bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of avelumab in multiple relapsed/refractory testicular germ cell cancer.
Authors: Mego Michal , Svetlovska Daniela , Chovanec Michal , Rejlekova Katarina , Obertova Jana , Palacka Patrik , Sycova-Mila Zuzana , De Giorgi Ugo , Mardiak Jozef 
Published: May 2019

e16045 Background: Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. PD-L1 expression is significantly higher in germ cell tumors (GCTs) in comparison to normal testicular tissue and high PD-L1 expression is associated with inferior progression-free and overall survival compared to patients with low PD-L1 expression. This study aimed to determine the efficacy and toxicity of PD-L1 antagonist, Avelumab, in patients with refractory GCTs. Methods: From November 2017 to January 2018, 8 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies (median 5, range 2 – 6); 5 tumors (62.5%) were absolutely refractory to cisplatin and 5 patients (62.5%) had visceral non-pulmonary metastases. Avelumab was administered at a dose of 10mg/kg biweekly until progression or unacceptable toxicity. The primary end point was 12-weeks progression-free survival (PFS). If < 8 responses to study therapy will be observed among the first 15 patients, the study will be terminated. Results: Median age was 29 years (range: 22 – 52 years). During a median follow-up period of 2.6 months (range: 0.3 - 14.4), 7 (87.5%) patients experienced disease progression and 6 patients (80.0%) died. Twelve-week PFS was 0%, median PFS was 1.4 months, 95%CI (0.9 – 1.4) and median OS was 2.7 months, 95% CI (1.0 – 3.3). No objective response was observed. Avelumab was well tolerated, no severe adverse event was observed. Conclusions: This study failed to achieve its primary end point and our data suggest lack of Avelumab efficacy in unselected multiple relapsed/refractory TGCTs. Clinical trial information: NCT03403777.
Impact of rural/urban residence on relative survival (RS) in patients with kidney cancer: An analysis of 14576 patients from the Austrian National Cancer Registry (ANCR).
Authors: Marszalek Martin , Karim-Kos Henrike E , Madersbacher Stephan , Rauchenwald Michael , Hackl Monika 
Published: May 2019

e16072 Background: Access to medical diagnostics and treatment might be limited for patients living in rural areas compared to urban residents. To evaluate the potential impact of urban/rural residence, we analyzed trends in RS for patients diagnosed with kidney cancer between 1998 and 2015 in Austria. Methods: All patients with kidney cancer aged ≥18 years, diagnosed between 1998 and 2015 were derived from the ANCR (N = 22,041). Patients were categorized into two groups: rural (N = 7,53) and urban (N = 10,552) based on a complex algorithm considering infrastructure, commuter interrelations, accessibility of centers and tourism at the time of diagnosis. Relative survival was calculated based on complete follow-up until December 31st, 2016. Poisson regression modeling was used to evaluate survival differences between the two groups and to calculate the relative excess risk of dying (RER). Analyses were performed for the total patient population and primary metastatic patients (M+, N = 2,490). Results: Distribution of age and surgical treatment did not differ between rural and urban patients. Five-year RS was 75% for rural patients compared to 73% for urban patients (RER for rural: 0.85, 95%CI 0.80-0.91). In M+ patients, 5-year RS was 14% for urban patients and 15% for rural patients (p = .02) Multivariate analysis showed that residence remained as an independent predictor for survival in the overall kidney cancer population (RER of rural patients 0.84, 95%CI 0.78-0.89). For M+ patients the RER of rural patients was 0.86 ( 95%CI 0.79-0.94) compared to urban M+ patients. For patients without surgery, rural patients were even stronger benefited in their survival than urban patients (overall population: RER 0.77, 95% CI 0.71-0.83; M+ patients: RER 0.81, 95%CI 0.72-0.91) wherereas in surgical patients RS did not differ between rural and urban patients. Conclusions: An advantage in RS was observed for kidney cancer patients living in rural areas. This advantage was evident in metastatic and non-metastatic patients, especially in patients who did not undergo surgery for (metastatic) kidney cancer. These results suggest that access to medical health care for kidney cancer patients in Austria is not limited by rural residence.
Real-world outcome study among patients with renal cell carcinoma (RCC) receiving checkpoint inhibitors (CPIs).
Authors: Phatak Hemant , Kim Ruth , Yu Ting , Dreyfus Jill , Gayle Julie A. , Wassel Christina L. , Krulewicz Stan , Zheng Ying 
Published: May 2019

