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4573 Background: Rapalogs, inhibitors of mTOR, are approved for treatment of advanced RCC. Recent reports of clonal heterogeneity challenge the concept of targeted monotherapy and the development of genomic biomarkers. Still, a subset of patients (pts) derives extended benefit from single agent rapalogs. This study analyzed such outliers so as to explore the genomic background of rapalog sensitivity in the setting of clonal heterogeneity. Methods: Cases were chosen based on time to treatment failure > 20 mos and tissue availability. DNA was extracted from spatially separate areas in primary tumors, metastases and the germline. Custom target capture and ultra-deep sequencing identified small indels, single base pair substitutions and copy number changes across all exons of 230 target genes. Results: 4 pts contributed 13 specimens (11 primary tumor samples, 2 metastases); mean exon coverage was 443X. Genomic alterations with activating effect on PI3K pathway signaling were seen in 11 of 13 specimens (Table). Clonal heterogeneity was present in all pts. For 2 pts, different mechanisms activated the pathway in separate sites, in 1 pt through separate genes. Conclusions: Pathway-activating genomic events across all sites explain rapalog benefit in 3 of 4 pts. Different disease sites in the same pt can harbor separate mechanisms activating the targeted pathway. This suggests that clonal convergence within the PI3K pathway can create an oncogenomic landscape sensitive to rapalogs despite branching clonal evolution. It supports the notion of sampling >1 disease site during future biomarker development. [Table: see text]

TPS4595 Background: The treatment of metastatic renal cell cancer (mRCC) with therapies targeting the vascular endothelial growth factor (VEGF) pathway delays disease progression; however, overcoming tumor resistance to these agents remains a therapeutic challenge. Activin receptor-like kinase 1(ALK1) is a type 1 receptor in the TGF-ß superfamily and is selectively expressed on activated endothelial cells. While VEGF drives the proliferative stage of angiogenesis, ALK1 is primarily involved in the maturation phase. Dalantercept is a human ALK1-Fc receptor fusion protein that binds to bone morphogenetic proteins (BMP) 9 and 10 (ligands for ALK1) and acts as a ligand trap. Preclinically, dalantercept showed delayed tumor growth in solid tumor models, including RCC models alone and in combination with sunitinib. In RCC models, the addition of dalantercept to sunitinib enhanced the reduction in tumor blood flow compared to sunitinib alone. Dalantercept showed anti-tumor activity in a completed phase 1 study in 37 pts. with advanced solid tumors. Based on this promising data, we hypothesize that ALK1 inhibition may be synergistic with axitinib, a VEGFR tyrosine kinase inhibitor (TKI), in pts. with mRCC. Methods: A two-part, multi-center, open label phase 2 study to evaluate safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of dalantercept plus axitinib as second line therapy is ongoing. In Part 1, dose escalation using a 3+3 design will assess the safety and PK of dalantercept SC every 3 weeks plus axitinib 5 mg PO BID until disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) has been determined, up to 20 pts. may be enrolled in an expansion cohort to establish safety for the recommended dose for Part 2. Part 2 will include 112 pts. randomized 1:1 to dalantercept plus axitinib vs. axitinib alone. Key eligibility criteria are one prior TKI in the first-line setting, ECOG

e15517 Background: Brain metastases (b-met) in RCC are associated with poor prognosis and median OS of about 7 months in the pre-targeted therapy (TT) era (Culine, Cancer 1998). The role of TT in this setting is not well established since patients (pts) with b-met were excluded from most clinical trials. The primary objective was to assess OS and central nervous system (CNS) safety of pts with b-met treated with TT. Methods: Pts with mRCC treated with ≥ 28 days of TT after b-met diagnoses were retrospectively identified. Kaplan-Meier method and Cox proportional hazards model were used to analyze the association between clinical features and OS. Results: 65 pts were identified, 52 (80%) treated with anti-angiogenic agents and 13 (20%) treated with mTOR inhibitors. Most pts had extracranial metastasis (98%) and 54% had ≥ 2 brain lesions. Fifty seven pts (88%) had local therapy for b-met before TT including surgery in 3 (5%), radiation therapy (RT) in 36 (55%) and both surgery and RT in 18 (28%). Median follow-up was 12.3 months (1.1 – 58.8) and median time from RCC diagnosis to b-met was 17.8 months (0 – 192.2). Median TT duration was 3.4 months (0.3 – 31.9) for 1st line and 1.9 months (0.2 – 23.6) for 2nd line. Median OS was 12.2 months (95% CI 8.0 to 15.5). On univariate analysis using various clinical and treatment variables, MSKCC risk group (P= 0.001), histology subtype (clear vs other) (P< 0.0001), and number of b-met at diagnosis (P= 0.004) correlated with OS and retained statistical significance on multivariate analysis (Table). CNS complications were identified in 5 pts (8%), including 2 with radiation necrosis and 3 with b-met hemorrhage. Conclusions: The use of TT in the multimodality treatment of pts with RCC and b-met appears safe with OS that compares favorably to historical results in the pre-TT era. Clear cell RCC, favorable MSKCC risk status, and solitary b-met are associated with better outcome. [Table: see text]

