bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with locally advanced urothelial cancer.
Authors: Hatakeyama Shingo , Tanaka Toshikazu , Hamaya Tomoko , Togashi Kyo , Iwamura Hiromichi , Okamoto Teppei , Yoneyama Takahiro , Ohyama Chikara , Miura Yuki 
Published: February 2022

254 Background: The CheckMate 274 trial demonstrated a benefit in disease-free survival (DFS) with adjuvant nivolumab therapy in patients at high risk of muscle-invasive UC and may become a standard of care in the future. In that study, postoperative pT3-4/ypT2-4 or pN+ was used as an inclusion criterion for the high-risk group, but the validity of this criterion in clinical practice remains unclear. Also, there is an urgent need for the proportion of patients who are eligible for adjuvant immunotherapy in clinical practice. We aimed to evaluate the effect of postoperative pathological findings related to the eligibility of adjuvant immunotherapy on oncologic outcomes in patients with localized and locally advanced muscle-invasive bladder carcinoma (MIBC) and upper tract urothelial carcinoma (UTUC). Methods: We retrospectively evaluated 1082 patients treated with radical cystectomy (n = 597) and nephroureterectomy (n = 485) between January 2000 and April 2021. Patients were divided into two groups: pT3-4 or pN+ without neoadjuvant chemotherapy and ypT2-4 or pN+ treated with neoadjuvant chemotherapy (trial-eligible group) or others (trial-ineligible group). The primary outcome was the effect of trial eligibility for adjuvant immunotherapy on disease-free survival (DFS) and overall survival (OS). Secondary outcomes included the additional effect of lymphovascular invasion (LVI) status to the clinical trial criteria on prognosis and a risk model development. Results: The median age of the patients was 69 and 72 years in the MIBC and UTUC groups, respectively. Fifty-two percent of patients met the trial inclusion criteria. Trial eligibility was significantly associated with poor DFS and OS among patients with MIBC and UTUC. LVI-positive status was significantly associated with poor prognosis among patients in the trial-eligible group. A very high risk (LVI+ or pN+ among the pT3-4 or ypT2-4) was significantly associated with poor prognosis. Conclusions: A total of 52% of patients were eligible for adjuvant immunotherapy. Trial eligibility was significantly associated with a poor prognosis. LVI+ and pN+ may play a key role in candidate selection for adjuvant immunotherapy.
Efficacy, safety, and biomarker analysis of neoadjuvant avelumab/axitinib in patients (pts) with localized renal cell carcinoma (RCC) who are at high risk of relapse after nephrectomy (NeoAvAx).
Authors: Bex Axel , Abu-Ghanem Yasmin , Van Thienen Johannes V. , Graafland Niels , Lagerveld Brunolf , Zondervan Patricia , Beerlage Harrie , van Moorselaar Jeroen , Kockx Mark , Van Dam Pieter-Jan , Szabados Bernadett , Blank Christian U. , Powles Thomas , Haanen John B. A. G. 
Published: February 2022

