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Background: The detection of occult bone metastases is a key factor in determining the management of patients with renal cell carcinoma (RCC), especially when curative surgery is considered. This prospective study assessed the sensitivity of 18F-labelled sodium fluoride in conjunction with positron emission tomography/computed tomography (18FNaF PET/CT) for detecting RCC bone metastases, compared with conventional imaging by bone scintigraphy or CT. Patients and methods: An adaptive two-stage trial design was utilized, which was stopped after the first stage due to statistical efficacy. Ten patients with stage IV RCC and bone metastases were imaged with 18F-NaF PET/CT and 99mTc-labelled methylene diphosphonate (99mTc-MDP) bone scintigraphy including pelvic single photon emission computed tomography (SPECT). Images were reported independently by experienced radiologists and nuclear medicine physicians using a 5-point scoring system. Results: Seventy-seven lesions were diagnosed as malignant: 100% were identified by 18F-NaF PET/CT, 46% by CT and 29% by bone scintigraphy/SPECT. Standard-of-care imaging with CT and bone scintigraphy identified 65% of the metastases reported by 18F-NaF PET/CT. On an individual patient basis, 18F-NaF PET/CT detected more RCC metastases than 99mTc-MDP bone scintigraphy/SPECT or CT alone (P = 0.007). The metabolic volumes, mean and maximum standardized uptake values (SUVmean and SUVmax) of the malignant lesions were significantly greater than those of the benign lesions (P < 0.001). Conclusions: 18F-NaF PET/CT is significantly more sensitive at detecting RCC skeletal metastases than conventional bone scintigraphy or CT. The detection of occult bone metastases could greatly alter patient management, particularly in the context when standard-of-care imaging is negative for skeletal metastases. [ABSTRACT FROM AUTHOR]

Allograft recipients are often unwell with significant organ dysfunction by the time delayed or failed engraftment is diagnosed. We attempted to identify factors associated with graft failure, or death due to infection, hemorrhage or graft failure in 712 patients undergoing allogeneic BMT. Low leukocyte counts between days 12 and 22 were strongly associated with subsequent graft failure or death. In multivariate analysis, a leukocyte count of 0.2 × 109/l on day 16 was the most powerful predictor of graft failure or death. Transplants from HLA-mismatched and unrelated donors were also associated with increased risk of both, and T cell depletion with increased risk of graft failure. On the basis of these findings, it may be possible to define graft failure in functional terms as early as 2 weeks after BMT rather than at 3 or 4 weeks. The use of growth factors can then be limited to patients most likely to benefit from them, and it may be possible to salvage patients at risk of complications of low counts early before their clinical condition deteriorates. We suggest that patients with leukocyte counts of 0.2 x 109/l or less 14–16 days after BMT should be started on G-CSF or GM-CSF even if they are clinically well, and consideration should be given to a second infusion of cells. [ABSTRACT FROM AUTHOR]

Background: Sorafenib is an orally available kinase inhibitor with activity at Raf, PDGFβ and VEGF receptors that is licensed for the treatment of advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). Current evidence-based post-nephrectomy management of individuals with localized RCC consists of surveillance-based follow up. The SORCE trial is designed to investigate whether treatment with adjuvant sorafenib can reduce recurrence rates in this cohort.Case Presentation: Here we report an idiosyncratic reaction to sorafenib resulting in fatal hepatotoxicity and associated renal failure in a 62 year-old man treated with sorafenib within the SORCE trial.Conclusion: This is the first reported case of sorafenib exposure associated fatal toxicity in the adjuvant setting and highlights the unpredictable adverse effects of novel adjuvant therapies. [ABSTRACT FROM AUTHOR]

Background: There is interest in using treatment breaks in oncology, to reduce toxicity without compromising efficacy., Trial Design: A Phase II/III multicentre, open-label, parallel-group, randomised controlled non-inferiority trial assessing treatment breaks in patients with renal cell carcinoma., Methods: Patients with locally advanced or metastatic renal cell carcinoma, starting tyrosine kinase inhibitor as first-line treatment at United Kingdom National Health Service hospitals., Interventions: At trial entry, patients were randomised (1 : 1) to a drug-free interval strategy or a conventional continuation strategy. After 24 weeks of treatment with sunitinib/pazopanib, drug-free interval strategy patients took up a treatment break until disease progression with additional breaks dependent on disease response and patient choice. Conventional continuation strategy patients continued on treatment. Both trial strategies continued until treatment intolerance, disease progression on treatment, withdrawal or death., Objective: To determine if a drug-free interval strategy is non-inferior to a conventional continuation strategy in terms of the co-primary outcomes of overall survival and quality-adjusted life-years., Co-Primary Outcomes: For non-inferiority to be concluded, a margin of ≤ 7.5% in overall survival and ≤ 10% in quality-adjusted life-years was required in both intention-to-treat and per-protocol analyses. This equated to the 95% confidence interval of the estimates being above 0.812 and -0.156, respectively. Quality-adjusted life-years were calculated using the utility index of the EuroQol-5 Dimensions questionnaire., Results: Nine hundred and twenty patients were randomised (461 conventional continuation strategy vs. 459 drug-free interval strategy) from 13 January 2012 to 12 September 2017. Trial treatment and follow-up stopped on 31 December 2020. Four hundred and eighty-eight (53.0%) patients [240 (52.1%) vs. 248 (54.0%)] continued on trial post week 24. The median treatment-break length was 87 days. Nine hundred and nineteen patients were included in the intention-to-treat analysis (461 vs. 458) and 871 patients in the per-protocol analysis (453 vs. 418). For overall survival, non-inferiority was concluded in the intention-to-treat analysis but not in the per-protocol analysis [hazard ratio (95% confidence interval) intention to treat 0.97 (0.83 to 1.12); per-protocol 0.94 (0.80 to 1.09) non-inferiority margin: 95% confidence interval ≥ 0.812, intention to treat: 0.83 > 0.812 non-inferior, per-protocol: 0.80 < 0.812 not non-inferior]. Therefore, a drug-free interval strategy was not concluded to be non-inferior to a conventional continuation strategy in terms of overall survival. For quality-adjusted life-years, non-inferiority was concluded in both the intention-to-treat and per-protocol analyses [marginal effect (95% confidence interval) intention to treat -0.05 (-0.15 to 0.05); per-protocol 0.04 (-0.14 to 0.21) non-inferiority margin: 95% confidence interval ≥ -0.156]. Therefore, a drug-free interval strategy was concluded to be non-inferior to a conventional continuation strategy in terms of quality-adjusted life-years., Limitations: The main limitation of the study is the fewer than expected overall survival events, resulting in lower power for the non-inferiority comparison., Future Work: Future studies should investigate treatment breaks with more contemporary treatments for renal cell carcinoma., Conclusions: Non-inferiority was shown for the quality-adjusted life-year end point but not for overall survival as pre-defined. Nevertheless, despite not meeting the primary end point of non-inferiority as per protocol, the study suggested that a treatment-break strategy may not meaningfully reduce life expectancy, does not reduce quality of life and has economic benefits. Although the treating clinicians' perspectives were not formally collected, the fact that clinicians recruited a large number of patients over a long period suggests support for the study and provides clear evidence that a treatment-break strategy for patients with renal cell carcinoma receiving tyrosine kinase inhibitor therapy is feasible., Trial Registration: This trial is registered as ISRCTN06473203., Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Programme (NIHR award ref: 09/91/21) and is published in full in Health Technology Assessment ; Vol. 28, No. 45. See the NIHR Funding and Awards website for further award information.