e16073 Background: North America has one of the highest rates of RCC, and in 2018, 65,340 new cases were diagnosed in the US alone. Tyrosine kinase inhibitors have been a mainstay treatment for RCC. However, the first CPI, nivolumab, was approved by the FDA as a second-line treatment for RCC in late 2015 and as a first-line therapy in combination with ipilimumab in 2018. In this study, real-world outcomes in patients with RCC receiving CPIs were examined. Methods: An observational study was conducted from March 1, 2015, to December 31, 2017, using the Premier Healthcare Database, a hospital discharge database. Patients with RCC aged ≥18 years were identified by ICD-9/10 codes and were included if they received a CPI during the study period, irrespective of treatment line. Comorbidities were assessed in a 6-month look-back period commencing at the time of first CPI treatment and RCC diagnosis. 34 distinct immune-related adverse events (irAEs) were identified in a 90-day look-back period from time of the irAE to determine if patients had received a CPI during that time. Patients were followed for 90 days after the irAE to determine if CPI treatment was reinitiated. Results: During the study period, 1228 patients with RCC received a CPI, of whom 719 (59%) had ≥1 irAE. Approximately 95% of patients received nivolumab and the remaining 5% received an off-label CPI. At the time of initial CPI treatment, patients who experienced any irAE during the study period had a higher Charlson Comorbidity Index (5.1±3.2 vs 4.2±3.0; p < 0.001) and were more likely to be hospitalized on an emergent basis than those without an irAE (9.0% vs 5.1%; p = 0.005). Patients with an irAE also had a higher average number of previous immune-related or immunocompromised comorbid conditions (0.33±0.57 vs 0.12±0.36; p < 0.001). After experiencing an irAE, 65% of patients reinitiated a CPI within 90 days. Conclusions: The majority of RCC patients receiving a CPI, mostly anti-PD-1 agents, experienced an irAE, and patients with irAEs had a higher comorbidity burden than those without irAEs. Most patients with irAEs reinitiated CPI treatment within 90 days.
Efficacy and safety of approved first-line tyrosine kinase inhibitor (TKI) treatment in patients with metastatic renal cell carcinoma (mRCC): A network meta-analysis based on phase II/III randomised clinical trials (RCTs).
Authors: Manz Kirsi , Fenchel Klaus , Eilers Andreas , Morgan Jon , Wittling Kirsten , Dempke Wolfram CM 
Published: May 2019

e16074 Background: During the last decade several novel treatment options including TKIs and immune checkpoint inhibitors have been developed for the treatment of mRCC patients. However, results from direct comparisons (head-to-head RCTs) to determine the optimal treatment are lacking for most of these agents. In this network meta-analysis we attempted to indirectly compare efficacy and safety of first-line TKIs in patients with mRCC. Methods: PubMed, Embase, Medline, the Cochrane Central Register of Controlled Trials were searched (English language only). Abstracts of conferences of relevant medical societies were also included from database inception (January 1, 2007) to January 15, 2019. A systematic manual search (including data requests from the publication authors) was also performed. For the purpose of this network meta-analysis only phase II/III RCTs assessing approved first-line TKI therapy for mRCC were analysed. The analysis was done using the software R with the netmeta package. Progression-free survival (PFS) was the primary endpoint; grade 3 and 4 adverse events (AEs) were secondary endpoints. Results: A database search identified 12 studies meeting the eligibility criteria reporting on 4,460 patients. For PFS cabozantinib and sunitinib were found to be superior to sorafenib, however, when compared to tivozanib, PFS did not significantly differ between the TKIs. Furthermore, tivozanib was found to have the highest probability of being the safest drug as first-line treatment in terms of grade 3 and 4 AEs (ranking safety, p score 0.9344). Conclusions: No significant PFS differences for all TKIs currently used for first-line treatment of mRCC have been found when compared with tivozanib. Compared with all approved TKIs tivozanib appears to be the best choice for first-line treatment of these patients because it has demonstrated the most favourable safety profile. These results may provide guidance to oncologists when making treatment decisions for mRCC patients.
The impact of gastric acid suppressive agents on pazopanib exposure.
Authors: Lubberman Floor , Gelderblom Hans , Hamberg Paul , Vervenne Walter , Van Herpen Carla M.L.- , Van Erp Nielka P. 
Published: May 2019

