bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of timing of antibiotic use on clinical outcomes in patients with urothelial cancer treated with immune checkpoint inhibitors (ICIs).
Authors: Weinstock Chana , Bandaru Pradeep , Fernandes Laura L , Chang Elaine , Girvin Andrew , Tang Shenghui , Agrawal Sundeep , Suzman Daniel L. , Singh Harpreet , Brave Michael Holman , Xu James , Goldberg Kirsten B. , Ibrahim Amna , Theoret Marc Robert , Pazdur Richard , Beaver Julia A. 
Published: May 2020

5045 Background: Although recent evidence has suggested that patients who receive antibiotics (ABX) during the course of ICI treatment might decrease overall survival (OS) (1), our previous analysis did not support a difference in OS in urothelial cancer patients who did and did not use ABX during the course of ICI treatment without regard to timing (2). This updated analysis aims to addresses the question of timing; specifically, use of ABX in the 30-day window pre- or post- initiation of ICI treatment. Methods: We pooled data from 7 trials that led to drug approval and which included 1747 patients with advanced urothelial cancer treated with an ICI. Five trials enrolled patients who received prior platinum and 2 enrolled cisplatin-ineligible patients. Concomitant medication datasets were searched for systemic ABX use. The association between ABX use and survival was evaluated using Kaplan-Meier estimates and Cox proportional hazards regression models stratified by study. Results: Overall, 56% of patients were exposed to antibiotics (ABX+) and 43% were not exposed (ABX-). In an exploratory analysis, median OS was similar between arms: 9.7 vs. 9.3 months in ABX+ vs. ABX- patients, respectively (HR 0.96). However, OS results differed in the 27% of patients who were exposed to antibiotics in the 30-day window pre- or post- initiation of ICI treatment, for whom median OS was 4.7 months vs. 11.5 months in the ABX+ vs. ABX- patients, respectively (HR 1.8). This remained true after controlling for baseline risk prognostic factors (Bajorin and Bellmunt scores). Similar trends were observed for progression-free survival (PFS). Conclusions: Patients treated with ABX while on therapy with an ICI for urothelial cancer had similar OS outcomes to those not treated with ABX. However, in an exploratory analysis looking at ABX use in the 30-day window pre- or post-initiation of ICI treatment, OS appeared decreased in ABX+ vs ABX- patients. Our exploratory analyses appear to show an association of OS/PFS with timing of antibiotics. References: 1) Routy B, Science (2017) 2) Weinstock C, ASCO 2019, abstract. [Table: see text]
Phase Ib/II neoadjuvant (N-) pembrolizumab (P) and chemotherapy for locally advanced urothelial cancer (laUC): Final results from the cisplatin (C)- eligible cohort of HCRN GU14-188.
Authors: Hoimes Christopher J. , Adra Nabil , Fleming Mark T. , Kaimakliotis Hristos Z. , Picus Joel , Smith Zachary L , Walling Radhika , Trabulsi Edouard John , Hoffman-Censits Jean H. , Koch Michael O. , Cary Clint , Abouassaly Robert , Eitman Cheryl , Fu Pingfu , Goolamier Gordon , Calaway Adam C , Ponsky Lee Evan , Kelly William Kevin 
Published: May 2020

5047 Background: Patients (pts) with laUC who are C-eligible for N- therapy may benefit from combination chemo-immunotherapy. Cohort 1 (C1) of the GU14-188 trial is a phase 1b/2 trial designed to assess the tolerability and efficacy of N- gemcitabine (G), C, and P in pts with laUC. The current standard of care is ddMVAC with a pathologic non-muscle invasive rate (PaIR, ≤pT1N0) of ~44%. Methods: Eligible pts for C1 were surgical candidates and C-eligible with cT2-4aN0M0 bladder UC. Enrollment followed a Simon 2-stage design for H0 of interval futility which was rejected at stage 1, and fully enrolled. Phase 1b (no DLT) /2 treatments were the same: P 200mg q3wks on day 8 x5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21 day cycle (cy), for 4 cy; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety: 1 dose of P, and for efficacy: 2 doses P and