bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated CD36 expression correlates with increased visceral adipose tissue and predicts poor prognosis in ccRCC patients.
Authors: Xu Wen-Hao , Qu Yuan-Yuan , Wang Jun , Zhang Hai-Liang , Ye Dingwei
Published: March 2019

571

Background: Growing evidence has proved obesity one of the confirmed important etiologic indicators for renal cell carcinoma (RCC). CD36 is underpinned to be involved in adipose absorption, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. This study aimed to investigate the mRNA expression of CD36 in anthropometric measures of adipose tissue and defining its value in predicting prognosis in ccRCC patients. Methods: Real-Time qPCR was detected from 367 paired ccRCC and adjacent normal tissues. Distributions of categorical clinical-pathological data together with levels of CD36 expression were compared with χ2-test. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured by MRI. Pearson’s correlation coefficient was utilized to quantify relations between body mass index (BMI), VAT%, SAT and CD36 expression respectively. Cox regression analysis were developed to address the influence of independent factors on prognostic value. Gene Set Enrichment Analysis (GSEA) was performed to select related genes and pathways from TCGA database. Results: In the current study, we demonstrated that CD36 mRNA was highly expressed in ccRCC tissues, and was found significantly increased in patients with advanced TNM stage ( p= 0.003, p< 0.001, p< 0.001), and high VAT% ( p= 0.004). Pearson’s correlation coefficient indicated CD36 amplification positively correlated with BMI ( r= 0.117, p= 0.025), VAT% ( r= 0.465, p< 0.001), while negatively with SAT ( r= -0.296, p= 0.002). Furthermore, ccRCC patients with elevated CD36 expression held shorter PFS and OS, with HR of 4.873 (3.300-7.196, p< 0.001) and 4.610 (2.956-7.189, p< 0.001). In 104 cases whose MRI scans were available, VAT was significantly correlated with poor PFS and OS. Significant genes were obtained from GSEA, and CD36 was found involved in the most significant pathways including fatty acid metabolism, angiogenesis and TGF-β signaling pathways. Conclusions: In conclusion, our study first reveal that elevated CD36 mRNA expression is positively correlated to distribution of abdominal adipose, particularly VAT%, which, in addition, notably predicts poor prognosis in ccRCC patients.
Outcomes of patients with metastatic clear cell renal cell carcinoma treated with second-line VEGFR-TKI after first-line immune checkpoint inhibitors.
Authors: Shah Amishi Yogesh , Kotecha Ritesh , Lemke Emily , Chandramohan Anuradha , Chaim Joshua , Msaouel Pavlos , Xiao Lianchun , Gao Jianjun , Campbell Matthew T , Zurita Amado J. , Wang Jennifer , Corn Paul Gettys , Jonasch Eric , Motzer Robert J. , Sharma Padmanee , Voss Martin Henner , Tannir Nizar M.
Published: March 2019

575

Background: Immune checkpoint inhibitors (ICI) are being increasingly utilized in front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) VEGFR-TKI therapy after 1L ICI therapy. Methods: This is a retrospective study of mccRCC patients treated with 2L VEGFR-TKI after progressive disease (PD) with 1L ICI. Patients were treated at MD Anderson Cancer Center or Memorial Sloan Kettering Cancer Center between December 2015 and February 2018. Objective response was assessed by blinded radiologists’ review using RECIST v1.1. Descriptive statistics and Kaplan-Meier method were utilized. Results: 70 patients were included in the analysis. Median age at mccRCC diagnosis was 59 years old; 8 patients (11%) had IMDC favorable-risk score, 48 (69%) had intermediate-risk score, and 14 (20%) had poor-risk score. As 1L therapy, 12 patients (17%) received anti-PD-(L)1 monotherapy with nivolumab or atezolizumab, 33 (47%) received nivolumab plus ipilimumab, and 25 (36%) received combination anti-PD-(L)1 plus bevacizumab. 2L TKI therapies included pazopanib, sunitinib, axitinib, and cabozantinib. On 2L TKI therapy, one patient (1.5%) achieved a complete remission (CR), 27 patients (39.7%) a partial response (PR), and 36 patients (52.9%) stable disease (SD), adding to a 94% disease control rate (DCR). Median progression-free survival (mPFS) was 13.2 months (95% CI: 10.1, NA). Estimated 1-yr overall survival (OS) probability was 79.6% (95% CI: 70.2 – 90.3). Median duration of 2L TKI therapy was 10.1 months. In total, 45.7% of subjects required a dose reduction, and 27% of patients discontinued treatment due to toxicity. Conclusions: In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy following 1L ICI, we observed 2L antitumor activity and tolerance comparable to historical data for first-line TKI. Further studies are needed to evaluate optimal strategies and sequencing of therapies in mccRCC.
Are immune checkpoint inhibitors (ICI) a valid option for papillary renal cell carcinoma (pRCC)? A multicenter retrospective study.
Authors: De Vries-Brilland Manon , Gross-Goupil Marine , Boughalem Elouen , Beuselinck Benoit , Thibault Constance , Chevreau Christine , Ladoire Sylvain , Barthelemy Philippe , Negrier Sylvie , Borchiellini Delphine , Huillard Olivier , Geoffrois Lionnel , Gravis Gwenaelle , Saldana Carolina , Thiery-Vuillemin Antoine , Seegers Valérie , Escudier Bernard , Ravaud Alain , Albiges Laurence
Published: March 2019