Here, in a multi-ancestry genome-wide association study meta-analysis of kidney cancer (29,020 cases and 835,670 controls), we identified 63 susceptibility regions (50 novel) containing 108 independent risk loci. In analyses stratified by subtype, 52 regions (78 loci) were associated with clear cell renal cell carcinoma (RCC) and 6 regions (7 loci) with papillary RCC. Notably, we report a variant common in African ancestry individuals ( rs7629500 ) in the 3' untranslated region of VHL, nearly tripling clear cell RCC risk (odds ratio 2.72, 95% confidence interval 2.23-3.30). In cis-expression quantitative trait locus analyses, 48 variants from 34 regions point toward 83 candidate genes. Enrichment of hypoxia-inducible factor-binding sites underscores the importance of hypoxia-related mechanisms in kidney cancer. Our results advance understanding of the genetic architecture of kidney cancer, provide clues for functional investigation and enable generation of a validated polygenic risk score with an estimated area under the curve of 0.65 (0.74 including risk factors) among European ancestry individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma., Methods: This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16., Findings: Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1)., Interpretation: Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma., Funding: UK National Institute for Health and Care Research., Competing Interests: Declaration of interests JEB reports having served as a consultant or adviser for Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; honoraria from Novartis, Ipsen, Amgen, Merck Sharp & Dohme, Bristol-Myers Squibb, and Bayer; research funding paid to their institution from the National Institute for Health and Care Research; and travel expenses from Ipsen. WG reports consulting fees from Janssen and AbbVie. CR reports honoraria from Bristol-Myers Squibb and Wisai. TE reports trusteeship of Kidney Cancer UK and MacMillan Cancer Support. PN reports consulting fees from Novartis, Agensis, Ionctura, Bristol-Myers Squibb, 4SC, Pfizer, Merck Sharp & Dohme, and Merck; honoraria from Novartis and Immunocore; travel, accommodation, and expenses from Immunocore; membership of REFINE Data Safety Monitoring Board; and trusteeship of Melanoma Focus. TP reports consulting fees from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics, and Mashup; honoraria from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Seattle Genetics; research funding paid to their institution from Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Seattle Genetics; and travel expenses from AstraZeneca, Ipsen, Merck Sharp & Dohme, Pfizer, and Roche. RJ reports consulting fees from Astellas Pharma, Bayer, Bristol-Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Roche; honoraria from Astellas Pharma, Bayer, Bristol- Myers Squibb, Ipsen, Janssen, Merck Serono, Merck Sharp & Dohme, Pfizer, Roche; research funding paid to their institution from Astellas Pharma, Clovis, Exelixis, and Bayer; and participation in a data safety monitoring board for Roche. NV reports consultancy fees from Bristol-Myers Squibb, 4D Pharma, and Merck Serono; honoraria from Bristol-Myers Squibb, EUSA Pharma, Eisai, and Ipsen; and travel expenses from Ipsen. MW reports consultancy fees from Bristol-Myers Squibb and Sciensus; honoraria from Eisai and Ipsen; and travel expenses from Bristol-Myers Squibb. TW reports honoraria from Bristol-Myers Squibb, Pfizer, Eisai, and Ipsen; travel expenses from Bristol-Myers Squibb, EUSA Pharma, and Ipsen; and participation on data safety monitoring boards for Bristol-Myers Squibb, Pfizer, Eisai, Ipsen, and Merck Sharp & Dohme. RM reports travel expenses from Janssen. PP reports research funding paid to their institution from Pfizer. JL reports consultancy fees from iOnctura, Apple Tree, Merck, Bristol-Myers Squibb, Eisai, Debipharm, and Incyte; honoraria from Eisai, Novartis, Incyte, Merck, TouchIME, TouchEXPERTS, Pfizer, Royal College of Physicians, Cambridge Healthcare, Royal College of General Practioners, VJ Oncology, and Agence Unik; research funding paid to their institution from Achilles, Bristol-Myers Squibb, Merck Sharp & Dohme, Nektar, Novartis, Pfizer, Immunocore, Roche, Aveo, and Pharmacyclics; and travel expenses from Pierre Fabre, Roche, and GlaxoSmithKline. GF reports consultancy fees from Bristol-Myers Squibb and Pfizer; honoraria from Bristol-Myers Squibb, Merck, and Pfizer; and travel expenses from Novartis and Bayer. DM reports funding from Otsuka and AbbVie to their institution; being a sub-panel member for the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research; and being a member of a National Institute for Health and Care Excellence Technology Appraisal Committee. VG reports funding from Siemens Healthineers to their institution. TMW reports research funding paid to their institution from Boston Scientific and Angidynamics. JBr reports being Chair of the NIHR Health Technology Assessment General Funding Committee and NIHR Health Technology Assessment funding paid to their institution. JH reports funding to their institution from the NIHR Health Technology Assessment. PS reports funding from an NIHR Senior Fellowship, European Research Council Advanced Awards; travel expenses from the European School of Oncology Training; and several patents on the development of DNA library cancer vaccines. FC reports honoraria from Bayer. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Surgery for renal cell carcinoma (RCC) with venous tumour thrombus (VTT) extension into the renal vein (RV) and/or inferior vena cava (IVC) has high peri-surgical morbidity/mortality. NAXIVA assessed the response of VTT to axitinib, a potent tyrosine kinase inhibitor., Methods: NAXIVA was a single-arm, multi-centre, Phase 2 study. In total, 20 patients with resectable clear cell RCC and VTT received upto 8 weeks of pre-surgical axitinib. The primary endpoint was percentage of evaluable patients with VTT improvement by Mayo level on MRI. Secondary endpoints were percentage change in surgical approach and VTT length, response rate (RECISTv1.1) and surgical morbidity., Results: In all, 35% (7/20) patients with VTT had a reduction in Mayo level with axitinib: 37.5% (6/16) with IVC VTT and 25% (1/4) with RV-only VTT. No patients had an increase in Mayo level. In total, 75% (15/20) of patients had a reduction in VTT length. Overall, 41.2% (7/17) of patients who underwent surgery had less invasive surgery than originally planned. Non-responders exhibited lower baseline microvessel density (CD31), higher Ki67 and exhausted or regulatory T-cell phenotype., Conclusions: NAXIVA provides the first Level II evidence that axitinib downstages VTT in a significant proportion of patients leading to reduction in the extent of surgery., Clinical Trial Registration: NCT03494816., (© 2022. The Author(s).)