RC. The primary endpoint of PaIR was assessed at RC and designed for 86% power with 4% significance to detect a difference from 23 to 48%. Secondary endpoints include relapse free survival and overall survival. Results: 43 pts were enrolled to C1 with a median (mdn) age 64, 63% male, 51% > cT2. Mdn per-pt doses given (attempted) for: P:5(5), C:4(4), G:8(8). The PaIR was 61.1% (95%CI 0.45, 0.75), P0 (ypT0N0) rate of 44.4%, and did not correlate with baseline PD-L1 score. Downstage to PaIR occurred in 53% of cT2, and 74% of cT3/4. Mdn time to RC from last dose was 5.3wks. Seven were not included in the primary analysis: 4 (9.3%) without RC, 1 progressed, 1 lost to f/u during C1, 1 did not receive required protocol therapy. There was 1 death on post-RC day 9 due to mesenteric ischemia. Of 4 pts who did not have RC, 3 refused and 1 due to gr4 thrombocytopenic purpura; 4pts are alive and without recurrence at mdn f/u of 32mo. One pt with presumed gr3 MI during cy 4 had a negative inpt cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts. At mdn f/u of 34.2mo (3.9-47.4), the estimated 36mo RFS, OS, and DSS is 63%, 82%, and 87%, respectively. Conclusion: Neoadjuvant GC with P in laUC has manageable toxicity and has improved pathologic outcomes compared to historic controls. Durable long-term survival in those with- and without -RC is noteworthy in this advanced cohort. KEYNOTE 866, NCT03924856, is a Phase III study of GC with perioperative P. Clinical trial information: NCT02365766 .
Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes.
Authors: Dudani Shaan , Gan Chun Loo , Wells Connor , Bakouny Ziad , Dizman Nazli , Pal Sumanta K. , Wood Lori , Kollmannsberger Christian K. , Szabados Bernadett , Powles Thomas , Beuselinck Benoit , Donskov Frede , Hansen Aaron Richard , Bjarnason Georg A. , Canil Christina M. , Srinivas Sandy , Agarwal Neeraj , Liow Elizabeth Chien Hern , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: May 2020

5063 Background: In patients with mRCC, the International mRCC Database Consortium (IMDC) criteria have been validated as a prognostic tool in patients treated with targeted therapy in the 1-4L settings and with 2L Nivolumab (Nivo). However, it is unknown whether the IMDC criteria can be used to risk stratify in recently approved 1L IO combination therapies, including Ipilimumab + Nivolumab (IOIO) and Axitinib + Pembrolizumab/Avelumab (IOVE). We sought to assess the ability of the IMDC criteria to risk stratify with the use of novel 1L IO combinations and provide updated benchmarks for older 1L and 2L treatments. Methods: Patients with mRCC starting systemic therapy between 2010-2019 were identified through the IMDC. IMDC risk score was calculated at the time of starting the line of therapy of interest. The primary endpoint was overall survival (OS) from time of initiating the treatment of interest. Results: From a total of 6596 unique patients, 5043 treated in the 1L setting and 2498 treated in the 2L setting were included in the analysis. Across the entire cohort, median age was 61, 73% were male, 16% had sarcomatoid features, 79% underwent nephrectomy and 88% had clear-cell histology. IMDC risk groups for 1L and 2L treatment were 17%, 57%, 27% and 10%, 60%, 30% for favourable-, intermediate- and poor-risk disease, respectively. IMDC criteria appropriately risk stratified into 3 prognostic groups in 1L IOIO and 1L IOVE combinations, in addition to older treatments: 1L VEGF TT, 2L VEGF TT, 2L Nivo and 2L Everolimus. Results are displayed in Table. Due to the novelty of 1L IO combinations, median follow up time was shorter and thus landmark OS values are presented. Conclusions: IMDC criteria may be used to risk stratify in recently approved 1L IO combination therapies in addition to older 1L and 2L treatments. These data provide contemporary benchmarks for OS that may be used for patient counseling and trial design. [Table: see text]
Characterizing sites of metastatic involvement in metastatic clear-cell, papillary, and chromophobe renal cell carcinoma.