582

Background: pRCC is the most common non-clear cell RCC (nccRCC) and represents up to 15% of RCC. Pivotal studies evaluating ICI mostly excluded nccRCC. Therefore the efficacy of ICI in pRCC remains to be demonstrated. Methods: We retrospectively investigated the activity and safety of PD-1/PD-L1 inhibitors (PD-1i) specifically in patients (pts) with metastatic pRCC from 15 centers in France and Belgium. Pts baseline characteristics, treatment outcome and safety were collected. Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). Results: From 02/2016 to 09/2018, 50 pRCC pts treated with PD-1i were included. Median age was 63 years (range: 27-84), 36 (72%) were male. Histology included 14 (28%) type 1 pRCC, 30 (60%) type 2 pRCC, 6 (12%) unclassified pRCC. PD-1i was used in first line setting in 5 pts (10%), in second line in 29 pts (58%) and in third line or beyond in 16 pts (32%). IMDC risk group at PD-1i start was 22% good, 44% intermediate and 33% poor. ICI used were PD-1 inhibitors in 47 pts (94%) and PD-L1 inhibitors in 3 pts (6%). PD-1 in was used as monotherapy in 94% of pts. With a median follow up of 10.7 months (95% Confidence Interval (CI): 6.8-14.8), the median TTF was 3.7 months (95% CI: 3.1, 10.1). In type 1, the median TTF was 7.1 months (95% CI: 3.2-NA) and 3.2 months (95% CI: 2.9-NA) in type 2. Median treatment duration was 3.2 months (range: 0.4-24.5, IQR: 2.4-6.4). Among the 45 pts evaluable for ORR, best response was complete response/partial response in 8 pts (16%), stable disease in 13 pts (26%) and progressive disease in 24 pts (48%). ORR was 25% in type 1 pRCC and 15% in type 2 pRCC. Median OS was 17.6 months (95% CI 11.4- not reached). TRAEs of grade 3-4 were noted in 6 patients (12%) which led to treatment discontinuation, no grade 5 were observed. Conclusions: This retrospective study is the largest cohort of metastatic pRCC treated with PD-1i to date. PD-1i exhibit limited activity in this pRCC population, with better TTF and ORR in type 1 pRCC. Our findings underline the need for further prospective clinical trials evaluating ICI combinations in pts with pRCC.
Sites of metastasis (mets) and association with clinical outcomes (CO) in metastatic renal cell carcinoma (mRCC) patients (pts) treated with cabozantinib (cabo).
Authors: Martini Dylan J , Shabto Julie M. , Liu Yuan , Carthon Bradley Curtis , Speak Alexandra , Hitron Elise , Russler Greta , Caulfield Sarah , Ogan Kenneth , Harris Wayne , Master Viraj A. , Kucuk Omer , Bilen Mehmet Asim
Published: March 2019

585

Background: Cabo is approved for the treatment for mRCC. We investigated the association of sites of mets and clinical outcomes (CO) in mRCC pts treated with cabo. Methods: We performed a retrospective analysis of 65 mRCC pts treated with cabo at Winship Cancer Institute from 2016 to 2018. Overall survival (OS) and progression-free survival (PFS) were measured from first dose of cabo to date of death and clinical or radiographic progression, respectively. Objective response was defined as a complete response (CR) or partial response (PR). Sites of mets were obtained from radiology and clinic notes and included bone, lymph node, brain, lung, and liver. Univariate analysis (UVA) and multivariate analysis (MVA) was performed using Cox proportional hazard or logistic regression model. Results: The median age was 63 years and most (68%) were males. The majority of pts (79%) had ccRCC and 48% received at least 2 prior systemic treatments. The distribution of mets were: bone (42%), lymph node (69%), brain (6%), lung (83%), and liver (40%). The UVA and MVA of association between sites of mets and CO are presented in Table. Pts with bone mets had significantly longer OS in UVA and trended towards longer OS and PFS in MVA compared to pts without bone mets. Conclusions: Bone mets may be a prognostic factor for improved CO in mRCC pts treated with cabo. Larger studies are needed to validate the results of this study. UVA and MVA† of bone metastases and CO. [Table: see text]
Neoadjuvant durvalumab +/- tremelimumab affects the expression of immune checkpoint (IC) molecules on myeloid derived suppressor cells (MDSC) in patients (pts) with locally advanced renal cell carcinoma (RCC).
Authors: Fallah Jaleh , Diaz-Montero C. Marcela , Rayman Patricia A. , Wei Wei (Auston) , Wood Laura S. , Martin Allison , Allman Kimberly D , Gilligan Timothy D. , Ornstein Moshe Chaim , Garcia Jorge A. , Rini Brian I.
Published: March 2019

