bluuebunny/crossref_metadata_2025_split huggingface dataset:
Defects in DNA repair genes and long-term survival in cisplatin-based neoadjuvant chemotherapy for muscle invasive bladder cancer (MIBC).
Authors: Miron Benjamin , Ross Eric A. , Anari Fern , O'Neill John , Hoffman-Censits Jean H. , Zibelman Matthew R. , Kutikov Alexander , Viterbo Rosalia , Greenberg Richard E. , Chen David , Lallas Costas D. , Trabulsi Edouard John , Alpaugh R. Katherine , Dulaimi Essel , Golemis Erica , Uzzo Robert , Plimack Elizabeth R. 
Published: May 2019

4536 Background: Although cisplatin-based neoadjuvant chemotherapy (NAC) has demonstrated an overall survival (OS) benefit in MIBC, only a subset of patients have pathologic complete response (pT0) at cystectomy. ATM, RB1 and FANCC mutations have shown correlation with pT0 to cisplatin-based NAC, as previously published. We now report updated OS and disease specific survival (DSS) from two phase II trials using these gene alterations as biomarkers. Methods: Patients with stage T2-T4 (N0 or N1) MIBC were enrolled in phase II trials of dose-dense NAC with MVAC (methotrexate, vinblastine, adriamycin, and cisplatin; NCT01031420) or GC (gemcitabine and cisplatin; NCT01611662). Patients were treated with NAC with plan for curative cystectomy. DNA from pretreatment tumor tissue was sequenced for coding exons of 287 cancer-related genes and analyzed for mutations. Survival in patients with one or more mutations in ATM, RB1, or FANCC genes was compared to those without mutations. Results: Of 58 pts treated, 38% (22/58 pts) had relevant mutations in the combined group of MVAC (13/34 pts) and GC (9/24 pts) trials. At a median follow-up of 56 months and minimum follow up of 16 months, patients with mutations had statistically significantly greater OS (p = 0.0043) and DSS (p = 0.0015). Median OS/DSS was not reached for patients with a mutation in any group. At 5 years post treatment, OS/DSS were greater in mutated vs non-mutated patients in all groups (see table). Conclusions: Long-term follow up reveals that previously reported improved responses to cisplatin-based NAC associated with mutations in ATM, RB1 and FANCC also confer a clinically meaningful and statistically significant survival benefit in these patients. These alterations may be useful as predictive biomarkers to allow clinicians to prioritize patients most likely to benefit from NAC prior to radical cystectomy. [Table: see text]
Proximity to oil refineries and risk of bladder cancer: A population-based analysis.
Authors: Dafashy Tamer , Phillips Daniel , Ray-Zack Mohamed Danny , Kerr Preston , Shan Yong , Baillargeon Jacques G. , Kuo Yong-Fang , Mehta Hemalkumar B , Williams Stephen Bentley 
Published: May 2019

4538 Background: Exposure to aromatic amines is a risk factor for bladder cancer. Incidence rates according to proximity to oil refineries are largely unknown. We sought to determine proximity of oil refineries and bladder cancer incidence in the State of Texas which is home to the largest number of oil refineries in the United States. Methods: We used the Texas Cancer Registry database to identify patients diagnosed with bladder cancer from January 1, 2001 to December 31, 2014. The U.S. census data from 2010 was used to ascertain overall population size, age and sex distributions. Heat maps of the 28 active oil refineries in Texas were developed. Incidence of bladder cancer were compared according to proximity ( < 10 vs. ≥ 10 miles) to an oil refinery. Risk ratios were adjusted using a Poisson regression model. Results: A total of 45,517 incident bladder cancer cases were identified of which 5,501 cases were within 10 miles of an oil refinery. In adjusted analyses, bladder cancer risk was significantly greater among males vs. females (Relative Risk (RR) 3.41, 95% Confidence Interval (CI), 3.33-3.50), and greater among people living within 10 miles from an oil refinery than those living outside a 10-mile radius from an oil refinery (RR 1.19, 95% CI, 1.08-1.31). Conclusions: People living within 10 miles from oil refineries were at greater risk for bladder cancer. Further research into exposure to oil refineries and bladder cancer incidence is warranted.