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Purpose: The 2003 Leibovich score guides prognostication and selection to adjuvant clinical trials for patients with locally advanced renal cell carcinoma (RCC) after nephrectomy. We provide a robust external validation of the 2003 Leibovich score using contemporary data from SORCE, an international, randomized trial of sorafenib after excision of primary RCC., Methods: Data used to derive the 2003 Leibovich score were compared with contemporary data from SORCE. Discrimination and calibration of the metastasis-free survival outcome were assessed in data from patients with clear-cell RCC, using Cox proportional hazards regression, Kaplan-Meier curves, and calculation of Harrell's c indexes. Secondary analyses involved three important SORCE groups: patients with any non-clear-cell subtype, papillary, and chromophobe carcinomas., Results: Four hundred seven recurrences occurred in 982 patients in the Leibovich cohort and 520 recurrences were recorded in 1,445 patients in the primary SORCE cohort. Clear discrimination between intermediate-risk and high-risk SORCE cohorts was shown; hazard ratio 2.74 (95% CI, 2.29 to 3.28), c-index 0.63 (95% CI, 0.61 to 0.65). A hazard ratio of 0.61 (95% CI, 0.53 to 0.70) confirmed poor calibration of the two cohorts. Discrimination was observed in secondary populations, with c-indexes of 0.64 (95% CI, 0.59 to 0.69) for non-clear-cell RCC, 0.63 (95% CI, 0.56 to 0.69) for papillary RCC, and 0.65 (95% CI, 0.55 to 0.76) for chromophobe RCC., Conclusion: The 2003 Leibovich score discriminates between intermediate-risk and high-risk clear-cell and non-clear-cell RCC groups in contemporary data, supporting its use for risk stratification in adjuvant clinical trials. Over time, metastasis-free survival for patients with locally advanced RCC has improved. Contemporary data from adjuvant RCC trials should be used to improve prognostication for patients with RCC., Competing Interests: Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported. Tim EisenEmployment: AstraZeneca, RocheLeadership: AstraZeneca, RocheStock and Other Ownership Interests: AstraZeneca, RocheResearch Funding: Bayer (Inst), Pfizer (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: AstraZeneca, RocheOther Relationship: Macmillan Cancer Support, Kidney Cancer UK Grant D. StewartHonoraria: Pfizer, Merck, EUSA PharmaConsulting or Advisory Role: Pfizer, Merck, EUSA Pharma, CMR SurgicalSpeakers' Bureau: PfizerResearch Funding: Pfizer, AstraZeneca, Intuitive Surgical, CRUKTravel, Accommodations, Expenses: Pfizer Axel BexConsulting or Advisory Role: Pfizer (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Ipsen (Inst), Eisai (Inst), Genentech (Inst)Speakers' Bureau: Pfizer, Novartis, Bristol Myers SquibbResearch Funding: Pfizer (Inst) Rick KaplanResearch Funding: AstraZeneca (Inst) Ian D. DavisResearch Funding: Astellas Pharma (Inst), Pfizer (Inst), Roche/Genentech (Inst), MSD Oncology (Inst), AstraZeneca (Inst), Janssen Oncology (Inst), Eisai (Inst), Bayer (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Movember Foundation (Inst), Exelixis (Inst), Ipsen (Inst), Medivation (Inst), Seattle Genetics (Inst), ANZUP Cancer Trials GroupPatents, Royalties, Other Intellectual Property: International Patent Application No: PCT/US2004/032147 (NY-ESO-1) through Ludwig Institute for Cancer Research Martin R. StocklerResearch Funding: Astellas Pharma (Inst), Celgene (Inst), Bayer (Inst), Bionomics (Inst), Medivation (Inst), Sanofi (Inst), Pfizer (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Roche (Inst), Amgen (Inst), Merck Sharp & Dohme (Inst), Tilray (Inst), BeiGene (Inst)Travel, Accommodations, Expenses: Medivation/Pfizer Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Amgen (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Exelixis (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Peloton Therapeutics (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Bernard EscudierHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, OncorenaConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Ipsen, AVEO, OncorenaResearch Funding: BMS France (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Ipsen, MSD James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, Merck Serono, Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), MSD (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, Merck Serono, iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV Mais Steven JoniauConsulting or Advisory Role: Janssen, AstraZeneca, Bayer, Astellas PharmaSpeakers' Bureau: Astellas Pharma, Janssen, IpsenResearch Funding: Janssen (Inst), Astellas Pharma (Inst), Ipsen (Inst), Bayer (Inst), Ferring (Inst)Travel, Accommodations, Expenses: Janssen, Ipsen, Astellas Pharma, Ferring Joaquim BellmuntStock and Other Ownership Interests: Rainier TherapeuticsHonoraria: UpToDateConsulting or Advisory Role: Pierre Fabre, Astellas Pharma, Pfizer, Merck, Genentech, Novartis, AstraZeneca/MedImmune, Bristol Myers SquibbResearch Funding: Millennium (Inst), Sanofi (Inst), Pfizer/EMD Serono (Inst)Travel, Accommodations, Expenses: Pfizer, MSD Oncology, Ipsen Mahesh K.B. ParmarResearch Funding: AstraZeneca (Inst), Astellas Pharma (Inst), Janssen (Inst), Clovis Oncology (Inst) Angela MeadeResearch Funding: AstraZeneca (Inst)No other potential conflicts of interest were reported.

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1- 13 C]pyruvate (HP- 13 C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP- 13 C-MRI and conventional proton ( 1 H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant ( k PL ) between 13 C-pyruvate and 13 C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing k PL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1 H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset ( p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP- 13 C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP- 13 C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Objective: This study offers direction for interaction between physical therapists and patients about cancer-related pain during physical training. The study may increase awareness of rehabilitation strategies for cancer-related pain during and after cancer treatment. Methods: Qualitative study, evaluating results of two qualitative studies. Data has been collected using semi-structured interviews, in which topics were discussed with patients and physical therapists. Respondents were adult patients with cancer in the Northern Netherlands with moderate to severe pain who followed physical training with a (oncologic) physical therapist. The physical therapists were respondents specialized in oncology and working with patients with cancer in a primary care setting in in the Netherlands. Data were analyzed using thematic analysis. Results: Eighteen patients and fifteen physical therapists were interviewed. Data was categorized in statements regarding "patients' needs", "patients' experiences" and "clinical reasoning of the physical therapist". "Patients' needs" for education were personal and included needs for information about the cause, course and effect of pain in relation to cancer and/or medical treatment, needs for practical tools for reducing pain, needs for strategies dealing with pain in daily activities, and needs for information about additional treatment and care options. When discussing 'patients' experiences', patients mentioned that physical therapists are cautious to express their expectations of the progress of pain and to offer pain education with respect to the cause of pain, dealing with pain and limitations in daily life, exercising, posture, learning self-care and information about additional treatment and care options in cancer-related pain. Patients provided insight into their educational, mental, and social support relative to experiences with physical therapists. Additionally, when discussing the communication they experienced with physical therapists, patients used descriptors such as accessibility, empathy, trust, knowledge and eliminating uncertainties. Interviews with physical therapists regarding their clinical reasoning process in cancer-related pain described that they identified pain from anamnesis (medical history review) and performed screening and analysis for pain secondary to cancer (treatment), as type of pain and pain influencing factors. Thoughts and experiences about pain, the use of pain clinometry, the establishment of objectives and interventions for physical therapy and multidisciplinary treatment of cancer-related pain were also described. Conclusion: Patients with cancer-related pain during physical training have personal needs regarding pain education and experience that specialized oncologic physical therapists focus on patient-centered information and self-management support. Specialized oncologic physical therapists analyze pain in the anamnesis and keep in mind the origin and impact of pain for the patient during screening and treatment. Different methods of pain management are used. It is recommended that physical therapists who give physical training take the initiative to repeatedly discuss pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eisen, Kooijstra, Groeneweg, Verseveld and Hidding.)

