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Introduction: Biomarkers are needed to identify patients with metastatic renal cell carcinoma (mRCC) most likely to benefit from immune checkpoint inhibitors. We examined associations between radiographically assessed body composition (BC) variables and body mass index (BMI) with clinical outcomes for patients with mRCC receiving first-line ipilimumab + nivolumab (ipi/nivo)., Patients and Methods: We retrospectively reviewed all patients with mRCC treated with first-line ipi/nivo at one institution before June 1, 2021 with an analyzable baseline computed tomography (CT) scan. BC variables (skeletal muscle index [SMI], subcutaneous adipose tissue index [SATI], and visceral adipose tissue index [VATI]) were measured using baseline CT scans. Relationships between BC variables and clinical outcomes were examined using Cox proportional hazard regression models., Results: Ninety-nine patients were analyzed (74% male, 64% overweight/obese, 75% low SMI). Controlling for age, IMDC risk, and sex (for BMI analyses), high vs. low SMI (HR=2.433, CI: 1.397-4.238, P=.0017), high vs. low SATI (HR=1.641, CI: 1.023-2.632, P=.0398), and obese BMI (≥ 30 kg/m 2 ) vs. normal/overweight BMI (<30 kg/m 2 ) (HR=1.859, CI: 1.156-2.989, P=.0105) were significantly associated with progression-free survival (PFS). Median overall survival (OS) for low SMI patients was higher (42.74 months, CI: 26.84, NR) than median OS for high SMI patients (27.01 months, CI: 15.28, NR) (adjusted HR=1.728, CI: 0.909-3.285, P=.0952). No BC variables were significantly associated with OS or objective response rate., Conclusions: Low SMI and low SATI were associated with significantly better PFS for patients with mRCC receiving first-line ipi/nivo. Radiographic BC variables may be useful prognostic biomarkers in this setting., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Multigene assays can provide insight into key biological processes and prognostic information to guide development and selection of adjuvant cancer therapy. We report a comprehensive genomic and transcriptomic analysis of tumor samples from 171 patients at high risk for recurrent renal cell carcinoma post nephrectomy from the S-TRAC trial (NCT00375674). We identify gene expression signatures, including STRAC11 (derived from the sunitinib-treated population). The overlap in key elements captured in these gene expression signatures, which include genes representative of the tumor stroma microenvironment, regulatory T cell, and myeloid cells, suggests they are likely to be both prognostic and predictive of the anti-angiogenic effect in the adjuvant setting. These signatures also point to the identification of potential therapeutic targets for development in adjuvant renal cell carcinoma, such as MERTK and TDO2. Finally, our findings suggest that while anti-angiogenic adjuvant therapy might be important, it may not be sufficient to prevent recurrence and that other factors such as immune response and tumor environment may be of greater importance., (© 2022. The Author(s).)

