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Immunotherapy (IO)-based combinations used to treat metastatic clear cell renal cell carcinoma (ccRCC) include dual immune checkpoint inhibition with ipilimumab and nivolumab (IO/IO) and several combinations of vascular endothelial growth factor receptor-targeting tyrosine kinase inhibitors (TKIs) with an immune checkpoint inhibitor (TKI/IO). IO/IO and TKI/IO approaches have not been compared directly, and it is unknown whether patients who do not respond to first-line IO/IO can salvage long-term survival by receiving a second-line TKI. Progression-free survival after second-line therapy (PFS-2) evaluates the ability to be salvaged by second-line therapy. We retrospectively evaluated 173 patients treated with first-line IO/IO or TKI/IO for metastatic ccRCC at Memorial Sloan Kettering Cancer Center and report PFS-2, overall survival, and response to second line of therapy (ORR

Immune checkpoint inhibitor therapy improves survival in patients with metastatic renal cell carcinoma (RCC) but has not been studied well preoperatively in patients with localized disease undergoing nephrectomy. We conducted a single-center study to evaluate the safety and feasibility of neoadjuvant nivolumab in patients undergoing nephrectomy for localized RCC. Eligible patients had a20% risk of recurrence, as estimated by a preoperative nomogram. Patients received nivolumab every 2 wk for four treatments prior to surgery. The primary endpoints were feasibility, defined as completing at least three treatments without significant surgical delay, and safety, defined as the rate of surgical complications. Treatment effects were assessed by radiomics and immunohistochemistry. A total of 18 patients (11 men; median age 60 yr) with clear cell RCC were enrolled. All received at least one dose of nivolumab and proceeded to nephrectomy without delay; 16/18 patients completed all four doses. Two patients discontinued nivolumab for immune-related adverse events, and four had surgical complications as per the Clavien-Dindo classification. Integrated pathology plus radiomic analysis demonstrated an association between post-treatment immune infiltration and low entropy apparent diffusion coefficient on magnetic resonance imaging. Nivolumab prior to nephrectomy was safe and feasible, without significant surgical delays and with an expected rate of immune-related adverse events. PATIENT SUMMARY: We evaluated the outcomes for patients with localized kidney cancer who received immunotherapy prior to surgery to remove their kidney tumor. In a small group of patients who had cancer confined to the kidney, this approach appeared safe and feasible.

Background This study assessed whether antiangiogenic treatment may potentiate immune checkpoint blockade in patients with advanced renal cell carcinoma. Patients and Methods This was an open-label, two-part, multicenter study involving treatment-naive patients with advanced renal cell carcinoma. Part 1 consisted of a phase I dose escalation and expansion of pazopanib plus pembrolizumab (combination therapy). Cohorts A and B received pazopanib in combination with pembrolizumab, whereas Cohort C received pazopanib monotherapy for 9 weeks before receiving the combination therapy. Part 2 was planned as a randomized three-arm study but was not conducted. Results Overall, 42 patients were enrolled (10 each in Cohorts A and B, 22 in Cohort C). The maximum tolerated dose was not reached and the recommended phase II dose was not declared, as Cohort C was closed early because of safety concerns. The overall response rates were 60% and 20% in Cohorts A and B, respectively. In Cohort C, the overall response rates were 33%, 25%, and 0% in the combination therapy, pembrolizumab monotherapy, and pazopanib monotherapy groups, respectively. The median progression-free survival rates were 21.95 months and 41.40 months in Cohorts A and B, respectively. Grade 3 or 4 adverse events (AEs) were observed in 90% of patients in Cohorts A and B. In Cohort C, the frequencies of grade 3 or 4 AEs, serious adverse events, and AEs leading to dose reduction were typically high in the combination therapy group. Conclusions Despite preliminary signs of efficacy, significant hepatotoxicity was observed in Cohorts A and B. The sequential schedule of pazopanib followed by pazopanib plus pembrolizumab showed reduced hepatotoxicity; however, other safety issues emerged with this approach.

