bluuebunny/crossref_metadata_2025 huggingface dataset:
First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (nccRCC): Results from KEYNOTE-427 cohort B.
Authors: McDermott David F. , Lee Jae-Lyun , Ziobro Marek , Gafanov Rustem Airatovich , Matveev Vsevolod Borisovich , Suárez Cristina , Donskov Frede , Pouliot Frederic , Alekseev Boris Y. , Wiechno Pawel , Tomczak Piotr , Climent Duran Miguel Angel , Shin Sang Joon , Silverman Rachel Kloss , Perini Rodolfo F. , Schloss Charles , Atkins Michael B.
Published: March 2019

546

Background: PD-1/L1 pathway inhibitors are effective in clear cell (cc)RCC, but efficacy of PD-1 inhibitors (or any therapy) in nccRCC has not been established. KEYNOTE-427 is a single-arm, open-label, phase 2 study of pembro monotherapy in patients (pts) with advanced ccRCC (cohort A) and nccRCC (cohort B). Cohort B results are presented. Methods: 165 pts with histologically confirmed nccRCC, no prior systemic therapy, measurable disease (RECIST v1.1), and KPS ≥70% enrolled. Pts received pembro 200 mg IV Q3W for 35 cycles (~2 y) or until progressive disease (PD), unacceptable toxicity, or withdrawal. Pts were followed after PD for overall survival. Primary end point: objective response rate (ORR) per RECIST v1.1 by blinded independent central review. Secondary end points included duration of response (DOR) and population description by International Metastatic RCC Database Consortium (IMDC) risk. Exploratory end points: ORR by histology and PD-L1 expression (combined positive score [CPS] ≥1 for PD-L1+). Results: Histology was confirmed by a central pathologist: papillary 72% (n=118), chromophobe 13% (n=21), unclassified 16% (n=26). 68% of patients were at intermediate/poor IMDC risk, and 62% were PD-L1+. At analysis, 49 pts had died and 3 had withdrawn. At a median follow-up duration of 11.1 mo (range, 0.9-21.3), 56% of pts discontinued pembro due to PD or clinical progression. Overall ORR was 24.8% (95% CI, 18.5-32.2; 8 [4.8%] CRs, 33 [20%] PRs); median DOR was not reached. ORR (95% CI) was 25.4% (17.9-34.3) with papillary, 9.5% (1.2-30.4) with chromophobe, and 34.6% (17.2-55.7) with unclassified nccRCC. ORR (95% CI) was 28.3% (16.8-42.3) with favorable and 23.2% (15.8-32.1) with intermediate/poor IMDC risk and 33.3% (24.3-43.4) and 10.3% (3.9-21.2) with CPS≥1 and CPS<1, respectively. Grade 3-5 treatment-related adverse events (TRAEs) occurred in 11% of pts; 6% discontinued due to TRAEs. 6 pts died due to AEs, 2 of which were TRAEs (pneumonia and cardiac arrest). Conclusions: Single-agent pembro showed encouraging antitumor activity in nccRCC, especially with papillary or unclassified histology. Safety profile of pembro was generally as expected. Clinical trial information: NCT02853344.
Results of a phase II study of atezolizumab and bevacizumab in non-clear cell renal cell carcinoma (nccRCC) and clear cell renal cell carcinoma with sarcomatoid differentiation (sccRCC).
Authors: McKay Rana R. , McGregor Bradley Alexander , Gray Kathryn , Steinharter John A. , Walsh Meghara K. , Braun David A. , Flaifel Abdallah , VanAllen Eliezer , Wei Xiao X. , Signoretti Sabina , Harshman Lauren Christine , Vaishampayan Ulka N. , Choueiri Toni K.
Published: March 2019

548

Background: NccRCC and sccRCC have historically been underrepresented in clinical trials. Even with targeted therapy, most patients have inferior survival compared to clear cell renal cell carcinoma. The combination of atezolizumab and bevacizumab has demonstrated safety and efficacy in ccRCC. In this multicenter, phase II, open-label, single arm trial we evaluate the efficacy of atezolizumab and bevacizumab in patients with nccRCC and sccRCC with >20% sarcomatoid differentiation. Methods: Eligible patients had an ECOG performance status of 0-2 and may have received prior therapy. Prior PD-1/PD-L1 therapy was not allowed. Patients underwent a mandatory baseline biopsy and subsequently received atezolizumab 120 mg and bevacizumab 15 mg/kg intravenously every 3 weeks. Patients remained on therapy until radiographic progression, unacceptable adverse events, or withdrawal. The primary end point was overall response rate (ORR) as determined by RECIST version 1.1. Results: 65 patients were enrolled of whom 52 had ≥1 response assessment and were included in this analysis. 36 patients had nccRCC (papillary n=14, chromophobe n=8, unclassified RCC n=3, collecting duct n=3, translocation n=3, other n=5), and 16 patients had sccRCC. 17 patients received prior systemic therapy, 16 of whom had nccRCC. The ORR was 31% in the overall cohort (Table 1). 10 patients (19%) developed grade 3 treatment-related adverse events (AEs), half of which were immune-related. There were no grade 4-5 AEs. Conclusions: In this study, we show that therapy with atezolizumab and bevacizumab was safe and demonstrated anti-tumor activity in nccRCC and sccRCC. Further analyses will report ORR by histologic subtype and PD-L1 expression status. Analysis of tissue and blood-based biomarkers of response are ongoing. Clinical trial information: NCT02724878. [Table: see text]
Novel predictive models of early death less than one year in patients with metastatic RCC treated with first-line tyrosine kinase inhibitors.
Authors: Kang Minyong , Joung Jae Young , Kim Tae Jin , Jeon Hwang Gyun , Jeong Byong Chang , Seo Seong Il , Jeon Seong Soo , Lee Hyun Moo , Sung Hyun Hwan
Published: March 2019