Background: Immunotherapy combinations including ipilimumab and nivolumab are now the standard of care for untreated metastatic renal cell carcinoma (mRCC). Biomarkers of response are lacking to predict patients who will have a favorable or unfavorable response to immunotherapy. This study aimed to use the OmniSeq transcriptome-based platform to develop biomarkers of response to immunotherapy., Methods: Two cohorts of patients were retrospectively collected. These included an investigational cohort of patients with mRCC treated with immune checkpoint inhibitor therapy from five institutions, and a subsequent validation cohort of patients with mRCC treated with combination ipilimumab and nivolumab from two institutions (Duke Cancer Institute and Cleveland Clinic Taussig Cancer Center). Tissue-based RNA sequencing was performed using the OmniSeq Immune Report Card on banked specimens to identify gene signatures and immune checkpoints associated with differential clinical outcomes. A 5-gene expression panel was developed based on the investigational cohort and was subsequently evaluated in the validation cohort. Clinical outcomes including progression-free survival (PFS) and overall survival (OS) were extracted by retrospective chart review. Objective response rate (ORR) was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1., Results: The initial investigation cohort identified 86 patients with mRCC who received nivolumab (80%, 69/86), ipilimumab/nivolumab (14%, 12/86), or pembrolizumab (6%, 5/86). A gene expression score was created using the top five genes found in responders versus non-responders (FOXP3, CCR4, KLRK1, ITK, TIGIT). The ORR in patients with high gene expression (GE high ) on the 5-gene panel was 29% (14/48), compared with low gene expression (GE low ) 3% (1/38, χ 2 p=0.001). The validation cohort was comprised of 62 patients who received ipilimumab/nivolumab. There was no difference between GE high and GE low in terms of ORR (44% vs 38.5%), PFS (HR 1.5, 95% CI 0.58 to 3.89), or OS (HR 0.96, 95% CI 0.51 to 1.83). Similarly, no differences in ORR, PFS or OS were observed when patients were stratified by tumor mutational burden (high=top 20%), PD-L1 (programmed death-ligand 1) expression by immunohistochemistry or RNA expression, or CTLA-4 (cytotoxic T-lymphocytes-associated protein 4) RNA expression. The International Metastatic RCC Database Consortium (IMDC) risk score was prognostic for OS but not PFS., Conclusion: A 5-gene panel that was associated with improved ORR in a predominantly nivolumab monotherapy population of patients with mRCC was not predictive for radiographic response, PFS, or OS among patients with mRCC treated with ipilimumab and nivolumab., Competing Interests: Competing interests: LCB declares the following relationships: Consulting with Seattle Genetics. JZ declares the following relationships: Consulting with Tempus. KD declares the following relationship: Consulting with Tyra BioSciences. EK declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. CK declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. YHL is/was an employee at OmniSeq. SP is/was an employee at OmniSeq. MKL declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. JT declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. KHD declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. LJT declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. FD declares that he has received research grants (to the institution) from AstraZeneca, Bristol Myers Squibb, Merck, Genentech/Roche, Taiho, Exelixis, Trishula, Leap Therapeutics, has received a speaker honorarium from Amgen, Eisai, Ipsen, Exelixis, Sirtex, Deciphera, Ipsen, Natera, and has received a consultancy honorarium from Natera, QED, Eisai, Exelixis, Genentech/Roche. RTG declares the following relationships: Bayer Pharma AG—consultant & speakers bureau, Invivo—consultant, Bard—consultant, DxTx Medical—consultant, Quibim—consultant, Bracco Diagnostics—consultant. SM declares the following relationships: AstraZeneca—consultant; Takeda Pharmaceuticals—speaker, honorarium. DJG declares the following relationships: Acerta Pharmaceuticals—research; American Association for Cancer Research—senior editor; Astellas—consultant, research, advisory board; AstraZeneca—consultant, advisory board; Axess Oncology—independent contractor; Bayer H/C Pharmaceuticals—research, consultant, speaker, honorarium, travel accommodations; SC, BMS—consultant, research, steering committee; Calithera—research; Capio Biosciences—scientific advisory board; EMD Serono—honorarium; Exelixis—research, consultant, speaker, honorarium, travel accommodations; Flatiron—consultant; Ipsen—honorarium; Janssen Pharmaceuticals—research, consultant, Independent Data Monitoring Committee; Leidos Biomedical Research—consultant; Merck Sharp & Dohme—consultant; Michael J Hennessey Associates—honorarium, consultant; Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—co-editor-in-chief; Modra Pharmaceuticals B.V.—advisory board; Myovant Sciences—consultant; Nektar Therapeutics—steering committee; Novartis—research; Physician Education Resource LLC—consultant; Pfizer—research, consultant, steering committee, honorarium; Sanofi—research, consultant, speaker, honorarium, travel accommodations; UroGPO—honorarium; UroToday—honorarium, travel accommodations; Vizuri Health Sciences, LLC—consultant; NCI—steering committee. YHL is/was an employee at OmniSeq. STG is/was an employee at OmniSeq. MKN is/was an employee at OmniSeq. SG declares the following relationships: Aveo—advisory board, personal, advisor/consultant; Bayer—advisory board, personal, advisor/consultant; BMS—advisory board, personal, advisor/consultant; Corvus—advisory board, personal, advisor/consultant; Eisai—advisory board, personal, advisor/consultant; EMD Serono—advisory board, personal, advisor/consultant; Exelixis—advisory board, personal, advisor/consultant; Merck—advisory board, personal, advisor/consultant; Pfizer—advisory board, personal, advisor/consultant; QED Therapeutics—advisory board, personal, advisor/consultant; Sanofi/Genzyme—advisory board, personal, advisor/consultant; Seattle Genetics—advisory board, personal, advisor/consultant; Agensys—local PI, institutional, no financial interest; Aravive—local PI, institutional, no financial interest; Aveo—local PI, institutional, no financial interest; Bayer—local PI, institutional, no financial interest; BMS—local PI, institutional, no financial interest; Calithera—local PI, institutional, no financial interest; Corvus—local PI, institutional, no financial interest; Eisai—local PI, institutional, no financial interest; Exelixis—local PI, institutional, no financial interest; Gilead—local PI, institutional, no financial interest; Merck—local PI, institutional, no financial interest; Novartis—local PI, institutional, no financial interest; Pfizer—local PI, institutional, no financial interest; Seattle Genetics—local PI, institutional, no financial interest; Surface Oncology—local PI, institutional, no financial interest. MZ declares the following relationships: Consulting or advisory roles for: Exelixis, Pfizer, Aveo, EMD Serono, Janssen, Blue Earth; Institutional research funding from Bristol Myers Squibb, Exelixis. CM is/was an employee at OmniSeq. MCO declares the following relationships: Consulting or advisory roles for Eisai, Exelixis, Pfizer, Aveo, Merck, and Bristol Myers Squibb; speakers bureaus for Bristol Myers Squibb and Exelixis; institutional research funding from Bristol Myers Squibb, Pfizer, Merck, AstraZeneca, Astellas; reimbursement for travel and accommodations expenses from Bristol Myers Squibb, Pfizer, and Exelixis. TZ declares the following relationships: Research funding (to Duke University) from Pfizer, Janssen, Acerta, AbbVie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Genentech; Speaking with Genomic Health and Sanofi Aventis; Consulting/Advisory board with AstraZeneca, Bayer, Pfizer, Janssen, Merck, Amgen, MJH Associates, BMS, Dendreon, Calithera, QED therapeutics, Aveo Therapeutics, Eli Lilly, SeaGen, Sanofi-Aventis, Pharmacyclics, Aptitude Health, PeerView, Clinical Care Options. Stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics and Nanorobotics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: In an era of rapid expansion of FDA approvals for oral anticancer agents (OAAs), it is important to understand the factors associated with survival among real-world populations, which include groups not well-represented in pivotal clinical trials of OAAs, such as the elderly, racial minorities, and medically complex patients. Our objective was to evaluate patient- and provider-level characteristics' associations with mortality among a multi-payer cohort of metastatic renal cell carcinoma (mRCC) patients who initiated OAAs., Methods: This retrospective cohort study was conducted using data from the North Carolina state cancer registry linked to multi-payer claims data for the years 2004 to 2015. Provider data were obtained from North Carolina Health Professions Data System and the National Plan & Provider Enumeration System. Included patients were individuals with mRCC who initiated an OAA and survived ≥90 days after beginning treatment. We estimated hazard ratios (HR) and corresponding 95% confidence limits (CL) using Cox hazard models for associations between patient demographics, patient clinical characteristics, provider-level factors, and 2-year all-cause mortality., Results: The cohort included 207 patients with mRCC who received OAAs. In multivariable models, clinical variables such as frailty (HR: 1.36, 95% CL: 1.11-1.67) and de novo metastatic diagnosis (HR: 2.63, 95%CL: 1.67-4.16) were associated with higher all-cause mortality. Additionally, patients solely on Medicare had higher adjusted all-cause mortality compared with patients with any private insurance (HR: 2.35, 95% CL: 1.32-4.18). No provider-level covariates investigated were associated with all-cause mortality., Conclusions: Within a real-world population of mRCC patients taking OAAs, survival differed based on patient characteristics. In an era of rapid expansion of FDA approvals for OAAs, these real-world data underscore the continued importance of access to high-quality care, particularly for medically complex patients with limited resources., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: The non-randomised, open-label, phase IIIb/IV multicohort CheckMate 920 trial explored the safety and efficacy with a less frequent, but continual nivolumab plus ipilimumab (NIVO+IPI) dosing regimen (cohort 1) to determine whether this modification could potentially retain efficacy benefits while improving on the manageable safety profile previously observed with this combination in patients with advanced renal cell carcinoma (aRCC)., Setting: Patients were enrolled from 48 largely community-based sites in the USA., Participants: 106 patients with previously untreated, predominantly clear cell aRCC received treatment., Interventions: Patients received NIVO 6 mg/kg plus IPI 1 mg/kg on day 1 of the first week of each 8-week cycle; the combination alternated with NIVO 480 mg monotherapy on day 1 of the fifth week of each 8-week cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or study end. The maximum treatment duration was 2 years. The primary endpoint was the incidence of high-grade (grade 3/4 and grade 5) immune-mediated adverse events (IMAEs) within 100 days of the last dose. Select secondary endpoints included time to onset and resolution of high-grade IMAEs, progression-free survival (PFS) and objective response rate (ORR). The incidence of treatment-related adverse events and the overall survival (OS) were the exploratory endpoints., Results: The most common grade 3/4 IMAEs were diarrhoea/colitis (7.5%) and rash (6.6%) and no grade 5 IMAEs occurred, with a minimum follow-up of 28.5 months. The median PFS was 4.8 (95% CI 3.0 to 8.3) months, the ORR in evaluable patients (n=96) was 34.4% (95% CI 25.0 to 44.8), and the median OS was not reached (95% CI 24.8 months to not estimable)., Conclusions: While no new safety signals were reported with less frequent, but continual NIVO+IPI dosing in CheckMate 920, the modified regimen was not associated with clinical benefits relative to the approved NIVO+IPI dose. These results support the continued use of the currently approved NIVO+IPI combination dosing schedule for patients with aRCC., Trial Registration Number: NCT02982954., Competing Interests: Competing interests: DJG reports consulting or advisory roles from Bayer, Exelixis, Pfizer, Sanofi, Astellas Pharma, Innocrin Pharma, Bristol Myers Squibb (BMS), Genentech, Janssen, Merck Sharp & Dohme, Myovant Sciences, AstraZeneca, Michael J Hennessy Associates, Vizuri and Constellation Pharmaceuticals; leadership from Capio Biosciences; speakers bureau from Sanofi, Bayer and Exelixis; travel, accommodations and expenses from Bayer, Exelixis, Merck, Pfizer, Sanofi, Janssen Oncology and UroToday; honoraria from Sanofi, Bayer, Exelixis, EMD Serono, OncLive, Pfizer, UroToday, Acceleron Pharma, American Association for Cancer Research, Axess Oncology, Janssen Oncology and Millennium Medical Publishing; and research funding (all institution) from Exelixis, Janssen Oncology, Novartis, Pfizer, Astellas Pharma, BMS, Acerta Pharma, Bayer, Dendreon, Innocrin Pharma, Calithera Biosciences and Sanofi/Aventis. DRS reports consulting or advisory roles (all institution) from Amgen, AstraZeneca, BMS, Curio Science, EMD Serono, Evidera, Exelixis, GlaxoSmithKline, Intellisphere, Ipsen Biopharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Mirati Therapeutics, Molecular Templates, Novartis, Novocure, Pfizer, Puma Biotechnology, Regeneron Pharmaceuticals, Roche/Genentech and Sanofi/Aventis; and research funding (all institution) from Aeglea BioTherapeutics, Agios, Apollomics, Arcus, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, BioNTech RNA Pharmaceuticals, Blueprint Medicine, Boehringer Ingelheim, BMS, Calithera, Celgene, Celldex, Clovis, Cyteir Therapeutics, Daiichi Sankyo, Denovo Biopharma, Eisai, Elevation Oncology, EMD Serono, Evelo Biosciences, G1 Therapeutics, Roche/Genentech, GlaxoSmithKline, GRAIL, Hutchison MediPharma, ImClone Systems, Incyte, ImmunoGen, Ipsen, Janssen, Kronos Bio, Lilly, Loxo Oncology, MacroGenics, MedImmune, Merck, Molecular Partners, Molecular Template, Nektar, Neon Therapeutics, Novartis, Novocure, Oncologie, Pfizer, PTC Therapeutics, PureTech Health, Razor Genomics, Repare Therapeutics, Rgenix, Takeda, Tesaro, Tizona Therapeutics, Transgene, UT Southwestern and Verastem. LNG reports employment from Florida Medical Clinic; leadership from Florida Cancer Specialists; honoraria from Ameris Pharma; consulting or advisory role from Janssen Oncology; and speakers bureau from Myriad Genetics. STK has no conflicts of interests to disclose. AMM reports consulting or advisory roles from Exelixis, Janssen and Eisai; and honoraria from the American Society of Clinical Oncology. JY reports consulting or advisory roles from BMS, Janssen and Lantheus. ARK reports remuneration for a consulting or advisory roles from Exelixis, AstraZeneca, Bayer, Pfizer, Novartis, Genentech, BMS and EMD Serono; speakers bureau from Janssen, Astellas Medivation, Pfizer, Novartis, Sanofi, Genentech/Roche, Eisai, AstraZeneca, BMS, Amgen, Exelixis, EMD Serono, Merck and Seattle Genetics/Astellas; travel, accommodations and expenses from Genentech, Prometheus, Astellas Medivation, Janssen, Eisai, Bayer, Pfizer, Novartis, Exelixis and AstraZeneca; stock ownership from ECOM Medical; and research funding (all institution) from Genentech, Exelixis, Janssen, AstraZeneca, Bayer, BMS, Eisai, MacroGenics, Astellas Pharma, BeyondSpring Pharmaceuticals, BioClin Therapeutics, Clovis Oncology, Bavarian Nordic, Seattle Genetics, Immunomedics and Epizyme. HM has no conflicts of interests to disclose. NT reports consulting or advisory roles from Amgen, IntrinsiQ and Foundation Medicine. SST reports consulting or advisory roles from Merck, Intellisphere, Natera, BMS and Exelixis; patent pending (institution); and research funding (all institution) from Genentech, BMS, Merck, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis and Clinigen Group. JZ reports employment and stock ownership from BMS. MA reports employment from BMS. JLJ reports employment and stock ownership from BMS. TEH reports employment from Texas Oncology; consulting or advisory roles from Bayer/Onyx, Pfizer, Novartis, Astellas Pharma, Johnson & Johnson, BMS, Eisai and Exelixis; speakers bureau from Pfizer, Johnson & Johnson, Eisai, Exelixis, Astellas Pharma and BMS; honoraria from Pfizer, Astellas Pharma, BMS, Exelixis, Eisai, Novartis, Johnson & Johnson and Bayer/Onyx; and research funding (all institution) from Pfizer, Johnson & Johnson, Exelixis, Eisai and BMS., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: CALGB 90206 was a phase III trial of 732 patients with metastatic renal cell carcinoma (mRCC) comparing bevacizumab plus IFNα (BEV + IFN) with IFNα alone (IFN). No difference in overall survival (OS) was observed. Baseline samples were analyzed to identify predictive biomarkers for survival benefit., Patients and Methods: A total of 32 biomarkers were assessed in 498 consenting patients randomly assigned into training (n = 279) and testing (n = 219) sets. The proportional hazards model was used to test for treatment arm and biomarker interactions of OS. The estimated coefficients from the training set were used to compute a risk score for each patient and to classify patients by risk in the testing set. The resulting model was assessed for predictive accuracy using the time-dependent area under the ROC curve (tAUROC)., Results: A statistically significant three-way interaction between IL6, hepatocyte growth factor (HGF), and bevacizumab treatment was observed in the training set and confirmed in the testing set (P < 0.0001). The model based on IL6, HGF, and bevacizumab treatment was predictive of OS (P < 0.001), with the high- and low-risk groups having a median OS of 10.2 [95% confidence interval (CI), 8.0-13.8] and 34.3 (95% CI, 28.5-40.5) months, respectively. The average tAUROC for the final model of OS based on 100 randomly split testing sets was 0.78 (first, third quartiles = 0.77, 0.79)., Conclusions: IL6 and HGF are potential predictive biomarkers of OS benefit from BEV + IFN in patients with mRCC. The model based on key biological and clinical factors demonstrated predictive efficacy for OS. These markers warrant further validation in future anti-VEGF and immunotherapy in mRCC trials. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725., (©2021 American Association for Cancer Research.)