Background The worldwide COVID-19 public health pandemic has restructured clinical care of cancer patients throughout the world. The specific changes in the management of genitourinary (GU) cancers in different cancer centers due to COVID-19 are not known and some clinical scenarios remain controversial. We conducted an opinion survey to determine what changes in cancer treatment strategies are occurring due to the COVID-19 pandemic. Methods A 20-item online survey was sent on 05/25/20 to 170 expert GU medical oncologists from Europe and North America. The survey solicited responses to changes in GU cancer management in the setting of the COVID-19 pandemic. Data was collected and managed via a secure REDCap Database. Results Surveys were completed by 78 (45.8%) of 170 GU oncologists between 05/25/20 and 06/25/20. Clinical practice changes due to COVID-19 in at least one scenario were reported by 79.1% of responders, most pronounced in prostate cancer (71.8%) and least in urothelial cancer (23%). Preferences for change in management varied by country with 78% of US oncologists indicating a change in their practice (37/47), 57% for Canadian oncologists (4/7) and 79% in Europe (19/24). Conclusions This study suggests international practice changes are occurring in GU cancer care during the COVID-19 pandemic. The variability in practice changes between countries may reflect differences in COVID-19 case load during the timepoint of data collection. These results, based on expert opinion during this rapidly changing crisis, may inform the oncologic community regarding the effects of COVID-19 on genitourinary cancer care., Highlights: ∗ Genitourinary (GU) cancer management has been affected by COVID-19 around the world ∗ We present an expert opinion survey to define GU cancer care changes during COVID-19 ∗ Practice changes were reported by 79.1% of responders and differed between countries ∗ Consensus was noted in some areas while other clinical scenarios remain controversial, Genitourinary (GU) cancer management has been affected by COVID-19 around the world. We present an expert opinion survey to define GU cancer care changes during COVID-19. Practice changes were reported by 79.1% of responders and differed between countries. Consensus was noted in some areas while other clinical scenarios remain controversial.

In the preceding two decades, several milestones have been reached in the management of patients with metastatic renal cell carcinoma (mRCC), including the development of novel targeted agents paralleling an increased understanding of the molecular biology of this disease process. Recently, a renewed enthusiasm for immunotherapy in the form of immune checkpoint blockade has resulted in significant strides in the treatment of mRCC. Despite these advances, treatment remains challenging for clinicians, and only modest survival benefits are observed with current treatment paradigms. The risk-stratification tools and investigated predictive and prognostic biomarkers in patients with mRCC are detailed in this review.

Background One of the main challenges in the management of renal cell carcinoma (RCC) is risk-stratifying patients who present with metastatic disease. Tumor size is an important predictor of survival in the localized setting; however, this feature has not been explored fully in patients presenting with M1 RCC. Objective To assess the impact of tumor size on survival in patients with metastatic RCC who underwent cytoreductive nephrectomy (CN). Design, setting, and participants We queried the Memorial Sloan Kettering (MSK) nephrectomy database for patients who presented with M1 disease and underwent CN between 1989 and 2016 (n = 304). Primary tumor size was obtained from pathology reports. Data from the International Metastatic Database Consortium (IMDC) were used for validation purposes (n = 778). Outcome measurements and statistical analysis Overall survival (OS) estimates were computed using the Kaplan-Meier method. Cox regressions were used to test the association between tumor size and OS in univariate and multivariable analyses. Tumors ≤4 cm were compared with larger masses. Secondary analyses were performed to assess the robustness of these findings. Results and limitations Clear cell tumors ≤4 cm were significantly associated with improved OS in both the MSK (hazard ratio [HR]: 0.35, 0.17–0.72, p = 0.004) and IMDC (HR 0.54, 0.36–0.83, p = 0.004) cohorts. The association was observed even after adjusting for known prognostic factors (HR 0.40, 0.14–1.14, p = 0.09 and HR: 0.54, 0.33–0.90, p = 0.02 in the MSK and IMDC cohorts, respectively). Limitations of this study include the absence of patients who were considered poor surgical candidates as well as potential selection bias. Conclusions The primary tumor size ≤4 cm was independently associated with improved OS in patients with metastatic clear cell RCC who underwent CN. Additionally, the association between primary size and survival was found to be nonlinear. These findings suggest that there is a group of small metastatic RCCs that can convey a better overall prognosis. The potential role of primary tumor size when risk stratifying patients with M1 RCC should be explored further to determine its utility during clinical decision making. Patient summary We evaluated the impact of small tumor size on prognosis in patients with metastatic kidney cancer who undergo removal of the primary tumor. Very small masses (≤4 cm) were associated with better prognosis in patients with clear cell tumors.

