bluuebunny/crossref_metadata_2025 huggingface dataset:
Detailed evaluation of hearing loss (HL) associated with high-dose (HD) carboplatin for salvage treatment of germ cell tumors (GCT).
Authors: Feldman Darren R. , Knezevic Andrea , Wilson Kaamilah , Bromberg Maria , Budnick Amy , McHugh Deaglan Joseph , Larsen Erik , Bajorin Dean F. , Motzer Robert J. , Tonorezos Emily S. , Patil Sujata , Funt Samuel Aaron
Published: February 2020

401

Background: HD carboplatin is an essential part of curative salvage high-dose chemotherapy (HDCT) for GCT. Although ototoxicity is a known side effect of HD carboplatin, data on severity and characteristics of HL in this population are limited. Methods: Eligible patients (pts) received salvage HD carboplatin for GCT at our center from 1993-2017 and had audiograms pre- and post-HDCT. All pts were planned for 3 sequential cycles of HD carboplatin; some had audiograms after each cycle. HL severity was classified by ASHA criteria (slight: 15-24dB; mild: 25-40dB; moderate: 41-55dB; moderately severe: 56-70dB; severe: 71-90dB; profound: >90dB). Change in hearing threshold at each frequency (0.25 – 8 kHz) was analyzed by clinical and treatment variables using the Wilcoxon rank-sum test. The proportion of pts recommended for hearing aids was also recorded. Results: Of 115 pts (median age 31, 77% nonseminoma), 96 received TI-CE and 19 received TI-TIC on a clinical trial (Feldman CGUC 2015). Pts varied by prior cisplatin exposure (77% with ≤4 vs 23% with 5-9 cycles) and number of HD carboplatin cycles (89% had 3, 10% had 2, and 2% had 1). Carboplatin AUC was 21 in 23%, 24 in 75%, and 28 in 3%. Moderate to profound HL was present in 23% pre-HD carboplatin vs 82% post, preferentially at high frequencies (Table). Of 89 pts with normal to mild HL at baseline, 78% developed moderate or worse HL post-HD carboplatin, including 61% with moderately severe or severe HL. Higher AUC (24 vs 21) and number of HD carboplatin cycles were associated with greater HL with HD carboplatin whereas prior cisplatin exposure was not. Due to moderate or severe HL in the vital speech frequency range (2 – 4kHz), 20 (17%) pts were recommended for hearing aids post-HD carboplatin. Conclusions: In the largest series to detail ototoxicity in pts receiving salvage HD carboplatin for GCT, we show HL, particularly at high frequencies, is a major dose-dependent toxicity. Most pts will have at least moderate high frequency HL after HD carboplatin with approximately 1 in 6 recommended for hearing aids. [Table: see text]
Is there a role for conventional-dose chemotherapy in relapsed germ cell tumors?
Authors: Manhaes Luana Toledo , Gomes Daniel Musse , Small Isabele , Araujo Luiz H. , Domingues Pedro Masson
Published: February 2020

404

Background: Patients with germ cell tumors (GCT) that relapse after first-line platinum-based chemotherapy can still be successfully rescued with second-line regimens. High-dose chemotherapy has shown favorable outcomes, and is a preferred option in most instances. Herein, we argued if conventional-dose chemotherapy (CDCT) could also be an alternative in selected patients. Methods: We performed a retrospective observational study, analyzing medical data of 57 GCT male patients treated with salvage chemotherapy after relapse to first-line platinum-based treatment from 2000 to 2015 at the Brazilian National Cancer Institute. Results: The median age was 28 years (range 15 to 49). 26 patients (46%) were Afro-Brazilian, 45 (79%) were non-seminoma, and 53 (93%) had primary testis tumors. 14 patients (25%) had bone, liver or brain metastasis at relapse, and in 35 (61%) the progression-free interval (PFI) after first-line was < 3months. The International Prognostic Factors Study Group (IPFSG) risk classification at relapse for very-low/low, intermediate and high/very-high risk were 8 (14%), 25 (44%), 24 (42%), respectively. After a median follow-up of 8 years, the 2-year PFS was 30% (95% IC, 20 % to 45 %) and the 2-year overall survival (OS) was 34% (95% IC, 23% to 49%). PFI < 3m after first-line (HR 2,38; p<0,005) and AFP > 1000 at relapse (HR 2,38, p<0,023) were negative prognostic factors for PFS and OS. The 2-year PFS and OS for IPFSG risk classification very-low/low, intermediate and high/very-high risk were 75% and 73%, 28% and 32%, 18% and 24%, respectively. Conclusions: In patients with relapsed GCT and very-low/low risk disease by the IPFSG classification, CDCT may be a reasonable option, achieving long-term survival rates. However, CDCT was associated with poor outcome in intermediate and high/very-high risk groups. Further studies should be conducted to assess the best treatment in this subset, since even in second-line, many of patients are still potentially curable.
Overall survival (OS) among Medicare beneficiaries receiving sipuleucel-T (sip-T) versus oral treatment for metastatic castration-resistant prostate cancer (mCRPC).
Authors: McKay Rana R. , Flanders Scott C. , Ferro Christine , Fitch Kate , Fabrizio Michael , Schweizer Michael Thomas
Published: February 2020