552

Background: Although the IMDC model can provide useful information on overall survival outcomes in patients with metastatic renal cell carcinoma (mRCC), this model maybe invaluable in patients who experience early death less than one year after initial systemic therapy. Here, we aimed to develop a new prognostic model which can predict early death in patients with mRCC receiving first line tyrosine kinase inhibitors (TKI). Methods: We retrospectively evaluated a total of 498 patients treated with first line line TKI among 537 patients with mRCC at our institution. The primary endpoint was the rate of early death within 1 year after first line TKI administration. We selected statistically significant factors predicting early death by performing multiple logistic regression. Modified IMDC model 1 based on existing IMDC model and model 2 composed of new variables were generated. The prediction accuracy was evaluated by calculating the concordance index (C-index). Area under curve (AUC) and net reclassification index (NRI) using ROC curve analysis were used to compare the predictive power between the models. Results: Overall mortality was 59.0% (n = 294) in 498 patients, and early mortality was 19.7% (n = 98) within 1 year after first line TKI administration. The C-index of the IMDC model for early death was 0.655. Five variables were selected: previous nephrectomy, BMI, multiple metastases, previous metastasectomy and serum albumin level. The C-index of the model 1, which includes five new variables plus variables in the IDMC model, is 0.823, showing a significant improvement over the IDMC model. In model 2, hemoglobin and neutrophil levels were added in new five variables, and the C-index was 0.822. For the IMDC model, there was a significant NRI difference in both models 1 and 2, but no significant difference in NRI between models 1 and 2. (-0.0368 [95% CI = -0.1416 - 0.0681]; p = 0.491). Conclusions: In this study, we suggest modified IMDC models for predicting ‘early death less than one year in patients with mRCC treated with first line TKI. These novel models can provide better treatment strategies and counseling in patients with mRCC who were treated by first line TKI.
Impact of disagreement between the IMDC and MSKCC risk groups on prognosis in patients with metastatic renal cell carcinoma.
Authors: Hatakeyama Shingo , Tanaka Toshiaki , Ikehata Yoshinori , Fujita Naoki , Yamamoto Hayato , Yoneyama Takahiro , Hashimoto Yasuhiro , Masumori Naoya , Kitamura Hiroshi , Ohyama Chikara
Published: March 2019

556

Background: As the clinical implication of the risk group disagreement between the risk models remains unclear, we aimed to investigate the impact of the risk group disagreement between the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) models on prognosis. Methods: We retrospectively evaluated 176 patients with metastatic renal cell carcinoma (mRCC) who were treated with tyrosine kinase inhibitors as first-line therapy in five hospitals between October 2008 and August 2018. The risk group classification differences between the MSKCC and the IMDC models were evaluated using criteria of agreement (identical risk group in both the MSKCC and IMDC models) and disagreement (not identical risk group in both the MSKCC and IMDC models). The agreement of risk stratification between the MSKCC and IMDC models was evaluated using Cohen’s k coefficient. Oncological outcomes were compared between the agreement and disagreement groups. Results: The number of patients with agreement, upgrade, and downgrade was 135/176 (77%), 39/176 (22%), and 2/176 (1.1%), respectively. Of 41 patients with disagreement, reclassification from the MSKCC-intermediate to the IMDC-poor-risk group was most frequent (n = 34/176, 19%). The Cohen’s k coefficient for agreement of the two risk models was substantial with k value of 0.613 ( P < 0.001). Significantly poorer prognosis was observed in patients with disagreement than in those with agreement. Conclusions: Disagreement between the MSKCC and IMDC models may have a negative impact on prognosis in patients with mRCC. Further study is necessary to validate our findings.
Modeling of prognostication and differential genomic expression in the tumor microenvironment of clear cell renal cell carcinoma.
Authors: Lee Sunyoung S. , Kwon Seok Joon , Lee Dong Eun , Lee Seongwon , Baird Andrew , Park Shinyoung , Dolan Jillian , George Saby
Published: March 2019

557

Background: Stroma in the tumor microenvironment (TME) influences prognosis and response to therapy. Few mathematical models exist to prognosticate patients (pts), based on mRNA expressivity in the TME. Methods: Clinical outcomes data and mRNA-seq of 533 pts with clear cell renal cancer were obtained from TCGA. Expressivity of 191 genes enriched in cellular and structural elements of TME and clinical data were analyzed via machine learning, multivariate nonlinear regression with confined optimization, and Kaplan-Meier (KM) analysis. Results: Prognostication was modeled with higher risk score (RS) representing worse prognosis in each stage (Table). P/G is the ratio of genes associated with poor (61 genes) to good (14) prognosis (refer to presentation). Based on RS, pts in each stage were clustered into 2 groups (high and low RS), showing 2 KM curves with p < 0.001 in each stage. Analysis of immune profiles in these 2 groups shows that in stage 1, expression of genes related to immune activation (IA) is not statistically different in high and low RS groups, but expression of genes related to immune inhibition (II) is higher in high RS group. In high RS groups of stage 2-4, IA genes are highly co-expressed with II genes. In high RS groups of all stages, expression of both IA and II genes increases as stage increases. In low RS groups, IA genes increase as stage increases, but II genes do not. Conclusions: Machine learning and mathematical modeling of RS and gene analysis show that IA genes are suppressed by high degree of II in high RS groups of advanced stages, contributing to worse prognosis. RS enables prognostication of pts encountered in the clinic, given genomic profiles. [Table: see text]
Treatment utilization trends and outcomes in renal liposarcoma (RLS): A National Cancer Database (NCDB) analysis.
Authors: Malla Midhun , Tripathi Abhishek , Zhang Ying , Patel Sanjay , Pareek Vipul
Published: March 2019