Summary Background Obesity is associated with an increased risk of developing clear cell renal cell carcinoma (RCC) but, paradoxically, obesity is also associated with improved oncological outcomes in this cancer. Because the biological mechanisms underlying this paradoxical association are poorly understood, we aimed to identify transcriptomic differences in primary tumour and peritumoral adipose tissue between obese patients and those at a normal weight. Methods In this cohort study, we assessed data from five independent clinical cohorts of patients with clear cell RCC aged 18 years and older. Overweight patients were excluded from each cohort for our analysis. We assessed patients from the COMPARZ phase 3 clinical trial, a cohort from the Cancer Genome Atlas (TCGA), and a Memorial Sloan Kettering (MSK) observational immunotherapy cohort for their inclusion into our study. We assessed overall survival in obese patients (those with a body-mass index [BMI] ≥30 kg/m2) and in patients with a normal weight (BMI 18·5–24·9 kg/m2, as per WHO's BMI categories), defined as the time from treatment initiation (in the COMPARZ and MSK immunotherapy cohorts) or surgery (in the TCGA cohort) to the date of any-cause death or of censoring on the day of the last follow-up. We also evaluated and validated transcriptomic differences in the primary tumours of obese patients compared with those of a normal weight. We compared gene-expression differences in peritumoral adipose tissue and tumour tissue in an additional, prospectively collected cohort of patients with non-metastatic clear cell RCC (the MSK peritumoral adipose tissue cohort). We analysed differences in gene expression between obese patients and those at a normal weight in the COMPARZ, TCGA, and peritumoral adipose tissue cohorts. We also assessed the tumour immune microenvironment in a prospective cohort of patients who had nephrectomy for localised RCC at MSK. Findings Of the 453 patients in the COMPARZ trial, 375 (83%) patients had available microarray data, pretreatment BMI measurements, and overall survival data for analyses, and we excluded 119 (26%) overweight patients, leaving a final cohort of 256 (68%) patients from this study for our analyses. From 332 patients in the TCGA cohort, we evaluated clinical and demographic data from 152 (46%) patients with advanced (ie, stages III and IV) clear cell RCC treated by nephrectomy; after exclusion of 59 (39%) overweight patients, our final cohort consisted of 93 (61%) patients. After exclusion of 74 (36%) overweight patients from the initial MSK immunotherapy study population of 203 participants, our final cohort for overall survival analysis comprised 129 (64%) participants. We found that overall survival was longer in obese patients than in those with normal weight in the TCGA cohort, after adjustment for stage or grade (adjusted HR 0·41, 95% CI 0·22–0·75), and in the COMPARZ clinical trial after adjustment for International Metastatic RCC Database (IMDC) risk score (0·68, 0·48–0·96). In the MSK immunotherapy cohort, the inverse association of BMI with mortality (HR 0·54, 95% CI 0·31–0·95) was not significant after adjustment for IMDC risk score (adjusted HR 0·72, 95% CI 0·40–1·30). Tumours of obese patients showed higher angiogenic scores on gene-set enrichment analysis-derived hallmark gene set angiogenesis signatures than did those of patients at a normal weight, but the degree of immune cell infiltration did not differ by BMI. We found increased peritumoral adipose tissue inflammation in obese patients relative to those at a normal weight, especially in peritumoral fat near the tumour. Interpretation We found aspects of the tumour microenvironment that vary by BMI in the tumour and peritumoral adipose tissue, which might contribute to the apparent survival advantage in obese patients with clear cell RCC compared with patients at a normal weight. The complex interplay between the clear cell RCC tumour and peritumoral adipose tissue microenvironment might have clinical relevance and warrants further investigation. Funding Ruth L Kirschstein Research Service Award, American Society of Clinical Oncology Young Investigator Award, MSK's Ludwig Center, Weiss Family Kidney Research Fund, Novartis, The Sidney Kimmel Center for Prostate and Urologic Cancers, and the National Institutes of Health (National Cancer Institute) Cancer Center Support Grant.

Background Mutations in the promoter region of the TERT gene have been detected in a variety of cancers. These mutations can potentially lead to unlimited cell divisions and result in poor clinical prognosis. Objective To determine the role and relevance of TERT promoter region mutations in both clear cell (ccRCC) and non–clear cell (nccRCC) renal cell carcinoma using ultra-deep and whole-genome sequencing methods on primary tumor samples. Design, setting, and participants DNA from 281 kidney tumors (147 ccRCC and 134 nccRCC) was sequenced between 2013 and 2015, and clinical outcomes for these patients from a single institution were retrospectively analyzed. Outcome measurements and statistical analysis Differences in patient characteristics and mutational status were tested using Fisher's exact test for categorical variables and the Wilcoxon rank sum test for continuous variables. Survival times were estimated using the Kaplan-Meier method and differences were tested using the log-rank test. Results and limitations TERT mutations occurred in 12.2% of ccRCC and 10.4% of nccRCC cases. In >80% of the cases, mutations were located at C228T and were found to co-occur only rarely with other relevant RCC driver genes. The median follow-up among survivors overall was 2.5 yr (range 0.1–18.3). TERT promoter mutations were significantly associated with cancer-specific survival in ccRCC (hazard ratio 2.68, 95% confidence interval 1.19–6.01; p =0.013). In nccRCC, TERT mutations were significantly associated with larger tumors and metastatic development. Assessment of further relevant clinical associations was precluded in the nccRCC group by the heterogeneous and small sample size. Conclusions Our data suggests that TERT mutational status reflects a distinct pathogenesis with an aggressive disease course in RCC. Stratifying patients with this unique tumorigenesis that leads to poor clinical outcomes could be a putative target for novel therapeutics. Patient summary We show a previously unrecognized frequency of TERT promoter mutations in both clear cell and non–clear cell renal cell carcinoma. TERT promoter mutations were associated with some worse outcomes in patients with clear cell renal cell carcinoma.