289 Background: Antibodies targeting PD-1/PD-L1 combined with vascular endothelial growth factor (VEGF) inhibitors are a first-line standard of care for metastatic RCC. Neoadjuvant use of these combinations may lead to downstaging and reduce the risk of recurrence. In addition, sequential tissue may allow identification of key immune biomarkers associated with outcome. Methods: Neoavax is a single arm phase II trial of 12 weeks neoadjuvant avelumab/axitinib prior to nephrectomy in 40 pts with high-risk non-metastatic clear-cell (cc) RCC (cT1b-4cN0-1M0, Grades 3-4). Primary endpoint is RECIST 1.1 partial response (PR) in the primary tumour (PT) in ≥25%. Secondary endpoints are disease-free survival (DFS), overall survival (OS) and safety. Biomarker analysis on sequential tissue is an exploratory endpoint. Expression of PD-L1 (SP263), CD8+, CD8-granzyme-B (CD8/GZMB)+, Foxp3+ cells, CD8/CD39+ and MHC-I were compared on pre-treatment biopsy and nephrectomy samples from 34 pts (NCT03341845). Results: Pts/tumour characteristics are shown in table. Twelve pts (30%) had a PR of the PT from a baseline mean diameter of 10.3 (range 5.6-16.4) cm. Median PT downsizing was 20 (0-43.5) % and median post-treatment vital tumour presence was 50 (1-100) %. At a median follow-up of 23.5 months, recurrence occurred in 13 (32%) pts at a median of 8 (2-23) months and 3 died of disease. Of the 12 pts with PT PR, 11 (92%) are disease-free. Median DFS and OS are not reached. Postoperative adverse events occurred in 8 pts (2 Clavien Dindo grade 3a). There were no treatment-related surgery delays and no PT progression. Post-treatment samples showed upregulation of PD-L1 expression (p <0.0001) and total CD8+ densities (p < 0.01) when compared to pre-treatment biopsies. Comparing samples of pts with PR vs no PR in the PT, no clear immune marker differences were observed. Post-treatment samples from pts that recurred were characterized by lower densities of total, intra-epithelial and stromal CD8+, intra-epithelial CD8+CD39+ (p<0.05) and total CD8+GZMB+ (p=0.1). Pre-treatment biopsies showed no clear differences. Conclusions: Neoadjuvant avelumab/axitinib for non-metastatic high-risk RCC leads to PR of the PT in 30% which is associated with DFS. Pts without recurrence had a significant increase in CD8+ densities compared to pts with recurrence suggesting expansion of a pre-existing immune response. Clinical trial information: NCT03341845. [Table: see text]
Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with clear cell RCC (ccRCC): Impact of FLCN genomic alteration (GA) status.
Authors: Bratslavsky Gennady , Necchi Andrea , Spiess Philippe E. , Grivas Petros , Jacob Joseph M , Kravtsov Oleksandr , Huang Richard S.P. , Parini Vamsi , Decker Brennan , Lin Douglas I. , Pavlick Dean C. , Danziger Natalie , Ross Jeffrey S. 
Published: February 2022

292 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with ccRCC. Methods: 108 chrRCC and 2110 ccRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female and younger than pts with ccRCC p <.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in only 2.3% of the ccRCC cases with 37% of the GA predicted to be germline. chrRCC did not reveal somatic or germline FLCN GA. GA/tumor were slightly higher in ccRCC vs chrRCC (3.6 vs 2.4; NS). GA more frequent in chrRCC included TP53, RB1 and PTEN. GA more frequent in the ccRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Putative biomarkers of immune checkpoint inhibitor (ICPI) response were infrequent in both groups with only a slightly higher, but still low, mean TMB in ccRCC vs chrRCC cases. IHC revealed moderate PD-L1 expression at low and minimal PD-L1 expression at high staining level, which was slightly increased in the chrRCC group. Conclusions: FLCN mutations that are associated with the familial incidence of chrRCC were not associated with sporadic chrRCC. Sporadic chrRCC has substantially different genomic profile from ccRCC and may harbor a few ‘targetable’ GA. The prediction of response to ICPI in RCC remains challenging with chrRCC featuring slightly higher PD-L1 expression and ccRCC featuring higher PBRM1 GA and higher TMB.[Table: see text]
Predictors of objective response to first-line immuno-oncology combination therapies in metastatic renal cell carcinoma: Results from the international metastatic renal cell database consortium (IMDC).
Authors: Navani Vishal , Ernst Matthew Scott , Wells Connor , Yuasa Takeshi , Takemura Kosuke , Donskov Frede , Basappa Naveen S. , Schmidt Andrew Lachlan , Pal Sumanta K. , Meza Luis A , Wood Lori , Ernst D. Scott , Szabados Bernadett , McKay Rana R. , Weickhardt Andrew James , Suárez Cristina , Kapoor Anil , Lee Jae-Lyun , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2022