Analysis of EGFR mutant urothelial carcinoma (UC) reveals distinct mutational landscape.
Authors: Madison Russell , Gupta Sumati , Ross Jeffrey S. , Pal Sumanta K. , Schrock Alexa Betzig , Miller Vincent A. , Heymach John , Necchi Andrea , Juckett Luke , Ali Siraj Mahamed , Chung Jon , Reddy Venkataprasanth P. 
Published: May 2019

4545 Background: Genomic alterations (GA) of EGFR, are well recognized as druggable oncogenic drivers in NSCLC, but the druggable GA EGFR L858R and exon 19 deletion (ex19del), are rarely observed in genitourinary cancer. We reviewed the genomic landscape of advanced upper tract and bladder UC (UTUC and BUC) to assess the frequencies of druggable EGFR GA. Methods: Tissue specimens from patients with UTUC (407) and BUC (2,402) were assayed using hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 or 114 loci. Results: EGFR alterations ( EGFR alt) were present in 17 UTUC and 93 BUC (4.2% and 3.9%). Age distribution between the two subgroups was similar, but UTUC was more prevalent in female patients (47% v 29%). BUC had a higher median TMB (5.2mut/mb v 7.8 mut/mb; p = 0.046) and the prevalence of MSI-H cases was not significantly different. TERT (55% v 71%) and TP53 (59% v 74%) were the most frequently mutated genes in EGFR alt UTUC and BUC. Within EGFRalt, amplifications were the most common alterations in both UTUC and BUC (13/17, 76%; 57/93, 61%). Amplifications were mutually exclusive from cases with EGFR short variants (SV) in BUC (0/34, 0%), and co-occurred with EGFR SV in four UTUC cases (4/8 50%). The majority of EGFR SV were EGFR exon 20 insertions ( EGFRexon20), which made up a larger proportion of EGFR alt in UTUC than BUC (7/17, 41% v 13/93, 14%; p = 0.01). Compared to other EGFR alt , EGFRexon20 trended towards mutual exclusivity of GA in commonly altered UC genes: TP53 (UTUC EGFRexon20 v EGFR alt other: 0% v 100%, p = 5.1E-5; BUC EGFRexon20 v EGFR alt other: 0% v 86%, p = 2.2E-7) , PIK3CA (14% v 10%; 0% v 19%) , RAF1 (0% v 10%; 0% v 16%) , or FGFR3 (0% v 10%; 0% v 6.3%) alterations. Only 2.2% (2/93) of BUC EGFRalt were L858R mutations and none were ex19del (0/93), while neither mutation was detected in UTUC. Conclusions: EGFRexon20 defines a subset of UC cases, and is the most common non-amplification GA seen in EGFR in UC, with some enrichment in UTUC. Consideration should be given to developing a trial for EGFR exon20 UC patients given the recent investigational work on inhibitors with activity against EGFRexon20, such as poziotinib and TAK-788.
KEYNOTE-052: Phase 2 study evaluating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC)— Updated response and survival results.