587

Background: In a single arm, open label phase 1b clinical trial the safety of neoadjuvant durvalumab +/- tremelimumab was studied in pts with (w) locally advanced RCC. Expression of IC molecules on immunomodulatory cells in peripheral blood (PB) and tumor (T) and the association w treatment (tx) was investigated. Methods: Pts with ≥ T2bN0-1M0 RCC received either durvalumab or combination durvalumab + tremelimumab prior to surgery. Blood samples were drawn prior to neoadjuvant tx, prior to surgery, and approximately 30 days after surgery before adjuvant tx. The percentage of MDSC (CD33+/HLADR-) and subtypes in PB and T and expression of PD1, PD-L1, and V-domain Ig suppressor of T cell activation (VISTA) were measured. MDSC subtypes included polymorphonuclear (PMN; CD15+/CD14-), monocytic (M; CD15-/CD14+) and uncommitted (UC; CD15-/CD14-). Linear mixed model was used for each MDSC subtype to estimate and compare cohorts over time. Results: Eighteen pts were enrolled: 4 women and 14 men, median age 62, 17 pts had T3-4 and 4 pts had N1 disease. Six pts received 1 dose of durvalumab and 12 pts received 1 dose of durvalumab + tremelimumab before surgery. Tx-related grade 3 adverse events (per CTCAE, v5.0) included thrombocytopenia, bilateral lower extremity weakness, hyperglycemia, chest pain, and diabetic ketoacidosis.One pt had grade 4 elevated lipase. One pt had sudden death from a non-drug related cardiac event 9 days after receiving combination therapy prior to surgery. PB and T samples from 17 pts were available. Expression of VISTA on M-MDSC and UC-MDSC were positively correlated in PB and T (Spearman’s rho = 0.61; P=0.03 for both). VISTA expression on UC-MDSC in PB was significantly higher in pts who received durvalumab monotherapy compared to those treated w durvalumab + tremelimumab (P=0.04). Frequencies of PD-L1 expression on M-MDSC and UC-MDSC in PB decreased significantly from pre- to post-neoadjuvant tx (P < 0.01). Conclusions: Neoadjuvant durvalumab + tremelimumab in pts w locally advanced RCC is feasible and affects the expression of IC molecules (PD-L1 and VISTA) on M-MDSC and UC-MDSC. Clinical trial information: NCT02762006.
Efficacy of alpha-1,3-galactosyltransferase-expressing allogeneic renal cell carcinoma immunotherapy in patients (pts) with refractory metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W , Drake Charles G. , Denmeade Samuel R. , Zakharia Yousef , Maughan Benjamin Louis , Kennedy Eugene Paul , Link Charles J. , Vahanian Nicholas N. , Hammers Hans J. , Agarwal Neeraj
Published: March 2019

590

Background: HyperAcute Renal (HAR) immunotherapy consists of two allogeneic renal cancer cell lines that have been genetically modified to express α(1,3)Gal, to which humans have an inherent pre-existing immunity. A previous report demonstrated that HAR is well tolerated in pts with mRCC (2017 GUASCO, abstract: 528). Herein, we report the efficacy of HAR immunotherapy in mRCC. Methods: Pts with refractory clear-cell mRCC were eligible for this phase 1 dose-escalation trial. Concomitant treatment (Rx) with other approved agents was permitted after initial 2 months (m) of HAR monotherapy. The trial followed a standard 3+3 design with cells injected intradermally weekly for 4 weeks then biweekly injections for 10 immunizations (150 x106cells then escalated to 300 x106cells). Co-primary objectives were safety and efficacy. Results: A total of 18 patients were enrolled (4 low dose, 14 high dose) between 06/2015 to 07/2016. Patients received a median of 1 systemic Rx prior to HAR immunotherapy, with 8 patients receiving 2 or more prior agents. IMDC risk categories at the time of initial metastatic disease were: favorable risk (33%), intermediate risk (66%), poor risk (0%). The ORR was 0% with a disease control rate of 50%. Median PFS for patients treated with HAR immunotherapy was 2.0 months (m) (range 1.7-30.3 m). For patients receiving the low dose HAR, median overall survival (OS) was 14.2 m (range 3.6-21.6 m), while median OS for high dose HAR was 25.3 m (5.8-29.3 m). At the time of data cutoff in 09/2018, 7 patients were still living. Detailed clinical data will be presented in the meeting. Conclusions: HAR immunotherapy in refractory mRCC was well tolerated and demonstrated potential efficacy for OS similar to currently approved salvage-line Rx. With a unique mechanism of action, HAR immunotherapy may be a candidate for inclusion in novel combinatorial regimens being developed in salvage therapy setting in pts with mRCC. Clinical trial information: NCT02035358.
The association of rising serum uric acid levels with survival in renal cell carcinoma.
Authors: Yim Kendrick , Bindayi Ahmet , McKay Rana R. , Mehrazin Reza , Raheem Omer , Field Charles , Bloch Aaron , Wake Robert , Ryan Stephen , Patterson Anthony , Derweesh Ithaar
Published: March 2019

608

Background: To investigate the association of serum uric acid (SUA) levels along with statin use in Renal Cell Carcinoma (RCC), as statins may be associated with improved outcomes in RCC and SUA elevation is associated with increased risk of chronic kidney disease (CKD). Methods: Retrospective study of patients undergoing surgery for RCC with preoperative and postoperative SUA levels between 8/2005-8/2014. Increased SUA was defined as > 7mg/dL for males and > 5.7 mg/dL for females. Analysis was carried out between patients with increased postoperative SUA vs. patients with decreased/stable postoperative SUA. Kaplan-Meier analysis (KMA) calculated overall survival (OS). Multivariable analysis (MVA) was performed to identify factors associated with increased SUA levels and all-cause mortality. Results: 905 patients were analyzed. Decreased/stable SUA levels were noted in 675(74.6%) and increased SUA levels were noted in 230(25.4%). A higher proportion of patients with decreased/stable SUA levels took statins (27.9% vs 18.3%, p = 0.004). Increased SUA had significantly greater de novo CKD (38.7% vs. 18.4%, p < 0.001) and proteinuria (30.9% vs. 20.7%, p = 0.002). KMA demonstrated improved 5-year OS for patients with decreased/stable SUA compared to increased SUA for stage I, (93% vs. 60%), stage II (87% vs. 50%), and stage III (88% vs. 62%) RCC (all p < 0.001). MVA revealed that increasing BMI (OR 1.05, p = 0.009), statin use (OR 0.11, p < 0.001), dyslipidemia (OR 2.66, p = 0.004), stage III/IV cancer (OR 1.89, p = 0.015 and OR = 10.78, p < 0.001), and postoperative de novo CKD stage 3 (OR 5.95, p < 0.001) were predictors for increased postoperative SUA levels. MVA revealed increasing BMI (OR 1.09, p = 0.002), increasing SUA (OR = 4.70, p < 0.001), stage IV RCC (OR = 7.7, p < 0.001, and de novo CKD stage 3 (OR 7.07, p < 0.001) to be independent risk factors for worsened all-cause mortality. Conclusions: Increasing SUA post operatively was associated with worsened outcomes in RCC patients. Decreased SUA levels were associated with statin intake and lower stage disease as well as lack of progression to CKD and anemia. Further investigation is requisite.
Duration of treatment (DOT) with targeted therapies (TT) or immunotherapy (IO) in PBRM1 mutated metastatic renal cell carcinoma (mRCC).
Authors: Dizman Nazli , Bergerot Paulo Gustavo , Bergerot Cristiane Decat , Hsu Joann , Pal Sumanta K.
Published: March 2019

