bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erdafitinib (ERDA; JNJ-42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRa): Phase 2 continuous versus intermittent dosing.
Authors: Loriot Yohann , Necchi Andrea , Park Se Hoon , García-Donas Jesús , Huddart Robert A , Burgess Earle Frederick , Fleming Mark T. , Rezazadeh Arash , Mellado Begona , Varlamov Sergei , Joshi Monika , Duran Ignacio , OHagan Anne , Avadhani Anjali Narayan , Zhong Bob , Stuyckens Kim , Dosne Anne-Gaëlle , Siefker-Radtke Arlene O. ,   On Behalf of the BLC2001 Study Group
Published: February 2018

411 Background: Although immune checkpoint inhibitors (ICI) have improved outcomes in some pts with platinum-resistant mUC, many pts (eg, pts with TCGA luminal 1 tumors, many of whom are FGFRa) may not benefit. ERDA, a pan-FGFR (1-4) inhibitor, demonstrated promising phase 1 activity: 11 partial responses among 24 FGFRa mUC pts. We report efficacy and safety of ERDA in the ongoing global open-label phase 2 study BLC2001 (NCT02365597). Methods: Pts had measurable mUC with specific FGFR2/ FGFR3 mutations or translocations per central lab Janssen assay, ECOG 0-2, and were chemorefractory (progressed during/following ≥ 1 line of prior systemic chemo or ≤ 12 mos of [neo]adjuvant chemo). Cisplatin-ineligible, chemo-naïve pts, and prior ICI treatment were allowed. Pts were randomized 1:1 to 28-d cycles of oral 6 mg/d continuous dosing (6 C) or 10 mg/d intermittent 7 d on/7 d off dosing (10 I) ERDA; the dose was further uptitrated if no significant treatment-related adverse events (TRAEs) were observed. The primary end point was ORR. Results: 78 pts received 6 C and 33 pts received 10 I (10 I cohort stopped early) ERDA. 31 pts in 6 C arm were further uptitrated. Across arms, 50% had ≥ 2 prior lines of therapy; 93% were chemorefractory. Confirmed ORRs (RECIST 1.1) were 35% and 24%, and disease control rates (CR+PR+SD) were 74% and 73% in the 6 C and 10 I arms, respectively. Adverse events (AEs) were manageable, and there were no treatment-related deaths (Table). Treatment is ongoing in 10 pts. Conclusions: ERDA (6 C or 10 I) has promising efficacy and tolerability in pts with FGFRa mUC. Based on these results and ERDA pharmacometric modeling, dosing was optimized at 8 mg/d (continuous), and this cohort is ongoing. Phase 3 study is planned. Clinical trial information: NCT02365597. [Table: see text]
Efficacy of programmed death 1 (PD-1) and programmed death 1 ligand (PD-L1) inhibitors in patients with FGFR mutations and gene fusions: Results from a data analysis of an ongoing phase 2 study of erdafitinib (JNJ-42756493) in patients (pts) with advanced urothelial cancer (UC).
Authors: Siefker-Radtke Arlene O. , Necchi Andrea , Rosenbaum Eli , Culine Stephane , Burgess Earle Frederick , O'Donnell Peter H. , Tagawa Scott T. , Zakharia Yousef , OHagan Anne , Avadhani Anjali Narayan , Zhong Bob , Santiago-Walker Ademi E. , Roccia Tito , Loriot Yohann 
Published: February 2018