Authors: O'Donnell Peter H. , Balar Arjun Vasant , Vuky Jacqueline , Castellano Daniel E. , Bellmunt Joaquim , Powles Thomas , Bajorin Dean F. , Grivas Petros , Hahn Noah M. , Plimack Elizabeth R. , Savage Mary J. , Fang Xiao , Godwin James Luke , Frenkl Tara L. , De Wit Ronald 
Published: May 2019

4546 Background: Initial results of the phase 2 KEYNOTE-052 (NCT02335424) study led to approval of pembro for cisplatin-ineligible patients (pts) with advanced UC. Updated results representing follow-up of over 2 y since last pt enrolled are presented. Methods: Pts had confirmed advanced UC, were cisplatin-ineligible (ECOG PS 2, CrCl ≥30 to ˂60 mL/min, grade ≥2 neuropathy/hearing loss, NYHA Class III heart failure), and received no prior chemotherapy for metastatic disease. Pts received pembro 200 mg IV Q3W until progression, unacceptable toxicity, withdrawal, or 24 mo of therapy, whichever occurred first. Primary end point was confirmed ORR (RECIST v1.1, independent central review). Key secondary end points: duration of response (DOR), overall survival (OS), and safety. Data cutoff was September 26, 2018. Results: Among pts assessed (N = 370), median age was 74 y, 85% had visceral disease, and 30% were PD-L1 positive (combined positive score [CPS] ≥10). Median follow-up was 11.4 mo (range, 0.1-41.2) for all pts and 29.3 mo (range 7-41.2) for responders. Confirmed ORR was 29% (95% CI, 24-34): complete response, 9% (n = 33); partial response, 20% (n = 73). Median DOR was 30.1 mo (95% CI, 18.1-not reached [NR]); 67% and 52% of pts had DOR ≥12 and ≥24 mo, respectively. Median OS was 11.3 mo (range 9.7-13.1); 12- and 24-mo OS rates were 47% and 31%, respectively. In pts with CPS ˂10 (n = 251) and ≥10 (n = 110), respectively, confirmed ORR was 20% (95%CI, 16-26) and 47% (95% CI, 38-57). Median DOR for pts with CPS < 10 and ≥10 was 18.2 mo (95% CI, 9.7-NR) and NR (95% CI, 18.1-NR); DOR ≥24 mo was 45% and 57%, respectively. Median OS for pts with CPS < 10 and ≥10 was 9.7 mo (95% CI, 7.6-11.5) and 18.5 mo (95% CI, 12.2-28.5); 24-mo OS rates were 24% and 47% respectively. Treatment-related adverse events (AEs) occurred in 67% of pts. Most common were fatigue and pruritus (18% each); 21% were grade ≥3, including 1 death (myositis). Conclusions: With extended follow-up, pembro continued to elicit clinically meaningful, durable antitumor activity in cisplatin-ineligible pts with advanced UC and was more pronounced in those with PD-L1 expression CPS ≥10. Pembro safety profile was as expected. Clinical trial information: NCT02335424.
Interim analysis of the fierce-21 phase 2 (P2) study of vofatamab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUC).
Authors: Mellado Begona , Castellano Daniel E. , Pang S , Urun Yuksul , Park Se Hoon , Vaishampayan Ulka N. , Pal Sumanta K. , Currie Graeme , Abella Esteban , Vogl Florian D. , Necchi Andrea 
Published: May 2019

4547 Background: Patients (pts) with mUC with FGFR3 mutations who have failed platinum-based chemotherapy have a poor prognosis. Their response to immune checkpoint inhibitors appears diminished 10% or less compared to WT pts. 20% of mUC pts harbor FGFR3 mutations or fusions (M/F). Vofatamab is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. FIERCE-21 is a Phase 1b/2 study designed to evaluate vofatamab monotherapy (VFM) or in combination with docetaxel (VFD). Methods: The P2 expansion enrolled mUC pts with FGFR3 M/F+ tumor (identified with FoundationONE CDx™), who failed ≥ 1 prior line of chemotherapy (including prior taxane for pts receiving VFM) or recurred ≤ 12 months of (neo)adjuvant chemotherapy. Pts had measurable disease and ECOG ≤ 1. Treatment consisted of vofatamab at 25 mg/kg alone and in combination with docetaxel at 75 mg/m2 q3w. Efficacy was assessed by investigators (RECIST 1.1). Primary objectives were safety and objective