Despite the established role of MTOR inhibitors (rapalogs) in treating advanced kidney cancer, therapeutic benefit varies and predictive biomarkers are lacking. Intratumor branching heterogeneity, a recently discovered hallmark of this disease, has raised concerns about the feasibility of developing genomic biomarkers for targeted agents in kidney cancer. We undertook an outlier approach to interrogate the genetic determinants underlying long-term therapeutic response (>20 months) to rapalogs in 6 patients. An integrated ultra-deep targeted-exome (∼500x) and standard whole-exome (∼100x) sequencing was performed. Additionally, to address intratumor and intertumor heterogeneity, spatially separated tumor specimens from the same individuals were analyzed whenever possible. Multiregional sequencing unveiled surprising MTOR pathway convergent evolution, manifested by MTOR pathway activation by means of distinct genomic events in spatially separate sites of disease within the same individual. Amongst the core components of the MTORC1 pathway, complete functional loss of TSC1 and TSC2, and a hyperactive MTOR mutant were discovered in 4 of 6 long-term responders. Mutations in MTOR Clustered at FAT and kinase domains confer hyperactivity and yet remain sensitive to rapamycin. Here, we affirm intratumor heterogeneity, identify genomic determinants of drug response, and discover pathway convergent evolution in the majority of long-term responders. We propose a “river” model in which intratumor and intertumor clonal heterogeneity in cancer patients evolves like a branching river that converges at critical nodes. These convergent points provide unique opportunities for the treatment of genetically diverged yet functionally converged cancers in any given patient. Citation Format: Martin H. Voss, A Ari Hakimi, Can G. Pham, A Rose Brannon, Ying-Bei Chen, Luis F. Cunha, Oguz Akin, Han Liu, Shugaku Takeda, Sasinya N. Scott, Nicholas D. Socci, Agnes Viale, Nikolaus Schultz, Chris Sander, Victor E. Reuter, Paul Russo, Emily H. Cheng, Robert J. Motzer, Michael F. Berger, James J. Hsieh. Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2013-3515

450 Background: Sarcomatoid variant describes a histomorphologic pattern with presence of spindle-cell features that can be seen across all subtypes of RCC. It is associated with an aggressive phenotype and poor prognosis. Outcome to mTOR inhibitor therapy was accessed in patients (pts) with ccRCC with sarcomatoid features. Methods: Patients with metastatic sarcomatoid ccRCC treated with mTOR inhibitors at our center were retrospectively identified. Demographic characteristics and treatment outcome were assessed. Overall response rate (ORR) was determined by formal response criteria (RECIST 1.1). Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Results: 29 pts were treated with temsirolimus (18) or everolimus (11). Median age was 57 years (53 to 61) and there were 21 male pts (72%). Median number of metastatic sites was 3 (1 to 7) and 18 pts (62%) had ≥ 3 metastatic sites. Distribution between Memorial Sloan-Kettering Cancer Center risk groups was 14% favorable, 72% intermediate, and 14% poor-risk disease. Median number of prior therapies was 1 (0 to 5) and 79% of pts received mTOR inhibitor as ≥ 2nd-line of therapy. Three patients (10.3%) achieved a partial response (PR), 11 (38%) stable disease (SD), and 15 (51.7%) had progressive disease (PD). Tumor shrinkage was observed in 9 pts (31%) and the mean change in tumor burden was +24% (-45% to +100%). Median PFS and OS were 3.4 months (CI: 1.4-5.3) and 8.3 months (CI: 4.8- 17), respectively. Conclusions: OS was poor in this heterogeneous group of pts. Future studies to characterize this variant at a molecular level are warranted and might identify predictive markers for clinical outcome in patients treated with mTOR inhibitors. [Table: see text]