310 Background: Predictors of objective response to first-line (1L) immuno-oncology (IO) combination therapies remain elusive. We sought to characterise clinical variables and their association with investigator assessed best overall response. Methods: Using the IMDC, we retrospectively identified patients treated with 1L ipilimumab nivolumab (IPI-NIVO) or approved IO/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). Patients were classified, per RECIST v1.1, as responders (complete or partial response (CR or PR)) or non-responders (stable or progressive disease (SD or PD)). Logistic regression was used to adjust for IMDC criteria. Results: Out of 1084 patients, 794 (73%) received IPI-NIVO and 290 (27%) received IOVE (axitinib+pembrolizumab, cabozantinib+nivolumab, axitinib+avelumab, lenvatinib+pembrolizumab). Favourable, intermediate and poor IMDC risk comprised 147 (16%), 517 (55%) and 272 (29%) respectively. Of the 898 patients with evaluable responses, 37 (4%) achieved a best response of CR, 343 (38%) PR, 315 (35%) SD and 203 (23%) PD. Corresponding median overall survival from time of 1L initiation was: not reached, 55.9, 48.1, and 13 months respectively (logrank p < 0.0001). In a multivariable model, lung metastases and cytoreductive nephrectomy (CN) (performed after diagnosis of metastatic disease and before 1L therapy) retained independent association with response, after adjustment for IMDC criteria. Factors not associated with response included (with univariable p values): gender (p = 0.58), age (p = 0.06), sarcomatoid histology (p = 0.99), smoking status (p = 0.39), liver (p = 0.63) and brain (p = 0.12) metastases. As in the VEGF monotherapy era, improved IMDC prognostic risk was associated with response. Results were similar when restricted to the IPI-NIVO cohort. Conclusions: Presence of lung metastases, CN and better IMDC risk group are associated with a higher probability of response to 1L immunotherapy combination regimens. Further work to identify reliable predictors of response to guide treatment selection and patient counselling is warranted.[Table: see text]
Mixed methods assessment of providers’ needs in the management of advanced renal cell carcinoma.
Authors: Campbell Matthew T , Lazure Patrice , Augustyniak Monica , Jaimes Edgar A. , Bilen Mehmet Asim , Lemke Emily , Jacobs Ginny , McFadden Pamela 
Published: February 2022

313 Background: There is a paucity of data regarding the challenges associated with the timely and accurate diagnosis of Renal Cell Carcinoma (RCC) and its effective multidisciplinary management. This study aimed to assess the knowledge and skills of healthcare providers (HCPs) managing and coordinating the care of patients with advanced RCC (aRCC) across multidisciplinary teams. Methods: A sequential mixed methods needs assessment was conducted across the United States with medical oncologists (ONCs), nephrologists (NEPHs), physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs). Interviews, transcribed and thematically analyzed, and online surveys, statistically analyzed, were triangulated. Results: A total of 305 HCPs completed an interview (n=40) or the survey (n=265): 78 ONCs, 62 NEPHs, 57 PAs, 55 NPs, 53 RNs. One third (33%) of HCPs reported suboptimal skills in adjusting the dose of a treatment for aRCC in the event of adverse reactions. Interviews underscored a lack of clarity for HCPs on when to reduce the dose or when to discontinue and/or switch to other drugs. Suboptimal knowledge and skills related to toxicities were found (Table). Breakdowns in communication across multidisciplinary teams were identified by 46% of HCPs. Of those, 61% occurred when monitoring side effects and 48% when referring to ONCs. Some NEPHs reported never, rarely, or sometimes being involved with ONCs in the management of nephritis (25%), chronic kidney disease (19%), or acute renal failure (24%). Interviews suggested the role of NEPHs in the care of aRCC is poorly recognized and that NEPHs are perceived to have limited time to spend in the care of cancer patients. Few NEPHs reported gaps in knowledge/skills managing key renal complications such as nephritis (13%/15%), chronic kidney disease (6%/15%), and acute renal failure (9%/9%). Conclusions: This study identified a need to improve HCPs’ knowledge of the signs/symptoms of treatment side effects, skills in identifying/referring patients to appropriate specialists, and skills in managing adverse events. Barriers to involving NEPHs in the co-management of aRCC included a lack of recognition of their role in managing treatment-induced renal complications.These results should inform educational interventions for professionals caring for aRCC patients.[Table: see text]
Real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.
Authors: Zakharia Yousef , Thomaidou Despina , Li Benjamin , Siu Gordan , Levin Rebecca , Vlahiotis Anna , Zanotti Giovanni 
Published: February 2022