42

Background: Since the mCRPC treatment landscape is evolving, we examined real-world use and outcomes of sipuleucel-T (sip-T) and oral agents (abiraterone acetate and enzalutamide) in men with mCRPC. Methods: Using Medicare FFS Identifiable Research data, we identified mCRPC men with a qualifying prostate cancer diagnosis (ICD-9 185, ICD-10 C-61) and an initial treatment claim (abiraterone, cabazitaxel, docetaxel, enzalutamide, radium 223, sip-T) in 2014. Continuous Part A, B, and D eligibility and no HMO enrollment was required through 2017 or until death. mCRPC index date is the date of a mCRPC therapeutic claim. Using 4 groups (sip-T first line, oral first line, sip-T any line, and oral any line [no sip-T]), survival was estimated using Kaplan-Meier methods (unadjusted). Hazard ratios (HR) were estimated using Cox’s proportional hazards regression modeling. Results: During 2014, 14,482 eligible men had mCRPC drug claims. We studied 6,853 naïve mCRPC men with no treatment claim in the prior 12 months. Over 150 permutations of anti-cancer agents were identified. See table for patient characteristics. Sip-T was used 2+ line in 4.5% of men receiving orals 1st. Median overall survival was longer for men who received sip-T, regardless if used 1st line (35 mo) or in any line (35 mo), compared with oral 1st line use (21 mo) or an oral any time without sip-T (21 mo). Similar survival was seen after adjusting for baseline opioid use. While most received sip-T as 1st line, survival rates were higher in men receiving sip-T in any line (48%) compared to men who never received any sip-T (29%). Conclusions: In this analysis, sip-T use was associated with a 45% reduction in risk of death and 14 mo survival benefit in the Medicare FFS population regardless of when used. Real-world analyses like this provide insight into how to optimize sip-T use to treat prostate cancer.[Table: see text]
Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.
Authors: Rosenberg Jonathan E. , Flaig Thomas W. , Friedlander Terence W. , Milowsky Matthew I. , Srinivas Sandy , Petrylak Daniel Peter , Merchan Jaime R. , Bilen Mehmet Asim , Carret Anne-Sophie , Yuan Nancy , Sasse Carolyn , Hoimes Christopher J.
Published: February 2020

441

Background: Platinum chemotherapy is the standard for patients (pts) with metastatic urothelial carcinoma (mUC) in the first line (1L) setting. In cisplatin-ineligible pts, gem/carbo is a standard therapy, but is poorly tolerated with limited durability and survival. PD-1/PD-L1 inhibitors, such as pembrolizumab (P), have shown promising durability in this setting for PD-L1 high patients. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4, which is highly expressed in UC. EV has shown activity in previously treated mUC. Initial EV + P data were previously presented (Hoimes ESMO 2019); this provides first durability data and an update on safety/ORR. Methods: This multicohort study (NCT03288545) evaluated the safety/activity of EV + P. We report a cohort of 1L cis-ineligible patients treated with EV 1.25 mg/kg + P. In each 3-week cycle, EV was administered on Days 1 and 8 and P on Day 1. The primary endpoint was safety/tolerability; secondary objectives included determination of recommended EV dose, ORR, DCR, DOR/PFS per RECIST v1.1, and OS. Results: As of 8 Oct 2019, 45 mUC pts (median age 69 yr [51–90]) received a median of 9 (range 1-22) cycles of EV + P. The most common treatment-emergent adverse events (AE) were fatigue (58%, 11% ≥G3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% ≥G3). One pt died due to an AE reported as related (multiple organ failure). With a median follow-up of 11.5 mo, confirmed investigator-assessed ORR was 73.3% (95% CI, 58.1, 85.4) including 15.6% CRs; DCR was 93.3%. The ORR in pts with liver metastasis was 53.3% (8/15). The ORR in pts with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). Of the 33 responders, 18 (55%) have ongoing responses including 11 responses beyond 10 months. The median DOR was not reached (range 1.2 to 12.9+ mo). The median PFS was 12.3 mo (95% CI, 7.98, -). Conclusions: In 1L cis-ineligible pts with mUC, EV + P, a potential platinum free option, demonstrates promising activity and durability, with a manageable safety profile. Further evaluation of EV + P in mUC and muscle-invasive UC is ongoing. Clinical trial information: NCT03288545.
PET imaging urothelial bladder cancer: A novel approach.
Authors: Thakur Mathew L. , Gomella Leonard G. , Tripathi Sushil K. , Salmanoglu Ebru , Keith Scott W. , Kelly William Kevin , Hoffman-Censits Jean H. , Kim Sung , Intenzo Charles M. , McCue Peter , Trabulsi Edouard John
Published: February 2020

443

Background: Urothelial bladder cancer (UBC) inflicts >80,000 new patients annually. Since treatment is stage-dependent, accurate staging is crucial. Conventional imaging and biopsy are often unreliable. A large number of PET tracers, developed to improve imaging, have limitations e.g. urinary excretion compromising their ability to assess the bladder lumen and invasive tumors. This study is to validate a hypothesis that high density VPAC receptors expression on UBC cell surface, can be targeted to PET image UBC, to determine loco-regional disease and metastatic lesions. Methods: Cu-64-TP3805 (4±10% mCi), with its high affinity (3.1 x 10−9M) for VPAC, was given IV to 19 UBC patients (44-80 yrs), scheduled for radical cystectomy. Those eligible for neoadjuvant chemotherapy were treated as such. Urine and blood samples were collected on the day of scan. Whole body PET/CT images acquired 60 to 90 min later and read by two physicians. Surgery was performed 1 to 4 weeks later. Imaging results were correlated with histology. Results: There were no adverse events. Urinary excretion of Cu-64-TP3805 was negligible. Blood clearance was biphasic (t ½ a = 22.3 ±2.7 min ~ 85% and t ½ β = 118.2 ± 4.9 min ~ 15%). VPAC PET bladder images were true positive (TP) in 11, true negative (TN) in 4, false positive (FP) in 1 and false negative (FN) in 3 patients with 79% sensitivity (95% CI 49%-95%), 80% specificity (95% CI 28%-100%), 92% PPV (95% CI 62%-100%), and 57% NPV (95% CI 18%-90%). Prostate images were TP in 8, TN in 6, and FP in 5 patients, with 100% sensitivity (95% CI 63%-100%), 55% specificity (95% CI 23%-83%), 62% PPV (95% CI 32%-86%), and 100% NPV (95% CI 54%-100%). The 5 FP images revealed HGPIN on re-analysis. For lymph nodes, images were TP in 1, TN in 14 and FN in 4 patients, with 25% sensitivity (95% CI 1%-81%), 100% specificity (95% CI 78%-100%), 100% PPV (95% CI 3%-100%), and 83% NPV (95% CI 59%-96%). In one patient, several lesions were seen in the spine and iliac crest. Biopsy was positive for metastasis. In smokers (N=12) there was diffused or focal tracer uptake in the lungs. In 7 non-smokers, 3 with CT depicted abnormality had tracer lung uptake and 4 did not. Conclusions: These first in human pilot study data depict Cu-64-TP3805 VPAC targeting to image UBC as worthy of further investigation.
Replacing TURBT with mpMRI for staging MIBC: Pilot data from the BladderPath study.
Authors: James Nicholas D. , Pirrie Sarah , Liu Wenyu , Amir Rashid , Gallagher Jean , Hughes Ana , Jefferson Kieran , Knight Allen , Nanton Veronica , Mintz Harriet Paige , Pope Ann , Catto James WF , Patel Prashant , Bryan Richard T.
Published: February 2020