391 Background: Temsirolimus and everolimus are standard agents in the management of advanced renal cell carcinoma, but the registration trials primarily enrolled patients with clear cell histology. We assessed outcome in patients with non-clear cell RCC (ncRCC) treated with mTOR inhibitors at our center. Methods: Clinical features and histologic subtypes were characterized for ncRCC patients treated with single-agent temsirolimus or everolimus. Outcome was analyzed using the Kaplan-Meier method to determine progression free survival (PFS) and overall survival (OS). Genomic analysis of outliers with either durable or poor response was done by next-generation sequence analysis of tumor tissue and germline DNA. Results: 65 patients received temsirolimus (n = 46) or everolimus (n = 19). Histologic subtypes included papillary (n = 16), chromophobe (n = 9), collecting duct (n = 6), translocation-associated (n = 3), and unclassified (n = 31) RCC. Median follow-up for survivors is 29 mos. Median treatment duration for 52 patients, who continue therapy or stopped due to progression or death, is 2 mos. 8 patients (12.3%) were treated for ≥ 1 year (max. 37 mos), including papillary (n = 3), chromophobe (n = 2) and unclassified (n = 3) RCC. Tumor analysis identified genomic determinants of long term response in 2 unclassified RCC (complete functional loss of TSC1 and TSC2, respectively). No such changes were seen in 2 patients with chromophobe RCC and rapid progression on therapy. Conclusions: A subset of ncRCC patients derives benefit from mTOR inhibitors, but most have poor outcome. Durable responses can be linked to oncogenomic alterations within the mTOR pathway, and future goals should include the identification and characterization of such predictive tissue biomarkers. [Table: see text]

375 Background: MicroRNAs (miRNA) are short, non-coding RNAs involved in post-transcriptional gene regulation. Several reports have assessed their role as blood based biomarkers given their tissue and cancer-specific expression. Using an integrative approach we sequenced the miRNA transcriptome of the plasma of several clear cell renal cell carcinoma (ccRCC) patients both before and after surgery as well as several controls. Methods: We performed next generation miRNA sequencing (miRNAseq) on eight pairs (pre- and post-operative plasma samples) and four non-cancer controls to identify potential biomarker candidates. We further integrated our data with the miRNAseq tumor data from the Cancer Genome Atlas (TCGA) study to determine whether plasma miRNA levels are representative of tumor miRNA expression in ccRCC. Results: Overall, 930 unique miRNAs were detected, including 272 at greater than or equal to 10 read counts. There was a global shift of miRNA expression toward the non-cancer controls in the postoperative samples compared to preoperative. We further identified several stably expressed miRNAs across all samples and controls including miR-16, miR-191, and miR-103. We also identified several potential biomarker candidates by looking at differential expression both in terms of preoperative and postoperative status, as well as tumor vs. control including miR-378 and miR-660. Intriguingly, the plasma miRNA expression patterns showed no relationship to the tumor expression patterns using the TCGA samples. Conclusions: Plasma miRNA expression patterns are consistently altered in ccRCC and, following surgery, globally revert to the non-cancerous levels of the controls. Several biomarker candidates have been identified and a panel is undergoing validation in larger cohorts. Plasma miRNA levels do not appear to reflect tumor levels in ccRCC.

