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Immune checkpoint inhibitor (ICI)-based combination therapies are the recommended first-line treatment for metastatic renal cell carcinoma (mRCC). However, no head-to-head phase-3 randomized controlled trials (RCTs) have compared the efficacy of different ICI-based combination therapies. Here, we compared the efficacy of various first-line ICI-based combination therapies in patients with mRCC using updated survival data from phase-3 RCTs. Three databases were searched in June 2023 for RCTs that analyzed oncologic outcomes in mRCC patients treated with ICI-based combination therapies as first-line treatment. A network meta-analysis compared outcomes including overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response (CR) rate. Subgroup analyses were based on the International mRCC Database Consortium risk classification. The treatment ranking analysis of the entire cohort showed that nivolumab + cabozantinib (81%) had the highest likelihood of improving OS, followed by nivolumab + ipilimumab (75%); pembrolizumab + lenvatinib had the highest likelihood of improving PFS (99%), ORR (97%), and CR (86%). These results remained valid even when the analysis was limited to patients with intermediate/poor risk, except that nivolumab + ipilimumab had the highest likelihood of achieving CR (100%). Further, OS benefits of ICI doublets were not inferior to those of ICI + tyrosine kinase inhibitor combinations. Recommendation of combination therapies with ICIs and/or tyrosine kinase inhibitors based on survival benefits and patient pretreatment risk classification will help advance personalized medicine for mRCC., (© 2024. The Author(s).)

Background: In the phase III JAVELIN Renal 101 trial, first-line avelumab + axitinib improved progression-free survival (PFS) and objective response rate versus sunitinib in patients with advanced renal cell carcinoma across all International Metastatic RCC Database Consortium (IMDC) risk groups (favorable, intermediate, and poor); analyses of overall survival (OS) remain immature. Here, we report post hoc analyses of efficacy from the third interim analysis (data cut-off, April 2020) by the numbers of IMDC risk factors and target tumor sites at baseline., Methods: Efficacy endpoints assessed were PFS, objective response, and best overall response per investigator assessment (RECIST v1.1) and OS. Best percentage change and percentage change from baseline in target tumor size over time during the study were also assessed., Results: In patients with 0, 1, 2, 3, or 4-6 IMDC risk factors, hazard ratios [HRs; 95% confidence interval (CIs)] for OS with avelumab + axitinib versus sunitinib were 0.660 (0.356-1.223), 0.745 (0.524-1.059), 0.973 (0.668-1.417), 0.718 (0.414-1.248), and 0.443 (0.237-0.829), and HRs (95% CIs) for PFS were 0.706 (0.490-1.016), 0.709 (0.540-0.933), 0.711 (0.527-0.960), 0.501 (0.293-0.854), and 0.395 (0.214-0.727), respectively. In patients with 1, 2, 3, or ≥4 target tumor sites, HRs (95% CIs) for OS with avelumab + axitinib versus sunitinib were 0.912 (0.640-1.299), 0.715 (0.507-1.006), 0.679 (0.442-1.044), and 0.747 (0.346-1.615), and HRs (95% CIs) for PFS were 0.706 (0.548-0.911), 0.552 (0.422-0.723), 0.856 (0.589-1.244), and 0.662 (0.329-1.332), respectively. Across all subgroups, analyses of objective response rate and complete response rate favored avelumab + axitinib versus sunitinib, and a greater proportion of patients treated with avelumab + axitinib had tumor shrinkage., Conclusions: In post hoc analyses, first-line treatment with avelumab + axitinib was generally associated with efficacy benefits versus treatment with sunitinib in patients with advanced renal cell carcinoma across subgroups defined by different numbers of IMDC risk factors or target tumor sites., Competing Interests: Disclosure YT has participated in consulting or advisory roles for Eisai, Merck Sharp & Dohme (MSD), and Ono Pharmaceutical; has received honoraria from Astellas Pharma, Bristol Myers Squibb Japan, Chugai Pharma, Novartis, Ono Pharmaceutical, and Pfizer; and has received research funding from Astellas Pharma, AstraZeneca, Chugai Pharma, Eisai, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Takeda. RJM has participated in consulting or advisory roles for AstraZeneca, Aveo, Calithera Biosciences, Eisai, Exelixis, Genentech/Roche, Incyte, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; has received travel, accommodations, and expenses from Bristol Myers Squibb; and has received research funding from Aveo, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Novartis, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. TKC reports institutional and personal, paid and/or unpaid support for research, advisory boards, consultancy, and honoraria from Aravive, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, CME events (Peerview, OncLive, MJH and others), Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, MSD, NiKang, Novartis, Nuscan, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, and Up-To-Date, outside the submitted work; reports institutional patents filed on molecular alterations and immunotherapy response/toxicity, and circulating tumor DNA; reports equity Osel, Pionyr, Precede Bio, and Tempest; has served in committees