446

Background: The diagnostic pathways for bladder cancer are largely unchanged for 30 years. The BladderPath trial objectives are to: improve staging, accelerate treatment, and reduce iatrogenic tumour spread by avoiding TURBT. We hypothesise that substituting TURBT with mpMRI will avoid unnecessary surgery, accelerate correct MIBC treatment and improve outcomes. Methods: A randomised phase 2/3 trial of standard of care (Pathway 1) versus risk-stratified mpMRI-directed care (Pathway 2) in visually-diagnosed incident bladder cancer. Patients with bladder lesions suspicious for malignancy at flexible cystoscopy are stratified by a 5-point Likert scale: strongly agree (1) or agree (2) that the lesion is NMIBC, equivocal (3) NMIBC or MIBC, and agree (4) or strongly agree (5) the lesion is MIBC. All patients are randomised; those with probable NMIBC (Likert 1 & 2) undergo TURBT in both pathways, and those with possible MIBC (Likert 3-5) undergo TURBT (Pathway 1) or mpMRI (Pathway 2). Endpoints: feasibility, time to correct MIBC therapy and clinical progression-free survival. We report preliminary feasibility data. Results: To date, 218 potentially eligible patients have been registered; on cystoscopy, 151 patients had no bladder lesions and 5 were excluded for other reasons. Of 62 patients randomised, we report results from 45 with preliminary data. Of the 21 patients in Pathway 1, 11 patients classified as probable NMIBC underwent TURBT (pathology: 11/11 NMIBC); 9/10 patients classified as possible MIBC underwent TURBT (pathology: 4/9 NMIBC & 5/9 MIBC) and 1 patient incorrectly underwent mpMRI (staging: MIBC). Of the 24 patients in Pathway 2, 11/12 patients classified as probable NMIBC underwent TURBT (pathology: 9/11 NMIBC & 2/11 MIBC) and one patient incorrectly underwent mpMRI (staging: NMIBC); 12 patients classified as possible MIBC underwent mpMRI (staging: 6/12 NMIBC & 6/12 MIBC). Conclusions: A 5-point Likert scale accurately identifies patients with a low risk of MIBC (Likert 1 & 2). It is feasible to randomise possible MIBC patients to TURBT or mpMRI for staging. The study is ongoing to investigate the intermediate outcome of time to correct therapy for MIBC and NMIBC and the final outcome of clinical progression-free survival. Clinical trial information: 35296862.
Oncofid-P-B for the treatment of BCG unresponsive carcinoma in situ (CIS) of bladder: Results of European multicenter phase I study at the end of 12- consecutive weeks intensive course.
Authors: Hurle Rodolfo , Guazzoni Giorgio Ferruccio , Colombo Piergiuseppe , Santoro Armando , De Cobelli Ottavio , Di Trapani Ettore , Nohales Gloria , Carlos Llorente , Duran-Merino Ramon , Lazzeri Massimo
Published: February 2020

486

Background: There is an unmet clinical need for new drugs able to delay or avoid cystectomy in patients with CIS unresponsive to BCG. Here, we report the safety and efficacy of Oncofid−P-B, is a new drug that originates from the chemical conjugation of paclitaxel with hyaluronic acid, in patients with CIS unresponsive or intolerant to BCG. Methods: This is an open-label, single arm, multicenter international study (Registered as EudraCT Number: 2016-004144-11) to assess safety, tolerability and efficacy of Oncofid-P-B administered in 20 patients with CIS, unresponsive or intolerant to BCG and unwilling or unfit for cystectomy. Oncofid-P-B was administered by intravesical instillation for 12 consecutive weeks (intensive phase). A 12 monthly (maintenance phase) in patients who were in complete response (CR) after the intensive phase is ongoing. The primary end-point was the overall safety profile. Secondary endpoints included i) efficacy after the intensive phase ii) compliance, iii) systemic absorption. The CR is defined as a negative cystoscopy including biopsy of the urothelium and negative cytology. Statistics will be calculated, as appropriate, for the quantitative variables. Results: Of the 20 enrolled patients who completed the intensive phase, CR was achieved in 15 patients (75%). Seven G1-G2 drug-related adverse events (AEs) were reported in only three patients over 240 instillations. No drug related serious AEs and no study withdrawal have been reported. In all plasma samples, the drug concentration was always below the Limit of Quantification (0.1ng/ml). Over 15 patients who ended the intensive course without CIS recurrence, five already completed the 12-month maintenance phase (four patients with no recurrence of CIS), thirteen were disease free after three months and six are completing the maintenance. Conclusions: The excellent safety profile of Oncofid-P-B is well positioned as compared with the most recent competitors, thus confirming its potential as therapeutic option in BCG unresponsive CIS patients, also with a prolonged treatment schedule, and deserves further clinical evaluation. Clinical trial information: 2016-004144-11.
A phase I/II feasibility study of cetuximab with 5FU and mitomycin C or cisplatin with concurrent radiotherapy in muscle invasive bladder cancer.
Authors: James Nicholas D. , Pirrie Sarah , Liu Wenyu , Ford Daniel , Zarkar Anjali , Southgate Elizabeth , Desai Amisha , Hussain Syed A.
Published: February 2020