559

Background: RLS is an extremely rare neoplasm with only few case reports documented in the literature. Due to the rarity of this disease, level 1 evidence guiding optimal patient management is lacking. Utilizing the NCDB, we analyzed the current treatment patterns and outcomes in patients with RLS in the United States. Methods: The NCDB was queried from 2004- 2015 for patients diagnosed with T1-4N0-1M0 RLS. Baseline patient characteristics were summarized using descriptive statistics. Impact of baseline demographic, clinicopathologic variables and treatment on overall survival (OS) was evaluated using univariate (UV) and multivariable (MV) cox proportional hazards analysis. Results: 136 patients diagnosed with non-metastatic RLS between 2004- 2015 were included in this analysis. Median age at diagnosis was 64.7 years. Males and females had equal preponderance (50% each). 89% (n = 121) were Caucasian, while only 6% were African American. T staging was based on AJCC 8th edition. 20% of patients had T1 disease, 17% had T2, while T3 and T4 stage was present in 26% and 37% of cases respectively. Only 7% (n = 10) had lymph node (LN) involvement. Dedifferentiated RLS was the most common histology (44%). 59% (n = 80) had radical nephrectomy, 12% (n = 17) had partial nephrectomy, and 17% had nephrectomy NOS. Adjuvant radiation and chemotherapy were used in 15% (n = 20) and 3.6% (n = 5) of patients respectively. Median OS was 41 months (20-76 mos). On UV analysis age ≤ 70 years and sex had a statistically significant effect on OS (HR: 0.387 and 0.549, p < 0.001 and 0.04 respectively). On MV analysis adjusting for age and sex, female patients had a significantly improved OS compared to males (47 vs 36.7mos, HR-0.45, CI: 0.250-0.804 p < 0.05). Conclusions: RLS is a rare and aggressive malignancy with poor outcomes even at localized stage. Age at diagnosis and sex had a statistically significant impact on OS. Given the lack of prospective data, our study provides insights into the prognosis of this rare disease. Additional studies are needed to better guide the optimal management of this rare disease.
The effect of loss of SETD2 on mitochondrial dysfunction in clear cell renal cell carcinoma.
Authors: Hapke Robert , Beckermann Katy , Rathmell Kimryn , Haake Scott Mattox
Published: March 2019

567

Background: SET domain-containing protein 2 ( SETD2) is among the most commonly mutated genes in clear cell renal cell carcinoma (ccRCC). Classically, SETD2 modulates chromatin structure via the methylation of lysine 36 on histone H3. However, histone-independent functions of SETD2 are emerging. We sought to discover novel SETD2-dependent changes to the cellular lysine methylation landscape during kidney cancer tumorigenesis. Methods: In this study, we used HKC human proximal tubule kidney cell lines, the likely nephrogenic region of origin for ccRCC. The proteomes of wild type (WT) and SETD2-knock out (KO) cells were labeled using stable isotope labeling by amino acids in cell culture (SILAC). Proteins were trypsinized and lysine-methylated peptides were immunoprecipitated. Relative abundance of lysine-methylated peptides and total peptides were calculated in the WT and SETD2-KO using nano-liquid chromatography/tandem mass spectrometry (LC/MS-MS). Results: > 30,000 peptides were quantified, including > 50 lysine methylated peptides. We observed decreased lysine methylation of eukaryotic elongation factor 1A1 (eEF1A1), including K165 trimethylation (K165me3) and K318 monomethylation (K318me1). eEF1A1 is classically known for delivery of aminoacyl-tRNA to the ribosome, and its function is modulated via the lysine methyltranferases eEF1AKMT1-4. eEF1AKMT3 is responsible for trimethylation of K165, and expression of this enzyme was decreased in SETD2-KO cells. In addition, we observed significant decrease in expression in proteins of the electron transport chain (ETC) complex 1 in SETD2-KO cells yet normal gene expression, suggesting a translational defect. Functionally, SETD2-KO cells are characterized by decreased cellular oxygen consumption rate and increased mitochondrial mass, suggestive of ETC dysfunction. Conclusions: We observe decreased expression of eEF1AKMT3 in SETD2-KO cells, resulting in decreased K165me3 of eEFA1A, decreased translation of ETC proteins, and mitochondrial dysfunction. As mitochondrial dysfunction is commonly observed in RCC, we expect this represents a novel mechanism of SETD2-mediated tumorigenesis.
Is cytoreductive nephrectomy necessary in metastatic renal cell carcinoma with primary kidney tumor in situ treated by sunitinib: Real-world data from a single Chinese center.
Authors: Xu Wen-Hao , Qu Yuan-Yuan , Wang Hong-Kai , Zhang Hai-Liang , Ye Dingwei
Published: March 2019