Background: Nivolumab plus ipilimumab (NIVO + IPI) has demonstrated long-term efficacy and safety in patients with previously untreated, advanced renal cell carcinoma (aRCC). Although most phase 3 clinical trials exclude patients with brain metastases, the ongoing, multicohort phase 3b/4 CheckMate 920 trial (ClincalTrials.gov identifier NCT02982954) evaluated the safety and efficacy of NIVO + IPI in a cohort that included patients with aRCC and brain metastases, as reported here., Methods: Patients with previously untreated aRCC and asymptomatic brain metastases received NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × 4 followed by NIVO 480 mg every 4 weeks. The primary end point was the incidence of grade ≥3 immune-mediated adverse events (imAEs) within 100 days of the last dose of study drug. Key secondary end points were progression-free survival and the objective response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (both determined by the investigator). Exploratory end points included overall survival, among others., Results: After a minimum follow-up of 24.5 months (N = 28), no grade 5 imAEs occurred. The most common grade 3 and 4 imAEs were diarrhea/colitis (n = 2; 7%) and hypophysitis, rash, hepatitis, and diabetes mellitus (n = 1 each; 4%). The objective response rate was 32% (95% CI, 14.9%-53.5%) with a median duration of response of 24.0 months; 4 of 8 responders remained without reported progression. Seven patients (25%) had intracranial progression. The median progression-free survival was 9.0 months (95% CI, 2.9-12.0 months), and the median overall survival was not reached (95% CI, 14.1 months to not estimable)., Conclusions: In patients who had previously untreated aRCC and brain metastases-a population with a high unmet medical need that often is underrepresented in clinical trials-the approved regimen of NIVO + IPI followed by NIVO showed encouraging antitumor activity and no new safety signals., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Introduction: The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC)., Methods and Materials: Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations., Results: Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection., Conclusion: The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

High tumoral expression of AXL was associated with inferior response to anti-PD-1 therapy and increased tumoral programmed death ligand 1 (PD-L1) expression in patients with metastatic renal cell carcinoma, with particularly poor outcomes in those with high AXL and PD-L1. AXL expression has potential as a biomarker and therapeutic target. See related article by Terry et al., p. 6749 ., (©2021 American Association for Cancer Research.)