Background Immune checkpoint inhibitors (ICIs) are being increasingly utilised in the front-line (1L) setting of metastatic clear-cell renal cell carcinoma (mccRCC). Limited data exist on responses and survival on second-line (2L) vascular endothelial growth factor–receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy after 1L ICI therapy. Patients and 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 Response Evaluation Criteria in Solid Tumours v1.1. Descriptive statistics and Kaplan–Meier method were used. Results Seventy patients were included in the analysis. Median age at mccRCC diagnosis was 59 years; 8 patients (11%) had international metastatic database consortium favourable-risk disease, 48 (69%) had intermediate-risk disease and 14 (20%) had poor-risk disease. As 1L therapy, 12 patients (17%) received anti–programmed death ligand-1 (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 response, 27 patients (39.7%) a partial response and 36 patients (52.9%) stable disease. Median progression-free survival (mPFS) was 13.2 months (95% confidence interval: 10.1, NA). Forty-five percent of subjects required a dose reduction, and twenty-seven percent of patients discontinued treatment because of toxicity. Conclusions In this retrospective study of patients with mccRCC receiving 2L TKI monotherapy after 1L ICI, we observed 2L antitumour activity and tolerance comparable to historical data for 1L TKI.

Introduction Small renal masses (SRMs) with evidence of clear cell renal cell carcinoma (ccRCC) are understudied. Current algorithms for the management of SRMs include surgical resection, ablation, and active surveillance. We sought to identify genomic biomarkers that could potentially refine the management of ccRCC in SRMs, especially in patients being evaluated for active surveillance. Methods We identified patients who had SRMs (4 cm or less) at time of surgery, had sequencing performed on their primary tumor and had a diagnosis of ccRCC. Patients were selected from 3 publicly available cohorts, The Cancer Genome Atlas ( n = 110), University of Tokyo ( n = 37), The International Cancer Genome Consortium ( n = 31), and from our own institutional prospective database ( n = 25). Among this cohort we analyzed mutations present in at least 5% of tumors, assessing for the enrichment of mutations and progression-free survival using the composite endpoint of recurrence or death of disease. Analysis was adjusted for multiple testing. A Cox regression model was used to assess clinical variables with significant mutations. Results In total, 203 patients were available for analysis. Median follow-up was 43.1 months among survivors. Mutations in VHL, PBRM1, SETD2, BAP1, KDM5C , and MTOR were present in more than 5% of tumors. Twenty-three patients (11.3%) had recurrence or died of their disease. Mutations in KDM5C were associated with inferior survival from either recurrence or death from disease, adjusted P 0.033. Conclusions We identified mutations in SRMs in ccRCC that are associated with recurrence and lethality. The strongest association was seen in those with KDM5C mutations. Use of these genomic biomarkers may improve stratification of patients with SRMs and for those who may be appropriate for active surveillance. Prospective evaluation of these markers is needed.

Background Next-generation sequencing (NGS) studies of matched pairs of primary and metastatic tumors in renal cell carcinoma (RCC) have been limited to small cohorts. Objective To evaluate the discordance in somatic mutations between matched primary and metastatic RCC tumors. Design, setting, and participants Primary tumor (P), metastasis (M), and germline DNA from 60 patients with RCC was subjected to NGS with a targeted exon capture–based assay of 341 cancer-associated genes. Somatic mutations were called using a validated pipeline. Outcome measurements and statistical analysis Mutations were classified as shared (S) or private (Pr) in relation to each other within individual P-M pairs. The concordance score was calculated as (S−Pr)/(S+Pr). To calculate enrichment of Pr/S mutations for a particular gene, we calculated a two-sided p value from a binomial model for each gene with at least ten somatic mutation events, and also implemented a separate permutation test procedure. We adjusted p values for multiple hypothesis testing using the Benjamini-Hochberg procedure. The mutation discordance was calculated using Mann-Whitney U tests according to gene mutations or metastatic sites. Results and limitations Twenty-one pairs (35%) showed Pr mutations in both P and M samples. Of the remaining 39 pairs (65%), 14 (23%) had Pr mutations specific to P samples, 12 (20%) had Pr mutations to M samples, and 13 (22%) had identical somatic mutations. No individual gene mutation was preferentially enriched in either P or M samples. P-M pairs with SETD2 mutations demonstrated higher discordance than pairs with wild-type SETD2 . We observed that patients who received therapy before sampling of the P or M tissue had higher concordance of mutations for P-M pairs than patients who did not (Mann-Whitney p =0.088). Conclusions Our data show mutation discordance within matched P-M RCC tumor pairs. As most contemporary precision medicine trials do not differentiate mutations detected in P and M tumors, the prognostic and predictive value of mutations in P versus M tumors warrants further investigation. Patient summary In this study we evaluated the concordance of mutations between matched primary and metastatic tumors for 60 kidney cancer patients using a panel of 341 cancer genes. Forty-seven patients carried nonidentical cancer gene mutations within their matched primary-metastatic pair. The mutation profile of the primary tumor alone could compromise precision in selecting effective targeted therapies and result in suboptimal clinical outcomes.