Authors: Dudani Shaan , de Velasco Guillermo , Wells Connor , Gan Chun Loo , Donskov Frede , Porta Camillo , Fraccon Anna , Pasini Felice , Lee Jae-Lyun , Hansen Aaron Richard , Bjarnason Georg A. , Beuselinck Benoit , Pal Sumanta K. , Yuasa Takeshi , Kroeger Nils , Kanesvaran Ravindran , Reaume M. Neil , Canil Christina M. , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: May 2020

5071 Background: There exists considerable biological and clinical variability between histologic variants of metastatic renal-cell carcinoma (mRCC). Data reporting on sites of metastatic involvement in less common histologies of mRCC are sparse. We sought to characterize the frequency of metastatic site involvement across the three most common histologies of mRCC: clear-cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). Methods: Using the International mRCC Database Consortium (IMDC) database, patients with mRCC starting systemic therapy between 2002-2019 were identified and sites of metastases at the time of systemic therapy initiation were documented. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases. The primary outcomes were prevalence of metastatic site involvement and overall survival (OS). Patients with mixed histology were excluded. Results: 10,105 patients were eligible for analysis. Median age at diagnosis was 60, 72% were male and 79% underwent nephrectomy. 92%, 7% and 2% of patients had ccRCC, pRCC, and chrRCC, respectively. Frequency of metastatic site involvement across the histologic subtypes is shown in Table. Lung, adrenal, brain and pancreatic metastases were more frequent in ccRCC, lymph node involvement was most frequent in pRCC, and liver metastases were most frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (brain/pleura) and 50 months (pancreas). OS by site of metastatic involvement was compared between histologies for the four most common sites of metastases (lung, lymph nodes, bone, liver). As compared to patients with ccRCC, patients with pRCC had lower OS regardless of site of metastasis (p < 0.05). Power was limited and thus differences in OS between ccRCC and chrRCC were not detectable. Conclusions: Sites of metastatic involvement differ based on histology in mRCC. These data highlight the clinical and biologic variability between histologic subtypes of mRCC and constitute the largest cohorts of patients with metastatic pRCC and chrRCC to report on sites of metastases. Sites of Metastatic Involvement by Histology. [Table: see text]
Genomic and transcriptomic correlates of clinical benefit from immunotherapy and targeted therapy among patients with metastatic renal cell carcinoma (mRCC).
Authors: Salgia Nicholas , Dizman Nazli , Lyou Yung , Bergerot Paulo Gustavo , Hsu Joann , Byron Sara Ann , Trent Jeffrey M. , Pal Sumanta K. 
Published: May 2020

5076 Background: Previous studies have delineated PBRM1 alterations as a prognostic indicator for response to nivolumab in mRCC (Miao et al Science 2018). However, further clinically-relevant biomarkers remain elusive in mRCC. Herein, we utilized genomic profiling to detect correlates of clinical benefit (CB) among patients (pts) with mRCC receiving VEGF-directed targeted therapy, immunotherapy, or both. Methods: Pts with mRCC who underwent clinical tumor-normal whole exome and whole transcriptome RNA sequencing (Ashion Analytics, Phoenix, AZ) were retrospectively identified at a single institution. Pts’ demographics and clinical variables including treatment type, treatment response, and survival outcomes were collected from an institutional mRCC database. Pts who had received immunotherapy or VEGF-directed therapy (or both) were eligible for analysis. CB was defined as pts who experienced a complete response, partial response, or maintained stable disease for at least 6 months on therapy. Two-tailed Fisher’s exact test was used to assess characteristics of genomic alterations and clinical benefit. Results: Out of 155 mRCC pts with genomic profiling, 58 pts with evaluable response and sufficient follow-up information were included in the analysis. The median age of the cohort was 63 years and 74% were male. The majority (81%) had clear cell histology. 43 pts received targeted therapy and 32 received immunotherapy (17 pts received both). No singular gene was associated with clinical benefit in the targeted therapy cohort. PBRM1 loss of function mutations were more frequent in pts on immunotherapy who experienced CB (p > 0.05). TERT promoter mutations were enriched in pts who experienced no CB on immunotherapy (p = 0.04). Differential gene expression analysis of the transcriptomes found 135 genes that were significantly upregulated in TERT-mutated samples, including SST, CYSLTR2, WNK2, and PTGES (adjusted p-value < 0.05). ENRICHR analysis found that MYC and KAT2A were key transcription factor pathways significantly enriched in pts with TERT mutation who experienced no CB from immunotherapy. Conclusions: These data support previous observations regarding the prognostic nature of PBRM1 in mRCC and offer novel findings associating TERT mutations with a lack of CB from immunotherapy. Our transcriptomic analysis implies that MYC-targeting agents and epigenetic modifiers (directed at KAT2A) could overcome immunotherapy resistance.