570

Background: To evaluate the role of cytoreductive nephrectomy (CN), which was an indispensable treatment in metastasis renal cell carcinoma (mRCC), compared with cytokine treatment, we assessed the survival benefit of CN in patients with mRCC treated by sunitinib in targeted therapy era. Methods: This retrospective study compared the progression-free survival (PFS) and overall survival (OS) between mRCC patients who did or did not undergo CN. We screened out and enrolled patients from April 2006 to November 2013 as suitable candidates for CN with primary kidney tumor in situ. Logistic regression models were used to measure the effects of the clinical and pathological covariates. The Kaplan-Meier method and log-rank test were performed to evaluate the possible survival differences between two groups. Results: Atotal of 70 patients were assigned to undergo CN followed with sunitinib and 48 received sunitinib alone. According to the survival analysis, the median PFS was 8.38 months and the median OS was 15.48 months, with 109 deaths observed. There were no significant difference between CN-sunitinib group and sunitinib-alone group in both PFS(7.2 versus 11.6 months, 95% confidence interval, 5.3 to 11.8; P= 0.525) and OS (16.7 versus 15.2 months, 95% confidence interval, 12.0 to 18.9, P= 0.839). However, stratified analysis revealed that PFS and OS might decrease after CN in the subgroups of patients with IMDC prognostic criteria of high-risk disease (PFS: 4.4 [95% CI, 3.5 to 5.3] vs. 6.3 [95% CI, 5.3 to 7.2]months, P= 0.002; OS: 8.8 [95% CI, 7.0 to 10.6] vs 9.9 [95% CI, 10.0 to 11.8] months, P= 0.011) and those with lymphatic metastasis (PFS: 4.4 [95% CI, 2.9 to 6.0] vs. 6.6 [95% CI, 2.1 to 11.2] months, P< 0.001; OS: 8.8 [95% CI, 6.9 to 10.7] vs 9.9 [95% CI, 7.1 to 10.7] months, P= 0.006). Conclusions: Cytoreductive nephrectomy may offer no survival benefits in those mRCC patients with primary kidney tumor in situ, and moreover, sunitinib-alone therapy perhaps contributes longer PFS and OS for the patients with IMDC high-risk disease and those with lymphatic metastasis.
Prognostic impact of neutrophil-to-lymphocyte ratio in renal cell carcinoma: A systematic review and meta-analysis.
Authors: Mollica Veronica , Di Nunno Vincenzo , Gatto Lidia , Santoni Matteo , Cosmai Laura , Porta Camillo , Massari Francesco
Published: March 2019

572

Background: Several clinical scores have been adopted in clinical practice for the prognostic estimation in patients with Renal Cell Carcinoma (RCC). Neutrophil-lymphocytes ratio (NLR) has shown to be a reliable and economic parameter associated with prognosis however its role has not been fully understood. Methods: We performed a systematic review and meta-analysis according to PRISMA guidelines to evaluate the prognostic value of NLR in terms of overall and progression free survival (OS/PFS) in both metastatic and non metastatic patients with RCC. We applied the inverse variance technique for the meta-analysis of the HRs and due to the intrinsic heterogeneity of the data we adopted a Random Effects model. 24 studies were selected for the final analysis, 21 for the comparison of NLR and OS and 15 for the comparison of NLR and DFS/PFS. Results: In overall population higher NLR resulted in worst OS benefit with a pooled HR of 1.80 (95% confidence interval of 1.61 – 2.00, I2 45%.) as well as in non metastatic (pooled HR of 1.57, 95% CI 1.27-1.94, I2 39%) and metastatic patients (2.05, 95% CI 1.74-2.41, I2 0%). Moreover, NLR resulted in worst PFS in overall population (pooled HR 1.69, 95% CI 1.42-2.01, I2 81%), in non metastatic (HR 1.52, 95% CI 1.23-1.87, I2 53%) and metastatic (HR 1.95, 95% CI 1.43-2.64 I2 90%). Conclusions: According to our results NLR ratio is a variable correlated to prognosis in RCC patients. The low level of heterogeneity among studies included suggests that it has a strong association with patients’ survival. Thus it appears as an attractive, dynamic and economic biomarker which could be adopted to further subdivide prognostic classes into even more accurate groups of prognosis in order to choose the best treatment strategy possible. Further prospective studies are needed to confirm our findings.
Exploratory endpoints in a FARETES study of the efficacy of testosterone in metastatic renal cell carcinoma (mRCC) patients.
Authors: Tsimafeyeu Ilya , Borisov Pavel , Zukov Ruslan , Zakurdaeva Kristina , Bondarenko Anastasia , Tishova Yulia
Published: March 2019

574

Background: In multicenter randomized phase 2 study (FARETES) we showed that male patients with mRCC receiving targeted therapy had significantly less fatigue and better symptom control with testosterone undecanoate (T) (MASCC 2018, LBA004). Here we described exploratory endpoints in FARETES study. Methods: Sixty male patients with clear cell mRCC, normal PSA level, low testosterone level and no evidence of hypothyroidism receiving first-line sunitinib or pazopanib with fatigue were randomly assigned (1:1) to either T (Nebido, 1,000 mg) and targeted therapy or targeted therapy alone (control group). T was injected intramuscular deeply on Day 1 of a new treatment cycle. Exploratory endpoints included rate of adverse events (AE) of targeted therapy, duration of targeted therapy, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of the data cutoff on October 17, 2018, median (range) follow-up was 15.2 (9.9 -16.5) months. No unexpected toxicity of T was observed. Grade 3-4 targeted therapy-related AE occurred in 11 (37%) and 3 (10%) patients in the control group and T group, respectively. Discontinuation due to AE was observed in 3% (1/30) of patients in the T group and in 17% (5/30) of patients in the control group. ORR and PFS were significantly better in the T group (all P < 0.05, Table). Median OS was not reached in either group. Clinical trial information: NCT03379012. Conclusions: T therapy could decrease rate of serious AE of targeted therapy. Male mRCC patients receiving T had longer duration of targeted therapy, better PFS and ORR. Larger trials are needed to evaluate efficacy of T in this group of patients.[Table: see text]
Concordance between PD-L1 assays for metastatic renal cell carcinoma (mRCC) and metastatic urothelial carcinoma (mUC).
Authors: Zhu Jason , Labriola Matthew , Cheris Sachica , Liu Xin , Perkinson Kathryn , Su Zuowei , McCall Shannon , Huang Jiaoti , Gupta Rajan , Armstrong Andrew J. , George Daniel J. , Zhang Tian
Published: March 2019