491

Background: Chemoradiotherapy (cRT) with 5FU and Mitomycin C (5FU/MMC) is an accepted standard of care for muscle invasive bladder cancer. Cetuximab is an approved radio-sensitiser in head and neck cancer and EGFR is over-expressed in bladder cancer. We report a phase 1/2 trial of the addition of cetuximab to standard cRT. Methods: Phase 1/2 single-arm, multicentre, open-label study conducted in 5 UK centres. Treatment: RT: 64 Gy/32 fractions, 5FU 2.5g/m2 over days 1-5 & 22-26, MMC 12g/m2 day 1, cetuximab 400mg/m2 day -8, 200mg/m2 day 1 and weekly x7. Main inclusion criteria: T2-4aN0M0 urothelial cancer, PS 0-1; prior neoadjuvant therapy permitted. Endpoints: Phase 1; feasibility and safety of cRT with cetuximab + 5FU/MMC in combination. Phase 2; local control (LC) at 3 months. Secondary outcomes: invasive loco-regional progression free survival (LPFS), noninvasive LPFS, metastasis free survival (MFS), overall survival (OS) & patient reported outcomes (PROMs). Sample size; phase 1 between 6 and 18, phase 2 up to 45 including those recruited in phase 1. Results: Between Sept 2012 and Oct 2016, 33 patients were recruited; 7 in phase 1 26 in phase 2. Median age 70.1 (IQR 65.4-80.2) yrs, 60.6% WHO Performance Status 0; 81.8% male, 26/33 neoAd chemotherapy. 3 patients ineligible post registration. 30 evaluable pts started RT, 1 patient didn’t complete RT due to serious adverse event (interstitial pneumonitis), 3 with delays. Phase 1, 6/7 pts completed Cetux therapy, 1 omitted 1 dose for grade 3 rash. LC was 77% (95% CI 58, 90). Overall median dose intensities Cetux 100%, MMC 99% 5FU 99.8%. 8 pts developed recurrence; 2 MIBC. The 6 & 12 month muscle-invasive LPFS was 93 &; non-invasive LPFS 97% & 85%, MFS 90% & 90%, OS 97% & 87%. PROMs showed a transient dip at 1 mo, back to baseline at 3 mo. Conclusions: Phase 1 data demonstrate it’s feasible and safe to add cetuximab to cRT with 5FU/MMC with high delivered dose intensities. Although recruitment failed to reach the pre-specified target for phase 2 exploratory analysis indicate the 3 month bladder control rates and recurrence rates are above those reported in BC2001 with good PROMs provides evidence to consider further evaluation of cetuximab. Clinical trial information: 80733590.
Effect of concurrent proton pump inhibitors (PPI) use in patients (pts) treated with immune checkpoint inhibitors (ICI) for metastatic urothelial carcinoma (mUC).
Authors: Morales-Barrera Rafael , Vidal Casinello Natalia , Bonfill Teresa , Domenech Montserrat , Suarez Rodriguez Cristina , Puente Javier , Joaquin Julia Giner , Figols Mariona , Galante Isabel , Carrion Albert , Lopez Hector , Gonzalez Macarena , Roche Sarai , Mateo Joaquin , Gallardo Diaz Enrique , Fernández Sáez Carlos , Valverde Morales Claudia Maria , de Torres Ines , Morote Juan , Carles Joan
Published: February 2020

500

Background: PPI are widely used in pts with cancer. PPI are associated with anti-inflammatory properties and direct effects on neutrophils and monocytes that might prevent inflammation. We investigate the role of PPI on outcomes of pt receiving ICI in mUC. Methods: Medical records from pts with mUC treated with ICI from May 2013 to May 2019 using a multi-institutional database was evaluated. Use of PPI was defined: 30 days prior, during the treatment and 30 days after the last dose of ICI. ORR were assessed according to RECIST v1.1. The X2 test was used to determine differences in rates. PFS and OS were estimated using Kaplan-Method and long rank test was used to assess differences between groups. All analyses were performed using SPSS v21. Results: Overall, 115 pts received therapy with ICI. Of these pts, 20 were not included due to the absence of information about PPI. Thus, 95 pts were included for the analysis. 50 (52.6%) pts received PPI. Median age was 68 years, 79 pts (83.2%) were male, 78 pts (82.1%) had ECOG PS 0-1, 20 pts (21.1%) had liver metastasis and 36 pts (37.9%) received ICI treatment as frontline therapy. ICI prescribed were atezolizumab (58.9%), pembrolizumab (17.9%), durvalumab (12.6%), nivolumab (6.3%) and durvalumab/tremelimumab (4.2%). Pts with no PPIs use had higher ORR (CR [8.9%] +PR [14.4%]) compared to those pt who use PPIs (CR [4.4%] + PR [8.9%]) (P=0.197). Median PFS was 10.05 mo (95% CI: 3.86-16.27) for non PPI users and 3.87 mo (95% CI:1.84-5.91) for PPI users (P=0.04). Median OS was 19.71 mo (95% IC:8.93-30.49) for non PPI users and 7.9 mo (4.4-11.45) for PPI users (P=0.072). Conclusions: We have observed shorter PFS and trend toward lower OS and ORR for PPI users. The real impact of PPI should be confirmed in prospective studies.
Does escalation results from phase Ib/II Norse study of erdafitinib (ERDA) + PD-1 inhibitor JNJ-63723283 (Cetrelimab [CET]) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and selected fibroblast growth factor receptor (FGFR) gene alterations.
Authors: Moreno Victor , Loriot Yohann , Valderrama Begona Pérez , Beato Carmen , Vano Yann-Alexandre , Fleming Mark T. , Duran Ignacio , Siena Salvatore , Tolbert Jaszianne A. , OHagan Anne , Akapame Sydney , Lau Yvonne Y. , Geoffrois Lionnel , Tagawa Scott T. , Mellado Begona , Siefker-Radtke Arlene O.
Published: February 2020