Use of immune checkpoint inhibitors (ICIs) after prior ICI in metastatic renal cell carcinoma (mRCC): Results from a multicenter collaboration.
Authors: Ravi Praful , Mantia Charlene , Su Christopher , Sorenson Karl , Rathi Nityam , Bakouny Ziad , Agarwal Neeraj , Costello Brian Addis , McKay Rana R. , Narayan Vivek , Alva Ajjai Shivaram , McGregor Bradley Alexander , Gao Xin , McDermott David F. , Choueiri Toni K. 
Published: May 2020

5077 Background: Several ICIs are used in first and subsequent lines of therapy for mRCC, either alone or in combination with another ICI or targeted therapy (TT). There are no data on the efficacy and safety of using an ICI in patients who have already received an ICI in a prior line of therapy. Methods: We reviewed patients with mRCC at 8 institutions who received 2 separate lines of ICI therapy (ICI-1, ICI-2), including as a single-agent and/or combination with other agents. The primary outcomes were overall response rate (ORR) and time to progression (TTP) with ICI-1 and ICI-2. Immune-related adverse events (irAEs) were graded using CTCAEv5.0. Results: 65 patients were included. Median age at diagnosis of mRCC was 60 years (range 30-86) and the majority had clear cell RCC (n=56, 86%). Median follow-up was 3.5 years (95% CI 2.9-4.4). Median lines at which ICI-1 and ICI-2 were received were 1 (1-6) and 3 (2-8) respectively. Reasons for discontinuing ICI-1 were disease progression (n=47, 72%), toxicity (n=15, 23%) or other (n=3, 5%). Therapies received at ICI-2 were single-agent ICI (n=26, 40%), or combinations of ICI with another ICI (n=20, 31%), TT (n=11, 17%) or other agent (n=8, 12%). Responses to ICI-1 and ICI-2 are shown in the Table; ORR to ICI-2 was significantly lower than to ICI-1 (23% vs. 36%, p=0.044). Amongst those who responded to ICI-2 (n=14), 7 (50%) received single-agent ICI, and the remainder received ICI in combination with another ICI (n=4, 29%) or TT (n=3, 21%); 7 patients (50%) had previously responded to ICI-1. The ORR to ICI-2 was higher in responders to ICI-1 (32%) compared to those with SD (17%) or PD (15%) to ICI-1. Median TTP (mTTP) at ICI-2 was shorter compared to ICI-1 (5.3 months vs. 8.5 months, Wilcoxon p=0.024). 29 patients (45%) experienced an irAE with ICI-2; 8 (12%) and 3 (5%) had a grade 3 or 4 irAE respectively, with 3 (30%) of these patients having previously had ≥grade 3 irAE to ICI-1. There were no treatment-related deaths. Conclusions: The ORR to ICI-2 was 23%, which is comparable to that seen with ICI after prior TT. Responses were seen even amongst those receiving single-agent ICI at ICI-2 and the likelihood of response to ICI-2 was higher if a patient had previously responded to ICI-1. No increase in toxicity with ICI-2 was apparent. Additional data from prospective studies are needed to determine whether sequential ICI has a role in treatment of mRCC. [Table: see text]
Impact of human papillomavirus (HPV) infection on the outcome of perioperative treatments for penile squamous-cell carcinoma (PSCC).