e16076 Background: Pazopanib has been registered for advanced soft tissue sarcoma (STS) and metastatic renal cell carcinoma (mRCC). The uptake of pazopanib is 40% reduced when a proton pump inhibitor is concomitantly used. Nevertheless, still a large group of cancer patients need a form of gastric acid suppressive agents (GAS, e.g. proton pump inhibitors or H2-anagonists) due to gastrointestinal adverse events. Recently, it was demonstrated that the use of pazopanib with GAS resulted in shorter overall survival and progression free survival in patients with STS. In order to limit the effect of GAS on pazopanib absorption, the advice is to take the GAS 1 hour after pazopanib. In that way the pazopanib is dosed at the lowest gastric pH value. However, the effect of this most optimal controlled intake on pazopanib absorption is unknown. Therefore, we investigated whether this controlled intake algorithm affects pazopanib exposure. Methods: In the DIET study, pazopanib trough concentrations (Ctrough) were measured at predefined moments. In this study a total of 80 patients with mRCC and STS were included. The concomitant use of GAS was recorded and taken according the intake algorithm. Patients were subdivided into two groups (with GAS or without GAS). Results: Of the 80 patients, 22 patients were treated with pazopanib in combination with GAS. In patients treated with pazopanib without GAS the geometric mean(GM) pazopanib Ctrough level was 29.1 mg/L (95% CI 26.4 -31.8) compared to 22.4 mg/L (95% CI 18.0-27.8) (p = 0.01) in those treated with GAS. Conclusions: Patient who use pazopanib with controlled intake of GAS had a 23% lower pazopanib exposure. Therefore, we advice that in patients, who are unable to quit their GAS agent, pazopanib trough concentrations should be monitored in order to prevent shorter treatment benefit. Clinical trial information: NCT02138526.
Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).
Authors: Labriola Matthew , Zhu Jason , Gupta Rajan , McCall Shannon , Jackson Jennifer , White James R , Weingartner Elizabeth , Kong Eric , Simone Peter , Papp Eniko , Gerding Kelly , Simmons John , George Daniel J. , Zhang Tian 
Published: May 2019

e16079 Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial, demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. PD-L1 status was tested via the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). DNA damage gene mutations were found in 8/10 (80%) metastatic tumor specimens and 14/24 (58%) primary tumors. Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies. Further studies with matched primary-metastatic samples would be beneficial to determine if DNA repair mutations occur more frequently in metastatic versus primary tumor specimens.
Clinical activity of ipilimumab plus nivolumab (Ipi/Nivo) in patients (pts) with metastatic non-clear cell renal cell carcinoma (nccRCC).
Authors: Gupta Ruby , Ornstein Moshe Chaim , Gul Anita , Allman Kimberly D , Ball Jessica , Wood Laura S. , Garcia Jorge A. , VonMerveldt Dendra , Hammers Hans J. , Rini Brian I. 
Published: May 2019

e16084 Background: Ipi/Nivo is a standard of care for pts with metastatic clear cell RCC. The clinical activity of Ipi/Nivo in patients with metastatic nccRCC remains poorly defined. Methods: Metastatic nccRCC pts who were treated with Ipi/Nivo at Cleveland Clinic or UT Southwestern were retrospectively reviewed. Ipi/Nivo was administered as per CHECKMATE 214. Computed tomography imaging was obtained at baseline and every 12 weeks to assess disease response per RECIST 1.1 criteria. Baseline pt characteristics, outcome to therapy and adverse effects as per CTCAE v5.0 were collected. Results: Eighteen pts with metastatic nccRCC histology who were treated with Ipi/Nivo were identified. The median age was 60 years (range, 32-81). Non clear cell histologies included adenocarcinoma of renal origin not otherwise specified (2), unclassified (3), papillary (6), chromophobe (5), translocation (1) and medullary histology (1). ECOG PS was 0 (7 pts); 1 (9 pts) and 2 (2 pts). Fourteen patients were male and four female. IMDC risk group at the time of initiation of Ipi/Nivo was favorable (2 pts), intermediate (14 pts) and poor (2 pt). Fourteen pts received Ipi/ Nivo as first line treatment, two pts received Ipi/Nivo after prior TKI and two pts received Ipi/ Nivo as third line treatment after prior chemotherapy and nivolumab monotherapy. In total, fourteen pts had restaging scans with four pts demonstrating partial response (PR 28%), two with stable disease (SD 14%) and eight with progressive disease (PD 58%). Four pts died (22%) – three from the disease and one from treatment related complication (encephalitis).Four pts experienced diarrhea- three pts (grade 2) and one pt ( grade 3) , three developed hepatotoxicity- one pt (grade 2) and two pts (grade 3), one pt each developed hypophysitis (grade 3), fatigue (grade 2) , rash (grade 2) and encephalitis (grade 3). All 100% pts required steroids, one each got infliximab and Mycophenolate Mofetil. . All 100% pts required steroids, one each got infliximab and Mycophenolate Mofetil. Conclusions: Ipi/Nivo is feasible and safe in patients with metastatic nccRCC with preliminary evidence of anti-tumor activity
Efficacy of receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy (PD-1/PD-L1) for treatment of osseous vs. soft tissue metastases of renal cell carcinoma (RCC).
Authors: Tai Katherine Yuxi , El Abiad Jad , Morris Carol , Levin Adam , Markowski Mark Christopher 
Published: May 2019