622

Background: Current evidence indicates improved outcome with IO in mRCC patients (pts) with PBRM1 loss of function mutations (Miao et al., Nature, 2018). We seek to demonstrate an association between PBRM1 mutation and treatment duration with IO and TT in a retrospective cohort. Methods: Consecutive patients with mRCC who had genomic profiling in the course of routine clinical care were identified from an institutional database. GP assessments included testing either tissue or blood with 1 of the 3 CLIA certified commercial panels (Foundation Medicine, Cambridge, MA; Ashion Analytics, Phoenix, AZ; Guardant Health, Redwood City, CA). Information regarding systemic treatment was collected. Median DOT with first targeted therapy and first immunotherapy received was calculated for each patient. DOT was compared across treatment groups in PBRM1+ and PBRM1- patients. Only PBRM1 mutations with functional significance documented in COSMIC were considered. Results: Among 104 pts (72:32 M:F) with mRCC, 82 pts received TT, 35 pts received IO, and 45 pts received both. GP was performed in blood and tissue in 84 and 63 pts, respective, and 25 pts (24%) with PBRM1 mutations were identified. Among PBRM1+ pts, median DOT was 8.8 months (95% CI, 7.6-9.6) mos and 2.3 mos (95% CI, 1.7 – 2.8) mos with TT and IO, respectively (p=0.049). Among PBRM1- pts, median DOT was 5.5 mos and 2.8 mos with TT and IO, respectively (p=0.544). There were 11 PBRM1+ pts and 34 PBRM- pts who received both TT and IO. The ratio of DOT on IO to DOT on TT (DOTIO/TT) was higher in PBRM1- pts than PBRM1+ pts (0.76 versus 0.37 respectively, p=0.014). Conclusions: We failed to replicate the results from Miao et al, suggesting clinical benefit with IO in PBRM1 mutated patients. PBRM1 mutation did appear to predict benefit with TT versus IO. Although limited by sample size, the contrasting results of the current study with literature highlight the importance of clinical validation in a large and prospective setting.
Patients’ perspective of quality-of-life issues in a randomized study in open surgery of patients with renal cell carcinoma.
Authors: Kroger Dahlin Britt-Inger , Thurm Mascha , Winso Ola , Ljungberg Borje
Published: March 2019

642

Background: This randomized study in patients treated with open surgery for renal cell carcinoma (RCC), aimed to evaluate if effective perioperative analgesia can be part of a multimodal approach to minimize morbidity and improve postoperative management [1]. To evaluate the patients’ perspectives, a survey was used before surgery and one month after surgery. Methods: Between 2012 and 2015, 135 patients with RCC, in all stages, were randomized to receive either spinal analgesia with added clonidine, or epidural analgesia in addition to general anesthesia: The patients were stratified according to surgical technique. Inclusion criteria: ASA score ≤ III, age > 18 years, and no chronic pain medication or cognitive disorders. The patient’s survey used was based on the EORTC QLQ-C30 formula. Wilcoxon Signed Rank test and Mann-Whitney-U tests were used for statistical evaluation. Results: Most patients (117 of 135, 86 %) responded to the survey postoperatively. Patients groups treated with partial nephrectomy or radical nephrectomy both had significantly reduced physical and social functioning while emotional functioning improved postoperatively. In both surgical groups the patients reported significant negative financial difficulties. Similar results was achieved for patients treated with either spinal or epidural anesthesia. The epidural group of patients experienced more negative social functioning but had an improved global health. When comparing the surgical procedures there was no significant difference in the quality of life parameters. However when comparing the analgesic groups, spinal anesthesia had significantly better physical and social functioning while the patients in the epidural group reported better global health. Conclusions: In this randomized controlled study on nephrectomy, patients treated with spinal analgesia with clonidine, had better physical and social functioning postoperatively than patients treated with epidural analgesia. Clinical trial information: NCT02030717.
Results of a phase II study to evaluate the safety and efficacy of RX-0201 in combination with everolimus in subjects with metastatic renal cell carcinoma (mRCC).
Authors: Agarwal Neeraj , Pal Sumanta K. , Lauer Richard C. , Chatta Gurkamal S. , Goel Sanjay , Singh Parminder , Sundararajan Srinath , Heaton Callie , Peterson Christine , Benaim Ely , Tagawa Scott T.
Published: March 2019