511

Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for pts with metastatic urothelial carcinoma (mUC) with susceptible FGFR3/2 gene alterations and progressed after ≥1 line of prior platinum-containing chemotherapy (PCC).1 CET, an IgG4, binds to anti-programmed cell death proteins (PD-1) and has shown activity in solid tumors.2 ERDA+CET may demonstrate complementary mechanisms as neoantigen release by ERDA may prime the tumor microenvironment for response. NORSE is a phase 1b/2 study to evaluate ERDA+CET in pts with mUC. Methods: Adult mUC pts with specific FGFR alterations who have progressed after ≥1 prior systemic therapy and no prior FGFR or PD-1/PD(L)-1 inhibitors enrolled in 3 dose levels (DL) of ERDA (DL1: 6 mg, DL2A: 8 mg, DL2: 8 mg with uptitration [UPT] to 9 mg) + CET (IV, 240 mg). Cohorts enrolled until dose limiting toxicity (DLT) or RP2D was identified. Primary endpoints: DLT and adverse events (AEs). Results: Of 15 pts (DL1: 4, DL2A: 3, DL2: 8), 11 continued on treatment at the time of the data cut. 14/15 pts experienced AEs; 3 experienced serious unrelated AEs (urinary tract infection, urosepsis, and large intestinal obstruction) all in DL1, 2 led to death; 10 experienced Grade >3 AEs and 2 experienced AEs of special interest, considered related to ERDA (Table). No DLTs were observed in any cohorts, 8 mg with UPT + CET was established as the RP2D. At data cut-off, investigator-assessed best overall response rate (CR+PR+uCR+uPR) in pts treated with the RP2D was 71% and disease control rate was 100% for RECIST 1.1 evaluable pts (n=7). Conclusions: 8 mg ERDA with UPT+240 mg CET was well tolerated and established as the RP2D. The combination of ERDA+CET is being further explored in the ongoing randomized phase 2 study in first-line cisplatin-ineligible mUC pts (NCT03473743). Clinical trial information: 2017-001980-19. [Table: see text]
Concurrent durvalumab and radiation therapy followed by adjuvant durvalumab in patients with locally advanced urothelial cancer of bladder (DUART): Btcrc-GU15-023.
Authors: Joshi Monika , Tuanquin Leonard , Kaag Matthew , Kilari Deepak , Holder Sheldon L. , Emamekhoo Hamid , Sankin Alexander , Merrill Suzanne B , DeGraff David , Warrick Joshua , Zheng Hong , Hauke Ralph J. , Gartrell Benjamin Adam , Stein Mark N. , Zakharia Yousef , Drabick Joseph J.
Published: February 2020

513

Background: Bladder cancer (BC) patients (pts) who are cisplatin ineligible/unfit for surgery, unresectable have limited treatment options. In this study, we investigate if the combination of radiation therapy (RT) and checkpoint inhibitor, durvalumab (durva) is safe and effective in these pts. Our results from phase (ph) Ib suggested that the combination was safe. Here we present the response rate post durvaRT and updated treatment related adverse events (TRAEs) amongst our evaluable pts in ph II. Methods: This is a single arm ph Ib-II study for T2-4 N0-2 M0 pts. The ph II primary endpoints a) PFS rate at 1 yr b) disease control rate (DCR); secondary endpoints were a) CR post durvaRT b) PFS c) OS. Pts were treated with durva (1500mg) Q4 wks x2 doses along with definitive RT (64.8Gy, 36 fractions over 7 wks) to the bladder and involved nodes followed by adjuvant durva Q4 wks x 1 yr. Response was evaluated with CT scan and cystoscopy+biopsy post durvaRT. We anticipated that durvaRT followed by durva would increase PFS at 1 yr from 50% to 75% when compared to RT; we assumed DCR of about 75%. A total of 26 pts were needed to reach a statistical power of at least 80% at one-sided alpha of 5% and to allow for 10% drop out rate. Results: Total N = 26 patients (male 19; female 7, median age 74yr). At the time of data cut off, 21/26 pts were evaluable for response post durvaRT. Post completion of durvaRT time point, clinical CR was seen in 15/21 pts (71.4%); PR 1/21 pts (4.7%); SD 4/21 (19%); PD 1/21 (4.7%). DCR was seen in 20/21 pts (95%) post durvaRT. Median follow up from D1 to last follow up was 6.1 mos. Grade ≥ 3 TRAE amongst 26 pts: anemia (1/26), lipase/amylase (1/26), immune nephritis (1/26), dyspnea (gr 4, copd/immune), fatigue (1/26), lymphopenia (6/26). Other TRAEs: Fatigue was the most common TRAE (16/26); UTI (5/26); cystitis (3/26). No fatal TRAEs were observed. Conclusions: DurvaRT demonstrated promising efficacy with clinical CR of 71.4% and DCR of 95% in unresectable, cisplatin ineligible locally advanced BC. It was generally well tolerated. Ph II study has completed accrual and longer-term results will further our understanding of this regimen’s efficacy in locally advanced BC. Clinical trial information: NCT02891161.
Phase I experience with rogaratinib in patients (pts) with urothelial carcinoma (UC) selected based on FGFR mRNA overexpression.
Authors: Kempf Emmanuelle , Penel Nicolas , Tournigand Christophe , Gajate Pablo , Tan Daniel Shao-Weng , Cassier Philippe , Nogova Lucia , Cathomas Richard , Schostak Martin , Janitzky Andreas , Wermke Martin , Sayehli Cyrus , Navarro Alejandro , Park Se Hoon , Piciu Ana-Maria , Bender Sebastian , Nogai Hendrik , Ellinghaus Peter , Joerger Markus , Schuler Martin H.
Published: February 2020