e16094 Background: Checkpoint inhibitors and RTKIs have changed the standard of care in metastatic RCC. However, anecdotal evidence suggests these therapies may be less effective for treating bone metastases than soft tissue metastases. Our study aimed to evaluate this potential difference in treatment response between osseous and visceral metastases. Methods: Our institutional Cancer Registry database was queried for RCC patients treated at Johns Hopkins Hospital from 1997-2017 (n = 2212). 68 patients were identified with measurable bone and soft tissue metastatic disease who were treated with RTKIs and/or PD-1 inhibitors over the study period. The extent of metastasis was quantified at the time of therapy initiation, 3 mos., 6 mos., and 1 yr. Changes in disease status from baseline were categorized as partial response (PR), complete response (CR), stable (S), mixed (M) or progressive disease (PD) based upon RECISTv1.1 and MDA criteria for soft tissue and bone metastases, respectively. These categories were further organized into Controlled Disease (PR, CR, S) or Evidence of Progression (M, PD) in order to generate a generalized linear effects model with visceral response as the independent variable and bone response as the dependent. Results: Visceral response correlates with bone response at 3 (p = 0.005, n = 76) and 6 months (p = 0.017, n = 48). At 3 mos. 46 patients were treated with RTKI and 30 with PD-1. At 6 mos. 31 patients were treated with RTKI and 17 with PD-1. Of patients with controlled visceral disease, only 19% had progression in bone at 3 mos. (32% at 6 mos.). Of patients with progression in soft tissue, 42% had controlled bone disease at 3 mos. (41% at 6 mos.). Conclusions: This suggests that, contrary to anecdotal reports of a divergent response to biologic therapy, osseous metastases do not appear to respond worse than soft tissue metastases upon treatment with these agents. [Table: see text]
Leveraging a robust patient-derived xenograft platform to characterize predictors for engraftment and oncologic outcomes in renal cell carcinoma patients.
Authors: Singla Nirmish , Woolford Layton , Stevens Christina , Tcheuyap Vanina , Onabolu Oreoluwa , Xie Zhiqun , McKay Renee , Wang Tao , Christie Alana , Gahan Jeffrey , Bagrodia Aditya , Raj Ganesh , Sagalowsky Arthur I. , Lotan Yair , Cadeddu Jeffrey A , Margulis Vitaly , Kapur Payal , Brugarolas James 
Published: May 2019

e16100 Background: Patient-derived xenograft (PDX) models of renal cell carcinoma (RCC) preserve the biological features of patient tumors, providing a platform for biomarker identification and preclinical drug testing. We sought to identify predictors of successful tumor engraftment and evaluate the prognostic value of engraftment in patients with RCC using a robust murine PDX platform. Methods: 1,200 specimens derived from nephrectomy, thrombectomy, metastasectomy, or biopsy were orthotopically (renally) implanted into NOD/SCID mice between 2008-2018. Non-RCC pathology was excluded. Stable engraftment was defined by successful passage of tumor tissue at least twice with histologic confirmation. Clinicopathologic characteristics were stratified by engraftment status, and multivariate (MVA) logistic regression was used to identify predictors of engraftment. Kaplan-Meier and Cox regression analyses were used to assess the prognostic value of engraftment on patient overall (OS) and disease-free (DFS) survival. Results: 1,003 independent PDX lines derived from 770 RCC patients were included. 157 (15.6%) lines successfully engrafted and exhibited higher tumor grade, stage, size, and presence of sarcomatoid or rhabdoid components. 79.3% of all tumors were of clear cell histology, and histologic distribution did not vary by engraftment status. We have completed whole exome sequencing and RNAseq on 197 and 213 PDX lines, respectively, and downstream analyses will be reported. On MVA, sarcomatoid (OR 5.71, p < 0.001), rhabdoid (OR 2.79, p = 0.046), and advanced stage (OR 1.72, p = 0.049) were significant predictors for engraftment, while high grade and metastatic tumor source were significant only on UVA. Engraftment was associated with poor OS (HR 2.11, p < 0.001) and DFS (HR 1.85, p = 0.020) in patients after controlling for sarcomatoid, rhabdoid, grade, stage, and age on MVA. Conclusions: Aggressive RCC biology correlates with successful engraftment in PDX models. Engraftment remains independently predictive of OS and DFS even after controlling for adverse pathologic features. Engraftment in mice may illuminate aspects of tumor biology not captured by clinicopathologic variables and provide insight into novel determinants of tumor aggressiveness and metastasis.