450 Background: FGFR3 mutations appear to be enriched in luminal 1 UC, which have low expression of markers associated with an immune response, including CD8-T-effector gene expression levels. Objective response rate (ORR) to PD-1 and PD-L1 inhibitors in luminal 1 tumors appear lower (10-19%) than in infiltrated luminal 2 and basal 3 tumors (ORR 31-34%). This suggests FGFR3 mutations occur within a group of tumors less likely to benefit from immune checkpoint inhibition (ICI). Here we describe outcomes of a subgroup of pts with FGFR2/3 mutations and gene fusions, previously treated with PD-1/PD-L1 inhibitors and included in an ongoing erdafitinib phase 2 study. Methods: Patients who had received prior immunotherapy for advanced UC were selected from those enrolled on BLC2001, an ongoing phase 2, open-label study of the pan-FGFR inhibitor erdafitinib in subjects with advanced UC with specific FGFR2/3 gene alterations (NCT02365597). We explored investigator-reported clinical outcomes including ORR and median time to progression (TTP) of pts treated with ICI preceding erdafitinib therapy. Results: 28/203 pts had previously received anti PD-1 or anti PD-L1 treatment. In this subgroup, the median age was 67.0 y; 82% were male, 79% had an ECOG score ≤1, 36% had liver metastases, and 93% had ≥2 prior lines of systemic therapy. The response rate to anti PD-1/PD-L1 agents was 3.6% (95% CI, 0.1%-18.3%) with one partial response. Median TTP was 3.4 mo (range 2-15 mo; 95% CI, 2.3-4.9). Conclusions: In this post-hoc analysis, FGFR mutations and gene fusions seem to select for a group of pts less likely to respond to immune checkpoint inhibition. Although caution is needed due to the retrospective nature of the data, the presence of these alterations may reflect an unmet need with currently approved agents. This finding highlights the need for FGFR alteration testing and an effective FGFR-targeted therapy. Clinical trial information: NCT02365597.
Phase Ib study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with urothelial cancer of the bladder: BTCRC-GU15-023 study.
Authors: Joshi Monika , Tuanquin Leonard , Kaag Matthew , Zakharia Yousef , Liao Jason , Merrill Suzanne , Musapatika Dana , DeGraff David , Zheng Hong , Warrick Joshua , Holder Sheldon L. , Stein Mark , Drabick Joseph J. 
Published: February 2018

455 Background: There is a significant variation in the treatment of locally advanced unresectable (T2-4 N0-2 M0) or cisplatin-ineligible (non-cis) bladder cancer (BC) patients (pts). The advent of immunotherapy (IO) in non-cis stage IV BC has been promising (response rate [RR] 23%; median survival 16 mo) but we are still in need of novel combinations for locally advanced unresectable BC. Durvalumab (Durva) is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1 on T-cell receptors. It has shown efficacy in platinum refractory BC with RR of 17%. Radiation (RT) is also effective in BC and can upregulate pro-inflammatory signals allowing for improved antitumor activity of IO. We report the safety data from phase Ib trial of combining RT with Durva (DurvaRT) in locally advanced BC. Methods: Treatment (Rx) naïve or post neoadjuvant chemotherapy pts with T3-4, N0-2, M0 who were either unresectable or unfit for surgery were treated with DurvaRT followed by Durva. Rx naïve locally advanced non-cis pts were also included in the study. DurvaRT: Durva 1500mg D1, D28 plus concurrent RT, 64.8Gy given in 36 fractions over 7weeks starting D1. These patients then started adjuvant Q4 weekly Durva after 4 weeks for 12 months. Primary end point for Ph Ib was safety of combining Durva with RT during 7-weeks period. Results: We enrolled 6 pts on phase Ib. 5/6 pts had completed the DurvaRT phase and none of them had any dose limiting toxicity. The table below summarizes the treatment related adverse events (TRAE). Post DurvaRT 3/4 pts have ongoing ORR; 1 pt. had progression; Rx response evaluation in 2 pts is ongoing. Clinical trial information: NCT02891161. Conclusions: DurvaRT was tolerable in pts with locally advanced unresectable BC, where there is a dearth for good Rx options. No grade 3 immune related AEs were observed during DurvaRT. Further investigation with DurvaRT is ongoing to evaluate the efficacy in this subset of pts (Clinical trial # NCT02891161).[Table: see text]
RUSSCO-RSP study of immunohistochemistry (IHC) diagnostic assays for PD-L1 expression in urothelial cancer (UC).
Authors: Tsimafeyeu Ilya , Zavalishina Larisa , Povilaitite Patrisia , Raskin Grigory , Andreeva Yulia , Petrov Alexey , Kharitonova Ekaterina , Pugach Inna , Rumyantsev Alexey , Frank Georgy , Tjulandin Sergei ,   RUSSCO-RSP study group
Published: February 2018