Introduction: Pharmacological combinations using immune checkpoint inhibition (ICI), tyrosine kinase inhibition (TKIs), and mammalian target of rapamycin inhibitors (mTOR) have improved survival in metastatic clear cell renal cell cancer (mccRCC). Despite improvements in survival, complete durable responses are rare., Areas Covered: Molecular pathways involved in mccRCC and drugs targets are highlighted. The background and rationale for combination therapy are covered. Results from combination trials are reviewed and potential approaches with biomarker-stratified treatment and novel experimental agents are examined. PubMed Central and ClinicalTrials.gov were searched. Search terms used to identify clinical trials were '(metastatic renal cell cancer OR renal cell carcinoma OR mccRCC OR mRCC OR RCC OR kidney cancer) AND (combination OR combined).', Expert Opinion: First-line standard of care has moved to combination therapy with ICI-ICI and TKI-ICI combinations; VEGF-mTORi is available in subsequent lines. Combining targeted treatments without validated biomarkers is imprecise, and combinations may lead to overtreatment of a subset of patients, exposing them to unnecessary toxicity. The aim of combinations must be clear: improvement in overall survival (OS) and complete response (CR). Recent data suggest a role for novel biomarker stratification rather traditional risk groups. Further combination approaches with triplets and quadruplets should be biomarker directed.

Background: Window-of-opportunity trials, evaluating the engagement of drugs with their biological target in the time period between diagnosis and standard-of-care treatment, can help prioritise promising new systemic treatments for later-phase clinical trials. Renal cell carcinoma (RCC), the 7 th commonest solid cancer in the UK, exhibits targets for multiple new systemic anti-cancer agents including DNA damage response inhibitors, agents targeting vascular pathways and immune checkpoint inhibitors. Here we present the trial protocol for the WIndow-of-opportunity clinical trial platform for evaluation of novel treatment strategies in REnal cell cancer (WIRE)., Methods: WIRE is a Phase II, multi-arm, multi-centre, non-randomised, proof-of-mechanism (single and combination investigational medicinal product [IMP]), platform trial using a Bayesian adaptive design. The Bayesian adaptive design leverages outcome information from initial participants during pre-specified interim analyses to determine and minimise the number of participants required to demonstrate efficacy or futility. Patients with biopsy-proven, surgically resectable, cT1b+, cN0-1, cM0-1 clear cell RCC and no contraindications to the IMPs are eligible to participate. Participants undergo diagnostic staging CT and renal mass biopsy followed by treatment in one of the treatment arms for at least 14 days. Initially, the trial includes five treatment arms with cediranib, cediranib + olaparib, olaparib, durvalumab and durvalumab + olaparib. Participants undergo a multiparametric MRI before and after treatment. Vascularised and de-vascularised tissue is collected at surgery. A ≥ 30% increase in CD8+ T-cells on immunohistochemistry between the screening and nephrectomy is the primary endpoint for durvalumab-containing arms. Meanwhile, a reduction in tumour vascular permeability measured by K trans on dynamic contrast-enhanced MRI by ≥30% is the primary endpoint for other arms. Secondary outcomes include adverse events and tumour size change. Exploratory outcomes include biomarkers of drug mechanism and treatment effects in blood, urine, tissue and imaging., Discussion: WIRE is the first trial using a window-of-opportunity design to demonstrate pharmacological activity of novel single and combination treatments in RCC in the pre-surgical space. It will provide rationale for prioritising promising treatments for later phase trials and support the development of new biomarkers of treatment effect with its extensive translational agenda., Trial Registration: ClinicalTrials.gov: NCT03741426 / EudraCT: 2018-003056-21 ., (© 2021. The Author(s).)