360 Background: We have previously shown that mutations in the epigenetic modifiers PBRM1, BAP1, SETD2 and KDM5C are associated with adverse tumor characteristics and, in some cases, worse cancer specific survival in clear cell renal cell carcinoma (ccRCC). We analyzed publically available data from the Cancer Genome Atlas Project (TCGA), to assess the impact of mutations in these genes on cancer-specific survival. Methods: We analayzed the genomic and clinical data from the TCGA cohort of 424 patients with primary ccRCC. The Kaplan-Meier method was used to estimate the survival probabilities, and log-rank test was used to test the univariate association between mutation status and overall survival. Cancer specific survival (CSS) was analyzed using the competing risk method. Multivariate Cox proportional hazard regression and competing risk models were also fitted to adjust for the validated Mayo Clinic SSIGN prognostic score. Results: Mutations in these epigenetic modifiers are frequent (PBRM1, 33.7%; SETD2, 11.6%; BAP1, 9.7%, KDM5C, 5.7%). BAP1 (p=0.002, HR 2.21 [1.34-3.62]), SETD2 (p=0.036, HR 1.68 [1.03-2.72]) and KDM5C (p=0.016, HR 2.18 [1.16-4.11]) are associated with worse CSS by competing risk. When adjusting for the prognostic SSIGN score, only mutations in KDM5C remain significant (p

4604 Background: Temsirolimus (T) and everolimus (E) are rapalog inhibitors of the mammalian target of rapamycin (mTOR) with efficacy in advanced RCC [NEJM;356(22):227-81; Lancet;372(9637):449-56]. With reported median progression-free survival (PFS) of 5.5 and 4.9 months (mo), respectively, benefit is typically modest, yet a subset of patients (pts) achieves long-term disease control evident by extended PFS. The oncogenomic background for this is unclear. Methods: We analyzed frozen specimens of tumor and adjacent normal kidney from pts with advanced RCC and documented long-term response to T or E, defined as PFS of ≥ 20mo. Samples from pts with PFS ≤ 2mo served as comparators. Specimens were subjected to whole exome sequencing; a targeted next-generation sequencing platform was used for deep sequencing and investigation of copy number variations (CNV) in 230 genes of interest. Results: In 5 pts with long-term response to T [n=3] or E [n=2], histologic subtypes were clear cell [n=3] and unclassified [n=2] RCC. Median number of prior treatments was 2 (1-3). Two pts remain on therapy, 3 have stopped drug for disease progression; treatment duration was 20, 25+, 27, 28, and 28+ mo. Three control pts progressed after 1, 2, and 2 mo on therapy. Mean target coverage was 86x for whole exome and 443x for targeted sequencing. Three of 5 long-term responders harbored acquired somatic mutations and/or CNV in genes encoding for members of the Phosphoinositide 3-Kinase (PI3K) / mTOR pathway. Effects on amino acid sequence and gene function suggest a hyperactive pathway in all 3. For the other 2 long-term responders genomic changes with possible indirect link to the pathway, but no apparent determinants of treatment response were seen. In 3 control patients with rapid disease progression no genomic alterations suggesting hyperactivation of the pathway were seen. Conclusions: In this retrospective discovery set of RCC pts with unusually long response to rapalog therapy, next generation sequencing using pre-treatment tissue specimens revealed plausible oncogenomic determinants of treatment benefit in 3 of 5 cases. These findings provide basis for further biomarker development and studies in a larger sample set are ongoing.

4532 Background: STM decline rates predict outcome for GCT pts during 1st-line conventional-dose chemotherapy. We investigated the importance of STM decline rates during salvage HDCT. Methods: HDCT included an initial low dose (LD) portion (1-2 cycles of paclitaxel plus ifosfamide [TI] + G-CSF) for stem cell collection followed by a high-dose (HD) portion (3 cycles of carboplatin + etoposide or TI + carboplatin). Eligible pts had elevated STM (AFP >15 and/or HCG >2.2) at the start of LD and completed ≥1 HD cycle. Slope and t1/2 were calculated for HCG and AFP for cycles 1-2 of LD and HD starting with the peak value during days (d) 1-6 of LD and HD to avoid interference from lysis. T1/2 for AFP ≤7d and HCG ≤3.5d were categorized as satisfactory (SAT); normalization within 7d was also considered SAT, regardless of t1/2. Pts with elevated AFP and HCG had to have adequate decline in both to be considered SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs. unsatisfactory (UNSAT) pts using the log-rank test. Results: Of 117 pts (115 male, 105 nonseminoma), the most common primary sites were testis (81) and mediastinum (26). 93, 19, and 5 pts completed 3, 2, and 1 HD cycles, respectively. Overall, 19/117 had SAT decline during LD (19/77 for HCG; 7/57 for AFP). For LD, there was no significant difference in PFS or OS for SAT vs. UNSAT decline. For HD, 17/96 had SAT decline (11/59 for HCG; 9/47 for AFP). SAT overall decline (HCG and AFP) during HD predicted superior PFS (p=0.0025) and OS (p=0.0046) with 2-year (yr) PFS 0.88 (0.59, 0.97) vs. 0.37 (0.26, 0.47) and 3yr OS 0.82 (0.55, 0.94) vs. 0.37 (0.26, 0.48). SAT HCG decline alone also predicted superior PFS (p=0.0018) and OS (p=0.004) with 2yr PFS 0.91 (0.51, 0.99) vs. 0.32 (0.19, 0.46) and 3yr OS 0.91 (0.51, 0.99) vs. 0.35 (0.22, 0.50) whereas only a non-significant trend for improved PFS (p=0.14) and OS (p=0.16) was seen for AFP alone. Conclusions: STM decline rates during the HD portion of salvage HDCT predicts favorable PFS and OS, mostly driven by HCG. However, UNSAT STM decline does not exclude long-term PFS/OS. STM decline rates during the initial LD portion of HDCT programs do not predict outcome; thus, UNSAT LD decline should not prohibit subsequent HDCT.