response-rate (ORR). Results: In the P2, 21 pts each received VFM and VFD. 57% of VFD pts had received at least 2, and 71% of VFM at least 3 prior lines of therapy. Best response to prior therapy was PD for 67% of VFD and 38% of VFM. The safety profile is consistent with previously reported data. TEAEs occurring in > 20% of pts were decreased appetite, diarrhea, pyrexia, asthenia, anemia, dyspnea, and fatigue. Most common vofatamab-related TEAEs in > 10% of pts were asthenia, diarrhea, decreased appetite and rash; all were Grade 1 or 2. In VFM, only 1 pt had a grade 3 TEAE and no pt discontinued treatment due to an AE. There were no cases of hyperphosphatemia, ocular or nail toxicity; 1 pt reported grade 2 skin toxicity. For pts receiving VM, median age was 70 yrs, ECOG 1 = 67%, Hgb < 10 g/dL 5%, liver metastases 19%. Responses have been seen in 7 pts to date including those receiving both VFM and VFD. Conclusions: Vofatamab both alone and combined with D in a q3w schedule are well tolerated with a low frequency of grade 3 TEAEs. Both VFM and VFD have demonstrated efficacy in terms of ORR. PFS/OS and DOR data will be presented at 7+ months for VFD and 9+ months for VFM. Clinical trial information: NCT02401542.
Recombinant humanized anti-PD-1 monoclonal antibody toripalimab in patients with metastatic urothelial carcinoma: Preliminary results of an open-label phase II clinical study.
Authors: Sheng Xinan , Chen Haige , Yao Xin , Hu Yi , Yao Xudong , Liu Ziling , Zhou Fangjian , Huang Yiran , Guo Jun ,   Shanghai Junshi Biosciences Co., Ltd.
Published: May 2019

4554 Background: Patients with advanced metastatic urothelial carcinoma (UC) who experience disease progression after standard therapy have limited treatment options. Phase I studies of toripalimab in subjects with heavily pretreated metastatic UC have demonstrated an acceptable safety profile and promising clinical activity. Here we report the preliminary safety and efficacy result of toripalimab in a phase II clinical study in Chinese patients with refractory/metastatic urothelial carcinoma. (Clinical trial ID: NCT03113266). Methods: Metastatic UC Patients will receive toripalimab, also known as JS001, 3 mg/kg Q2W until disease progression or unacceptable toxicity. All patients with measurable disease will be assessed for clinical response every 8 weeks according to RECISTv1.1. Tumor PD-L1 expression and tumor mutational burden will be measured for correlation with clinical response. Results: From May 2017 to February 10, 2019, 79 patients were enrolled from 7 participating centers. The median age was 61 years with 57.5% male. By the cut-off date of Jan 20, 2019, common treatment related AEs were mostly grade 1 or 2, including anemia, hyperglycemia, ALT increased, AST increased and hypothyroidism. Among 65 evaluable patients, 2 complete responses, 18 partial responses, and 13 stable diseases were observed, for an objective response rate (ORR) of 30.8% and a disease control rate of 50.8%. 70% (14/20) responses were ongoing by the cut-off date. PD-L1 expression results were obtained from 56 subjects. PD-L1+ patients (n=16, 28.6%) had significant better ORR than PD-L1- patients (n=40), 62.5% versus 15.0% ( p<0.01). Conclusions: Toripalimab has demonstrated encouraging clinical activity in chemo-refractory UC patients and a manageable safety profile. Toripalimab elicited a favorable 62.5% ORR in PD-L1 positive patients, while PD-L1 negative patients also achieved a 15% ORR, including one complete response. Patients will be continuously monitored for additional safety and efficacy readouts (DOR, PFS and OS). Clinical trial information: NCT03113266.
Circulating tumor cell (CTC) enumeration in patients (pts) with metastatic genitourinary (mGU) tumors treated in a phase I study of cabozantinib and nivolumab (CaboNivo) +/- ipilimumab (CaboNivoIpi).