Authors: Giannatempo Patrizia , Bandini Marco , Zhu Yao , Ye Dingwei , Ornellas Antonio Augusto , Watkin Nick , Ager Michael , Hakenberg Oliver W. , Heidenreich Axel , Raggi Daniele , Haidl Friederike , Marandino Laura , Pederzoli Filippo , Briganti Alberto , Montorsi Francesco , Chipollini Juan , Azizi Mounsif , Albersen Maarten , Spiess Philippe E. , Necchi Andrea 
Published: May 2020

5088 Background: PSCC patients (pts) with palpable inguinal lymph node (ILN) disease have a poor overall survival (OS). Multimodal perioperative treatments are usually offered despite the lack of clinically meaningful efficacy. Pending the availability of novel effective systemic therapy, the optimization of conventional treatments in better selected pts is needed. Methods: Within an international, multicenter database of 924 PSCC pts who received ILN dissection from USA, Europe, Brazil and China, 494 had information on HPV, and 52 (10.5%) had HPV+ PSCC, predominantly assessed with immunohistochemistry (53%). Multivariable logistic regression analyses evaluated the association between pt factors and HPV status. Multivariable Cox analyses (MVA) assessed predictors of overall mortality (OM), including HPV status, pathologically-involved ILN ratio (ILNR), extranodal extension, margin status, vascular invasion (VI), perioperative RT (pRT) and perioperative chemotherapy (pCT). Comparisons between HPV status and ILNR were performed using interaction tests. Kaplan-Meier method was used to define the OS benefit related in HPV-stratified sub-groups. Results: Median age at diagnosis was 58yrs. Overall, pCT and pRT were used in 227 (46%) and 50 (10%) pts. The median follow-up was 62 months. Neither clinical factors nor country were associated with HPV status. On MVA, ILNR (HR:1.01, p = 0.01) and extranodal extension (HR: 1.5, p = 0.02) were statistically significantly associated with OM, but HPV was not (p = 0.2). However, in the subgroup of pts who received pRT, HPV status was associated with favorable OM (HR: 0.11, 95%CI: 0.03-0.5, p = 0.004) together with negative VI (p = 0.03), and the use of adjuvant CT (p = 0.04). A significant interaction was found on OM between HPV+ status and increasing ILNR, with a cutoff at 50% (p = 0.05). Results are limited by their retrospective nature and small numbers in each subgroup. Conclusions: In the largest available dataset of ILND for PSCC, we observed that pRT seemed to be more effective in the subgroup of HPV+ PSCC. These results should be considered as hypothesis-generating and may inspire both the future prospective trials or the ongoing InPACT study.
A pooled analysis of the efficacy and safety of cabozantinib post immunotherapy in patients with advanced renal cell carcinoma.
Authors: Oya Mototsugu , Tamada Satoshi , Tatsugami Katsunori , Nakaigawa Noboru , Osawa Takahiro , Kanayama Hiro-Omi , Kondoh Chihiro , Sassa Naoto , Nishimura Kazuo , Nozawa Masahiro , Masumori Naoya , Miyoshi Yasuhide , Kimura Akiko , Kuroda Shingo , Motzer Robert J. , Choueiri Toni K. , Tomita Yoshihiko 
Published: May 2020

5089 Background: While studies have demonstrated survival benefits of first-line regimens including immuno-oncology agents (IO) in advanced renal cell carcinoma (aRCC), optimal treatment following IO is unknown. In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients (pts) with aRCC, after VEGFR-TKI therapy. The Japanese phase II C2001 study (NCT03339219), targeting a population similar to that of METEOR, showed similar efficacy and safety results. Here, we present a post-hoc pooled analysis of pts who had received prior IO therapy from METEOR and C2001. Methods: A pooled analysis was performed in pts who received 60mg/day of oral cabozantinib once daily enrolled in the METEOR or C2001. Patients were divided into two groups with previous IO treatment (pre-w/ IO subgroup) or without previous IO treatment (pre-w/o IO subgroup). Analyses of ORR, PFS, OS, and safety were performed as measures of clinical outcome in each subgroup. Results: 365 pts (pre-w/ IO subgroup: 33 pts, pre-w/o IO subgroup:332 pts) were included for efficacy analysis and 366 pts (pre-w/ IO subgroup: 33 pts, pre-w/o IO subgroup:333 pts) for safety analysis. Minor differences in baseline characteristics were noted between the analysis subgroups but are not expected to substantially affect efficacy outcomes. The ORR was 21.2% (95% CI: 9.0-38.9%) for pre-w/ IO subgroup, and 17.2% (95% CI: 13.3-21.7%) for pre-w/o IO subgroup. PFS rate and OS rate at 6 months pre-w/ IO was 65.5%, 90.8% and pre-w/o IO was 58.3%, 90.6%, respectively. Although there were some differences in the safety profile, almost all AEs were manageable by dose modifications. There were no differences in AEs associated with IO treatment, such as pneumonitis, endocrinolopathy or infusion related reaction. No new safety signals were noted in any subgroups. Conclusions: Safety and treatment efficacy of cabozantinib were maintained in the pooled analysis of pts from METEOR and C2001 irrespective of prior IO treatment. Funded by Takeda Pharmaceutical Company Limited, Tokyo, Japan. Clinical trial information: NCT03339219, NCT01865747 .