527

Background: Aberrant activation of the fibroblast growth factor receptor (FGFR) pathway is implicated in many cancers, including UC. In a recent Phase I dose-escalation study, rogaratinib, an oral pan-FGFR1-4 inhibitor, demonstrated favorable efficacy and safety in pts with solid cancers selected based on FGFR1-3 mRNA overexpression. We report results from the Phase I expansion cohort with rogaratinib in pts with UC selected by FGFR1-3 mRNA overexpression and/or FGFR3-activating mutations (NCT01976741). Methods: Pts with advanced/metastatic UC were screened for FGFR1-3 mRNA overexpression using RNA in situ hybridization (RNAscope) and NanoString assay in fresh or archival tumor samples. Pts received rogaratinib 800 mg po BID continuously. Tumor response and safety were assessed. Results: 74 pts with UC were treated with rogaratinib; 73.0% were male, median age was 66 years (range 45-85), and 93.2% had stage IV disease. Rogaratinib was well tolerated, with adverse events being mostly mild or moderate. The most common treatment-emergent adverse events (TEAEs) are shown in the Table. The most common drug-related TEAEs (any grade) were diarrhea (52.7%), increased blood phosphorus (41.9%), and decreased appetite and dry mouth (31.1% each). No ocular toxicities were reported. Increased blood creatinine and acute kidney injury (AKI), regardless of relatedness, were reported in 16.2% and 2.7% of pts, respectively; 1 case of AKI was confirmed as acute tubular necrosis. Of 72 evaluable pts, 15 (20.8%) achieved an objective response; complete and partial responses were observed in 1 (1.4%) and 14 (19.4%) pts, respectively. Stable disease was achieved by 34 pts (47.2%), with a disease control rate of 68.1%. Conclusions: Rogaratinib demonstrated a favorable safety and efficacy profile in pts with tumor FGFR1-3 mRNA-positive UC. TEAEs observed in >25% of pts. Clinical trial information: NCT01976741. [Table: see text]
Cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICI) or targeted therapy (TT): A propensity score-based analysis.
Authors: Bakouny Ziad , Xie Wanling , Dudani Shaan , Wells Connor , Gan Chun Loo , Donskov Frede , Shapiro Julia , Davis Ian D. , Parnis Francis , Ravi Praful , Steinharter John A. , Agarwal Neeraj , Alva Ajjai Shivaram , Wood Lori , Kapoor Anil , Ruiz Morales Jose Manuel , Kollmannsberger Christian K. , Beuselinck Benoit , Heng Daniel Yick Chin , Choueiri Toni K.
Published: February 2020

608

Background: The role of CN for mRCC treated with ICI is not well defined. Our aim was to evaluate the role of CN for mRCC treated by ICI or TT using a propensity score-based analysis. Methods: We retrospectively assessed patients who were diagnosed with de novo mRCC and who had started first line systemic therapy (ICI or TT) between 2009 and 2019 using the International Metastatic RCC Database Consortium (IMDC). Overall Survival (OS) was compared between patients receiving CN and those treated by systemic therapies alone, using the Kaplan-Meier method and Cox regressions, in the TT and ICI arms separately. In order to account for treatment selection bias, inverse probability of treatment weighting (IPTW) of propensity scores, based on 14 confounding variables, was used and variables were considered balanced if standardized mean difference (SMD) < 0.1. For variables with SMD≥0.1, residual confounding was adjusted for using multivariable models. Results: 3856 patients had been treated by TT (2470 CN+ & 1386 CN-) and 198 by ICI (143 CN+ & 55 CN-). Median follow-up was 38.5 months. After IPTW, baseline characteristics were largely balanced between the CN+ and CN- arms, in the TT and ICI groups (14/14 and 12/14 with SMD < 0.1, respectively). CN was associated with significantly improved OS in both the ICI (Hazard Ratio [HR] = 0.39 [0.19-0.83]) and TT (HR = 0.56 [0.51-0.62]) groups. The interaction term between CN and therapy type (ICI vs TT) was not statistically significant (p = 0.43). The point estimates of the HRs were consistent in sensitivity analyses using multivariable models. Conclusions: In a propensity score-based analysis, CN was found to be associated with a significant OS benefit in patients treated by either ICI or TT. While this study is not a substitute for randomized controlled trials (e.g. CARMENA), the results suggest that CN may still play a role in selected patients in the ICI era.[Table: see text]
Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: Analysis of the STAR TOR registry.
Authors: Moran Michael , Hubbe Marcus , Rink Michael , Bergmann Lothar , Strauss Arne , Bernhardt Stephan , Schmid Marianne , Boegemann Martin , Schlack Katrin
Published: February 2020

628

Background: Metastatic renal cell carcinoma (mRCC) treatment is partly informed by risk group. The two most commonly used prognostic models, the International Metastatic RCC Database Consortium (IMDC) and the Memorial Sloan-Kettering Cancer Center (MSKCC), stratify patients (pts) into favorable (0 risk factors [RFs]), intermediate (1–2 RFs) or high risk (≥3 RFs) groups. This study examined real-world outcomes according to IMDC and MSKCC RFs in sunitinib-treated pts with mRCC. Methods: Data were extracted on 19 June 2019 from a large, prospective German multicenter registry (STAR-TOR). Only pts with sufficient data for risk stratification by IMDC and MSKCC were included in this analysis. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The impact of RFs on survival was assessed using Cox’s regression analysis and the chi square test. Results: According to IMDC or MSKCC, 16.7% and 15.3%, 26.2% and 30.8%, 18.7% and 24.7%, and 38.5% and 29.2 of pts had 0, 1, 2 and ≥3 RFs, respectively. In IMDC intermediate pts, only < 1 year diagnosis to therapy (24.8%) was the most common RF; in MSKCC intermediate pts, < 1 year diagnosis to therapy with low hemoglobin (19.9%) were the most common. OS was not significantly different for pts with 0 vs 1 (p = 0.24), or 2 vs ≥3 (p = 0.16) IMDC RFs, but was significant according to MSKCC RFs (0 vs 1, p = 0.04; 2 vs ≥3, p < 0.01). OS was significantly longer for pts with 1 vs 2 RFs for IMDC (p = 0.03) and MSKCC (p = 0.04), but PFS was not (IMDC, p = 0.29; MSKCC, p = 0.12). OS was significantly longer for 0 vs 2, 0 vs ≥3, and 1 vs ≥3 RFs for IMDC and MSKCC RFs (all comparisons, p < 0.01). Similar results were observed for PFS with the exception of 0 vs 1 IMDC RF (p = 0.01). Conclusions: The intermediate risk group appears to be heterogeneous. OS for pts with 1 RF may align with the favorable risk group and pts with 2 RFs may align with the poor risk group.[Table: see text]
Effect of comorbidities/comedications on treatment outcomes with sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC): Subgroup analyses from the STAR-TOR registry.
Authors: Bernhardt Stephan , Hubbe Marcus , Rink Michael , Bergmann Lothar , Boegemann Martin , Moran Michael , Schlack Katrin , Strauss Arne , Schmid Marianne
Published: February 2020