577

Background: Immune checkpoint inhibitors (ICIs) are now standard of care for mRCC and mUC patients (pts). PD-L1 status is gaining importance as a predictive biomarker, particularly for cisplatin-ineligible mUC. Four different PD-L1 assays vary in thresholds of PD-L1 positivity dependent on tumor type, with limited concordance studies. Given real-world limitations in PD-L1 testing, concordance between assays are needed to distinguish positive (pos)/negative (neg) results and treatment selection. We undertook comparisons of Dako 28–8 and Ventana SP142 assays in mRCC and Dako 22C3 and Ventana SP263 assays in mUC. Methods: 32 patients with mRCC and 18 patients with mUC who had received ICI therapy at Duke Cancer Institute were identified. FFPE archival tumor samples for pts with mRCC were evaluated with Dako 28–8 and Ventana SP142 PD-L1 immunohistochemistry (IHC) assays. For pts with mUC, FFPE archival tumor samples were evaluated with Dako 22C3 and Ventana SP263 PD-L1 IHC assays. Scoring was validated by two pathologists using the scoring system for each assay. PD-L1 status was subsequently correlated to best RECIST response (objective response rate (ORR) defined as stable disease or better)). Results: The majority of mRCC cases (29/32, 91%) were concordant between Dako 28-8 and Ventana SP142 assays (8 cases pos and 21 cases neg), with 3 discordant cases (1 case pos for Dako 28-8 but neg for Ventana SP142 and 2 cases neg for Dako 28-8 but pos for Ventana SP142). The majority of mUC cases (17/18, 94%) were also concordant between Dako 22C3 and Ventana SP263 assays (2 pos cases and 15 neg cases), with 1 indeterminate Dako 22C3 test due to background lymph node. In mRCC, the ORR for PD-L1 pos cases was 45% (5/11) versus 33% (8/24) for PD-L1 neg cases. In mUC, the ORR for PD-L1 positive cases was 50% (1/2) versus 31% (5/16) for PD-L1 neg cases. Conclusions: There was strong concordance between PD-L1 tumor/immune cell assays chosen for comparison in both mRCC and mUC with similar performance characteristics. Although PD-L1 positivity enriches for response to ICIs, many patients respond who are PD-L1 negative. PD-L1 status could be used interchangeably for the majority of cases when selecting treatment in mRCC and mUC.
Receipt of systemic therapy in older versus younger patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Hahn Andrew W , Haaland Ben , Rathi Nityam , Dizman Nazli , Maughan Benjamin Louis , Pal Sumanta K. , Agarwal Neeraj
Published: March 2019

580

Background: More than half of pts diagnosed with mRCC are age 65 or older. However, older pts are often under-accrued/under-represented in clinical trials, partly due to concerns about their ability to tolerate systemic therapy (Rx). Given this, efficacy data from the registration trials may not apply to older pts. Herein, we investigate whether older patients with mRCC are less likely to receive various lines of systemic Rx than their younger counterparts. Methods: Clinical data was obtained from a prospectively maintained mRCC registry at the Huntsman Cancer Institute, University of Utah. Older pts were defined as ≥65 yrs at initiation of first-line systemic Rx for mRCC. Univariate analyses of the lines of systemic Rx received were performed using the Chi-squared test. Comparison of ordered categorical variables was made with the Wilcoxon rank sum test. Results: 264 pts who received first-line Rx for mRCC between 2004-2018 were included, and 108 of them were older pts. For older pts, median age at first-line Rx was 71.1 years and 78.7% had clear cell histology, whereas, the median age for younger pts was 53.4 years and 75.6% had clear cell histology. There was no difference in the baseline IMDC risk categories in older vs. younger pts (p = 0.907). A similar proportion of older and younger pts received at least two lines of systemic Rx (66.9% vs. 62.4%, p = 0.532). Furthermore, when analyzed across all lines of treatment, there was no difference in the number of systemic Rx between older and younger pts (p = 0.593). The median OS was similar in both groups: older 30 months (95% CI 21-44 months) vs. younger 34 months (95% CI 30-46 months) (p = 0.639). Conclusions: Older pts with mRCC receive a similar number of systemic Rx as their younger counterparts, and have similar survival outcomes. These findings can inform clinicians when selecting first and salvage-line treatment for older pts, and warrant proportionate accrual and representation of older pts in clinical trials.
Investigation of IMPDH2 overexpression in renal cell carcinoma (RCC) & its association with oncologic outcomes.
Authors: Sendilnathan Arun , Velagapudi Ramya Krishna , Marinos Velarde Alejandro , Jandarov Roman , Zhu Zheng , Randhawa Jaskirat Singh , Dillehay McKillip Kelsey , Yoshino Hirofumi , Kofuji Satoshi , Okumura Koichi , Naffouje Rand , Koch Matthew , Ao Xiang , Finley Kara , Sasaki Atsuo
Published: March 2019