4656 Background: Most patients with GCT are diagnosed and treated below age 50. For patients ≥50, less is known about possible differences in biology, outcome and tolerability of treatment. Methods...

Allergens involved in sensitivity to Alternaria have not been well defined. We used crossed radioimmunoelectrophoresis (CRIE) to study antigens in a crude A. alternata extract, which were capable of binding IgE in human serum. Sera from 35 patients sensitive to Alternaria, 10 not sensitive to Alternaria, and five normal controls were examined. CRIE with hyperimmune rabbit sera demonstrated 22 antigens in the Alternaria extract. After exposure of CRIE gels sequentially with patient serum and 125I-labeled anti-human IgE, autoradiography demonstrated that three of the antigens bound IgE in sera of Alternaria-sensitive subjects. Our results suggest that multiple allergens are involved in A. alternata sensitivity.

We recently cared for two patients who experienced acute asthma with exposure to dander of the cotton top tamarin, a species of New World monkey. Both patients had serologic evidence for an IgE antibody to monkey dander as determined by RAST and a positive immediate skin test response to an extract prepared from monkey dander. Furthermore, by RAST we were able to determine that cotton top tamarin urine and newborn cotton top tamarin dander had antigens that reacted with IgE in the serum of the affected patients. Thus we report two patients with asthma to monkey dander that appears to be mediated by an IgE mechanism. We also found that serum from a subject exposed to another species of New World monkey, the capuchin, yielded a positive RAST to the cotton top tamarin, suggesting that allergenic cross-reactivity may exist between the two species.

Tumor-infiltrating immune cells have been linked to prognosis and response to immunotherapy; however, the levels of distinct immune cell subsets and the signals that draw them into a tumor, such as the expression of antigen presenting machinery genes, remain poorly characterized. Here, we employ a gene expression-based computational method to profile the infiltration levels of 24 immune cell populations in 19 cancer types.We compare cancer types using an immune infiltration score and a T cell infiltration score and find that clear cell renal cell carcinoma (ccRCC) is among the highest for both scores. Using immune infiltration profiles as well as transcriptomic and proteomic datasets, we characterize three groups of ccRCC tumors: T cell enriched, heterogeneously infiltrated, and non-infiltrated. We observe that the immunogenicity of ccRCC tumors cannot be explained by mutation load or neo-antigen load, but is highly correlated with MHC class I antigen presenting machinery expression (APM). We explore the prognostic value of distinct T cell subsets and show in two cohorts that Th17 cells and CD8Our analysis sheds light on the immune infiltration patterns of 19 human cancers and unravels mRNA signatures with prognostic utility and immunotherapeutic biomarker potential in ccRCC.