646

Background: RX-0201 is a novel 20-mer oligonucleotide that binds to mRNA coding for AKT-1, preventing AKT-1 expression and limiting the amount of downstream p-AKT. In vitro RX-0201, in combination with everolimus, additively inhibited Caki-1 cell growth. RX-0201, in combination with everolimus, to treat mRCC was evaluated in a Phase 1b/2 clinical study. Methods: This Phase 1b/2 study (2‐stage design, NCT02089334 ) evaluated the efficacy and safety of RX‐0201 in combination with everolimus in eligible subjects with mRCC. Eligible subjects must have had confirmed histologic or cytologic evidence of renal cancer with a clear cell component, measurable disease as defined by RECIST, received at least 1 course of therapy with a VEGFR inhibitor and progressed within 6 months of planned first dose of on study treatment. In Phase 1 subjects were enrolled at increasing doses of RX-0201 (delivered via continuous IV for 14 days) in combination with 10 mg/day everolimus in a modified 3+3 design. The target dose of RX-0201 identified in Phase 1, 250 mg/m2/day, was further evaluated in Phase 2. Primary objectives included the safety and efficacy at the recommended Phase 2 dose. The Phase 2 primary endpoint was progression free survival (PFS) benefit for at least 4.5 months. Results: Eleven subjects (7 males, 4 females) with mRCC were treated with RX-0201 (250 mg/m2/day) + everolimus (10 mg/ day) in Phase 2. The median age was 63 years, ECOG performance status at screening was 0 to 1, and 55% received ≥ 3 prior therapies. The median PFS in evaluable subjects was 4.9 months. Four subjects had stable disease after 6 months of treatment. The most frequent related adverse events ( > 15%) were G1/2 epistaxis, G3 fatigue, G1/2 nausea and G1 vomiting. Conclusions: In this mRCC population with extensive prior therapy, RX‐0201 in combination with everolimus was safe, well-tolerated, and showed promising efficacy. The results also support the therapeutic significance of the AKT-1/mTOR pathway in mRCC. Clinical trial information: NCT02089334.
Safety and efficacy of immune checkpoint inhibitors (CPI) in metastatic renal cell cancer (RCC) and urothelial cancer (UC) patients (pts) with pre-existing autoimmune disorders (AD).
Authors: Martinez Chanza Nieves , Xie Wanling , Kaymakcalan Marina D. , Nassar Amin , Abou Alaiwi Sarah , Nuzzo Pier Vitale , Flippot Ronan , Hamid Anis , El Bakouny Ziad , Wei Xiao X. , McGregor Bradley Alexander , Sonpavde Guru , Choueiri Toni K. , Harshman Lauren Christine
Published: March 2019

653

Background: The pivotal clinical trials of CPI generally excluded pts with AD given concern for serious exacerbations. There is limited data on the safety and efficacy of CPI in this population. Methods: We conducted a retrospective single center analysis of RCC and UC pts treated with CPI. Pts were grouped by presence or absence of AD. We catalogued the incidence of new irAEs (CTCAEv4), AD exacerbations, objective response rate (ORR, RECIST 1.1), and overall survival (OS, Kaplan Meier). Competing risk models estimated cumulative incidences of irAEs and CPI discontinuation using 6 months (mos) as a benchmark. Results: 271 RCC and 220 UC pts were identified. Median followup was 21 mos for RCC and 13 mos for UC. 25 (9%) RCC and 27 (12%) UC had pre-existing AD; most commonly dermatologic and rheumatologic. A minority (3% RCC/4% UC) had clinically active AD requiring concurrent immunomodulators. AD exacerbations occurred in 8 (32%) RCC and 12 (44%) UC; median time to exacerbation was 86 (25-270) and 27 (8-300) days, respectively. Cumulative incidence of new irAEs at 6 mos was numerically higher in RCC AD pts (50% vs 37%). CPI discontinuation and clinical outcomes were similar among AD and non-AD pts (Table). Conclusions: CPI are active in advanced RCC and UC pts with pre-existing AD. Exacerbations and new irAEs should be expected, but AD pts can experience similar outcomes and rates of drug discontinuation. Larger scale investigations are warranted. [Table: see text]
Relation between clinicopathological findings and PD-1 or PD-L1 status in non-clear cell renal cell carcinoma by a multicenter study.
Authors: Matsumoto Hiroaki , Nagao Kazuhiro , Samoto Masahiro , Mori Junichi , Shimizu Kosuke , Inoue Ryo , Yamamoto Yoshiaki , Yano Seiji , Hirata Hiroshi , Shimabukuro Tomoyuki , Matsuyama Hideyasu
Published: March 2019