The combination of ipilimumab plus nivolumab (I+N) has greatly improved outcomes in patients with intermediate or poor-risk untreated metastatic renal cell carcinoma (mRCC). However, little is known about the outcomes of patients with brain metastasis (BrM) treated with I+N. A search was performed to retrospectively identify all patients with mRCC treated with I+N in the Duke Cancer Institute and the Cleveland Clinic Taussig Cancer Center, followed by a chart review. Patients were included if they had BrM at the time of I+N initiation. Cohort characteristics are summarized with descriptive statistics. Kaplan-Meier method was used to estimate overall survival (OS) and global, intracranial, and extracranial progression-free survival (PFS) for the cohort and log rank test was used to compare OS and PFS between patient groups. Radiographic response was categorized by RECIST. Fisher's exact test was used to correlate patient factors with radiographic response. From October 2017 to December 2020, 19 patients with BrM received I+N for mRCC with a median follow-up time of 27.1 months (range 15.0-35.6). By International Metastatic RCC Database Consortium (IMDC) risk criteria, 16% had favorable, 58% had intermediate, and 26% had poor-risk disease. 68% were systemic therapy naïve, and 77% of patients had clear cell histology. 95% had received local CNS directed therapy with surgery, radiotherapy, or both. The objective response rate was 44% (0% complete response) with three of six patients treated in the second line or greater setting experiencing a partial response. The median PFS was 7.6 months (95% CI 5.6 to 14.9). The median extracranial PFS was 8.5 months (95% CI 5.6 to 19.7), and median intracranial PFS was 14.7 months (95% CI 7.2 to not reached). No variables assessed were significantly associated with radiographic response (gender, IMDC risk, presence of bone metastasis, line of therapy, or presence of immune related adverse events). In our retrospective cohort of patients with mRCC with BrM, I+N, in combination with CNS-directed local therapy, appears to have clinical efficacy as previously described with responses seen beyond the first-line setting. Further investigation is warranted in this population given exclusion from prior clinical trials., Competing Interests: Competing interests: LCB declares the following relationships: consulting with Seattle Genetics. KD declares the following relationship: consulting with Tyra BioSciences. WW declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. EK declares that she has no conflicts of interest that might be relevant to the contents of this manuscript. CK declares that he has no conflicts of interest that might be relevant to the contents of this manuscript. DG declares the following relationships: Acerta Pharmaceuticals—Research, American Association for Cancer Research—Sr Editor, Astellas—Consultant, Research, Advisory Board, Astrazeneca—Consultant, Advisory Board, Axess Oncology—Independent Contractor, Bayer H/C Pharmaceuticals—Research, Consultant, Speaker, Honorarium, Travel accommodations, SC, BMS—Consultant, Research, Steering Committee, Calithera—Research, Capio Biosciences—Scientific Advisory Board, EMD Serono—Honorarium, Exelixis—Research, Consultant, Speaker, Honorarium, Travel accommodations, Flatiron—Consultant, Ipsen—Honorarium, Janssen Pharmaceuticals—Research, Consultant, Independent Data Monitoring Committee (IDMC), Leidos Biomedical Research—Consultant, Merck Sharp & Dohme—Consultant, Michael J Hennessey Associates—Honorarium, Consultant, Millennium Medical Publishing, Clinical Advances in Hematology & Oncology—Co-Editor-in-Chief, Modra Pharmaceuticals B.V.—Advisory Board, Myovant Sciences—Consultant, Nektar Therapeutics—Steering Committee, Novartis—Research, Physician Education Resource—Consultant, Pfizer—Research, Consultant, Steering Committee, Honorarium, Sanofi—Research, Consultant, Speaker, Honorarium, Travel accommodations, UroGPO—Honorarium, UroToday—Honorarium, Travel accommodations, Vizuri Health Sciences—Consultant, NCI—Steering Committee. BR declares the following relationships: Research funding (to Vanderbilt University) from Pfizer, Hoffman-LaRoche, Incyte, AstraZeneca, Taris, Seattle Genetics, Arrowhead Pharmaceuticals, Immunomedics, BMS, Mirati Therapeutics, Merck, Surface Oncology, Dragonfly Therapeutics, Aravive and Exelixis; Consulting with Bristol Myer Squibb, Pfizer, Roche/Genentech, Aveo, Synthorx, Compugen, Merck, Corvus, Surface Oncology, 3DMedicines, Aravive, Alkermes, Arrowhead, GSK, Shionogi, Eisai. Stock ownership in PTC Therapeutics. MCO declares the following relationships: Consulting with BMS, Merck, Pfizer, Aveo, Exelixis and Eisai. TZ declares the following relationships: Research funding (to Duke University) from Pfizer, Janssen, Acerta, Abbvie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas and Genentech; Speaking with Genomic Health and Sanofi Aventis; Consulting with AstraZeneca, Bayer, Pfizer, Foundation Medicine, Janssen, Merck, Amgen, MJH Associates, and BMS. Stock ownership/employment (spouse) from Capio Biosciences, Archimmune Therapeutics and Nanorobotics., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy., Methods: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if p interaction  < 0.05 for the interaction between treatment and biomarker., Results: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis., Conclusions: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC., Trial Registration: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013)., (© 2021. The Author(s).)

Background: Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature., Methods: This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ 2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival., Results: Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST., Conclusions: AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients., (© 2021 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib., Patients and Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS)., Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib., Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN., (©2021 American Association for Cancer Research.)

Introduction: Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches., Methods: We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1., Results: We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event., Conclusion: To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We report a case using combination cabozantinib plus nivolumab to salvage disease control in a patient with refractory metastatic renal cell carcinoma. The patient had previously experienced disease progression from high-dose interleukin-2, sunitinib, pazopanib, cabozantinib, and nivolumab, all given sequentially. Combination cabozantinib plus nivolumab resulted in 22 months of disease control. Vascular endothelial growth factor inhibitors including cabozantinib have immunomodulatory effects when combined with immune checkpoint inhibitors, with multiple ongoing phase III trials exploring the cabozantinib plus nivolumab combination in the first-line setting. To our knowledge, this is the first reported case of progression on nivolumab and cabozantinib when given as sequential monotherapies but stable disease on combination cabozantinib plus nivolumab., (© 2020 AlphaMed Press.)

Background: MET (also known as hepatocyte growth factor receptor) signalling is a key driver of papillary renal cell carcinoma (PRCC). Given that no optimal therapy for metastatic PRCC exists, we aimed to compare an existing standard of care, sunitinib, with the MET kinase inhibitors cabozantinib, crizotinib, and savolitinib for treatment of patients with PRCC., Methods: We did a randomised, open-label, phase 2 trial done in 65 centres in the USA and Canada. Eligible patients were aged 18 years or older with metastatic PRCC who had received up to one previous therapy (excluding vascular endothelial growth factor-directed and MET-directed agents). Patients were randomly assigned to receive sunitinib, cabozantinib, crizotinib, or savolitinib, with stratification by receipt of previous therapy and PRCC subtype. All drug doses were administered orally: sunitinib 50 mg, 4 weeks on and 2 weeks off (dose reductions to 37·5 mg and 25 mg allowed); cabozantinib 60 mg daily (reductions to 40 mg and 20 mg allowed); crizotinib 250 mg twice daily (reductions to 200 mg twice daily and 250 mg once daily allowed); and savolitinib 600 mg daily (reductions to 400 mg and 200 mg allowed). Progression-free survival (PFS) was the primary endpoint. Analyses were done in an intention-to-treat population, with patients who did not receive protocol therapy excluded from safety analyses. This trial is registered with ClinicalTrials.gov, NCT02761057., Findings: Between April 5, 2016, and Dec 15, 2019, 152 patients were randomly assigned to one of four study groups. Five patients were identified as ineligible post-randomisation and were excluded from these analyses, resulting in 147 eligible patients. Assignment to the savolitinib (29 patients) and crizotinib (28 patients) groups was halted after a prespecified futility analysis; planned accrual was completed for both sunitinib (46 patients) and cabozantinib (44 patients) groups. PFS was longer in patients in the cabozantinib group (median 9·0 months, 95% CI 6-12) than in the sunitinib group (5·6 months, 3-7; hazard ratio for progression or death 0·60, 0·37-0·97, one-sided p=0·019). Response rate for cabozantinib was 23% versus 4% for sunitinib (two-sided p=0·010). Savolitinib and crizotinib did not improve PFS compared with sunitinib. Grade 3 or 4 adverse events occurred in 31 (69%) of 45 patients receiving sunitinib, 32 (74%) of 43 receiving cabozantinib, ten (37%) of 27 receiving crizotinib, and 11 (39%) of 28 receiving savolitinib; one grade 5 thromboembolic event was recorded in the cabozantinib group., Interpretation: Cabozantinib treatment resulted in significantly longer PFS compared with sunitinib in patients with metastatic PRCC., Funding: National Institutes of Health and National Cancer Institute., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting. Materials & methods: Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS). Results: In 609 patients, DFS was similar for baseline PLR <140 versus ≥140 overall (median: 6.4 vs 5.9 years; hazard ratio: 0.9; 95% CI: 0.7-1.2). A ≥25% decrease in PLR at week 4 overall was associated with longer DFS versus no change (hazard ratio: 0.8; 95% CI: 0.6-1.0). Conclusion: Baseline PLR was not prognostic for DFS with adjuvant sunitinib treatment in patients with renal cell carcinoma. Clinical Trials Registration: NCT00375674 (ClinicalTrials.gov).