for ACCRU, ASCO/ESMO, GU Steering Committee, KidneyCan, and NCCN; reports that medical writing and editorial assistance support may have been funded by communications companies in part; has mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/foreign components; reports that the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter; and is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan Mass Challenge, and Loker Pinard Funds for Kidney Cancer Research at DFCI. BIR has participated in consulting or advisory roles for 3D Medicines, Aravive, Arrowhead Pharmaceuticals, Aveo, Bristol Myers Squibb, Corvus Pharmaceuticals, Eisai, GlaxoSmithKline, Pfizer, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Shionogi, Surface Oncology, and Synthorx; reports leadership with MJH Life Sciences; has received travel, accommodations, and expenses from Bristol Myers Squibb, Pfizer, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA; reports stock and other ownership interests from PTC Therapeutics; and has received research funding from Aravive, Arrowhead Pharmaceuticals, AstraZeneca/MedImmune, Bristol Myers Squibb, Dragonfly Therapeutics, Immunomedics, Incyte, Exelixis, Pfizer, Roche/Genentech, Seagen, Surface Oncology, Taris, and EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. HM has received honoraria, consulting or advisory fees, and research funding from Pfizer. MO has participated in consulting or advisory roles for Bayer; has received honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb Japan, Chugai Pharma, Janssen, MSD, Novartis, Ono Pharmaceutical, Pfizer, Sanofi, and Takeda; and has received research funding from Astellas Pharma. LA has participated in consulting or advisory roles for Astellas Pharma, AstraZeneca, Bellerophon Therapeutics, Bristol Myers Squibb, Corvus Pharmaceuticals, Eisai, Janssen, Ipsen, Merck, MSD, Novartis, Pfizer, and Roche; has received travel, accommodations, and expenses from Bristol Myers Squibb and MSD; and has received research funding from Bristol Myers Squibb. MA is an employee of Pfizer R&D Japan. YU is an employee of Pfizer R&D Japan and holds stock in Pfizer. JW is an employee and reports stock and other ownership interest with Pfizer. AdiP reports employment, stock, and other ownership interest with Pfizer, and has received honoraria from Pfizer. MS has participated in consulting or advisory roles for Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, MSD, and Roche; has received travel, accommodations, and expenses from Bristol Myers Squibb, Ipsen, and Roche; and has received honoraria from Alkermes, Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Janssen Oncology, and MSD., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To compare the efficacy of first-line immune checkpoint inhibitor (ICI)-based combinations in metastatic renal cell carcinoma (mRCC) patients stratified by chronological age. Methods: According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, hazard ratios for overall survival (OS) from randomized controlled trials were synthesized. Results: Five RCTs were eligible for meta-analyses. ICI-based combinations significantly improved OS compared with sunitinib alone, both in younger (<65 years) and older (≥65 years) patients, whereas the OS benefit was significantly better in younger patients (p = 0.007). ICI-based combinations did not improve OS in patients aged ≥75 years. Treatment rankings showed age-related differential recommendations regarding improved OS. Conclusion: OS benefit from first-line ICI-based combinations was significantly greater in younger patients. Age-related differences could help enrich shared decision-making.

The intestinal microbiome is by now an undebatable key player in the clinical outcome of ICI therapies. However, no microbiome profiling method to aid therapy decision is yet validated. We conducted a multi-centric study in patients with stage III/IV melanoma, NSCLC, or RCC receiving ICI treatment. The stool microbiome profile of 63 patients was analyzed with BiomeOne ® , a microbiome-based algorithm that anticipates whether a patient will achieve clinical benefit with ICIs prior to therapy initiation. Classification of patient samples as Rs and NRs was achieved with a sensitivity of 81% and a specificity of 50% in this validation cohort. An ICI-favorable response was characterized by an intestinal microbiome rich in bacteria such as Oscillospira sp., Clostridia UCG-014, Lachnospiraceae UCG-010 sp., Prevotella copri , and a decrease in Sutterella sp., Lactobacillales, and Streptococcus sp. Patients who developed immune-related adverse events (irAEs) had an overall increased microbial diversity and richness, and a stool microbiome depleted in Agathobacter . When compared with the programmed death-ligand 1 (PD-L1) expression test in the subcohort of NSCLC patients ( n = 38), BiomeOne ® exhibited a numerically higher sensitivity (78.6%) in identifying responders when compared with the PD-L1 test (67.9%). This study provides an evaluation of BiomeOne ® , the first microbiome-based test for prediction of ICI response, to achieve market authorization. Validation with further indications and expansion to other microbiome-based interventions will be essential to bring microbiome-based diagnostics into standard clinical practice.