654

Background: We investigated correlation of their pathological findings and their prognostic factors in non-clear cell renal cell carcinoma (ncRCC) diagnosed by both regional pathology (RP) and central pathology (CP) in multicenter study. Methods: In January 2005 to December 2014, 140 cases of ncRCC diagnosed by radical or partial nephrectomy were assessed. We assessed their pathological diagnosis by one central pathologist using the 2016 WHO classification tumor of the kidney. We assessed the correlation between clinical parameters or pathological findings and their prognosis. Then, we performed immunohistochemical analysis using PD-1 related antibody in ncRCC. Results: Median follow up was 32.7 months (1-134). Median age was 66 years, 99 males and 41 females. Pathological stage was pT1a: 58, pT1b: 30, pT2a: 17, pT2b: 6, pT3a: 21, pT3b: 2, pT4: 3 cases, respectively. In RP, histology was papillary (PAP): 60 (42.9%), chromophobe (CHR): 49 (35.0%), containing with sarcomatoid components (SAR): 14 (10.0%) and other histology: 17 (12.1%) cases, respectively. The tumors evaluable by CP were 127 cases, PAP: 52 (40.9%), CHR: 31 (24.4%), SAR: 20 (15.7%) and other histology: 24 cases (18.8%), respectively. The overall concordance rate was 59.5% between RP and CP. In multivariate analysis, SAR was extremely poor prognosis in ncRCC. The high neutrophil lymphocyte ratio (NLR) and at high CRP value were also poor prognostic factors. So, we stratified three risk groups using three factors, namely NLR, CRP and SAR. In overall survival, there were significant prognostic differences within three groups (p = 0.0014). In immunohistochemistry, PD-1 or PD-L1 expression correlated with poor overall, cancer specific and recurrence free survival in ncRCC. In multivariate analysis, PD-L1 expression was most significant prognostic factor for ncRCC. Conclusions: These results suggest that Risk stratification by three risk factors is useful prognostic model and the expression of PD-1 and PD-L1 may be a useful prognostic factor in ncRCC.
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: March 2019

659

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 every12 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: Thirteen 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 (3), chromophobe (3), translocation (1) and medullary histology (1). Nine pts had ECOG PS 0; four pts had ECOG PS 1. Eleven patients were male and two female. IMDC risk group at time of initiation of Ipi/Nivo was favorable (2 pt), intermediate (10 pts) and poor (1 pt). Nine pts received Ipi/ Nivo as first line treatment, three pts received Ipi/Nivo after prior TKI and one pt received Ipi/ Nivo as third line treatment after prior chemotherapy and nivolumab monotherapy. In total, eight pts have thus far undergone restaging scans with three pts demonstrating partial response (PR), one pt demonstrating stable disease (SD) and four pts demonstrating progressive disease (PD). Two pts experienced grade 2 diarrhea, one after 4 cycles and another after 3 cycles of Ipi/Nivo and required prednisone. One pt demonstrated grade 3 hepatotoxicity after 2 cycles of Ipi/Nivo and required prednisone and Mycophenolate Mofetil while another pt demonstrated grade 1 hepatotoxicity after 3 cycles of Ipi/ Nivo requiring prednisone. One pt experienced grade 2 pancreatitis requiring steroids after one dose of Ipi/Nivo. One pt experienced grade 2 fatigue after 1 cycle of Ipi/Nivo requiring prednisone. Conclusions: Ipi/Nivo is feasible and safe in patients with metastatic nccRCC with preliminary evidence of anti-tumor activity. Updated clinical data will be presented.
Preliminary results of phase I clinical trial of high doses of seleno-L-methionine (SLM) in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.
Authors: Garje Rohan , Brown James A. , Nepple Kenneth Gerard , Dahmoush Laila , Bellizzi Andrew , Bonner Jaime , Mott Sarah L , Zamba Gideon , Laux Douglas Earl , Milhem Mohammed M. , Rustum Youcef M. , Zakharia Yousef
Published: March 2019

660

Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.
Mechanisms underlying the association between sarcopenia and poor oncologic outcomes in clear cell renal cell carcinoma.
Authors: Sanchez Alejandro , Kuo Fengshen , Petruzella Stacey , Akin Oguz , Paris Michael , Russo Paul , Chan Timothy An-thy , Mourtzakis Marina , Hakimi A. Ari , Furberg Helena
Published: March 2019

662

Background: Sarcopenia (low skeletal muscle mass) is associated with poor outcomes in patients with ccRCC. The mechanisms underlying this association are unclear. To understand this association, we examined gene expression differences by sarcopenic status in patients with ccRCC. Methods: The cohort consisted of 62 ccRCC patients treated by nephrectomy and previously transcriptomically-profiled in the Cancer Genome Atlas. Computed tomography scans without contrast performed within two months of surgery were reviewed to determine skeletal muscle cross-sectional area. Sarcopenia (yes/no) was defined according to gender-specific international consensus definitions. Baseline differences in clinicopathologic characteristics were assessed using the Chi-squared test for categorical and t-test for continuous variables. Differential expression analyses were performed using the R package “DESeq2.” Gene set enrichment analyses (GSEA) and single-set GSEA were used to evaluate differences in MSigDB Hallmark gene sets and estimate immune cell infiltration, respectively. P-values were corrected for multiple testing (p-adjust). Results: The cohort was predominantly male (82%), white (97%) and had localized disease (58%). Median age was 58.9 years (SD: 12.1). Sarcopenic (47%) patients were older (p < 0.001), obese (p < 0.001), and presented with higher AJCC stage (p = 0.006). In primary tumor specimens, sarcopenic patients demonstrated increased expression of angiogenic, inflammatory (e.g., IL-6, TNF-alpha), and epithelial mesenchymal transition programs (p-adjust < 0.05). Furthermore, sarcopenic patients had higher macrophage (p = 0.003) and Th17 immune cell infiltration (p = 0.003). Conclusions: Our findings suggest that ccRCC patients who are sarcopenic harbor gene expression programs associated with more aggressive biology. Increased macrophage infiltration and decreased Th17 immune cell infiltration have been previously associated with worse prognosis in ccRCC. It is not clear whether sarcopenia is a cause or consequence of tumor aggressiveness. Validation of these results in a larger cohort of patients and orthogonal validation are ongoing.
Assessment of intratumor heterogeneity using imaging texture features in clear cell renal cell carcinoma.
Authors: Udayakumar Durga , Dwivedi Durgesh , Zhang Ze , Xi Yin , Wang Tao , Madhuranthakam Ananth J , Kapur Payal , Fulkerson Michael , Diaz de Leon Alberto , Lewis Matthew , Cadeddu Jeffrey A , Margulis Vitaly , Brugarolas James , Bagrodia Aditya , Pedrosa Ivan
Published: March 2019