314 Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the demographic and clinical characteristics, treatment and outcomes of patients receiving 1L AXI+PEM in a real-world setting. Methods: Medical record data were extracted from the Flatiron Health Database, which includes ̃280 cancer clinics across 800 sites in the US. Patients had confirmed Stage IV or metastatic RCC and initiated 1L AXI+PEM on or after 1/1/2018 to 3/31/2021. Tumor response is reported as best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, and 12 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and fifty-five patients received 1L AXI+PEM, with follow-up of 9.7 (0.1–24.3) months. Most patients were male (69.6%), and age was 68.0 (21.0–84.0) years. At diagnosis, 55.5% of patients had Stage IV RCC and 77.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (24.4%) patients, respectively. At the time of analysis, 270 patients (76.1%) received only 1L therapy with AXI+PEM, while 85 patients (24.3%) received ≥1 subsequent line of treatment. VEGF-R inhibitors were the most commonly used second-line (2L) treatment (51 patients, 60.0%), with cabozantinib as the most frequently used VEGF-R inhibitor (40 patients, 47.1%). rwPFS at 3 months and 1 year was achieved by 248 patients (69.9%) and 77 patients (21.7%), respectively. rwOS ranged from 293 patients (82.5%) surviving at 3 months to 142 patients (40.0%) surviving at 1 year. Best overall response rate to 1L was 47.9% (complete or partial response observed in 170/355 patients). Conclusions: This study provides real-world evidence for the use and effectiveness of 1L AXI+PEM in patients with advanced RCC. AXI+PEM was used across all IMDC risk groups. While these initial finding support the use of AXI+PEM, additional follow-up is warranted to provide further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US receiving 1L AXI+PEM.
Real-world experience of axitinib as second-line treatment in metastatic renal cell carcinoma: Analysis of the Swedish population.
Authors: Strambi Angela , Jakobsson Maria , Nilsson Fredrik , Arpegard Johannes , Dalén Johan 
Published: February 2022

315 Background: Axitinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, was approved in 2012 for the treatment of metastatic renal cell carcinoma (mRCC) after failure of prior treatment with sunitinib or a cytokine. Outside of randomized clinical trials, it is important to describe the clinical outcomes of more heterogeneous populations. This analysis aimed to describe time-to-treatment discontinuation (TTD) and overall survival (OS) for second-line (2L) axitinib in a real-world setting for a nationwide Swedish mRCC cohort. Methods: This retrospective analysis utilized the Swedish Health Data Registers, covering the entire Swedish population. Patients (aged ≥ 18 years) with mRCC had ≥ 1 filled prescription of axitinib in the 2L setting, after an anti-angiogenic targeted therapy, from marketing approval until December 2019. This analysis relied on data relating to dispensed pack size, strength and according to dosing as recommended by the product label. A grace period of 90 days was allowed between filled prescriptions including medication accumulated from overlapping prescriptions. Kaplan-Meier methods were used to describe TTD and OS. Results: In total, 110 patients received 2L axitinib. Patients were predominantly male (n = 84, 76.4%) with a mean (SD) age of 60.9 (9.6) years at diagnosis and 65.5 (9.9) years at 2L treatment initiation. Median (95% confidence interval [CI]) time to TTD was 5.2 (3.7, 6.1) months, with 6 (5.5%) patients still receiving treatment at the time of analysis. Median OS (95% CI) was 12.2 (7.7, 14.2) months; 25.5% (n = 28) of patient data remained censored at the time of analysis. Conclusions: OS in this analysis of a real-world Swedish population was generally consistent with that of the pivotal 2L axitinib clinical trial in patients with mRCC who previously received sunitinib (median [95% CI] 15.2 [12.8, 18.3] months; Motzer et al. Lancet Oncol 2013; 14: 552–62). TTD was consistent with the reported progression-free survival (median 6.5 months [95% CI] 5.7–7.9]). These results provide reassurance for the effectiveness of 2L axitinib in an unselected patient population in a real-world setting.
CABOSEQ: The efficacy of cabozantinib post up-front immuno-oncology combinations in patients with advanced renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Navani Vishal , Wells Connor , Boyne Devon J. , Cheung Winson Y. , Brenner Darren , McGregor Bradley Alexander , Labaki Chris , Schmidt Andrew Lachlan , McKay Rana R. , Pal Sumanta K. , Meza Luis A , Donskov Frede , Beuselinck Benoit , Ernst Matthew Scott , Otiato Maxwell , Ludwig Lisa , Powles Thomas , Szabados Bernadett , Choueiri Toni K. , Heng Daniel Yick Chin 
Published: February 2022