631

Background: Sunitinib remains an important treatment option for mRCC, but the effect of comorbidities/comedications on sunitinib treatment outcomes have not been fully explored. Methods: Data were collated from STAR-TOR, an ongoing real-world registry. Cutoff date for analysis was 19 June 2019. This subgroup analysis assessed the presence or absence of hypertension (HTN), and the use or non-use of statins and proton pump inhibitors (PPIs), determined at the time of entry to the registry. Treatment endpoints were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). OS and PFS were analyzed by Kaplan-Meier methods. Differences within subgroups were tested using Log-rank test for OS and PFS, and Fisher’s exact test for ORR. Results: 557 sunitinib-treated pts were analyzed; 366 had HTN and 191 did not, 130 used statins and 427 did not, and 165 used PPIs and 392 did not. Median (m) OS (95% confidence intervals) was similar in pts with and without HTN (25.4 [21.1, 31.5] vs 21.5 [15.2, 28.0] months; p = 0.215). mPFS (8.0 [6.5, 9.9] vs 6.3 [5.4, 8.2] months; p = 0.140) and ORR (31.2% vs 30.9%; p = 1.000) were also similar in pts with and without HTN. mOS was similar in pts who used statins vs those who did not (27.8 [20.2, 35.4] vs 24.0 [19.4, 27.3] months; p = 0.884), while mPFS was significantly longer in pts who used statins (9.4 [6.5, 13.6] vs 6.9 [5.7, 8.2] months; p = 0.044). ORR was 37.8% vs 29.0% in pts who did and did not use statins (p = 0.072). mOS was significantly shorter in pts who used PPIs vs those who did not (20.2 [14.9, 28.3] vs 25.7 [22.7, 33.0] months; p = 0.021). mPFS (5.8 [4.6, 8.2] vs 8.0 [6.5, 9.8] months; p = 0.091) and ORR (26.6% vs 33.0%; p = 0.177) were similar in pts who did and did not use PPIs. Conclusions: In sunitinib-treated pts with mRCC in a real-world registry, mPFS was significantly longer and there was a trend toward better ORR in pts who used statins, whereas mOS was significantly shorter and there was a trend toward shorter mPFS in pts who used PPIs. Common comedications may affect sunitinib treatment outcomes in pts with mRCC.
Preoperative metastatic disease burden to predict overall survival following cytoreductive nephrectomy independent of IMDC risk category.
Authors: Shapiro Daniel D. , Karam Jose A. , Spiess Philippe E. , Raman Jay D. , Westerman Mary E. , Sexton Wade J. , Zemp Logan , Bilotta Alyssa , Allen Glenn O. , Lauer Kate V. , Matin Surena F. , Wood Christopher G. , Abel E. Jason
Published: February 2020

652

Background: Studies suggest that overall survival (OS) following cytoreductive nephrectomy (CN) is associated with preoperative tumor measurements including primary tumor diameter, number of metastatic sites, sum of metastatic tumor diameters and primary tumor percent of overall burden. Current risk models, however, do not account for tumor burden. This study evaluated associations between OS and preoperative tumor measurements for patients treated with CN during the targeted therapy era. Methods: Data for consecutive mRCC patients treated with CN at 4 institutions from 2006-2017 were analyzed after determining IMDC risk category, primary tumor (PT) diameter, number of metastatic sites, sum of metastatic tumor diameters and PT percentage of overall burden. Univariate and multivariable (MV) Cox models evaluated tumor measurement and IMDC risk associations with OS. Results: A total of 617 patients were available for analysis. Median PT diameter was 10.0 cm (IQR 7-13cm), number of metastatic sites was 2 (IQR 1-2), sum of metastatic tumor diameters was 4.5 cm (IQR 2-10cm) and PT percent of overall burden was 73.7% (IQR 60-85%). After univariate analysis, all 4 tumor burden measures were associated with OS (p≤0.001 for all). MV models evaluating IMDC risk category with individual tumor burden measurements demonstrated that all measures were predictive as continuous variables: PT diameter (HR 1.03, 95% CI 1.01-1.06, p=0.007), sum of metastatic tumor diameters (HR 1.04, 95% CI 1.02-1.05, p<0.001), PT percent of overall burden (HR 0.43, 95% CI 0.27-0.68, p<0.001), and number of metastatic sites (HR 1.52, 95% CI 1.25-1.85, p<0.001). Additional MV models were created using clinically significant tumor measurement cutoffs and IMDC risk groups. OS was independently associated with IMDC intermediate (HR 3.17, 95% CI 1.84-5.44, p<0.001) and poor risk (HR 3.85, 95% CI 2.21-6.70, p<0.001), PT percentage of overall burden <90% (HR 1.41, 95% CI 1.05-1.89, p=0.021), and >2 metastatic sites (HR 1.60, 95% CI 1.29-2.00, p<0.001). Conclusions: PT and metastatic disease burden are independently associated with OS following CN. Future risk models should include tumor burden measurements.
Selecting the surgical approach in complex reoperative partial nephrectomies: Does robotics have a role?
Authors: Gurram Sandeep , Telfer Siobhan , Li Winston , Chalfin Heather , Linehan W. Marston , Ball Mark Wayne
Published: February 2020