Background Parallel development of preclinical models that recapitulate treatment response observed in patients is central to the advancement of personalized medicine. Objective To evaluate the use of biopsy specimens to develop patient-derived xenografts and the use of corresponding cell lines from renal cell carcinoma (RCC) tumors for the assessment of histopathology, genomics, and treatment response. Design, setting, and participants A total of 74 tumor specimens from 66 patients with RCC were implanted into immunocompromised NOD- SCID IL2Rg −/− mice. Four cell lines generated from patients' specimens with clear cell pathology were used for comparative studies. Outcome measurements and statistical analysis Preclinical models were established and assessed. Engraftment rates were analyzed using chi-square testing. Analysis of variance (two-way analysis of variance) was conducted to assess tumor growth. Results and limitations Overall, 33 RCC mouse xenograft models were generated with an overall engraftment rate of 45% (33 of 74). Tumor biopsies engrafted comparably with surgically resected tumors (58% vs 41%; p =0.3). Xenograft tumors and their original tumors showed high fidelity in regard to histology, mutation status, copy number change, and targeted therapy response. Engraftment rates from metastatic tumors were higher but not more significant than primary tumors (54% vs 34%; p =0.091). Our engraftment rate using metastases or biopsies was comparable with recent reports using resected primary tumors. In stark contrast to corresponding cell lines, all tested xenografts recapitulated patients' clinical response to sunitinib. Conclusions Patient-derived xenograft models can be effectively established from tumor biopsies. Preclinical xenograft models but not matched cell lines reflected clinical responses to sunitinib. Patient summary Matched patient-derived clear cell renal cell carcinoma xenografts and cell lines from responsive and refractory patients treated with sunitinib were established and evaluated for pharmacologic response to anti–vascular endothelial growth factor treatment. Both models accurately reflected the genetic characteristics of original tumors, but only xenografts recapitulated drug responses observed in patients. These models could serve as a powerful platform for precision medicine.

Background Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. Patients and Methods This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next-generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan–Meier method. Results The median age in the cohort was 28 (range, 12-72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1-10.9) and for 12 patients who received platinum-based therapy, median progression-free survival was 2.5 months (95% CI, 1.2-not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next-generation targeted sequencing showed no recurring mutations. Conclusions Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

Background Analyses of associations between clinicopathologic outcomes and recurrent somatic mutations in clear cell renal cell carcinoma (ccRCC) have been limited to individual cohorts. Objective To define clinicopathologic associations between specific mutations and ccRCC disease characteristics. Design, setting, and participants DNA sequencing data were pooled from three collaborative genomic cohorts ( n =754) and our institutional database ( n =295). All patients had clinical data and identification of somatic mutations from their primary tumors. Outcome measurements and statistical analysis Analysis of gene mutations for associations with maximal tumor size (linear regression) and pathologic stage (logistic regression). Cancer-specific survival (CSS) and recurrence-free survival (RFS) were calculated using competing risks methods. Analyses were adjusted for cohort site, and results were adjusted for multiple testing ( q value). Relevant genes were used in multivariable models that included confounding variables and the validated Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score. Results and limitations Association with tumor size was found for mutations in BAP1 ( q =0.013). No mutations were found to be associated with stage after adjusted analysis. Mutations in BAP1 ( q =0.004) and TP53 ( q =0.001) were associated with decreased CSS in a multivariable model; only TP53 ( q =0.005) remained significant when SSIGN score was included. SETD2 mutations ( q =0.047) were associated with decreased RFS in multivariable models, including models with SSIGN score. Conclusions In >1000 patients with ccRCC, pooled analysis and multivariable modeling demonstrated that three mutated genes have statistically significant associations with poor clinical outcomes. This included the more commonly mutated BAP1 and SETD2 and the less frequently mutated TP53 . After adjustment for clinical confounders, mutations of TP53 and SETD2 were associated with decreased CSS and RFS, respectively. Patient summary Using rigorous statistical methods, this study affirmed that certain mutations in clear cell renal cell carcinoma may portend inferior survival and an increased risk of recurrence.