561 Background: PBRM1 and BAP1, both of which encode chromatin modulating proteins, have recently been identified as frequently mutated tumor suppressor genes in RCC. However, their correlation with outcomes of targeted therapies is unknown. We explored correlations between overall survival (OS) and mutations in archival tumor samples from RECORD-3, a randomized phase 2 trial comparing first-line everolimus (EVE) then sunitinib (SUN) to first-line SUN then EVE at progression in 471 treatment-naïve mRCC patients (J Clin Oncol 2014; 32:2764). Methods: Somatic mutations in exons of 341 cancer related genes were identified by a next generation sequencing (NGS) assay (MSK IMPACT). Association between genotypes and OS was assessed by Cox PH models and log-rank tests. Results: DNA of 258 archival tumor and 181 matched germline samples was successfully analyzed (median coverage 530X). Three molecular subgroups Gr1 (BAP1 MT [mutant], PBRM1 WT [wild-type]/MT; 17.4%), Gr2 (PBRM1 MT, BAP1 WT; 38.4%), and Gr3 (PBRM1 WT, BAP1 WT; 44.2%) with different OS outcomes after sequential EVE-SUN or SUN-EVE were identified (Table). In the sequential EVE-SUN arm, median OS (months) was shortest with Gr1 (9.8; 95% CI, 7.8–20.0), longest with Gr2 (39.6; 95% CI, 31.7–not estimable), and intermediate with Gr3 (18.1; 13.7–30.0), whereas in the SUN-EVE arm there was no significant difference among groups. When comparing OS between treatment sequences within molecular groups, a trend suggested differences for EVE-SUN vs SUN-EVE in Gr1 (HR 1.5), Gr2 (0.8), and Gr3 (1.2), although comparisons were not statistically significant. Conclusions: Our results suggest that these genotypes may represent distinct RCC molecular subtypes with potentially different predictive/prognostic values on targeted therapies. Different treatment sequences may be considered depending on the genotypes. Clinical trial information: NCT00903175. [Table: see text]

453 Background: Loss of the VHL tumor suppressor in clear cell renal cell carcinoma (ccRCC) leads to the accumulation of Hypoxia Inducible Factor (HIF) and aberrant transcription of downstream targets such as VEGF. Inhibition of VEGF is the underlying therapeutic principle of several approved targeted agents; however, other HIF transcriptional targets remain to be explored. Increased expression of the HIF transcriptional target CUB domain-containing protein 1 (CDCP1) is associated with poor survival in ccRCC. CDCP1 is a substrate and binding partner for Src-family tyrosine kinases (SFKs) and dictates substrate specificity. Crosstalk between the SFK signaling cascade and the HIF pathway may result in feed forward signal amplification. Upregulation of Src signaling increases HIF-dependent transcription by both VHL-dependent and -independent mechanisms. Reciprocally, HIF accumulation can activate Src through PDGFRα, focal adhesion kinase, and CDCP1. Methods: Data from The Cancer Genome Atlas (TCGA) was used to assess mRNA expression and protein phosphorylation as well as clinical parameters and outcome in patients with ccRCC. Correlations were analyzed via Mann-Whitney U-test. Survival data was obtained using the TCGA portal, and analyzed by logrank test. To investigate the therapeutic potential of Src inhibition, the IC50 of Dasatinib in primary tumors derived cell lines were determined by an AlamarBlue Assay. Results: Increased Src and CDCP1 mRNA expression and decreased phosphorylation on the Src inhibitory site Y527 correlated with increased Fuhrman grade. Decreased phosphorylation on the inhibitory site Y527 correlated with worse median overall survival (78.4 vs. 19.7 months, p< 0.00001). Similarly, increased Src and CDCP1 mRNA expression correlated with worse overall survival (78.4 vs. 26.9 months, p < 0.00001, 78.4 vs. 37.2 months, p = 0.005). In vitro inhibition of Src with Dasatinib induces growth inhibition of primary cell lines with sarcomatoid or rhabdoid features, histomorphologic criteria associated with higher grade disease and worse prognosis. Conclusions: The Src pathway might be biologically relevant for ccRCC, and Src inhibition may have therapeutic potential.

4531 Background: RECORD-3 is a phase 2 trial that compared 1st-line EVE then sunitinib (SUT) with first-line SUT then EVE at progression (1:1 randomization). The study did not meet its primary endp...

4522 Background: VEGF- and mTOR-directed therapies achieve inferior outcomes in pts with advanced ncRCC compared to clear cell RCC. Limited benefit from monotherapy supports study of combination re...

4509 Background: Several large genomic analyses of RCC have recently identified prevalent mutations in epiegenetic regulators with prognostic significance. However, the impact of these novel mutati...