594

Background: Approximately 40% of locoregional RCC patients relapse after nephrectomy leading to lower 5 year survival rates of 53% (stage III) & 8% (metastatic). No biomarkers of prognostic significance are in clinical use at this time. It is important to identify biomarkers that can better inform clinicians the nature of disease & personalize treatment. It is even better if the biomarkers are targetable with drugs. Inosine 5”-mono-phosphate dehydrogenase type II (IMPDH2), a rate limiting enzyme in the de novo guanine nucleotide biosynthesis is upregulated in many tumor types. Work by Sasaki laboratory showed increased GTP synthesis by IMPDH2 upregulation is important for cell growth, metastasis & cell maintenance in Gliobastoma Multiforme cell lines. Hypothesis: We are investigating the feasibility of using IMPDH2 expression in RCC as a diagnostic & prognostic biomarker. Methods: 45 cases of clear cell RCC (all stages) were identified by chart review. Slides reviewed to identify blocks with carcinoma, normal tissue & interface. Tissue microarray (TMA) was constructed using the fully automated TMA Master. TMA sectioned and stained with H &E & IMPDH2 antibody. Staining interpretation: TMA stained with IMPDH2 were reviewed based on IRS scoring system (PP x SI) - percentage positive(PP) cells (Negative-0, ≤ 10% -1, ≥ 11%- ≤ 50%- 2, ≥ 51%-≤ 80% -3, and ≥ 81%-4) & staining intensity (SI) (Negative-0, Weak-1, Moderate-2, and Strong-3). The scoring pathologist was blinded to the clinical data & outcomes of patients. Results: Preliminary results show IMPDH2 is overexpressed in RCC and tumor-normal interface compared to normal kidney. Further analyses are ongoing if IMPDH2 overexpression correlates with pertinent clinical & pathological variables including TNM stage, histologic grade (Fuhrman Grade) & oncologic outcomes including overall survival (OS) & risk of relapse. Conclusions: In the era of Sunitinib being approved as an adjuvant therapy (but not widely used due to lack of OS data), the above data will be important to verify if IMPDH2 can be used as a clinically useful test & may give insight to future personalized & targeted treatment strategies (IMPDH2 inhibitors like mycophenolate) for RCC.
Association of elevated C-reactive protein with oncologic outcomes in renal CELL carcinoma: A multicenter analysis.
Authors: Patel Sunil Hemant , Meagher Margaret Frances , Saito Kazutaka , Patil Dattatraya , Bindayi Ahmet , Eldefrawy Ahmed , Ryan Stephen , Cotta Brittney , Yim Kendrick , Nasseri Ryan , Hamilton Zachary , Yasuda Yosuke , Fujii Yasuhisa , Master Viraj A. , Derweesh Ithaar
Published: March 2019

596

Background: C-reactive protein (CRP) is a systemic inflammatory marker which has been associated with overall survival (OS) in Renal Cell Carcinoma (RCC) patients in Asia. Data supporting utility of CRP as a predictive marker in non-Asian populations are sparse and controversial. We analyzed utility of pre-treatment CRP as a predictor of survival and oncological outcomes in a multicenter cohort of RCC patients. Methods: Retrospective international 3 center analysis of patients of patients with RCC with pretreatment CRP values from 2006-2017. CRP > 0.5mg/dl was used as threshold for elevation and the cohort was subdivided into two groups for descriptive analysis (normal-CRP ≤0.5 and elevated-CRP > 0.5). Primary outcome was recurrence-free survival (RFS). Secondary outcome was overall survival (OS). Kaplan-Meier (KMA) and multivariable analyses (MVA) were utilized to delineate survival outcomes and their predictors. Results: Overall 2695 patients were analyzed (1791 Male/904 female, CRP≤0.5 1198/CRP > 0.5 1496; mean follow-up 36 months). Patients with elevated CRP had higher incidence of hypertension (p = 0.001), BMI (p < 0.001), and tumor size (3.91 cm vs. 6.05 cm, p < 0.001). MVA for RFS demonstrated elevated CRP (OR = 0.542, p = 0.005), increasing tumor size (OR = 0.915, p < 0.001), and high tumor grade (OR = 0.322 p < 0.001) to be independent risk factors. MVA for all-cause mortality demonstrated elevated CRP (OR = 12.396, p = 0.005), increasing tumor size (OR = 1.126, p < 0.001), high tumor grade (OR = 2.474, p < 0.001), and receipt of PN (OR = 1.826, p = 0.001) to be independent risk factors. For normal vs. elevated CRP, KMA revealed 5-year RFS of 90% vs. 85% (p = 0.001), 95% vs 85% (p = 0.163), 85% vs 62% (p = 0.001), 50% vs 60% (p = 0.513) for Stages 1, 2, 3, and 4, respectively. KMA revealed 5-year OS of 98% vs 80% (p = 0.001), 95% vs 80% (p = 0.103), 95% vs 65% (p = 0.001), 99% vs 40% (p < 0.001) for Stages 1, 2, 3, and 4, respectively. Conclusions: Pre-treatment CRP was an independent predictor of recurrence free survival and overall survival in a multicenter cohort of RCC patients. While further confirmation is requisite, our findings suggest incorporation of CRP into nomographic and risk stratification protocols.
Real-world experience with sunitinib treatment in patients with metastatic renal cell carcinoma: Clinical outcome according to risk score.
Authors: Schmidinger Manuela , Porta Camillo , Oudard Stephane , Dénéchère Gwénaël , Brault Yves , Serfass Lucile , Costa Nuno Matos , Larkin James M. G.
Published: March 2019