663

Background: Intratumoral heterogeneity (ITH) relates to aggressiveness in clear cell renal cell carcinoma (ccRCC), the most common and aggressive subtype of kidney cancer. Percutaneous biopsies have high diagnostic accuracy. However, ITH lowers their reliability in larger, heterogeneous tumors. Haralick texture features extracted from a gray level co-occurrence matrix (GLCM) is a robust method to assess intrinsic tumor imaging characteristics. Some of these features, including entropy as a measure of ITH, have recently been used in differentiating malignant from benign tumors in various organs. We aim to understand how tumor entropy extracted from magnetic resonance (MR) imaging correlate with tumor grade (aggressiveness) and gene expression heterogeneity in ccRCC. Methods: This IRB-approved, prospective study included T2-weighted (T2W) and arterial spin labeled (ASL) MR images of 62 patients with ccRCC. The GLCM was constructed for regions-of interest (ROI) within the tumor and 13 Haralick texture features were estimated. Correlations between texture features and tumor grade were evaluated by logistic regression and quantified by the area under the receiving operating characteristic (ROC) curve (AUC). RNA sequencing of 182 tumor samples in 49 resected tumors was performed. Entropy was correlated with standard deviation (SD) of normalized gene expression levels in multiple samples from the same tumor. Spearman correlation (rho) was computed for each gene. False discovery rate q values < 0.05 were considered statistically significant. Results: Entropy was higher in high-grade than low-grade tumors (11.28 ± 0.52 vs. 10.95 ± 0.65) on T2W (q = 0.028) and ASL (10.45 ± 1.15 vs. 9.65 ± 1.29) (q = 0.013). Entropy had an AUC of 0.70 (T2) for high-grade prediction and was weakly correlated with tumor size (R2 = 0.2). Higher T2 and ASL entropy correlated with higher SD of gene expression. Gene ontology analysis of top correlated genes revealed strong enrichment of genes in metabolic processes. Conclusions: Higher MRI entropy predicts high tumor grade and correlates with increased heterogeneity in gene expression of metabolic processes.
Genomic and clinical determinants of recurrence in localized clear cell renal cell carcinoma (ccRCC).
Authors: Bakouny Ziad , Abou Alaiwi Sarah , Nassar Amin , Flippot Ronan , Nuzzo Pier Vitale , Bossé Dominick , Wei Xiao X. , McGregor Bradley Alexander , Harshman Lauren Christine , Signoretti Sabina , Kwiatkowski David J. , Choueiri Toni K.
Published: March 2019

664

Background: Multiple clinical risk scores and gene expression models have predicted recurrence in localized ccRCC. However, few studies explored genomic alterations (GA) predicting recurrence. Methods: We assessed genomic and clinical correlates of disease-free survival (DFS) in surgically treated localized ccRCC using a targeted next generation sequencing (NGS) platform (Oncopanel/PROFILE) and publicly available NGS and clinical data from TCGA. Univariable and stepwise multivariable Cox regression models (stratified by database) were performed. Results: 478 patients (123 patients from our institution and 355 patients from TCGA) were included. 150 (31.4%) patients experienced a DFS event (recurrence or death) and 94 (19.7%) died at 3.1 years (yrs) of median follow-up. Median DFS was 6.3 (5.4-7.2) yrs and the 5-yr overall survival rate was 70.8% (64.9-76.7). On multivariable analysis, 4 clinical factors and mutations in 3 genes were significantly associated with recurrence (Table). Conclusions: Our study suggests that PTEN, BAP1 and KDM5C GA may improve on clinical factors for prediction of localized ccRCC recurrence. Further work is needed to determine if these GA could improve existing validated risk models. [Table: see text]
The impact of PBRM1 mutations on overall survival in greater than 2,100 patients treated with immune checkpoint blockade (ICB).
Authors: Hakimi A. Ari , Ged Yasser , Flynn Jessica , Hoen Douglas R , Di Natale Renzo G , Blum Kyle A , Makarov Vladimir , Kuo Fengshen , Carlo Maria Isabel , Lee Chung-Han , Voss Martin Henner , Ostrovnaya Irina , Chan Timothy An-thy , Motzer Robert J.
Published: March 2019