Background: Cabozantinib Versus Sunitinib as Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial (CABOSUN) was a randomized, open-label, phase 2 trial evaluating first-line cabozantinib versus sunitinib in patients with advanced renal cell carcinoma (aRCC). This post hoc analysis evaluated quality-adjusted survival using Quality-adjusted Time Without Symptoms of disease or Toxicity of treatment (Q-TWiST)., Methods: Survival plots for cabozantinib and sunitinib (650-day follow-up) were partitioned into 3 health states: time spent before disease progression without toxicity (TWiST; toxicity based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0] grade 3/4 adverse events), time spent before disease progression with toxicity (TOX; durations of adverse events based on published literature), and time after disease recurrence (relapse) or progression to death (REL). Q-TWiST was the sum of the mean time spent in each state, with each state weighted to reflect patient preferences (from 0 [worst] to 1 [best]) using utility scores. TWiST was always weighted as 1. Overall survival and time to disease progression were based on all randomized patients (157 patients); TOX was based on all randomized and treated patients (150 patients)., Results: Across all utility combinations tested, Q-TWiST was found to be longer with cabozantinib versus sunitinib (range of differences, +24 days to +137 days). Q-TWiST differences that were found to be statistically significant (+92 days [95% confidence interval, 5-178 days] to +137 days [95% confidence interval, 60-214 days]) were of a clinically meaningful effect size (≥80 days), and were based on utility values that included those considered relevant for patients with aRCC (REL utility weight of 0.355, TOX utility weight of 0-1, and TWiST utility weight of 1)., Conclusions: In patients with aRCC, first-line cabozantinib was found to provide longer quality-adjusted survival compared with sunitinib. These findings may help to inform clinical decision making., Lay Summary: Cabozantinib and sunitinib are drugs that are used to treat patients with advanced kidney cancer. Clinical trials have shown that cabozantinib offers benefits over sunitinib, giving patients more time before their cancer progresses. It is important that this additional time before disease progression does not come at the expense of patients' quality of life, which can be affected by treatment side effects and/or ongoing cancer symptoms. Both quantity and quality of life are central to optimal treatment. In the current analysis of patients with advanced kidney cancer who were initiating treatment for the first time, cabozantinib provided more quality time before cancer progression compared with sunitinib., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: In the S-TRAC trial, adjuvant sunitinib improved disease-free survival (DFS) compared with placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence. This post hoc exploratory analysis investigated the neutrophil-to-lymphocyte ratio (NLR) for predictive and prognostic significance in the RCC adjuvant setting., Experimental Design: Kaplan-Meier estimates and Cox proportional analyses were performed on baseline NLR and change from baseline at week 4 to assess their association with DFS. Univariate P values were two-sided and based on an unstratified log-rank test., Results: 609 of 615 patients had baseline NLR values; 574 patients had baseline and week 4 values. Sunitinib-treated patients with baseline NLR <3 had longer DFS versus placebo (7.1 vs. 4.7; HR, 0.71; P = 0.02). For baseline NLR ≥3, DFS was similar regardless of treatment (sunitinib 6.8 vs. placebo not reached; HR, 1.03; P = 0.91). A ≥25% NLR decrease at week 4 was associated with longer DFS versus no change (6.8 vs. 5.3 years; HR, 0.71; P = 0.01). A greater proportion of sunitinib-treated patients had ≥25% NLR decrease at week 4 (71.2%) versus placebo (17.4%). Patients with ≥25% NLR decrease at week 4 received a higher median cumulative sunitinib dose (10,137.5 mg) versus no change (8,168.8 mg) or ≥25% increase (6,712.5 mg)., Conclusions: In the postnephrectomy high-risk RCC patient cohort, low baseline NLR may help identify those most suitable for adjuvant sunitinib. A ≥25% NLR decrease at week 4 may be an early indicator of those most likely to tolerate treatment and derive DFS benefit., (©2020 American Association for Cancer Research.)

The primary treatment for localized renal cell carcinoma (RCC) is surgical resection with curative intent. Despite this, many patients, especially those with high-risk features, will develop recurrent or metastatic disease. Antiangiogenic therapies targeting vascular endothelial growth factor have been a mainstay of treatment of advanced RCC for more than 10 years. Evidence supporting the use of these therapies in the adjuvant setting is mixed, although one clinical trial, S-TRAC, has shown improvements in disease-free survival with 1 year of adjuvant sunitinib among patients with clear cell histology and high-risk features, leading to the first US Food and Drug Administration approval of an adjuvant therapy for high-risk RCC patients. Further investigation into combination therapies with immunotherapy, neoadjuvant approaches, and patient selection will be key to determining optimal adjuvant therapy regimens to improve outcomes and increase cure rates for patients with localized RCC.

Sensitive detection of circulating tumor cells (CTCs) from patients' peripheral blood facilitates on-demand monitoring of tumor progression. However, clinically significant capture of renal cell carcinoma CTCs (RCC-CTCs) remains elusive due to their heterogenous surface receptor expression. Herein, a novel capture platform is developed to detect RCC-CTCs through integration of dendrimer-mediated multivalent binding, a mixture of antibodies, and biomimetic cell rolling. The nanoscale binding kinetics measured using atomic force microscopy reveal that dendrimer-coated surfaces exhibit an order of magnitude enhancement in off-rate kinetics compared to surface without dendrimers, which translated into cell capture improvements by ~60%. Selectin-induced cell rolling facilitates surface recruitment of cancer cells, further improving cancer cell capture by up to 1.7-fold. Lastly, an antibody cocktail targeting four RCC-CTC surface receptors, which included epithelial cell adhesion molecule (EpCAM), carbonic anhydrase IX (CA9), epidermal growth factor receptor (EGFR), and hepatocyte growth factor receptor (c-Met), improves the capture of RCC cells by up to 80%. The optimal surface configuration outperforms the conventional assay solely relying on EpCAM, as demonstrated by detecting significantly more CTCs in patients' samples (9.8 ± 5.1 vs. 1.8 ± 2.0 CTCs mL -1 ). These results demonstrate that the newly engineered capture platform effectively detects RCC-CTCs for their potential use as tumor biomarkers., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S. Hong and A.Z. Wang are co-founders of Capio Biosciences, Inc., a biotech startup that is commercializing CapioCyte™ CTC technology. M.J. Poellmann is an employee of Capio Biosciences.T. Zhang has received research funding (to Duke) from Abbvie, Acerta, Janssen, Merck, Merrimack, Novartis, OmniSeq, Pfizer, and PGDx; speaking fees from Exelixis, Genentech, Roche, Sanofi Aventis, and Genomic Health; and has consulted for AstraZeneca, Bristol-Myers Squibb, Foundation Medicine, Janssen, Pfizer, Pharmacyclics, Amgen, and Sanofi Aventis. Stock ownership/employment (spouse) from Capio Biosciences., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Biomarkers predicting immunotherapy response in metastatic renal cell cancer (mRCC) are lacking. PD-L1 immunohistochemistry is a complementary diagnostic for immune checkpoint inhibitors (ICIs) in mRCC, but has shown minimal clinical utility and is not used in routine clinical practice., Methods: Tumor specimens from 56 patients with mRCC who received nivolumab were evaluated for PD-L1, cell proliferation (targeted RNA-seq), and outcome., Results: For 56 patients treated with nivolumab as a standard of care, there were 2 complete responses and 8 partial responses for a response rate of 17.9%. Dividing cell proliferation into tertiles, derived from the mean expression of 10 proliferation-associated genes in a reference set of tumors, poorly proliferative tumors (62.5%) were more common than moderately (30.4%) or highly proliferative (8.9%) counterparts. Moderately proliferative tumors were enriched for PD-L1 positive (41.2%), compared to poorly proliferative counterparts (11.4%). Objective response for moderately proliferative (29.4%) tumors was higher than that of poorly (11.4%) proliferative counterparts, but not statistically significant ( p = .11). When cell proliferation and negative PD-L1 tumor proportion scores were combined statistically significant results were achieved ( p = .048), showing that patients with poorly proliferative and PD-L1 negative tumors have a very low response rate (6.5%) compared to moderately proliferative PD-L1 negative tumors (30%)., Conclusions: Cell proliferation has value in predicting response to nivolumab in clear cell mRCC patients, especially when combined with PD-L1 expression. Further studies which include the addition of progression-free survival (PFS) along with sufficiently powered subgroups are required to further support these findings., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Until recently, the sole treatment for patients with nonmetastatic renal cell carcinoma (RCC) was nephrectomy followed by observation. As metastatic RCC (mRCC) remains largely incurable (5-year survival rate ∼12%), adjuvant treatment, with potential to prevent/delay disease recurrence, is needed. In November 2017, sunitinib was approved in the USA as the first adjuvant therapy for patients at high risk for recurrent RCC postnephrectomy based on results from the S-TRAC trial. Patients eligible for adjuvant treatment have no evidence of disease and may be less willing to tolerate side effects. Therefore, proactive adverse event management is critical for keeping patients on adjuvant treatment and requires understanding the subtle differences in the adverse event profile of sunitinib in the adjuvant versus metastatic RCC setting.