Purpose: To detect early response to sunitinib treatment in metastatic clear cell renal cancer (mRCC) using multiparametric MRI., Method: Participants with mRCC undergoing pre-surgical sunitinib therapy in the prospective NeoSun clinical trial (EudraCtNo: 2005-004502-82) were imaged before starting treatment, and after 12 days of sunitinib therapy using morphological MRI sequences, advanced diffusion-weighted imaging, measurements of R2* (related to hypoxia) and dynamic contrast-enhanced imaging. Following nephrectomy, participants continued treatment and were followed-up with contrast-enhanced CT. Changes in imaging parameters before and after sunitinib were assessed with the non-parametric Wilcoxon signed-rank test and the log-rank test was used to assess effects on survival., Results: 12 participants fulfilled the inclusion criteria. After 12 days, the solid and necrotic tumor volumes decreased by 28% and 17%, respectively (p = 0.04). However, tumor-volume reduction did not correlate with progression-free or overall survival (PFS/OS). Sunitinib therapy resulted in a reduction in median solid tumor diffusivity D from 1298x10-6 to 1200x10-6mm2/s (p = 0.03); a larger decrease was associated with a better RECIST response (p = 0.02) and longer PFS (p = 0.03) on the log-rank test. An increase in R2* from 19 to 28s-1 (p = 0.001) was observed, paralleled by a decrease in Ktrans from 0.415 to 0.305min-1 (p = 0.01) and a decrease in perfusion fraction from 0.34 to 0.19 (p<0.001)., Conclusions: Physiological imaging confirmed efficacy of the anti-angiogenic agent 12 days after initiating therapy and demonstrated response to treatment. The change in diffusivity shortly after starting pre-surgical sunitinib correlated to PFS in mRCC undergoing nephrectomy, however, no parameter predicted OS., Trial Registration: EudraCtNo: 2005-004502-82., Competing Interests: The authors have read the journal’s policy and have the following competing interests: ANP has received a speaker fee and travel expenses from GE Healthcare. SJW has received travel expenses from IPSEN. GDS has received educational grants from Pfizer, Astra Zeneca, and Intuitive Surgical; consultancy fees from Merck, Pfizer, EUSA Pharma and CMR Surgical; travel expenses and speaker fees from Pfizer. AW received a single Scientific Advisory Board fee from Roche. TE has received research support from Pfizer and AstraZeneca, and honoraria from Pfizer. TE was employed by AstraZeneca during part of the study duration and is now employed by Roche, and holds stock in AstraZeneca and Roche. Pfizer provided the study drug Sunitinib and an educational grant for the translational endpoint analysis, reported separately. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Background: The NLST reported a significant 20% reduction in lung cancer mortality with three annual low-dose CT (LDCT) screens and the Dutch-Belgian NELSON trial indicates a similar reduction. We present the results of the UKLS trial., Methods: From October 2011 to February 2013, we randomly allocated 4 055 participants to either a single invitation to screening with LDCT or to no screening (usual care). Eligible participants (aged 50-75) had a risk score (LLPv2) ≥ 4.5% of developing lung cancer over five years. Data were collected on lung cancer cases to 31 December 2019 and deaths to 29 February 2020 through linkage to national registries. The primary outcome was mortality due to lung cancer. We included our results in a random-effects meta-analysis to provide a synthesis of the latest randomised trial evidence., Findings: 1 987 participants in the intervention and 1 981 in the usual care arms were followed for a median of 7.3 years (IQR 7.1-7.6), 86 cancers were diagnosed in the LDCT arm and 75 in the control arm. 30 lung cancer deaths were reported in the screening arm, 46 in the control arm, (relative rate 0.65 [95% CI 0.41-1.02]; p=0.062). The meta-analysis indicated a significant reduction in lung cancer mortality with a pooled overall relative rate of 0.84 (95% CI 0.76-0.92) from nine eligible trials., Interpretation: The UKLS trial of single LDCT indicates a reduction of lung cancer death of similar magnitude to the NELSON and NLST trials and was included in a meta-analysis of nine randomised trials which provides unequivocal support for lung cancer screening in identified risk groups., Funding: NIHR Health Technology Assessment programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation., Competing Interests: JKF has received fees from AstraZeneca (Speaker's Bureau) and advisory boards of Epigenomics; NUCLEIX Ltd. AstraZeneca, iDNA; Grant Support: Janssen Research & Development, LLC. RCR is on the advisory boards of AstraZeneca and Roche. DRB has received speaker remuneration from AstraZeneca, Roche, MSD, BMS, Johnson and Johnson. KB has received personal fees from Astra Zeneca outside the submitted work. TE receives research support from AstraZeneca, Bayer, Pfizer; is employed by Roche (from March 2020) and was employed by AstraZeneca (to March 2020) and has stock in AstraZeneca and Roche; is a trustee of Macmillan Cancer Support.  AN has current grants and contracts with BRC, DART; Honoraria Aidence BV, AstraZeneca; Support from BLF, and as the clinical lead for NTLHC. No competing interests from all other co-authors., (© 2021 The Authors.)

The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations. Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39. CTA #: 20363/0380/001-0001. MREC #: 17/LO/1875. ClinicalTrials.gov Identifier: NCT03288532 RAMPART grant number: MC&#95;UU&#95;12023/25. . RAMPART Protocol version 5.0., (Copyright © 2021. Published by Elsevier Inc.)

Background: 20-60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting., Methods/design: RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3-11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART)., Trial Registration: ISRCTN #: ISRCTN53348826, NCT #: NCT03288532, EUDRACT #: 2017-002329-39, CTA #: 20363/0380/001-0001, MREC #: 17/LO/1875, ClinicalTrials.gov Identifier: NCT03288532, RAMPART grant number: MC&#95;UU&#95;12023/25, TransRAMPART grant number: A28690 Cancer Research UK, RAMPART Protocol version 5.0., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

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.)

Background: The treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex., Materials and Methods: We performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations., Results: Diverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib., Conclusion: A wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice., Competing Interests: Disclosure SA: MSD (C/A), Sanofi-Genzyme (C/A) recipient: my institution. MSchmaus: none. TE: AstraZeneca Personal: (RF, E, OI), Bayer (RF), Pfizer (RF), Roche (E, OI); Institution: AstraZeneca (RF), Roche (RF). BE: Pfizer (C/A), BMS (C/A), Ipsen (C/A), Roche (C/A), Oncorena (C/A), Aveo (C/A). VG: Astra Zeneca (CA, H, OI; RF), Bristol-Myers Squibb (C/A, H, OI; RF), Roche Pharma AG (C/A, H), MSD Oncology (C/A, H, OI; RF), Ipsen (C/A, H; RF), Bayer (H; RF), Merck Serono (C/A, H), Janssen Cliag (C/A, H), Pfizer (C/A, H), Lilly (C/A, H), PharmaMar (H), EUSAPharm (C/A, H), Novartis (C/A, H, RF), EISAI (H), Onkowissen (C/A). JL: Achilles Therapeutics (C/A, grant support), Bristol-Myers Squibb (C/A, grant support), Merck Sharp & Dohme (C/A, grant support), Nektar (C/A, grant support), Novartis (C/A, grant support), Pfizer (C/A, grant support), Roche–Genentech (C/A, grant support), Immunocore (C/A, grant support), AstraZeneca (C/A), Boston Biomedical (C/A), Eisai (C/A), EUSA Pharma (C/A), GlaxoSmithKline (C/A), Ipsen (C/A), Imugen (C/A), Incyte (C/A), iOnctura (C/A), Kymab (C/A), Merck Serono (C/A), Pierre Fabre (C/A), Secama (C/A), Vitaccess (C/A), Covance (C/A), Aveo (C/A), Pharmacyclics (C/A). DMcD: BMS (H, C/A), Pfizer (H, C/A), Merck (H, C/A), Alkermes, Inc. (H, C/A). JO: none. CP: Bristol-Myers Squibb (personal fees), Merck Sharpe & Dohme (personal fees), Novartis (personal fees), Ipsen (personal fees), EUSA (personal fees), Eisai (personal fees), Janssen (personal fees), AstraZeneca (personal fees), General Electric (personal fees), Pfizer (grants and personal fees). BIR: Merck (C/A), BMS (C/A), AVEO (C/A), Pfizer (C/A), Roche (C/A), Pfizer (RF), Merck (RF), BMS (RF), AVEO (RF), Astra-Zeneca (RF), Roche (RF). MSchmidinger: Pfizer, BMS, Ipsen, MSD, Merck, Exelixis, EISAI, EUSA, Roche, Novartis, Alkermes. CNS: Pfizer (C/A), MSD (C/A), Merck (C/A), AstraZeneca (C/A), Astellas (C/A), Sanofi-Genzyme (C/A), Roche-Genentech (C/A), Incyte (C/A). CR: Pfizer (C/A), Bristol-Myers Squibb (C/A), Roche Pharma AG (C/A), MSD Oncology (C/A), Merck (Schweiz) AG (C/A) recipient for all: my institution. Astellas Pharma (RF) recipient: my institution. PMP: AstraZeneca (RF), Celgene (RF), Takeda (RF): Educational grants to the institution. Legend: (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: SORCE is an international, randomized, double-blind, three-arm trial of sorafenib after surgical excision of primary renal cell carcinoma (RCC) found to be at intermediate or high risk of recurrence., Patients and Methods: We randomly assigned participants (2:3:3) to 3 years of placebo (arm A), 1 year of sorafenib followed by 2 years of placebo (arm B), or 3 years of sorafenib (arm C). The initial sorafenib dose was 400 mg twice per day orally, amended to 400 mg daily. The primary outcome analysis, which was revised as a result of external results, was investigator-reported disease-free survival (DFS) comparing 3 years of sorafenib versus placebo., Results: Between July 2007 and April 2013, we randomly assigned 1,711 participants (430, 642, and 639 participants in arms A, B, and C, respectively). Median age was 58 years, 71% of patients were men, 84% had clear cell histology, 53% were at intermediate risk of recurrence, and 47% were at high risk of recurrence. We observed no differences in DFS or overall survival in all randomly assigned patients, patients with high risk of recurrence, or patients with clear cell RCC only. Median DFS was not reached for 3 years of sorafenib or for placebo (hazard ratio, 1.01; 95% CI, 0.83 to 1.23; P = .95). We observed nonproportional hazards; the restricted mean survival time (RMST) was 6.81 years for 3 years of sorafenib and 6.82 years for placebo (RMST difference, 0.01 year; 95% CI, -0.49 to 0.48 year; P = .99). Despite offering treatment adaptations, more than half of participants stopped treatment by 12 months. Grade 3 hand-foot skin reaction was reported in 24% of participants on sorafenib., Conclusion: Sorafenib should not be used as adjuvant therapy for RCC. Active surveillance remains the standard of care for patients at intermediate or high risk of recurrence after nephrectomy and is the appropriate control of our current international adjuvant RCC trial, RAMPART., Competing Interests: Cancer Research UK and Bayer had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. Staff funded by the Medical Research Council and University College London contributed to study design, data collection, data analysis, data interpretation, and writing of this report.