Background Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. Objective To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participants Targeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysis Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitations Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1 , BAP1 , and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. Conclusions PBRM1 , BAP1 , and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summary Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Bevacizumab has shown benefit in the first-line setting in combination with interferon; however, data on use as monotherapy are limited. In this retrospective analysis of 71 patients we assessed the efficacy of bevacizumab monotherapy in patients whose disease progressed during treatment with other targeted drugs. Bevacizumab monotherapy resulted in prolonged disease control and few discontinuations for adverse events, including for patients who were heavily pretreated.Bevacizumab has shown benefit in the first-line treatment of metastatic clear cell renal cell carcinoma (ccRCC) in combination with interferon α. In this retrospective analysis we assessed the efficacy of bevacizumab monotherapy in patients whose disease progressed during treatment with vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors, and/or mammalian target of rapamycin inhibitors.A retrospective analysis was performed on metastatic ccRCC patients who received bevacizumab monotherapy after their disease progressed during treatment with previous targeted therapies. The primary objective was to assess overall survival (OS) and the secondary objectives includes progression-free survival (PFS), therapy duration, and incidence of serious adverse events assessed during visits to the Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center.Seventy-one patients were treated with bevacizumab as monotherapy in the salvage setting. Most patients were heavily pretreated with 36 patients (51%) who received bevacizumab as a fourth-line or later agent, and 33 patients (46%) who received at least 2 previous VEGF targeted agents. Eighteen patients (25%) had a Karnofsky Performance Status (KPS)80%, and 20 patients (28%) were classified as poor risk according to MSKCC criteria. Median OS was 11.5 months (95% confidence interval [CI], 6.4-17.4), and median PFS was 1.9 months (95% CI, 1.7-4.1). Nine patients (13%) had a prolonged time of therapy of12 months. Four patients (6%) discontinued therapy because of adverse events. Poor KPS (80%) and MSKCC poor-risk classification were prognostic for poor OS with hazard ratios of 4.09 (P.001) and 2.84 (P = .021), respectively.Bevacizumab monotherapy resulted in prolonged disease control and few discontinuations because of adverse events in patients whose disease had progressed during treatment with other targeted therapies, including patients who were heavily pretreated.

Better understanding of the molecular biology of renal cell carcinoma (RCC) has led to the development of several targeted anti-cancer agents, several of which have since received approval for treatment of advanced disease. Two of these, the intravenous agent temsirolimus and the oral everolimus, exhibit antitumor effects through inhibition of the mammalian target of rapamycin (mTOR) pathway. This article reviews their mechanisms of action in the context of the current understanding of RCC pathophysiology, the clinical data leading to their approval, class-specific toxicities, potential molecular mechanisms behind treatment resistance and novel treatment approaches for RCC that incorporate mTOR blockade.

Combination immune checkpoint blockade has demonstrated promising benefit in lung cancer, but predictors of response to combination therapy are unknown. Using whole-exome sequencing to examine non-small-cell lung cancer (NSCLC) treated with PD-1 plus CTLA-4 blockade, we found that high tumor mutation burden (TMB) predicted improved objective response, durable benefit, and progression-free survival. TMB was independent of PD-L1 expression and the strongest feature associated with efficacy in multivariable analysis. The low response rate in TMB low NSCLCs demonstrates that combination immunotherapy does not overcome the negative predictive impact of low TMB. This study demonstrates the association between TMB and benefit to combination immunotherapy in NSCLC. TMB should be incorporated in future trials examining PD-(L)1 with CTLA-4 blockade in NSCLC.

Purpose To establish prognostic genomic biomarkers for patients with metastatic clear cell renal cell carcinoma (ccRCC). Materials and methods We identified 60 patients who presented with metastatic ccRCC at our institution between 2001 and 2015 and had genomic sequencing on their primary tumor. We pooled these patients with 107 other patients with the same inclusion criteria from three well-known public databases. Five commonly mutated genes were chosen for analysis: VHL , PBRM1 , BAP1 , SETD2 , and KDM5C . Overall survival (OS) was estimated using the Kaplan-Meier method and the log-rank test was used for comparisons between groups. Results Median OS in the cohort was 2.5 years. Higher Fuhrman grade was associated with decreased median OS ( P SETD2 ( P = 0.027) and KDM5C ( P = 0.019) were associated with reduced risk of death (hazard ratio [HR] = 0.58 [95% CI: 0.35–0.94] and HR = 0.43 [95% CI: 0.22–0.85], respectively). BAP1 mutations ( P = 0.008) were associated with increased risk of death (HR = 1.81 [95% CI: 1.16–2.83]). There were significantly more female patients with a BAP1 mutation than females in the overall cohort ( P = 0.001). Conclusions Mutations in BAP1 negatively affected OS, whereas SETD2 and KDM5C mutations were associated with prolonged OS in our pooled cohort of 167 patients with metastatic ccRCC. Our results expand upon efforts at understanding genomic biomarkers in localized disease. Those efforts set the stage for our novel investigation examining associations of select recurrent somatic mutations in stage IV patients with ccRCC.