Since the approval of immunotherapy checkpoint inhibitors for first-line treatment of metastatic renal cell carcinoma, new and clinically relevant questions have emerged that ongoing clinical trials and trials in development will address. These questions include how to integrate combination immunotherapy approaches like ipilimumab/nivolumab with targeted therapies against vascular endothelial growth factor (VEGF) receptors, which patients can discontinue treatment, and who needs ipilimumab to maximize clinical responses. Furthermore, with new approvals of treatment regimens combining checkpoint inhibitors with targeted therapies, new questions arise in the clinic regarding optimal treatment selection for first-line clear cell renal cell carcinoma. This review will highlight the contemporary clinical trials in metastatic clear cell renal cell carcinoma that try to address some of these knowledge gaps., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The approval of immunotherapeutic agents and immunotherapy-based combination strategies in recent years has revolutionized the treatment of patients with advanced renal cell carcinoma (aRCC). Nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor monoclonal antibody, was approved as monotherapy in 2015 for aRCC after treatment with a VEGF-targeting agent. In April 2018, the combination of nivolumab and ipilimumab, a CTLA-4 inhibitor, was approved for intermediate- and poor-risk, previously untreated patients with aRCC. Then, in 2019, combinations therapies consisting of pembrolizumab (anti-PD-1) or avelumab (anti-PD-ligand (L) 1) with axitinib (a VEGF receptor tyrosine kinase inhibitor) were also approved to treat aRCC and are likely to produce dramatic shifts in the therapeutic landscape. To address the rapid advances in immunotherapy options for patients with aRCC, the Society for Immunotherapy of Cancer (SITC) reconvened its Cancer Immunotherapy Guidelines (CIG) Renal Cell Carcinoma Subcommittee and tasked it with generating updated consensus recommendations for the treatment of patients with this disease.

Cabozantinib treatment prolonged progression-free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, including in groups defined by IMDC risk group, bone metastases, age, and tumor burden. Clinical trial identification number NCT01835158., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© 2019 The Authors. The Oncologist published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Purpose: Programmed death-ligand 1 (PD-L1) status by IHC is prognostic in metastatic renal cell carcinoma (mRCC), and its role as a potential predictive biomarker is under investigation. Using tumor tissue from the METEOR (NCT01865747) and CABOSUN (NCT01835158) clinical trials, we explored whether PD-L1 expression and the extent of the immune cell infiltrate can serve as prognostic and/or predictive biomarkers for cabozantinib and other targeted agents., Experimental Design: IHC double staining for PD-L1 and CD45/CD163 (immune cell markers) was performed on tumor tissue from METEOR ( n = 306) and CABOSUN ( n = 110) clinical trials. Immune cell density and MET expression levels were also analyzed. Our primary aim was to correlate progression-free survival (PFS) by independent central review with PD-L1 status in patients treated with cabozantinib, everolimus (METEOR), or sunitinib (CABOSUN). Overall survival (OS) was also interrogated., Results: Tumor cell (TC) PD-L1 expression (≥1% cutoff) was detected in 29% and 23% of tumors from patients in the METEOR and CABOSUN trials, respectively. On univariate analysis, patients with PD-L1-positive TC had poorer PFS and OS than patients with PD-L1-negative TC on both trials, independent of therapy. On multivariable analysis and when combining the two trials, the association between TC PD-L1 expression and OS was statistically significant for all patients ( P = 0.034) and for patients treated with cabozantinib only ( P = 0.038). Cabozantinib was associated with improved PFS (HR < 0.70) and OS (HR < 0.85) compared with everolimus and sunitinib irrespective of PD-L1 expression., Conclusions: Higher PD-L1 expression results in worse clinical outcomes in mRCC treated with targeted therapy. Furthermore, PD-L1 expression is not predictive of response to cabozantinib therapy., (©2019 American Association for Cancer Research.)

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumor-immune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first- and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: In the S-TRAC trial, adjuvant sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between SNPs in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC., Patients and Methods: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in sunitinib versus placebo groups and between genotypes within each of three (sunitinib, placebo, and combined sunitinib plus placebo) treatment groups. P values were unadjusted., Results: In all, 286 patients (sunitinib, n = 142; placebo, n = 144) were genotyped. Longer DFS [HR; 95% confidence interval (CI)] was observed with sunitinib versus placebo for VEGFR1 rs9554320 C/C (HR 0.44; 95% CI, 0.21-0.91; P = 0.023), VEGFR2 rs2071559 T/T (HR 0.46; 95% CI, 0.23-0.90; P = 0.020), and eNOS rs2070744 T/T (HR 0.53; 95% CI, 0.30-0.94; P = 0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with sunitinib, placebo, and combined therapies ( P ≤ 0.05), and A/A versus C/C with sunitinib ( P = 0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo ( P = 0.038) and combined ( P = 0.006) groups., Conclusions: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings., (©2018 American Association for Cancer Research.)