Authors: Apolo Andrea B. , Mortazavi Amir , Hu Zishuo Ian , Schonhoft Joseph , Chu Lincy , Anderson Amanda K. L. , Wang Yipeng , Dittamore Ryan , Pal Sumanta K. , Lara Primo , Stein Mark N. , Steinberg Seth M. , Mayfield Christian , Cordes Lisa M. , Mallek Marissa , Costello Rene , Diaz Carlos , Trepel Jane B , Bottaro Donald P. 
Published: May 2019

4555 Background: CTCs may serve as biomarkers for clinical outcomes in GU tumor pts. We examined the association between baseline CTC enumeration, CTC heterogeneity, CTC morphologic subtypes, and progression-free-survival, overall survival and response to therapy with combination CaboNivo or CaboNivoIpi. Methods: 123 samples from 52 pts with mGU tumors treated with CaboNivo (38 pts) or CaboNivoIpi (14 pts) drawn at Baseline, Cycle (C) 2 Day (D) 1, and C3D1 were processed using the Epic Sciences platform. CTCs were defined as cytokeratin (CK)+, CD45-, distinct morphology, intact nucleus. PD-L1 expression was also assessed. Results: From 07/20/2016-09/01/2018, 52 pts [urothelial carcinoma (UC) N = 33; plasmacytoid N = 1; Clear cell renal cell carcinoma N = 4; bladder adenocarcinoma N = 8; bladder squamous cell carcinoma N = 2; bladder small cell N = 2; renal medullary N = 2] were treated. Median age was 61.5 years (range 20-82); 35 (67%) were male. N = 37 (71%) had visceral involvement, N = 15 (29%) with liver involvement, N = 11 (21%) with bone involvement. CTCs were found in the peripheral blood of 26/40 (65%) pts at baseline. 1/40 pts (bladder adenocarcinoma) had PDL1+ CTCs at Baseline. Median CTC/mL at Baseline, C2D1, C3D1, were not significantly different. CTC counts of > 2 and > 4 at C2D1 were potentially associated with shorter OS (p = 0.071 and p = 0.045 without adjustment for multiple cutoffs for evaluation). PFS results exhibited similar trends. Unsupervised clustering of CTC images identified 5 main CTC subtypes, of which the presence of one was significantly associated with shorter OS (p = 0.0014, not adjusted for multiple testing). Additionally, we observed a trend towards patients with higher CTC heterogeneity at C2D1 having longer OS, when adjusting for the risk associated with CTC enumeration (p = 0.084). Conclusions: CTC were detected in pts with mGU tumors treated with CaboNivo and CaboNivoIpi. CTC values were somewhat but not statistically lower in responders vs. non-responders. On treatment lower CTCs and the absence of aggressive CTC subtypes were associated with better clinical outcomes. Ongoing analyses include single cell genomics, and analysis of T-cell populations. Clinical trial information: NCT02496208.
Impact of antibiotic use on clinical outcomes in patients with urothelial cancer receiving a programmed death protein 1 or programmed death ligand 1 (anti-PD-1/L1) antibody.