Background: Patients with metastatic renal cell carcinoma (mRCC) treated with targeted systemic therapies have demonstrated favourable outcomes in randomised controlled trials, however real-world evidence is limited. Thus, this study aimed to determine the effectiveness of targeted systemic therapies for patients with mRCC in routine clinical practice in the UK., Methods: A retrospective, observational, longitudinal study based on chart review of newly diagnosed adult mRCC patients treated at two UK hospitals from 2008 to 2015 was conducted. Targeted systemic therapies recommended for use in mRCC patients were evaluated across first to third lines of therapy (1LOT-3LOT). Important exclusions were treatment with cytokine therapy and within non-standard of care clinical trials. Primary outcome measure was overall survival (OS); data were analysed descriptively and using Kaplan-Meyer analysis., Results: 652 patients (65.3% male, 35.0% ≥70 years) were included. In 1LOT, 98.5% of patients received sunitinib or pazopanib. In 2LOT and 3LOT, 99.0 and 94.4% received axitinib or everolimus. Median OS was 12.9, 6.5 and 5.9 months at 1LOT, 2LOT and 3LOT respectively. Estimated OS at 1-year was 52.4% (95% CI: 48.6-56.4%) in 1LOT, 31.5% (25.2-39.5%) in 2LOT and 23.8% (10.1-55.9%) in 3LOT. Median OS from 1LOT in favourable, intermediate and poor MSKCC were 39.7, 15.8 and 6.1 months respectively., Conclusions: In this study, treatment was consistent with current National Institute for Health and Care Excellence (NICE) guidelines for mRCC patients. Although the study population favoured poorer prognosis patients, outcomes were more favourable than those for England at the same time. However, overall survival in this 'real-world' population remains poor and indicates significant unmet need for effective and safe treatment options to improve survival among mRCC patients.