Introduction: Genomic events leading to activation of mechanistic target of rapamycin (mTOR) are common in renal cell carcinoma (RCC). Everolimus is an allosteric mTOR inhibitor with efficacy in metastatic RCC. We characterized the genomic profile of RCC tumors from metastatic sites and assessed whether particular alterations correlate with clinical response to everolimus., Patients and Methods: An open-label, single-arm phase 2 biomarker study of everolimus 10 mg daily was conducted in metastatic RCC patients. Needle biopsy or metastasectomy was performed on metastatic tumors before everolimus initiation. Next-generation sequencing was performed using a targeted hybrid capture panel detecting alterations within exons and key introns of ≥ 300 cancer-associated genes. Disease assessments were obtained every 8 weeks using standard radiographic modalities and evaluated by Response Evaluation Criteria in Solid Tumors criteria., Results: Objective response was seen in 1 (4.2%) of 24 patients. Two patients (8.3%) had stable disease lasting > 6 months. Median (90% confidence interval) overall and progression-free survival were 20.1 (8.6, NA) and 3.8 (2.4, 5.4) months, respectively. Next-generation sequencing was successful on 18 pretreatment specimens and 3 on-treatment specimens. Alterations in the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway were identified in 8 (44%) of 18 pretreatment samples. An mTOR E2419D mutation was identified in the patient who experienced partial response. Alterations in VHL, PBRM1, SETD2, KDM5C, and ATM were common in the RCC metastases before initiation of everolimus., Conclusion: Nearly half of heavily pretreated RCC metastases may harbor mutations in components of the PI3K-AKT-mTOR pathway. Commonly mutated genes in primary RCC were also altered at a high frequency in RCC metastases., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov number NCT00375674). A prospectively designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit. Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of programmed cell death ligand 1 (PD-L1), CD4, CD8, and CD68. DFS was compared between < versus ≥ median IHC parameter using the Kaplan-Meier method. For biomarkers with predictive potential, receiver operating characteristics curves were generated. Results: Baseline characteristics were similar in patients with ( n = 191) and without ( n = 419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8 + T-cell density ≥ versus < median [median (95% CI), not reached (6.83-not reached) versus 3.47 years (1.73-not reached); hazard ratio (HR) 0.40 (95% CI, 0.20-0.81); P = 0.009] treated with sunitinib ( n = 101), but not with placebo ( n = 90). The sensitivity and specificity for CD8 + T-cell density in predicting DFS were 0.604 and 0.658, respectively. Shorter DFS was observed in placebo-treated patients with PD-L1 + versus PD-L1 - tumors (HR 1.75; P = 0.103). Among all patients with PD-L1 + tumors, DFS was numerically longer with sunitinib versus placebo (HR 0.58; P = 0.175). Conclusions: Greater CD8 + T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk nonmetastatic RCC should also be further explored. Clin Cancer Res; 24(7); 1554-61. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Nivolumab is approved for patients with metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. The clinical activity of nivolumab in patients with non-clear cell RCC subtypes remains unknown as these patients were excluded from the original nivolumab trials., Methods: Patients from 6 centers in the United States who received at least one dose of nivolumab for non-clear cell mRCC between 12/2015 and 06/2017 were identified. A retrospective analysis including patient characteristics, objective response rate according to RECIST v1.1 and treatment-related adverse events (TRAEs) was undertaken., Results: Forty-one patients were identified. Median age was 58 years (33-82), 71% were male, and majority had ECOG PS 0 (40%) or 1 (47%). Histology included 16 papillary, 14 unclassified, 5 chromophobe, 4 collecting duct, 1 Xp11 translocation and 1 MTSCC (mucinous tubular and spindle cell carcinoma). Among 35 patients who were evaluable for best response, 7 (20%) had PR and 10 (29%) had SD. Responses were observed in unclassified, papillary and collecting duct subtypes. In the entire cohort, median follow-up was 8.5 months and median treatment duration was 3.0 months. Median PFS was 3.5 months and median OS was not reached. Among responders, median time to best response was 5.1 months, and median duration of response was not reached as only 2 out of 7 responders had disease progression during follow-up. TRAEs of any grade were noted in 37% and most commonly included fatigue (12%), fever (10%) and rash (10%). Nivolumab treatments were postponed in 34% and discontinued in 15% of patients due to intolerance. No treatment-related deaths were observed., Conclusions: Nivolumab monotherapy demonstrated objective responses and was well tolerated in a heterogeneous population of patients with non-clear cell mRCC. In the absence of other data in this treatment setting, this study lends support to the use of nivolumab for patients with metastatic non-clear cell renal cell carcinoma.

Immune checkpoint inhibitors targeting the PD-1 pathway have greatly changed clinical management of metastatic urothelial carcinoma and metastatic renal cell carcinoma. However, response rates are low, and biomarkers are needed to predict for treatment response. Immunohistochemical quantification of PD-L1 was developed as a promising biomarker in early clinical trials, but many shortcomings of the four different assays (different antibodies, disparate cellular populations, and different thresholds of positivity) have limited its clinical utility. Further limitations include the use of archival specimens to measure this dynamic biomarker. Indeed, until PD-L1 testing is standardized and can consistently predict treatment outcome, the currently available PD-L1 assays are not clinically useful in urothelial and renal cell carcinoma. Other more promising biomarkers include tumor mutational burden, profiles of tumor infiltrating lymphocytes, molecular subtypes, and PD-L2. Potentially, a composite biomarker may be best but will need prospective testing to validate such a biomarker.

Background: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03)., Objective: To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS)., Design, Setting, and Participants: Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial., Outcome Measurements and Statistical Analysis: Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade., Results and Limitations: Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively., Conclusions: A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy., Patient Summary: Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib., Trial Registration: ClinicalTrials.gov NCT00375674., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

The Metastatic Renal Cell Cancer Registry, a large, nationally representative, prospective registry of patients with metastatic renal cell carcinoma (mRCC), aims to understand real-world treatment patterns and outcomes of patients with mRCC in routine clinical practice across the United States. This observational study is designed to enroll 500 patients with previously untreated mRCC from approximately 60 academic and community treatment sites; as of December 7, 2016, 500 patients have enrolled at 54 sites. Key endpoints include real-world data on reasons for treatment initiation and discontinuation; treatment regimens; disease progression; patient-reported outcomes; and healthcare resource utilization in this patient population.

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23 to 44) for cabozantinib versus 12% (95% CI, 5.4 to 21) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.

Background: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy., Methods: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety., Results: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects., Conclusions: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Background: The therapeutic armamentarium for metastatic renal cell carcinoma has rapidly expanded over the past decade to include a number of anti-angiogenic therapies and more recently, an immunotherapy. Biomarkers in the peripheral circulation are easily accessible, can provide important prognostic value, and have the potential to give important information about disease progression and treatment sensitivity or response., Main Findings: Herein, we review a variety of circulating markers including circulating protein markers (VEGF-A, inflammatory cytokines, and LDH), circulating nucleic acids (cell free DNA and micro RNAs), and circulating cellular factors (circulating tumor cells, circulating endothelial cells, and immune cell subsets). We discuss these biomarkers in the context of their ability to provide prognostic and predictive information to anti-angiogenic and immunotherapeutic agents., Principal Conclusions: While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Non-clear cell renal cell carcinomas are histologically and genetically diverse kidney cancers with variable prognoses, and their optimum initial treatment is unknown. We aimed to compare the mTOR inhibitor everolimus and the VEGF receptor inhibitor sunitinib in patients with non-clear cell renal cell carcinoma., Methods: We enrolled patients with metastatic papillary, chromophobe, or unclassified non-clear cell renal cell carcinoma with no history of previous systemic treatment. Patients were randomly assigned (1:1) to receive everolimus (10 mg/day) or sunitinib (50 mg/day; 6-week cycles of 4 weeks with treatment followed by 2 weeks without treatment) administered orally until disease progression or unacceptable toxicity. Randomisation was stratified by Memorial Sloan Kettering Cancer Center risk group and papillary histology. The primary endpoint was progression-free survival in the intention-to-treat population using the RECIST 1.1 criteria. Safety was assessed in all patients who were randomly assigned to treatment. This study is registered with ClinicalTrials.gov, number NCT01108445., Findings: Between Sept 23, 2010, and Oct 28, 2013, 108 patients were randomly assigned to receive either sunitinib (n=51) or everolimus (n=57). As of December, 2014, 87 progression-free survival events had occurred with two remaining active patients, and the trial was closed for the primary analysis. Sunitinib significantly increased progression-free survival compared with everolimus (8·3 months [80% CI 5·8-11·4] vs 5·6 months [5·5-6·0]; hazard ratio 1·41 [80% CI 1·03-1·92]; p=0·16), although heterogeneity of the treatment effect was noted on the basis of histological subtypes and prognostic risk groups. No unexpected toxic effects were reported, and the most common grade 3-4 adverse events were hypertension (12 [24%] of 51 patients in the sunitinib group vs one [2%] of 57 patients in the everolimus group), infection (six [12%] vs four [7%]), diarrhoea (five [10%] vs one [2%]), pneumonitis (none vs five [9%]), stomatitis (none vs five [9%]), and hand-foot syndrome (four [8%] vs none)., Interpretation: In patients with metastatic non-clear cell renal cell carcinoma, sunitinib improved progression-free survival compared with everolimus. Future trials of novel agents should account for heterogeneity in disease outcomes based on genetic, histological, and prognostic factors., Funding: Novartis and Pfizer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: Although narrow eligibility criteria improve the internal validity of clinical trials, they may result in differences between study populations and real-world patients, threatening generalizability. Therefore, we evaluated whether patients treated for metastatic renal cell cancer (mRCC) in routine clinical practice are similar to those enrolled onto clinical trials., Patients and Methods: In this cohort study, we compared baseline characteristics of patients with mRCC in phase III clinical trials of new targeted therapies and those in a retrospective registry composed of academic (Duke) and community (ACORN Network) practices., Results: A total of 438 registry patients received sunitinib, sorafenib, temsirolimus, or pazopanib (most commonly used agents) in first-line treatment. Registry patients receiving tyrosine kinase inhibitors (sunitinib, sorafenib, or pazopanib) were more likely to have poor-risk disease by Memorial Sloan Kettering Cancer Center criteria (poor, 7.4% v 2.9%; P < .001; favorable, 30.1% v 43.8%; P < .001) and to have impaired performance status (Eastern Cooperative Oncology Group > 1, 11.1% v 0.6%; P < .001). However, registry patients receiving temsirolimus were less likely to have poor-risk disease (poor, 10.2% v 69.4%; P < .001; favorable, 16.9% v 0%; P < .001). Thus, 39.0% of registry patients would have been excluded from the phase III clinical trial testing the drug they received., Conclusion: Patients with mRCC treated with tyrosine kinase inhibitors in real-world clinical practice are sicker than those enrolled onto pivotal clinical trials, and more than one third are trial ineligible. Application of clinical trial findings to dissimilar populations may result in patient harm. Clinical research with more inclusive eligibility criteria is needed to appropriately guide real-world practice., (Copyright © 2015 by American Society of Clinical Oncology.)

