.0). The hazard ratios (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.20 (0.14–0.29) and 0.40 (0.30–0.53), respectively. Conclusions: Our validated prognostic model incorporates factors routinely collected in chemotherapy-naive men with mCRPC treated with enzalutamide and identifies subsets of men with widely differing survival times. Clinical trial information: NCT01212991.
Real-world outcomes in second-line treatment of metastatic castration-resistant prostate cancer (mCRPC): The Prostate Cancer Registry.
Authors: Chowdhury Simon , Birtle Alison J. , Bjartell Anders , Costa Luis , Feyerabend Susan , Galli Luca , Kalinka-Warzocha Ewa , Kramer Gero , Lumen Nicolaas , Maroto Pablo , Matveev Vsevolod B , Paiss Thomas , Pisconti Salvatore , Spaeth Dominique , Veiga Francisco Gomez , Antoni Laurent , Klumper Edwin , Wapenaar Robert , van den Berg Erik , Lee Emma
Published: September 2018

5028

Background: The Prostate Cancer Registry is a prospective, international observational study that began in June 2013 and will assess the characteristics and management of > 3000 mCRPC patients (pts) in routine clinical practice for ≤ 3 years. Methods: Data were collected from men with mCRPC irrespective of treatment (tx). This interim analysis reports baseline characteristics, txs and outcomes in pts with ≥ 12-month follow-up receiving second-line mCRPC tx following docetaxel as the only prior mCRPC tx. Results: The most commonly initiated second-line mCPRC txs (n ≥ 50) were abiraterone acetate + prednisone (AAP, n = 177), enzalutamide (ENZ, n = 94), or cabazitaxel (CAB, n = 70). Characteristics and outcomes are shown in the table below. TTP was not significantly different for AAP vs ENZ, AAP vs CAB or ENZ vs CAB (propensity score adjusted p = 0.5954, p = 0.5888 and p= 0.4808, respectively). Conclusions: In this real-world study, clinical outcomes reveal that, in pts receiving second-line mCRPC tx after docetaxel, TTP was similar across tx groups; QoL improved most in AAP and ENZ groups and no deterioration was observed most in AAP and CAB groups. Clinical trial information: NCT02236637. [Table: see text]
Sipuleucel-T (sip-T) to induce cytolytic T lymphocyte (CTL) activity against target antigens in men with hormone-sensitive and castration-resistant prostate cancer (CRPC).
Authors: Drake Charles G. , Antonarakis Emmanuel S. , Petrylak Daniel Peter , Quinn David I. , Kibel Adam S. , Chang Nancy N. , Dearstyne Erica , Campogan Dwayne , Haynes Heather , Vu Tuyen , Sheikh Nadeem Anwar , Small Eric Jay
Published: September 2018

5046

Background: Sip-T is an FDA-approved autologous cellular immunotherapy for patients with asymptomatic or minimally symptomatic metastatic CRPC (mCRPC), manufactured from peripheral blood mononuclear cells (PBMCs) cultured with the immunogen PA2024 (prostatic acid phosphatase [PAP] conjugated to granulocyte macrophage colony-stimulating factor). Treatment with sip-T induces cellular and humoral immune responses to both PA2024 and PAP (Antonarakis, ASCO 2015; Petrylak, ECC 2015; Small Clin Cancer Res 2015). To further elucidate the mechanism of sip-T–induced immune responses, we evaluated proliferative and cytolytic characteristics of PA2024- and PAP-specific T cells. Methods: Antigen-specific proliferation of CD4 (T helper [TH]) and CD8 (CTL) T cells was quantified using flow cytometry. To assess CTL lytic activity, cell-surface CD107a expression, indicating lysosomal fusion with the cell membrane and expulsion of lytic enzymes, was measured after stimulation with PAP or PA2024. CTL lytic activity was assessed in 13 patients (from 3 sip-T trials [NCT01431391, NCT01981122, and NCT01487863] in hormone-sensitive PC and mCRPC patients) and 1 healthy donor (control). Results: In sip-T–treated patients, a significant increase in proliferation of both CTLs and TH cells was detected in response to PA2024 (p < 0.05) and PAP (p < 0.10) at week 6 compared with baseline. Increased PA2024-specific proliferation was maintained in TH cells through week 26 (p < 0.05). CTL CD107a expression increased in sip-T patient samples stimulated with PAP and PA2024 but not in the healthy donor control. Preliminary analyses suggest that patients with longer overall survival (OS) may have greater CTL CD107a activity. Conclusions: Sip-T treatment was associated with well-maintained antigen-specific cellular responses, including robust CTL responses, demonstrating sip-T induces antigen-specific tumor lysis and providing a biologic basis for OS benefit in mCRPC patients. Ongoing work will examine whether patients with longer OS display greater CTL activity. Clinical trial information: NCT01431391; NCT01981122; NCT01487863.
Circulating tumour cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer.
Authors: De Laere Bram , Van Oyen Peter , Ghysel Christophe , Ost Piet , Demey Wim , Hoekx Lucien , Schrijvers Dirk L. , Brouwers Barbara Anna Henk , Lybaert Willem , Everaert Els Grieta , Ampe Jozef , Van Kerckhove Piet , De Maeseneer Daan Joost , Strijbos Michiel Hendrik , Bols Alain , Fransis Karen , Van den Eynden Gert , Vandebroek Jean , Van Laere Steven J , Dirix Luc Yves
Published: September 2018