318 Background: There are limited data to understand the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). The activity of subsequent 3L approved therapies post CABO has not been established. Methods: Using the IMDC dataset, we examined all patients who received 2L CABO. We sought to identify the overall response rate (ORR), time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, approved IOVE combinations and other 1L approaches. Additionally, we examined these outcomes for patients that received an approved 3L treatment post 2L CABO. Hazard ratios were adjusted for IMDC risk groups. Results: 346 patients were identified who had all received 2L CABO (78 post 1L IPI NIVO, 46 post 1L IOVE, 222 post 1L other). Of the entire cohort, 12.6%, 62.6% and 24.8% were IMDC favourable, intermediate and poor risk, respectively. 84% had clear cell histology, 18.5% had a sarcomatoid component and 38.3% had bone metastases at diagnosis. Outcomes for patients that received 2L CABO, stratified by 1L therapy are outlined in the table, followed by outcomes for patients that received subsequent 3L therapy post 2L CABO. After adjustment for IMDC criteria, the HR for 2L CABO OS and TTF for IOVE vs IPI-NIVO were 1.73 (95% CI 0.83-3.62 p = 0.14) and 1.62 (0.89-2.95 p = 0.11), respectively. Conclusions: There is clinically meaningful activity of CABO post IPI-NIVO, IOVE and other standard 1L approved therapies. Broadly, time to event endpoints and response rates are similar irrespective of 1L therapy. Approved systemic therapies post CABO, mainly single agent VEGF inhibitors also have activity, though as expected this is diminished compared to earlier lines of therapy. These are real world benchmarks with which to counsel our patients when using single agent CABO.[Table: see text]
Randomized phase II study to assess the efficacy and tolerability of sunitinib by dose administration regimen in anti-angiogenic naïve patients with metastatic renal cell carcinoma (mRCC): Final analysis of SURF study.
Authors: Thiery-Vuillemin Antoine , Gravis Gwenaelle , Schlürmann Friederike , Bompas Emmanuelle , Rolland Frederic , Gross-Goupil Marine , Vano Yann-Alexandre , Guillot Aline , Barthélémy Philippe , Joly Charlotte , Laramas Mathieu , Dourthe Louis-Marie , Maurina Tristan , Gauthier Hélène , Taillandy Kristell , Meurisse Aurelia , Vernerey Dewi , Albiges Laurence 
Published: February 2022

344 Background: SUN is approved in mRCC setting at the dose of 50mg daily for 4 weeks followed by 2 weeks rest (4/2 schedule). The 4/2 schedule often requires dose modifications for toxicity. Current recommendation is to reduce the dose to 37.5mg per day. Alternative schedules (2 weeks of treatment followed by one-week rest (2/1 schedule) have shown promising results. SURF trial evaluated prospectively schedule 2/1 when toxicity occurs. Methods: SURF [NCT02689167] is a prospective, non-comparative randomized study. Patients (pts) with mRCC (clear cell) were included at SUN initiation. When a dose adjustment of SUN was required, patients were randomized between 4/2 schedule at 37.5mg daily and experimental 2/1 schedule at 50mg daily. Primary objective was to assess duration of SUN treatment among the 73 first evaluable pts. Overall 226 pts were enrolled with 133 randomized. All other analyses are shown for the 133 randomized patients. Results: Pts were 75.2% males, with a median age 63.7 years for 94% with a Karnofsky ≥ 80%. Of them, 54.9% had partial/total nephrectomy. IMDC risk score was favourable (45.1%), intermediate (46.6%) or poor (8.3%). Pts characteristics were well balanced between 2 arms. Metastatic sites were lungs (60.5%), bones (16.3%), lymph nodes (15.5%). At 6 months, 48 patients (65.8%) of the 2/1 schedule were still on treatment (above predefined threshold for positivity). Other data are listed on the table. No new safety signal was identified. Permanent SUN discontinuation due to toxicity was 22.2% in control arm vs 12.3% in experimental arm. Conclusions: SURF is the largest prospective randomised trial evaluating two different SUN schedules modifications in mRCC in case of toxicity. This positive trial confirms the role of adapting SUN to a 2/1 schedule rather than reducing SUN dose to the classical 4/2 schedule. Clinical trial information: NCT02689167. [Table: see text]