658

Background: Minimally invasive surgery (MIS) has shown equal oncologic efficacy as the open approach for treating small renal masses but results in improved perioperative parameters. Surgical principles also dictate that the open technique should be considered when facing difficult surgeries though this is experience and not evidenced based. The goal of our study is to explore differences in outcomes amongst open or robotic approaches in complex reoperative partial nephrectomies. Methods: 194 patients who had prior renal surgery from 2008 to 2019 were identified, the majority of which presented with multiple tumors due to known or suspected hereditary kidney cancer syndrome. Patients were stratified into the following cohorts based on surgical history: open after open surgery, open after MIS, robotic after open surgery, and robotic after MIS. Perioperative outcomes were compared amongst cohorts. Results: Significant differences were noted in estimated blood loss (EBL), number of tumors resected, and postoperative complications as assessed by Clavien score. Univariate regression analysis of EBL showed that the number of tumors resected (p <.0001, coefficient: 111 ml), number of prior renal procedures (p=.012, coefficient: 419 ml), hilar clamping (p = .015, coefficient: 840 ml), and intended surgical approach (p = .001; coefficient: 905 ml) were significant. On multivariate analysis, number of tumors resected (p<.0001, coefficient: 97 ml) was the only significant factor. Univariate analysis on post-operative complications showed that number of prior surgeries (p = 0.03, OR: 1.5) and final intended approach (p < .0001, OR: 4.6) were significant. On multivariate analysis, the final intended surgical approach (p = .001, OR: 4.3) was shown to be significant. Conclusions: These data show that the surgical approach of prior procedures is not a significant factor that affects perioperative outcomes, but the use of robotic surgery was associated with decreased post-operative complications in reoperative renal surgery . While open surgery will likely continue to be the standard of care for complex reoperative procedures, these data suggest that robotic surgery is safe and well tolerated in select cases.
Mental perception of prostate cancer (PCa) disease in patients aged 60 years and older initiating gonadotropin-releasing hormone agonist (GnRHa) therapy.
Authors: Hennequin Christophe , Rozet Francois , Mongiat-Artus Pierre , Pello Leprince Ringuet Nathalie , Houchard Aude , Roupret Morgan
Published: February 2020

67

Background: PCa mostly affects elderly men and impacts their health-related quality of life (HRQOL), but little is known on differences by age groups. Our purpose was to analyze HRQOL with EORTC QLQ-ELD-14 questionnaire, a 7-dimension questionnaire specific of elderly cancer patients. Methods: From March 2018, a prospective, multicenter, non-interventional study was conducted in France (PRISME, NCT03516110). Urologists, radiation oncologists and medical oncologists recruited, as part as the normal consultation process, patients who met the following inclusion criteria: aged 60 years and older, with histologically confirmed PCa, candidate for GnRHa therapy. Patients were included (1:2:1) in prespecified age groups ([60-70[, [70-75[, ≥ 75 years). They reported HRQOL using ELD-14. Results: Overall, 528 patients were included in the interim analysis of baseline results. Mean (±SD) age was 72.9±6.5 years. There were 145, 207 and 176 patients, respectively, in the [60-70[, [70-75[ and ≥ 75 years groups. 93.8% of patients had a Karnofsky score ≥ 80%; 73.4% had at least one comorbidity at baseline and 67.9% were receiving at least one concomitant systemic treatment. Reason for GnRHa initiation was high risk localized or locally advanced tumor in 57.6%, metastatic stage in 19.8%, biochemical recurrence after local treatment in 14.7%. ELD-14 results on dimensions were as follows: “Mobility” was significantly worse in the 75y+ group (21.2±25.0) than in the [60-70[ (8.8±18.0) and [70-75[ (11.1±17.4) groups. “Burden of illness” decreased with age, with mean scores of 37.7±27.7, 31.0±25.3, and 28.3±25.1 (significantly different between [60-70[and 75y+ groups). No difference were observed on “Worries about future”, “Worries about others”, “Family support” and “Maintaining purpose” (motivation and positive outlook), however there was a large variability (SD > 34) within each group for the last two dimensions. Conclusions: HRQOL interim analysis through ELD-14 showed few differences between age groups, and noticed variability within groups instead of between groups, meaning that mental perception of the disease could be more subject- than age-related.
Outcomes of systemic therapy in relapsed renal cell carcinoma (RCC) treated with adjuvant sunitinib (AS).
Authors: de Velasco Guillermo , Ruiz-Granados Álvaro , Reig Oscar , Massari Francesco , Climent Duran Miguel Angel , Verzoni Elena , Graham Jeffrey , Llarena Roberto , De Tursi Michele , Donskov Frede , Iglesias Clara , Pandha Hardev S. , Garcia del Muro Xavier , Procopio Giuseppe , Oudard Stephane , Castellano Daniel , Albiges Laurence
Published: February 2020

701

Background: There are no available data on the usefulness of targeted therapy (TT) as the first-line treatment for patients with RCC recurrence after AS. We aim to explore the outcomes of systemic therapy with recurrent RCC after AS including re-exposure to sunitinib. Methods: A multi-institutional retrospective study was conducted on RCC patients who relapsed after AS. The primary end point was progression-free survival (PFS). Secondary end points were overall response rate (ORR) and overall survival (OS). Results: 34 relapses were recorded, 25 patients (73,5%) were male. 25 patients were treated with systemic therapy at first-line after relapse: 65% of patients received Vascular Endothelial Growth Factor (VEGF)-TT (including 7 patients retreated with sunitinib), 21,7% mTOR inhibitors and 13% immunotherapy. The median time to relapse was 20,3 months (IQR 5,2-20,4) from diagnosis, and 7,5 months (IQR 1,0-8,5) months from AS ending. At a median time of follow-up of 23,5 months, 24/25 patients had progressed on first-line systemic therapy. The median PFS was 12,0 months (IC95% 6,6-17,8 months). There was no statistical difference in PFS among the different treatments or the re-exposed to sunitinib. PFS was not statistically different between those relapsing on or after AS ( < 6 or > 6 months after AS). ORR was 20,3%. Median OS was 28,7 months (IC95% 24,4-33,0). Conclusions: This study suggests that TT may still improve PFS and OS in RCC patients who relapsed after AS.