Background: The coronavirus pandemic has provoked discussions among healthcare providers how to manage cancer patients when faced with the threat of severe acute respiratory syndrome related coronavirus 2 (SARS-CoV-2) infection. Immune checkpoint inhibitor (ICI) containing regimens are standard of care in the majority of metastatic clear cell renal cell carcinoma (mccRCC) patients. It remains unclear whether therapies should be modified in response to the COVID-19 pandemic., Methods: We performed an online survey among physicians involved in the treatment of mccRCC, and 41 experts responded. Questions focused on criteria relevant for treatment decision outside the pandemic and the modifications of systemic therapy during COVID-19., Findings: For the majority of experts (73%), the combination of International metastatic renal cell carcinoma Database Consortium (IMDC) risk category and patient fitness are two important factors for decision-making. The main treatment choice in fit, favourable risk patients outside the pandemic is pembrolizumab/axitinib for 53%, avelumab/axitinib, sunitinib or pazopanib for 13% of experts each. During the pandemic, ICI-containing regimens are chosen less often in favour of a tyrosine kinase inhibitors (TKI) monotherapy, mainly sunitinib or pazopanib (35%).In fit, intermediate/poor-risk patients outside the pandemic, over 80% of experts choose ipilimumab/nivolumab, in contrast to only 41% of physicians during COVID-19, instead more TKI monotherapies are given. In patients responding to established therapies with ICI/ICI or ICI/TKI combinations, most participants modify treatment regimen by extending cycle length, holding one ICI or even both., Conclusion: mccRCC treatment modifications in light of the coronavirus pandemic are variable, with a shift from ICI/ICI to ICI/TKI or TKI monotherapy., Competing Interests: Competing interests: SA: MSD (C/A), Sanofi-Genzyme (C/A) recipient: my institution. TE: Personal: AstraZeneca (RF, E, OI), Bayer (RF), Pfizer (RF), Roche (E, OI); Institution: AstraZeneca (RF), Roche (RF). BE: Pfizer (C/A), BMS (C/A), Ipsen (C/A), Roche (C/A), Oncorena (C/A), Aveo (C/A). SF: Bayer (TS), Astellas (RF, TS). VG: Astra Zeneca (C/A, H, OI, RF), Bristol-Myers Squibb (C/A, H, OI, RF), Roche Pharma AG (C/A, H), MSD Oncology (C/A, H, OI, RF), Ipsen (C/A, H, RF), Bayer (H, RF), Merck Serono (C/A, H), Janssen Cliag (C/A, H), Pfizer (C/A, H), Lilly (C/A, H), PharmaMar (H), EUSAPharm (C/A, H), Novartis (C/A, H, RF), EISAI (H), Onkowissen (C/A). JML: Achilles Therapeutics (C/A, grant support), Bristol-Myers Squibb (C/A, grant support), Merck Sharp & Dohme (C/A, grant support), Nektar (C/A, grant support), Novartis (C/A, grant support), Pfizer (C/A, grant support), Roche–Genentech (C/A, grant support), Immunocore (C/A, grant support), AstraZeneca (C/A), Boston Biomedical (C/A), Eisai (C/A), EUSA Pharma (C/A), GlaxoSmithKline (C/A), Ipsen (C/A), Imugen (C/A), Incyte (C/A), iOnctura (C/A), Kymab (C/A), Merck Serono (C/A), Pierre Fabre (C/A), Secama (C/A), Vitaccess (C/A), Covance (C/A), Aveo (C/A), Pharmacyclics (C/A). DM: BMS (H, C/A), Pfizer (H, C/A), Merck (H, C/A), Alkermes, Inc. (H, C/A). AO: Personal: Astellas (TS), Bayer (TS), Sanofi (TS), Janssen (TS). Instituional: Astellas (C/A, SB), Bayer (C/A, SB), Sanofi (C/A), Roche (C/A), Janssen (C/A, RF, SB), MSD (C/A), Molecular Partners (C/A), Teva (RF). CP: Bristol-Myers Squibb (personal fees), Merck Sharpe & Dohme (personal fees), Novartis (personal fees), Ipsen (personal fees), EUSA (personal fees), Eisai (personal fees), Janssen (personal fees), AstraZeneca (personal fees), General Electric (personal fees), Pfizer (grants and personal fees). BR: Merck (C/A), BMS (C/A), AVEO (C/A), Pfizer (C/A), Roche(C/A), Pfizer (RF), Merck (RF), BMS (RF), AVEO (RF), Astra-Zeneca (RF), Roche (RF). MS: Pfizer, BMS, Ipsen, MSD, Merck, Exelixis, EISAI, EUSA, Roche, Novartis, Alkermes. CS: Pfizer (C/A), MSD (C/A), Merck (C/A), AstraZeneca (C/A), Astellas (C/A), Sanofi-Genzyme (C/A), Roche-Genentech (C/A), Incyte (C/A). CR: Pfizer (C/A), Bristol-Myers Squibb (C/A), Roche Pharma AG (C/A), MSD Oncology (C/A), Merck (Schweiz) AG (C/A) recipient for all: my institution. Astellas Pharma (RF) recipient: my institution. Legend: (C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (TS) Travel Support; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board, Speaker Bureau (SB)., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Anti-angiogenic agents, such as the multi-tyrosine kinase inhibitor sunitinib, are key first line therapies for metastatic clear cell renal cell carcinoma (ccRCC), but their mechanism of action is not fully understood. Here, we take steps towards validating a computational prediction based on differential transcriptome network analysis that phosphorylated adapter RNA export protein (PHAX) is associated with sunitinib drug treatment. The regulatory impact factor differential network algorithm run on patient tissue samples suggests PHAX is likely an important regulator through changes in genome-wide network connectivity. Immunofluorescence staining of patient tumours showed strong localisation of PHAX to the microvasculature consistent with the anti-angiogenic effect of sunitinib. In normal kidney tissue, PHAX protein abundance was low but increased with tumour grade (G1 vs. G3/4; p < 0.01), consistent with a possible role in cancer progression. In organ culture, ccRCC cells had higher levels of PHAX protein expression than normal kidney cells, and sunitinib increased PHAX protein expression in a dose dependent manner (untreated vs. 100 µM; p < 0.05). PHAX knockdown in a ccRCC organ culture model impacted the ability of sunitinib to cause cancer cell death ( p < 0.0001 untreated vs. treated), suggesting a role for PHAX in mediating the efficacy of sunitinib.

Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established., Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine., Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings., Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

Background: The current World Health Organization classification recognises 12 major subtypes of renal cell carcinoma (RCC). Although these subtypes differ on molecular and clinical levels, they are generally managed as the same disease, simply because they occur in the same organ. Specifically, there is a paucity of tools to risk-stratify patients with papillary RCC (PRCC). The purpose of this study was to develop and evaluate a tool to risk-stratify patients with clinically non-metastatic PRCC following curative surgery., Methods: We studied clinicopathological variables and outcomes of 556 patients, who underwent full resection of sporadic, unilateral, non-metastatic (T1-4, N0-1, M0) PRCC at five institutions. Based on multivariable Fine-Gray competing risks regression models, we developed a prognostic scoring system to predict disease recurrence. This was further evaluated in the 150 PRCC patients recruited to the ASSURE trial. We compared the discrimination, calibration and decision-curve clinical net benefit against the Tumour, Node, Metastasis (TNM) stage group, University of California Integrated Staging System (UISS) and the 2018 Leibovich prognostic groups., Results: We developed the VENUSS score from significant variables on multivariable analysis, which were the presence of VEnous tumour thrombus, NUclear grade, Size, T and N Stage. We created three risk groups based on the VENUSS score, with a 5-year cumulative incidence of recurrence equalling 2.9% in low-risk, 15.4% in intermediate-risk and 54.5% in high-risk patients. 91.7% of low-risk patients had oligometastatic recurrent disease, compared to 16.7% of intermediate-risk and 40.0% of high-risk patients. Discrimination, calibration and clinical net benefit from VENUSS appeared to be superior to UISS, TNM and Leibovich prognostic groups., Conclusions: We developed and tested a prognostic model for patients with clinically non-metastatic PRCC, which is based on routine pathological variables. This model may be superior to standard models and could be used for tailoring postoperative surveillance and defining inclusion for prospective adjuvant clinical trials.

Individuals appraise events as a consequence of their own actions (i.e. internal locus of control, LoC) or as the outcome of chance or others' will (i.e. external LoC). We hypothesized that having a more external LoC would be associated with higher risk of tobacco and alcohol use. Few studies have examined this association using large prospective data. We evaluated within the Avon Longitudinal Study of Parents and Children (ALSPAC) the associations between LoC at 16 and tobacco and alcohol consumption at 17 and 21 years using logistic regression. A more external LoC at age 16 ( N = 4656) was associated with higher odds of being a weekly smoker at age 17 (OR 1.18, 95% CI 1.10-1.25) and 21 (OR 1.14, 95% CI 1.07-1.21) and with dependence measured using the Fagerström Test of Nicotine Dependence at age 17 (OR 1.26, 95% CI 1.05-1.51) and 21 (OR 1.25, 95% CI 1.05-1.49). Individuals with external LoC at age 16 were more likely to be hazardous drinkers according to the Alcohol Use Disorders Identification Test at age 17 (OR 1.09, 95% CI 1.04-1.15) but not at 21 (OR 1.01, 95% CI 0.96-1.06). Having a more external LoC at age 16 is associated with increased tobacco consumption at age 17 and 21 and alcohol consumption at 17 years. LoC may represent an intervention target for preventing substance use and dependence., Competing Interests: The authors have no conflict of interests to declare.

Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation., Methods and Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose., Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TE declared employment, research support, and stock in AstraZeneca and research support from Bayer and Pfizer. PCH is a population health fellow of Cancer Research UK. GDS is a member of the Editorial Board of PLOS Medicine.