606

Background: ADONIS, an ongoing, observational study in 9 EU countries, evaluates treatment patterns/outcomes in patients (pts) with metastatic renal cell carcinoma treated with 1st-line (1L) sunitinib (SU) and/or 2nd-line (2L) axitinib (AX) post SU. Analysis of the data is planned in 4 parts, to occur stepwise as data matures; evaluation of SU efficacy in intermediate (INT) risk pts is presented here. Future analyses include sequencing data, SU followed by AX and other treatments (cabozantinib, nivolumab and others); SU and AX therapy management strategies, and quality of life. Methods: Pts enroll at start of 1L SU or 2L AX post SU. Data cutoff: May 31, 2018. Analysis focused on 1L SU. Results: 467 pts, median age 64 y (range 31–90), 77.7% were male, with ECOG PS < 2 = 90.2% and ECOG PS ≥ 2 = 9.8% at SU initiation. Overall median progression-free survival (mPFS) was 10.4 mo (95% CI 9.3–12.5), and median overall survival (mOS) 34.0 mo (95% CI 28.3–46.6). Data on individual risk factors (RF) were available for 120 pts, allowing analysis by INT 1RF and INT 2RF groups for this subset. Clinical trial information: NCT02184416. Conclusions: For pts overall and by risk group stratification, survival estimates were aligned with improvements in clinical practice over the past decade. In pts with INT risk with 1RF, OS was very similar to pts with good risk. However further exploration is needed to confirm these observations.[Table: see text]
The association between hospitals’ risk-adjusted emergency department visits and survival and costs in kidney cancer patients.
Authors: Segel Joel E , Schaefer Eric W. , Raman Jay D. , Hollenbeak Christopher S.
Published: March 2019

609

Background: As payers turn to alternative payment models, including the CMS Oncology Care Model, risk-adjusted emergency department (ED) visits are being incorporated as a quality. Yet little is know about this metric compares to existing metrics such as risk-adjusted mortality rates and costs. Methods: Using 2007-2012 SEER-Medicare data, we used logistic regression to model occurrence of an ED visit within 30 and 365 days for all kidney cancer patients receiving initial surgery. Our model controlled for demographics, stage, histology, systemic targeted therapy, and comorbidities. Based on model predictions, we created a ratio of actual versus predicted ED visits for hospitals to identify hospitals with higher and lower than predicted ED visit rates. We estimated the association between the hospitals’ ED visit ratio and hospitals’ risk-adjusted 365-day mortality rates, and 6- and 12-month total costs and total costs (less ED visits). Results: In our sample of 6,078 patients, 15.5% had an ED visit within 30 days of surgery and 43.5% within 365 days. For hospitals with ≥10 patients, we found no statistically significant association between 30-day or 365-day risk-adjusted ED visit rate and their 365-day risk-adjusted mortality rate. While hospitals’ 30-day ED visit rates were significantly associated with 6- and 12-month costs, the association was largely driven by the cost of the ED visit itself. Conversely, hospitals’ 365-day ED visit rates were significantly associated with 12-month costs after excluding the cost of the ED visit. Conclusions: Our results suggest hospitals’ risk-adjusted ED visit rates capture a qualitatively different measure of quality than the more commonly reported mortality rates and is significantly associated with patient cost.
Real-world assessment of clinical outcomes among first-line (1L) sunitinib (SUN) patients (pts) with metastatic renal cell carcinoma (mRCC) by the international mRCC database consortium (IMDC) risk group.
Authors: Savard Marie-France , Wells J Connor , Graham Jeffrey , Steinharter John A. , McGregor Bradley Alexander , Donskov Frede , Bjarnason Georg A. , Vaishampayan Ulka N. , Hansen Aaron Richard , Iafolla Marco Adelmo James , Zanotti Giovanni , Huynh Lynn , Duh Mei Sheng , Heng Daniel Yick Chin
Published: March 2019

610

Background: Prognostic factors such as the IMDC criteria have included all types of targeted therapy. This study assesses clinical outcomes and provide benchmarks for mRCC pts treated specifically with 1L SUN in the real world to provide contemporary benchmarks for outcomes and survival. Methods: Clear cell mRCC pts initiating SUN as 1L therapy between 2010-2018 were included in a retrospective database study. Kaplan Meier analysis was used to estimate median time to treatment discontinuation (TTD) and overall survival (OS: time to death) by IMDC risk groups based on Karnofsky Performance Status < 80%, diagnosis to treatment interval < 1 year, anemia, neutrophilia, hypercalcemia and thrombocytosis. Results: Among 1,769 1L SUN pts with clear cell in the RW clinical database, 318 (18%) had favorable, 1,031 (58%) had intermediate and 420 (24%) had poor IMDC risk. Across the favorable, intermediate, and poor risk groups, pts had similar mean age in years, gender distribution, and year of SUN initiation (age: 63.8, 62.9 and 62.6; male: 74%, 75%, and 72%; SUN initiation year of 2010-2013: all 71%). In the favorable risk group, 99% received nephrectomy vs 88% in intermediate and 66% in poor risk group. Median TTD was 15.0, 8.5, and 4.2 months (mos) in the favorable, intermediate, and poor risk groups, respectively, and was 7.1 mos in the combined intermediate/poor risk groups. Median OS was 52.1, 31.5, and 9.8 mos in the favorable, intermediate, and poor risk groups, respectively, and was 23.2 mos in the combined intermediate/poor risk groups. Conclusions: This real world study based on a contemporary cohort of 1L SUN mRCC pts found a median OS of 52 mos which sets a new benchmark for clear cell mRCC in the favorable risk group. OS in the intermediate and poor risk groups are similar to previous reports. This affects pt counselling and clinical trial design.
Safety and feasibility of nephrectomy after receipt of immune checkpoint inhibitors for renal cell carcinoma.
Authors: Singla Nirmish , Elias Roy , Ghandour Rashed , Freifeld Yuval N , Bowman Alex Isaac , Woldu Solomon L. , Gahan Jeffrey , Bagrodia Aditya , Brugarolas James , Hammers Hans J. , Margulis Vitaly
Published: March 2019