666

Background: PBRM1 is the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC). We have previously shown favorable outcomes in PBRM1-mutated ccRCC tumors treated with vascular endothelial growth factor (VEGF) inhibitors. Recent data suggested PBRM1 mutations may sensitize ccRCC and non RCC malignancies to ICB therapy. We queried the impact of PBRM1 loss on overall survival (OS) across 2,152 patients treated with ICB. Methods: PBRM1 mutations were assessed in metastatic ccRCC patients who received first line (n = 82) or second line (n = 61) ICB or ICB/VEGF combinations. Additionally, 41 cohorts of non-RCC malignancies treated with ICB and combination (n = 2,009) were analyzed. Mutations were assessed by next generation targeted sequencing using archival tissue. Association of mutation status and overall survival (OS) was tested by multivariate Cox regression analysis (MVA) and adjusted for tumor mutation burden (TMB), copy number alterations (CNA), loss of function(LOF) mutations (non RCC cohort) and IMDC risk (for ccRCC patients). Results: PBRM1 mutations were not associated with improved OS in ICB the entire ccRCC cohort (HR 1.37; CI 0.79-2.4; p = 0.265), the first line (p = 0.624) or second line setting (p = 0.39) or as combination with VEGF inhibitors (p = 0.2). Several RCC subgroups were investigated (see Table at bottom). In the non-RCC cohorts (n = 2,009) PBRM1 mutations were not significantly associated with OS on univariate analysis (HR = 0.73, p = 0.22 for LOF and HR = 0.84,p = 0.34 for non LOF), and remained insignificant after adjusting for TMB, total CNA, and drug class (CTLA4, PD-1/PDL-1 and combinations) (HR = 1.07, p = 0.78 for LOF and HR = 1.08,p = 0.67 for non LOF). Conclusions: Neither in ccRCC nor in the pan-cancer cohort did PBRM1 mutations appear to be associated with improved overall survival with ICB therapy.[Table: see text]
Real-world outcomes of genetic testing in a GU genetics clinic and evaluation of current guidelines.
Authors: Pace Annelise , Woodson Ashley Henriksen , Slack-Tidwell Rebecca , Daniels Molly S. , Pilie Patrick Glen , Litton Jennifer Keating , Hoskovec Jennifer M. , Jonasch Eric
Published: March 2019

668

Background: Several known hereditary cancer syndromes confer an increased risk for genitourinary (GU)-related malignancies. Various guidelines indicate when to refer patients to genetic counseling for GU cancers, but there are limited data on the performance of these guidelines in clinical practice, and the association between testing outcome and clinical and familial features that may delineate a heritable syndrome. The purpose of this study is to determine the most common indications for ordering genetic testing in a GU Genetics Clinic and evaluate the relationship between the indication for germline testing and outcome. Methods: An IRB-approved retrospective chart review was performed for 350 patients seen in a GU Genetics Clinic at a single comprehensive cancer center from 2014-2018. Subgroups of patients were formed based on their indication for genetic testing. Exact binomial tests were used to compare the proportion of patients with a positive (pathogenic or likely pathogenic) germline variant for those with vs. without each indication. Results: All patients had a genetic evaluation due to a personal or family history of GU cancer. The majority (324 of 350, 92.5%) were evaluated for either renal cell carcinoma (RCC) or prostate cancer (PrCa). Among patients seen for RCC-related evaluation (n = 159), 23 patients (14.5%) tested positive. Meeting published clinical criteria for a hereditary RCC syndrome significantly predicted positive testing ( P< 0.001). No other indication for testing, including RCC diagnosis ≤ 46 years, predicted for positive germline genetic test results. No positive patients were identified by age of RCC onset alone. Among patients seen for PrCa-related evaluation (n = 173), 13 (7.5%) individuals tested positive; all positive variants were in ATM or BRCA2. A single patient (1/13) was identified by metastatic PrCa status alone. Conclusions: Our data suggest current algorithms lack specificity for selecting individuals with RCC or PrCa at risk for germline mutations, and need to be revised. Evaluation of pedigrees and identifying presence of syndromic features are essential and increase the probability of identifying individuals at risk for harboring a germline mutation.
Ipilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC).
Authors: Gul Anita , Shah Neil J. , Mantia Charlene , Hammers Hans J. , Ornstein Moshe Chaim , McDermott David F. , Atkins Michael B. , Rini Brian I.
Published: March 2019

669

Background: Ipi/Nivo is now FDA approved for the first line treatment of patients (pts) with intermediate and poor risk mRCC but activity in IO refractory mRCC patients is still not well reported. Here we seek to report activity of Ipi/Nivo in IO refractory mRCC pts. Methods: In this retrospective review, we identified a total of 30 pts with mRCC from 4 academic medical centers across the USA who received salvage Ipi/Nivo after disease progression on IO therapy. Pts with only predominant clear cell histology were captured. Ipi/Nivo was administered as per CHECKMATE 214. Investigator-assessed response rate were noted. Immune related adverse events (irAE) were captured in accordance with CTCAE v5.0. Results: The baseline demographics included median age of 60 years (21-82), ECOG PS 0-2, and 73% (22) male and 27% (8) female. IMDC risk categories at the time of salvage Ipi/Nivo initiation were 23% (7), 60% (18) and 3% (1) with favorable, intermediate and poor risk, respectively. The median number of prior systemic therapies was 3 (1-6). Prior IO therapies included nivolumab monotherapy (14), avelumab plus axitinib (3), high dose interleukin-2 (3), pembrolizumab monotherapy (2) and Ipi/Nivo, nivolumab plus hypoxia inducible factor (HIF) inhibitor, atezolizumab plus interferon, atezolizumab monotherapy, pembrolizumab plus bevacizumab, pembrolizumab plus axitinib, varlilumab plus atezolizumab and an oral adenosine inhibitor (1 each). The median time on prior IO therapy was 7 months (1-50), best response was 3% (1) CR, 40% (12) PR, 23% (7) SD and 33% (10) PD. 73% (22) had restaging scans to assess response to ipi/nivo of which 17% (5), 3% (3) and 47% (14) showed PR, SD and, PD respectively. 37% (11) developed any grade irAEs and 6% (2) had grade ≥3 irAE including one patient with splenic rupture and one with rash and pneumonitis. Conclusions: Ipi/Nivo is feasible and safe in IO-refractory mRCC population with preliminary evidence of anti-tumor activity. Updated response data will be presented.