Most reports of allergy to fish describe systemic symptoms upon ingestion of fish muscle or contact urticaria in commercial fish handlers. We report three recreational fishermen with symptoms of asthma, angioedema, rhinitis and urticaria upon exposure to surface mucin from bluegills (Lepomis machrochirus) . All three had symptoms upon handling bluegills. Subsequently, two of them experienced wheezing and/or angioedema while in proximity to contaminated fishing clothing. One of them later developed symptoms upon eating bluegills. Prick skin testing was positive to crude bluegill surface mucin in all three individuals and to bluegill and cod muscle in one. Bluegill surface mucin was defatted in ether and acetone and extracted in phosphate buffered saline. Sodium dodecyl-polyacrylamide gel electrophoresis (SDS–PAGE) showed at least 20 distinct protein bands by Coomassie Blue staining. Many of these were glycoproteins by periodic acid schiff (PAS) staining. Immunoblotting showed at least seven IgE binding protein bands with molecular weights between 10 and 100 kDa. Radioallergosorbent (RAST) assay using a bluegill surface-mucin solid phase demonstrated that serum IgE binding in the three individuals was 4–25 times that of pooled serum from nonatopic controls. IgE binding using a serum pool from the three allergic patients was inhibited by extracts of bluegill mucin and muscle and cod muscle but not by tuna, crab or peanut. Our results demonstrate that bluegill surface mucin contains specific glycoproteins which bind IgE in sensitive individuals. Hypersensitivity to these surface proteins may cause systemic allergic symptoms.

Aim: Carboplatin and paclitaxel are mainstays of treatment for metastatic solid tumors, and the PI3K/mTOR pathway is one of the most commonly dysregulated in cancers. The combination of PI3K inhibition and platinum-based chemotherapy may enhance anti-cancer effect. Methods: Patients with metastatic solid tumors were treated with two regimens: Group 1 received carboplatin AUC 5 and paclitaxel 175mg/m2, on day 1 of a 21 day cycle with pegfilgrastim support; Group 2 received carboplatin AUC 5 (day 1) and paclitaxel 80mg/m2 (days 1, 8 and 15) on a 28-day cycle without growth factor support. In both groups, the pan-PI3K inhibitor buparlisib (BKM120) was administered daily with dose escalation of 50, 80 or 100mg/day, with optional continuation of BKM120 until progression, after cessation of chemotherapy following Cycle 6. The primary endpoint was Recommended Phase II Dose (RP2D). Results: Between 5 Apr 2011 and 28 Jan 2013, 30 subjects were enrolled. Median age was 53 (range 23-71). The most common tumor types were non-small cell lung cancer (N = 5) and ovarian cancer (N = 5). 16 patients were treated in Group 1 and 14 in Group 2. The median number of cycles was 4.5 (Group 1) or 6 (Group 2). Dose reductions and treatment delays during all cycles were more common in Group 2. The most common adverse events (AE) of any grade in Group 1 were fatigue, hyperglycemia, alopecia, arthralgias, alkaline phosphatase elevation and thrombocytopenia. In Group 2, the most common AEs were hyperglycemia, leucopenia, neutropenia, thrombocytopenia, fatigue and alopecia. The DLTs were elevated alkaline phosphatase (N = 1) and uncomplicated neutropenia (N = 2). The MTD for BKM120 was 100mg/d in Group 1 and 80mg/day in Group 2. Among 25 patients with measurable disease, the objective response rate was 28% (1CR, 4 PR, 2uPR). 5 patients with evaluable disease (not measurable by RECIST) experienced clinical benefit (clinical stability with no new radiographic lesions) for ≥ 10 cycles. Correlative studies in process include analysis of PIK3CA mutation status and PTEN expression status in pre-treatment tumor samples, and pharmacokinetic analysis of BKM120. Conclusions: BKM120 at 100 mg/d + carboplatin AUC 5 + paclitaxel 175mg/m2, both on day 1 of a 21 day cycle with growth factor support, is a well-tolerated regimen with promising activity in advanced solid tumors. Disclosure: M. Fury: MGF has served on an advisory board for Novartis within the last 12 months. All other authors have declared no conflicts of interest.

Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has shown durable responses and encouraging overall survival (OS) data in mRCC. IPI, a fully human monoclonal antibody to CTLA-4, improved OS in melanoma and has antitumor activity in mRCC. The combination of these agents showed encouraging antitumor activity and an acceptable safety profile in advanced melanoma. We report preliminary results of this combination in mRCC. Methods: Patients (pts) with mRCC were randomized to nivolumab 3 mg/kg + IPI 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + IPI 3 mg/kg (N1 + I3) IV every 3 wk for 4 doses then nivolumab 3 mg/kg IV every 2 wk until progression/toxicity (protocol-defined post-progression treatment allowed). The primary objective was to assess safety; secondary objective was to assess efficacy (RECIST 1.1). Results: 21 and 23 pts were randomized to the N3 + I1 and N1 + I3 arms, respectively. Most pts (n = 35; 80%) had prior systemic therapy (N3 + I1: 17; N1 + I3: 18). Treatment-related adverse events (AEs) were seen in 39 pts (89%); 8 pts (18%; N3 + I1: 2; N1 + I3: 6) discontinued due to related AEs. Grade 3-4-related AEs occurred in 20 pts (46%; N3 + I1: 6; N1 + I3: 14), most commonly ↑ lipase (21%, n = 9), ↑ ALT (14%, n = 6), diarrhea (9%, n = 4), and ↑ AST (7%, n = 3). No grade 3-4 pneumonitis was seen. Objective response rate (ORR) was 43% (N3 + I1) and 48% (N1 + I3); median duration of response (DOR) was 31.1 wk (7 ongoing) in N3 + I1 and not reached (9 ongoing) in N1 + I3 (Table). Responses occurred by first tumor assessment (wk 6) in 44% of pts in the N3 + I1 arm and 55% of pts in the N1 + I3 arm. Stable disease (SD) as best overall response was seen in 5 (24%) (N3 + I1) and 8 (35%) (N1 + I3) pts. Arm N3 + I1 n = 21 Arm N1 + I3 n = 23 ORR, n (%) 9 (43) 11 (48) SD, n (%) 5 (24) 8 (35) DOR, range (wk) 4.1+ - 42.1+ 12.1+ - 35.1 + Median progression-free survival, wk (95% CI) 36.6 (6.0, ) 38.3 (18.3, ) CI, confidence interval Conclusions: Nivolumab + IPI showed acceptable safety and encouraging antitumor activity in mRCC, with most responses ongoing. Studies are ongoing to explore this combination in a Phase III trial. Disclosure: H. Hammers: Has received Honoraria from Ono Pharma USA; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: I have worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BM.; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb. I have received Honoraria from: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Aim: Antiangiogenic agents S and P are standard of care in mRCC, but effects are not durable. N, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has clinical activity in mRCC. VEGF TKIs have been shown to suppress Tregs and MDSCs making the immune environment more conducive for T cell-mediated antitumor activity. Combining VEGF TKIs with positive immune modulation may result in greater and more durable therapeutic benefit. We report preliminary results of a phase I trial of N in combination with S or P in mRCC. Methods: mRCC pts received N in combination with S (50 mg, 4 wk on/2 wk off; arm S) or P (800 mg daily; arm P) until progression/unacceptable toxicity. Starting dose of N was 2 mg/kg IV every 3 wk (N2), with planned escalation to 5 mg/kg IV every 3 wk (N5). Based on tolerability, arm S N5 was expanded to treatment-naive pts. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD) for the combinations; secondary objective was antitumor activity. Results: 7 pts each were treated on arms S N2 and N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached; thus N5 was expanded by 19 pts (total n = 33). Arm P had 20 pts at N2; 4 DLTs (elevated ALT/AST [n = 3], fatigue [n = 1]) were observed, leading to closure of the arm. Grade 3-4-related adverse events (AEs) were observed in 27/33 pts (82%) in arm S and 14/20 pts (70%) in arm P. Most common related grade 3-4 AEs were elevated ALT and hypertension (18% each), hyponatremia and lymphocyte count decreased (15% each) in arm S, and elevated ALT and AST, and diarrhea (20% each) and fatigue (15%) in arm P. Grade 3 pneumonitis occurred in 1 pt (arm S, N5). Grade 3-4-related AEs led to discontinuation in 10/33 pts (30%; 2 N2, 8 N5) in arm S and 4/20 pts (20%) in arm P. Objective response rate was 52% (17/33) in arm S and 45% (9/20) in arm P. Responses occurred by first assessment (6 wk) in 41% (arm S) and 56% (arm P) of pts. Duration of response (wk) was 18.1-80+ in arm S and 12.1-90.1+ in arm P. Progression-free survival rate at 24 wk was 79% for arm S and 55% for arm P. Conclusions: N plus S showed encouraging antitumor activity and a manageable safety profile in pts with mRCC. Arm P was closed due to DLTs. Disclosure: A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb I have received Honoraria from: Bristol Myers Squibb; E.R. Plimack: I have received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: Has worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; H. Hammers: Has received Honoraria from Ono Pharma USA. All other authors have declared no conflicts of interest.

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.