619

Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 98 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. One patient died of progressive disease > 3 months after surgery; one patient required thoracentesis and another required paracentesis of a sterile fluid collection in the hepatic resection bed. No complications were noted in the remaining 7 patients, none of whom required readmission. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, use of neoadjuvant ICI for selected patients may warrant attention.
Prognostic value of gain of chromosome 5q in localized renal cell carcinoma.
Authors: Lebacle Cedric Michel , Pooli Aydin , Rao Nagesh , Wood Erika Louise , Kroeger Nils , Liu Sandy , Faiena Izak , Chamie Karim , Belldegrun Arie S. , Shuch Brian , Drakaki Alexandra , Pantuck Allan J.
Published: March 2019

623

Background: While gain of chromosome 5q is a frequently seen cytogenetic abnormality noted to occur in patients with renal cell carcinoma (RCC), little is known about its prognostic significance. We investigated the association of gain of 5q with disease-free survival (DFS) in patients with localized (non-metastatic T1-2) RCC. Methods: All patients from UCLA with primary tumor stage T1-2 RCC who had tumor cytogenetic analysis on tumor specimen were included. Alterations in chromosome 5q was specifically reviewed in this study. Logistic regression analyses were used to assess association of gain of 5q with final histopathology, ISUP grading, and T-stage. Cox proportional hazard modeling and Kaplan-Meier analyses were used to assess the impact of gain of 5q on DFS. Recurrence was defined as any local recurrence or development of new metastasis. Results: A total of 676 patients were included in this study. Gain of 5q occurred in 108 (16%) patients and was more commonly seen in clear cell versus non-clear cell tumors (19% vs. 9%, p = .002). Gain of 5q was associated with low grade ISUP (1 or 2) of clear-cell RCC (p = 0.011). On survival analysis, there was a 67% decreased risk of RCC recurrence for patients with gain of 5q (HR = 0.33, p = 0.018). The 5- and 10-year risk of recurrence was 2% vs. 16% and 14% vs. 28% for patients with and without gain of 5q, respectively (p = 0.013). In multivariable Cox analysis, the gain of 5q was an independent prognostic factor (p = .026 with ISUP grade and p = .025 with T-stage). These findings were confirmed among clear-cell RCC subgroup. Conclusions: Gain of chromosome 5q is an independent prognostic factor associated with decreased risk of recurrence in patients with localized T1-2 renal cell carcinoma. Identifying patients with a gain of 5q will improve the stratification of the risk of recurrence, could allow to adapt the follow-up protocols and avoid adjuvant treatment.
Combination anti-angiogenic tyrosine kinase inhibition and anti-PD1 immunotherapy in metastatic renal cell carcinoma: A retrospective analysis of safety, tolerance, and clinical outcomes.
Authors: Laccetti Andrew L. , Economides Minas P. , Venkatesan Aradhana M. , Gao Jianjun , Jonasch Eric , Corn Paul Gettys , Zurita Amado J. , Tannir Nizar M. , Msaouel Pavlos , Shah Amishi Yogesh , Campbell Matthew T
Published: March 2019

630

Background: Emerging phase III data support combination antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) as front line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol experience and later line treatment with this therapeutic approach including tolerance, response and survival. Methods: We conducted a retrospective analysis of mRCC patients (pts) who received combination TKI-IO between 11/2015 and 05/2018 at MD Anderson Cancer Center. Chart review detailed baseline characteristics, TKI-IO treatment, toxicity and survival. An independent radiologist, blinded to pts history and clinical data, assessed radiographic response using RECIST v1.1. Results: 36 mRCC pts were identified for study inclusion: median (med) age 63.5 years, 72% clear cell histology, 53% intermediate risk (19% good, 28% poor) by IMDC, med metastatic sites 2, med prior therapies 2, previous TKI 94% and previous IO 47%. Combinations included nivolumab (nivo)-cabozantinib (15), nivo-low dose pazopanib(ldP) (13), nivo-axitinib (5), nivo-lenvatinib (2) and pembrolizumab-axitinib (1). Median time on TKI-IO was 5.6 months (m) (95% CI: 5.2 - 7.7). 56% of pts initiated TKI prior to IO addition at progression and 36% of pts initiated IO prior to TKI addition. ORR was 35% (29% PR and 6% CR); disease control rate was 78% (43% stable disease). With med follow-up of 8.0 m (95% CI: 6.4 – 9.4), med PFS was 7.7 m (95%CI: 5.8 - 9.5), med OS was not reached. Med PFS for pts receiving nivo-ldP was not reached. TKI-IO therapy was well tolerated with only 1 pt demonstrating grade 3 or 4 immune related toxicity (nephritis). 92% of pts experienced any grade of adverse events (ADE) with ADE of interest as follows: diarrhea (25%), hypothyroidism (17%), and pneumonitis (8%). Conclusions: To our knowledge, this is the first case series of off-label combinations of TKI-IO for mRCC. TKI-IO, particularly nivo-ldP, is safe, well tolerated and efficacious. Although further prospective research is essential, TKI-IO could be considered for select mRCC patients, particularly in the setting of TKI or IO refractory disease.