5049

Background: A heterogeneous landscape of patients with metastatic castration-resistant prostate cancer (mCRPC) exists in current clinical practice. We investigated the prognostic value of CTC enumeration and dynamics, in the context of second-line endocrine therapies (i.e. abiraterone or enzalutamide). Methods: In a prospective, multicentre study blood samples were collected from patients with mCRPC at baseline (n = 147) and follow-up (n = 95/147(64.6%)). At baseline, patients were stratified in favourable ( < 5 CTCs/7.5mL) and unfavourable (≥5 CTCs/7.5mL) groups, whereas at follow-up, in those demonstrating a stable, in- or decreasing CTC count. PFS and OS were compared between groups. PSA changes at 10-12 weeks were evaluable in 83 patients. Results: Patients with ≥5 CTCs/7.5 mL (n = 59) at baseline had a shorter PFS (3.9 vs. 11.3 months, p< 0.0001) and OS (9.34 months vs. not reached, p< 0.0001). Patients demonstrating increasing CTCs (n = 21) on therapy had a shorter PFS (4.03 vs. 10.36 vs. 13.08 months, p < 0.0001) and OS (11.2 months vs. not reached, p < 0.0001), compared to patients with decreasing (n = 41) and stable (n = 33) CTCs, respectively. Multivariate Cox regression showed that the number of CTCs (HR (95%CI): 1.0054 (1.0006–1.010), p= 0.0260) and an increasing follow-up CTC count (HR (95%CI): 2.8987 (1.2856–6.536), p= 0.0103) were independent predictors of PFS. CTC increase was the sole independent predictor for OS (HR (95%CI): 7.3512 (1.7953–30.101), p= 0.0055). At 10-12 weeks, a PSA response of ≥30% and ≥50% was achieved in 46/83 (55.4%) and 33/83 (39.8%) patients, respectively, which was statistically different between chemo-naive or -pretreated patients (≥30%: p= 0.0395), patients with increasing, stable or decreasing CTC counts (≥30%: p= 0.0019; ≥50%: p= 0.0032), and patients with increasing or stable/decreasing CTC counts (≥30%: p= 0.0006; ≥50%: p= 0.0014). Conclusions: CTC levels are associated with PFS and OS in mCRPC patients, starting a new line of endocrine therapy. Follow-up CTC enumeration is associated with PSA response and its dynamics is an independent predictor of PFS and OS, thereby demonstrating the pharmacodynamic properties of CTCs.
Incidence of intrathoracic (IT) metastases detected by 68Ga-PSMA-11 PET in early stage prostate cancer (PC).
Authors: Aggarwal Rahul Raj , Cooperberg Matthew R. , Nguyen Hao Gia , Small Eric Jay , Ryan Charles J. , Feng Felix Yi-Chung , Chang Albert , Greene Kirsten L , Carroll Peter , Hope Tom
Published: September 2018

5056

Background: Standard imaging in early stage PC has focused on detecting metastases (mets) within the abdomen and pelvis. The incidence of IT mets (lung, mediastinal, or supraclavicular) mets is unknown, but presumed to be negligible. Whole body 68Ga-PSMA PET has greater sensitivity compared to conventional imaging, affording the opportunity to estimate the incidence of IT mets. Methods: Newly diagnosed or biochemically recurrent (BCR) PC patients (pts) with apparent localized disease on standard imaging were enrolled on a prospective study of 68Ga-PSMA PET imaging between June 2015 and January 2017 and were analyzed for incidence of IT mets. Positive lesions were defined as uptake higher than blood pool. When appropriate, patients underwent confirmatory biopsy of the PSMA-avid IT lesions. Results: 364 pts underwent 68Ga-PSMA PET imaging, including 121 (33%) pts with newly diagnosed PC and 243 (67%) pts with BCR. 145 pts (40%) had at least 1 PSMA-avid metastasis. PSMA-avid IT mets were detected in 20 pts (5.5% of overall cohort; 13.8% of those with ≥ 1 PET-positive mets), including 3 newly diagnosed (2.5%) pts and 17 (7.0%) pts with BCR. 9 of 20 pts (45%) had IT mets as the only detectable site of metastasis on PET. Biopsy of the PSMA-avid IT lesion was found to harbor PC in 5/5 patients (100%). Sites of detection included: supraclavicular node, n = 9 (2.5%); mediastinal node(s), n = 10 (3.6%), and visceral lung, n = 4 (1.0%). In the entire study cohort of 364 pts, 43% of pts had a Gleason Score ≥ 8 at diagnosis, median PSA was 4.87 ng/mL (range: 0.04 – 83.7), and the median PSA doubling time was 6.2 months (range: 0.4 – 78.3) in patients with BCR. There were no significant differences in PSA, PSA doubling time, Gleason grade, or stage between patients harboring IT metastases vs. those who did not. Conclusions: IT mets are detected by 68Ga-PSMA PET imaging at an appreciable frequency in early stage PC with apparent localized disease by conventional imaging, which may significantly impact management in these cases. Further studies are warranted to validate these findings and determine the optimal strategy for the detection and treatment of supradiaphragmatic metastases in newly diagnosed and biochemically recurrent PC. Clinical trial information: NCT02918357.