489 Background: This collaborative Russian Society of Clinical Oncology (RUSSCO) and Russian Society of Pathology (RSP) study assess the extent of concordance between three validated, commercially available PD-L1 IHC assays for UC patients. Methods: Tumors from 100 UC patients were stained with SP142 (Ventana), 22C3 (Dako) and SP263 (Ventana) clones as used in the clinical trials of second-line therapy of atezolizumab, pembrolizumab and durvalumab. Four trained pathologists independently evaluated the percentages of tumor (TC) and tumor infiltrating immune cells (IC) staining positive at any intensity. One test-specific cutoff rule for each assay in this analysis was pre-specified as: IC ≥5% for SP142, TC+IC ≥10% or TC ≥10% for 22C3, and TC ≥25% or IC ≥25% for SP263. Results: 300 IHC slides were scored. Patients were predominantly male (89%) with T1 (45%) and T2 (45%) stages, respectively. The percent of IC staining across 3 assays is shown to be higher than for TC staining (45% vs. 8% for SP142; 55% vs. 24% for 22C3; 72% vs. 27% for SP263). Pearson Correlation Coefficients for IC were: 0.5, 0.69 and 0.85 between SP142/22C3, SP263/22C3 and SP142/SP263, respectively. Pearson Correlation Coefficients for TC were: 0.93, 0.99 and 0.91 for the same pairs. Table indicates the agreement analysis using recommended individual cutoffs for each test. Conclusions: If a patient with UC is classified as negative by one of the three single tests using the corresponding recommended cutoff rule, the patient will be classified as negative by any other test with a high likelihood (91%-100%), and, therefore, repeated testing can be avoided.[Table: see text]
Fibroblast growth factor receptor 3 (FGFR3), peroxisome proliferator-activated receptor gamma (PPARg), and outcomes with nivolumab (nivo) in metastatic urothelial cancer (UC).
Authors: Galsky Matt D. , Saci Abdel , Szabo Peter , Wang Li , Zhu Jun , Azrilevich Alex , Fischer Bruce S. , Necchi Andrea , Siefker-Radtke Arlene O. , Sharma Padmanee 
Published: February 2018

511 Background: Prior studies have correlated FGFR3 mutations (mut) and increased PPARg expression with decreased T-cell infiltration raising the possibility that these might represent mediators of PD-1/PD-L1 blockade resistance in luminal UC and targets for combination strategies. The causality of these associations remains unclear and the clinical relevance in PD-1/PD-L1 blockade treated patients has been underexplored. Methods: Archival tumor specimens from patients enrolled on CheckMate 275, a phase 2 trial of nivo in patients with platinum-resistant metastatic UC, underwent whole exome sequencing (WES) and gene expression profiling (HTG EdgeSeq). CD8 expression was determined by immunohistochemistry. Results: WES and gene expression data was available for 139 and 217 patients, respectively; the baseline characteristics and outcomes of both cohorts were similar to the full CheckMate 275 cohort. FGFR3mut were detected in 15 patients (11%) and correlated with higher FGFR3 gene expression. Neither FGFR3mut nor FGFR gene expression correlated with CD8 expression (Pearson's r -0.13; p=0.16) or with response rate (RR), progression-free survival (PFS), or overall survival (OS); RR in FGFRmut vs. FGFRwt = 20% vs 20%. PPARg gene expression was inversely correlated with CD8 (Pearson’s r -0.44; P <0.001) and IFNg gene expression (Pearson’s r -0.52; P <0.001). Higher PPARg gene expression was associated with inferior outcomes (Table); RR in PPARg highest vs lowest tertile = 15% vs 24%. Conclusions: FGFR3 alterations (mut/increased expression) do not preclude response to nivo and were not associated with decreased CD8. Higher PPARg expression was associated with decreased CD8, lower RR to nivo, and significantly shorter PFS and OS. These data support exploring therapeutic modulation of PPARg or downstream mediators in an effort to overcome resistance to PD-1/PD-L1 blockade. Cox proportional hazards model. [Table: see text]
Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies.
Authors: Nadal Rosa Maria , Mortazavi Amir , Stein Mark , Pal Sumanta K. , Davarpanah Nicole N. , Parnes Howard L. , Ning Yang-Min , Cordes Lisa M. , Bagheri Mohammadhadi H. , Lindenberg Liza , Thompson Ryan , Steinberg Seth M. , Moore Tina , Lancaster Tiffany , Velez Milisyaris , Mena Esther , Costello Rene , Bottaro Donald , Dahut William L. , Apolo Andrea B. 
Published: February 2018