Authors: Weinstock Chana , Maher Virginia Ellen , Fernandes Laura L , Tang Shenghui , Agrawal Sundeep , Brave Michael Holman , Ning Yang-Min , Singh Harpreet , Suzman Daniel L. , Xu James , Goldberg Kirsten B. , Sridhara Rajeshwari , Ibrahim Amna , Theoret Marc Robert , Beaver Julia A. , Pazdur Richard 
Published: May 2019

4557 Background: Previous data has suggested that patients treated with anti-PD-1/L1 antibodies who receive antibiotics during their therapy might have dramatically decreased progression-free and overall survival 1,2. This has clinical implications for management of patients with suspected bacterial infection while on treatment with these agents. We assessed the relationship between antibiotic use and tumor response rate, progression-free survival, and overall survival in a large dataset of patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. Six were single arm trials and one was a randomized controlled trial whose control arm is not included in these analyses. Concomitant medication datasets were searched for systemic antibiotic used by each patient while on treatment. Results: Overall, 51% of patients (n=892) were exposed to antibiotics (ABX+) and 49% (n=855) were not exposed (ABX-). In these exploratory analyses, small numeric differences in OS, PFS, and ORR were seen in ABX+ vs. ABX- patients. Median OS was 9.23 vs. 9.86 months, median PFS was 105 vs 101 days, and ORR was 20% vs. 21% in ABX+ vs. ABX- patients, respectively. Conclusions: Patients who were treated with antibiotics while on therapy with an anti-PD-1/L1 antibody for urothelial cancer had similar outcomes to those who were not treated with antibiotics. Numeric differences in outcomes were not significant and did not duplicate previous analysis demonstrating a median OS that was doubled in ABX- patients1. Our exploratory analyses do not appear to demonstrate a clear need for practitioners to avoid antibiotic use in patients treated with PD-1/L1 agents for fear of significantly impacting clinical outcomes. References: 1) Tinsley et. al., ASCO annual meeting 2018, abstract 3010 2) Routy et. al., Science 05 Jan 2018: Vol. 359, Issue 6371. [Table: see text]
Phase I/II study of axitinib (axi) and nivolumab (nivo) in patients with metastatic renal cell carcinoma (mRCC).
Authors: Zibelman Matthew R. , Geynisman Daniel M. , Molina Ana M. , Malizzia Lois , Devarajan Karthik , Luong Diana , Sullivan Elizabeth , Carducci Michael Anthony , Plimack Elizabeth R. 
Published: May 2019

4567 Background: Drug combinations targeting vascular endothelial growth factor (VEGF) and the programmed death one (PD-1) pathway have demonstrated encouraging efficacy in patients (pts) with mRCC. We are conducting a phase I/II trial combining the VEGF-targeting tyrosine kinase inhibitor (TKI) axi and the PD-1 inhibitor nivo in mRCC pts. Methods: The phase I portion of this investigator-initiated, multi-center trial enrolled pts with TKI-refractory mRCC (any line) and no prior anti-PD-1. It used a 3+3 design, with axi dosing starting at 3 mg orally BID, escalating to a target dose of5 mg BID. Nivo dosing was fixed at 240 mg IV Q2 weeks or 480 mg Q4 weeks. Eligible pts received axi alone for a one week induction, followed by combination dosing. There was a 4 week period to assess for dose limiting toxicities (DLTs). The primary endpoint for phase I was safety and establishment of a recommended phase II dose (RP2D) for axi. Safety and early efficacy data for the phase I cohort are presented. Results: Twelve pts received treatment during the phase I portion, with all evaluable for toxicity. Ten were 2nd line and 2 were 3rd line or beyond. One DLT was noted in the first cohort of three pts (grade 3 autoimmune disorder), thus that cohort was expanded. No further DLTs were reported at axi 3 mg BID, or at further expansion to 5 mg BID. Grade 3 adverse events (AEs) at least possibly related to one of the drugs included expected side effects HTN, hyperglycemia, and transaminitis. One patient received steroids for an immune related AE (grade 3 transaminitis) that resolved to grade 1 with steroids. No grade 4-5 AEs occurred. Axi at 5 mg BID was chosen as the RP2D. With 10 pts evaluable for efficacy, 4 pts had partial responses, 4 pts had stable disease, and 2 had progressive disease. Updated efficacy data will be presented. Conclusions: The phase I portion of this phase I/II trial has demonstrated expected safety and established 5 mg BID as the RP2D axi dose. This ongoing VEGF TKI/PD1 trial incorporating two drugs already approved for mRCC pts has shown encouraging signs of efficacy and has now expanded to include treatment naïve pts in addition to TKI-refractory pts as part of phase II. Clinical trial information: NCT03172754.