Introduction: The AXIS trial established axitinib as a standard of care treatment for patients with metastatic renal cell carcinoma (mRCC) after failure of a prior tyrosine kinase inhibitor. Axitinib dosing begins at 5  mg twice daily, with escalation of doses to 7  and 10  mg after consecutive 2-week intervals if tolerated (as per the drug label). Given clinical concerns about drug-related toxicity, we have used a pragmatic strategy where dose escalations were made only after disease progression or where rapid responses were clinically required., Methods: We performed a retrospective review of electronic health records and radiology of all patients with mRCC treated with axitinib for >2 weeks at Addenbrooke's Hospital, Cambridge, UK, over a 37 -month period to determine the clinical and radiological effects of dose escalations made according to the above strategy., Results: 42 patients fitting these criteria were identified, 29 having ≥1  dose escalation event (DEE). 60 DEEs were identified (median of two per patient), and the objective radiological consequences of 53 DEEs could be evaluated. The disease control rate (partial response or stable disease) after the first DEE instituted for disease progression was similar to that after the second DEE (68.8% vs 70%). 56.6 % of all DEEs and 63.6 % of DEEs made as a result of disease progression resulted in disease control. The median OS from the commencement of axitinib for all dose-escalated patients was 19.9 months, and 16.5 months for the entire cohort. The mean dose (for all patients) at 90 days after starting axitinib was 5.92  mg., Conclusion: These data suggest that dose escalation of axitinib after disease progression may be an effective dosing strategy for patients with mRCC, and this may be a preferred option in patients in whom there are particular concerns about drug-related toxicity, quality of life optimisation or healthcare-associated costs., Competing Interests: Competing interests: AM is employed by AstraZeneca. KF has received honoraria for advisory board activities from Esai, Ipsen, Roche and Novartis, and speaker fees from Bristol Myers Squibb and Pfizer. TE is employed by AstraZeneca and has received honoraria for consultancy and advisory board activities from GSK, Pfizer, Roche, Novartis and Bristol Myers Squibb.

Context: Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC)., Objective: To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC., Evidence Acquisition: A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed. We identified reports and reviewed them according to the Consolidated Standards of Reporting Trials and Standards for the Reporting of Diagnostic Accuracy Studies criteria. Of eight full-text articles that were eligible for inclusion, five studies (two of five were updated analyses) were retained in the final synthesis. Study characteristics were abstracted and the number needed to treat (NNT) per trial was estimated., Evidence Synthesis: The three randomized controlled phase III trials included the following comparisons: sunitinib versus placebo or sorafenib versus placebo (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal Carcinoma [ASSURE] study, n=1943), sunitinib versus placebo (S-TRAC, n=615), and pazopanib versus placebo (Pazopanib As Adjuvant Therapy in Localized/Locally Advanced RCC After Nephrectomy study, n=1135). The NNT ranged from 10 (S-TRAC) to 137 (ASSURE study). The pooled analysis showed that VEGFR-targeted therapy was not statistically significantly associated with improved DFS (hazard ratio [HR random ]: 0.92, 95% confidence interval [CI]: 0.82-1.03, p=0.16) or OS (HR random : 0.98, 95% CI: 0.84-1.15, p=0.84) compared with the control group. The adjuvant therapy group experienced significantly higher odds of grade 3-4 AEs (OR random : 5.89, 95% CI: 4.85-7.15, p<0.001). In exploratory analyses focusing on patients who started on the full-dose regimen, DFS was improved in patients who received adjuvant therapy (HR random : 0.83, 95% CI: 0.73-0.95, p=0.005)., Conclusions: This pooled analysis of reported randomized trials did not reveal a statistically significant effect between adjuvant VEGFR-targeted therapy and improved DFS or OS in patients with intermediate/high-risk local or regional fully resected RCC. Improvement in DFS may be more likely with the use of full-dose regimens, pending further results. However, adjuvant treatment was associated with high-grade AEs., Patient Summary: Vascular endothelial growth factor receptor-targeted therapy after nephrectomy for localized kidney cancer is not associated with consistent improvements in delaying cancer recurrence or prolonging life and comes at the expense of potentially significant side effects., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: The efficacy of VEGF-targeting therapies in clinical trials led to their recommendation in clinical guidelines for use across the advanced or metastatic renal cell carcinoma (RCC) treatment landscape, however, tolerability (including off-target effects) has remained a challenge. Tivozanib is a selective inhibitor of all three VEGFRs, with limited off-target interaction, which demonstrates efficacy with improved tolerability relative to multikinase VEGFR-TKIs. Areas covered: Covered here is the clinical development of tivozanib in advanced RCC, including the pivotal Phase III, multicenter, open-label, randomized clinical study comparing tivozanib with sorafenib for the treatment of VEGF- and mTOR therapy-naïve advanced RCC patients. Also covered are ongoing trials, exploring the efficacy and safety of tivozanib in the setting of refractory disease and the utility of tivozanib in combination with checkpoint inhibitors for advanced RCC. Combination of a VEGFR-TKI and immunotherapy is promising in advanced RCC, if the treatment regimens have acceptable tolerability. Here the selectivity of tivozanib may contribute to an acceptable tolerability profile when used in combination therapy. Expert commentary: The approval of tivozanib provides an additional option for the first-line treatment of advanced or metastatic RCC patients in Europe and allows use of a VEGFR-TKI with selectivity for VEGFRs in this setting.

Background: Decisions about adjuvant therapy involve trade-offs between possible benefits and harms., Objective: We sought to determine the survival benefits that clinical investigators would judge as sufficient to warrant treatment with adjuvant sorafenib in the SORCE trial after nephrectomy for apparently localised renal cell carcinoma (RCC)., Methods: A subset of clinical investigators in the SORCE trial completed a validated questionnaire that elicited the minimum survival benefits they judged sufficient to warrant one year of adjuvant sorafenib in scenarios with hypothetical baseline survival times of 5 years and 15 years, and baseline survival rates at 5 years of 65% and 85%., Results: The 100 participating SORCE investigators had a median age of 42 years, and 74 were male. For one year of sorafenib versus no therapy, the median benefits in survival times the investigators judged sufficient to warrant treatment were an extra nine months beyond five years and an extra 12 months beyond 15 years; the median benefits in survival rates were an extra 5% beyond baseline survival rates of both 65% and 85% at five years. The patients recruited in the SORCE trial by these investigators judged smaller benefits sufficient to warrant adjuvant sorafenib for both survival rate scenarios ( p ≤0.0001). The survival benefits the investigators judged sufficient to warrant one year of adjuvant therapy with sorafenib for RCC were similar to those of other clinicians considering three months of adjuvant chemotherapy for lung cancer, but smaller than those of clinicians considering six months of adjuvant chemotherapy for breast cancer., Conclusion: SORCE investigators judged larger benefits necessary to warrant adjuvant sorafenib than their patients. The benefits required by the investigators were similar or smaller than those other clinicians considered sufficient to warrant adjuvant chemotherapy for other cancers. Clinicians should recognise that their patients and colleagues may have preferences that differ from their own when considering the potential benefits and harms of adjuvant treatment.

Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR -mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non-druggable genetic information that may guide clinical management., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)