515 Background: Tolerability and efficacy of CaboNivo and CaboNivoIpi were demonstrated in the initial phase I cohort, prompting longer follow-up and the addition of expansion cohorts to further evaluate both combinations Methods: Phase I cohort had 7 dose levels (DL). Recommended phase 2 doses for CaboNivo=Cabo 40mg/Nivo 3mg/kg (DL2) & CaboNivoIpi=Cabo 40mg/Nivo 3mg/kg/Ipi 1mg/kg (DL6) (Nadal ESMO 2017).In expansion cohorts, pts were treated: [1] DL8: Cabo 40mg/Nivo 1mg/kg/Ipi 3mg/kg; [2]DL2: mUC, metastatic renal cell carcinoma (mRCC), adenocarcinoma bladder (AcB): post-PD-1-PDL1 inhibitor mUC (p-mUC), and [3] DL6 mRCC. Objectives: safety, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) & overall survival (OS). Results: 75 pts enrolled. Median age 59 yo. 83% male, 17% female. 47 treated with CaboNivo (mUC n=24; AcB n= 9; germ cell tumor (GCT) n= 5; castrate-resistant prostate cancer (CRPC) n= 4; bladder squamous cell carcinoma (SCC) n= 2; penile n=1; mRCC n= 7). 28 treated with CaboNivoIpi: (mUC n=8; penile n=3; CRPC n=7; Sertoli n=1; mRCC n=6; bladder small cell carcinoma n=1; renal medullary carcinoma (RMC) n=2). Any grade (G) adverse events (AEs) (CaboNivo 96% & CaboNivoIpi 96%)/G3–4 AEs (CaboNivo 62% & CaboNivoIpi 71%). Most common any G, CaboNivo: fatigue 70%, diarrhea 60%, AST/ALT 60%, hypophosphatemia (hypoP) 45% & CaboNivoIpi: fatigue 71%, diarrhea 68%, hypoP 50%, AST/ALT 43%. Most common G3-4, CaboNivo: lipase 17%, hypoP 15%, fatigue 6% & CaboNivoIpi: hypoP 21%, AST/ALT 14%, lipase 14%. Selected irAs: colitis (2.6%), hepatitis (2.6%), pneumonitis (2.6%), aseptic meningitis (1.3%). ORR: 36%; 3CR (2mUC, 1SCC) & 20PR (5mUC, 2SCC, 7mRCC, 2Penile, 2AcB, 1CRPC, 1RMC). mDOR: 24.1 mo [95% CI: 14.7-NR], mPFS: 7.2 mo [95%CI: 5.1-18.4], mOS:18.8 mo [95%CI: 10.6-NR]. OS 6/12 mo: 83%/61%. Cohort of p-mUC pts(n=5):1PR/3SD/1PD Conclusions: Updated results from phase I and expanded cohorts confirm initial safety findings and promising antitumor activity for both combinations in mUC, mRCC, and rare GU malignancies Clinical trial information: NCT02496208.
Patient-reported anxiety with localized prostate cancer treated with stereotactic body radiation therapy (SBRT).
Authors: Aghdam Nima , Pepin Abigail , Johnson Colin , Danner Malika , Ayoob Marilyn , Yung Thomas M. , Lei Siyuan , Collins Brian Timothy , Dritschilo Anatoly , Suy Simeng , Lynch John , Collins Sean P. 
Published: February 2018

52 Background: Anxiety is a common aliment among elderly men. It may be negatively impacted by the diagnosis of cancer. Effective cancer treatment may alleviate anxiety. The EORTC QLQ-ELD14 (ELD14) is a validated questionnaire, which evaluates patient reported anxiety. Using the ELD14 questionnaire, this study assesses the trends in prostate cancer patient’s anxiety before and after treatment with SBRT. Methods: All patients with localized prostate cancer who received SBRT at Georgetown University Hospital from 2007 to 2016 were eligible for inclusion in this cross-sectional cohort. The ELD14 questionnaire was used to assess quality of life before and following treatment. Initially, approximately 267 patients (median age of 70) responded to the ELD14 questionnaire. This study is focused on questions related to patient’s anxiety regarding their families, future, health and end of life. The responses to these questions were grouped into three clinically relevant categories (not at all, a little and quite a bit to very much). Results: Prior to treatment, 19% of patients felt quite a bit or very much worried about their families coping with their illness. This decreased to 9% at 24 months post-SBRT (p = 0.007). Initially, 27% of patients reported concerns for the future of their families, which subsequently decreased to 20% at 24 months (p = 0.15). At initial consult, 32% of patients reported being worried about their future health. This decreased to 13% at 24 months (p < 0.001). Twenty percent of patient reported concern about their future at initial consult; this declined to 11% at 24 months (p = 0.03). And finally, self reported anxiety about end of life was 18% at the initial consult and 12% at 24 months (p = 0.16). Conclusions: Self-reported anxiety surrounding family, health and future is prevalent amongst prostate cancer patients at initial evaluation. Significant reduction in anxiety is observed in our cohort post-SBRT. Further investigations in the causes of pre and post-treatment anxiety may offer valuable insight into preventable root causes and improvement in patient’s quality of life.
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.