Background: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor tyrosine kinase signaling, have both been shown to provide clinical benefit in patients with advanced renal cell carcinoma (RCC). We sought to determine the safety and efficacy of combination therapy with these agents in patients with advanced RCC., Methods: We conducted a phase 1b dose escalation trial of sunitinib and everolimus in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary end point was to determine the maximum tolerated dose/recommended phase 2 dose., Results: A total of 4 out of a planned 30 subjects were enrolled onto this study (M:F = 2:2; mean age 52 years, 50% with Karnofsky performance status < 80). The first 3 patients were enrolled onto a 4 + 2 dosing schedule of daily sunitinib 50 mg and weekly everolimus 30 mg. Mean time receiving drug was 99 days. One partial response was seen. Toxicities included mucositis, thrombocytopenia, anemia, fatigue, dehydration, and hypoglycemia. Because of multiple grade 3 to 4 toxicities, the protocol was amended to 2 + 1 dosing of sunitinib 37.5 mg and daily everolimus 5 mg. The first patient on this schedule died from multiorgan failure with septic shock after 1 cycle of treatment. Subsequently, the study was closed. Pharmacokinetic results inconclusively suggest that toxicities could be attributed to the drug exposure., Conclusion: Combined use of everolimus and sunitinib in the treatment of metastatic RCC was not well tolerated in this small cohort., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: On the basis of evidence that resistance to vascular endothelial growth factor (VEGF) receptor inhibition is caused by hypoxia-driven residual VEGF and other proangiogenic factors, combinations of agents from these classes were hypothesized to improve treatment outcomes relative to single-agent VEGF pathway blockade., Patients and Methods: A total of 361 patients with metastatic clear cell renal cell carcinoma were randomly assigned equally to arm A (bevacizumab monotherapy 10 mg/kg intravenously [IV] every 2 weeks), B (bevacizumab 10 mg/kg IV every 2 weeks and temsirolimus 25 mg IV every week), C (bevacizumab 5 mg/kg IV every 2 weeks and sorafenib 200 mg orally twice daily on days 1 to 5, 8 to 12, 15 to 19, and 22 to 26), or D (sorafenib 200 mg twice daily and temsirolimus 25 mg IV weekly). Progression-free survival was the primary end point., Results: Among 331 eligible treated patients, median PFS was 7.5 months for bevacizumab alone (90% CI, 5.8 to 10.8 months), 7.6 months for bevacizumab plus temsirolimus (90% CI, 6.7 to 9.2 months), 9.2 months for bevacizumab plus sorafenib (90% CI, 7.5 to 11.4 months), and 7.4 months for sorafenib plus temsirolimus (90% CI, 5.6 to 7.9 months). Hazard ratios from stratified Cox proportional hazards models were 1.01, 0.89, and 1.07 (with respective P values of .95, .49, and .68) for the three combinations, respectively, compared with bevacizumab alone. Adverse events did not differ significantly among treatment arms., Conclusion: The activity of sorafenib, temsirolimus, and bevacizumab administered in doublet combinations did not significantly improve median progression-free survival in comparison with bevacizumab monotherapy., (© 2015 by American Society of Clinical Oncology.)

Background: With the advent of small-molecule "targeted" therapies, the prevailing treatment paradigm for metastatic renal cell carcinoma (mRCC) is that all patients who are able to tolerate systemic therapy should receive it. However, oncologists often defer the initiation of systemic therapy for patients with mRCC. The outcomes of and clinical reasoning behind the initial management of patients with mRCC without systemic therapy have not been well described., Methods: We conducted a retrospective cohort study of all patients with mRCC treated within the Duke University Health System and diagnosed from January 1, 2007, to January 1, 2011. We defined our cohort as patients who did not receive systemic therapy during the first year after mRCC diagnosis. The clinical rationale for the lack of immediate treatment was ascertained by manual chart review., Results: A total of 60 of 268 patients (22%) with mRCC managed without initial systemic therapy were included in our study. The median age was 61.2 years, the median duration from diagnosis of localized RCC to development of mRCC was 41.9 months, and 91% of patients had Eastern Cooperative Oncology Group functional status of ≤ 1. Of the patients, 60% were managed with surgical metastasectomy alone, 12% received multiple local treatment modalities, 13% received active surveillance, 7% were managed supportively, and 8% were categorized as "other.", Conclusions: The majority of patients in our cohort had favorable disease characteristics and experienced favorable outcomes with surgery alone. Our results suggest that this population could represent 20% of patients with mRCC in tertiary care settings. Prospective data are needed to evaluate deferred systemic therapy as a management strategy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Comparing prognostic factors for overall survival (OS) in community-practice metastatic renal cell carcinoma (mRCC) patients receiving second-line everolimus with those previously reported in clinical trials., Research Design and Methods: Two separate chart sets (2009 - 2012) were used to develop and validate a prognostic model for patients initiating second-line everolimus after first-line tyrosine kinase inhibitor (TKI)., Main Outcome Measures: Prognostic factors for OS have been identified and validated in separate samples., Results: One-year OS probabilities in the study (n = 220) and validation (n = 97) samples were 68 and 67%; median OS was 19 and 23 months - higher than the 1-year OS of 60% and median OS of 14.8 months of RECORD-1. Karnofsky performance score < 80%, duration of mRCC < 1 year, progression on first-line TKI, liver metastasis and clear cell histology were significant prognostic factors for shorter survival. One-year OS estimates were 84% for validation sample patients with 0 - 2 risk factors, 63% for 3 risk factors and 22% for 4 - 5 risk factors (log-rank p < 0.001)., Conclusion: Real-world prognostic factors for OS following second-line everolimus for mRCC were largely consistent with those previously identified in trial data; however, OS was longer in the practice setting than in clinical trials and was not associated with type of first-line TKI.