Background: We report updated data for avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma from the third interim analysis of the phase III JAVELIN Renal 101 trial., Patients and Methods: Progression-free survival (PFS), objective response rate (ORR), and duration of response per investigator assessment (RECIST version 1.1) and overall survival (OS) were evaluated in the overall population and in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups; safety was also assessed., Results: Overall, median OS [95% confidence interval (CI)] was not reached [42.2 months-not estimable (NE)] with avelumab plus axitinib versus 37.8 months (31.4-NE) with sunitinib [hazard ratio (HR) 0.79, 95% CI 0.643-0.969; one-sided P = 0.0116], and median PFS (95% CI) was 13.9 months (11.1-16.6 months) versus 8.5 months (8.2-9.7 months), respectively (HR 0.67, 95% CI 0.568-0.785; one-sided P < 0.0001). In patients with IMDC favorable-, intermediate-, poor-, or intermediate plus poor-risk disease, respectively, HRs (95% CI) for OS with avelumab plus axitinib versus sunitinib were 0.66 (0.356-1.223), 0.84 (0.649-1.084), 0.60 (0.399-0.912), and 0.79 (0.636-0.983), and HRs (95% CIs) for PFS were 0.71 (0.490-1.016), 0.71 (0.578-0.866), 0.45 (0.304-0.678), and 0.66 (0.550-0.787), respectively. ORRs, complete response rates, and durations of response favored avelumab plus axitinib overall and across all risk groups. In the avelumab plus axitinib arm, 81.1% had a grade ≥3 treatment-emergent adverse event (TEAE), and incidences of TEAEs and immune-related AEs were highest <6 months after randomization., Conclusions: Avelumab plus axitinib continues to show improved efficacy versus sunitinib and a tolerable safety profile overall and across IMDC risk groups. The OS trend favors avelumab plus axitinib versus sunitinib, but data remain immature; follow-up is ongoing., Trial Registration: ClinicalTrials.govNCT02684006; https://clinicaltrials.gov/ct2/show/NCT02684006., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).

Background: Immune checkpoint inhibitors (ICI) are regarded as a standard of care in multiple malignancies. We hypothesized that serum parameters are of prognostic value in ICI treated patients suffering from solid tumours., Methods: Data from 114 patients treated with ICIs for solid malignancies from 2015 to 2019 at the Medical University of Vienna were collected retrospectively. Data included baseline characteristics, cancer type, serum parameters such as lactate dehydrogenase (LDH), C-reactive protein (CRP), albumin (Alb) and lymphocyte counts as well as overall survival (OS) and progression free survival. Additionally, the Gustave Roussy Immune Score (GRIm score) and the Glasgow prognostic score (GPS) were calculated. Cox regression models including time-dependent effects and strata for tumour type were used. Prognostic factors were pre-selected using a relaxed LASSO approach., Results: The majority of patients were male (64.9%). The most common cancer types were non-small cell lung cancer (30.7%) and renal cell carcinoma (21.9%). Increased LDH and CRP were associated with poor 6-month OS (Hazard ratios (HR)=1.16 and 1.06 per 20% LDH/CRP increase; 95% CI 1.07-1.26 and 95% CI 1.03-1.09, respectively; p  < .001). Both GRIm Score and GPS had a significant influence on OS (GRIm: HR = 2.84, 95% CI 1.72-4.69; p  < .001 for high vs. low; GPS HR 3.57, 95% CI 1.76-7.25; p  < .001 for poor vs. good). The proportion of explained variation (PEV) of our full multivariable model was significantly higher compared to the GRIm and GPS (PEV = 29.5% vs. 14.8% and 14.65%). When grouped into quartiles according to the individual 8-weeks change, both increased LDH and CRP correlated with poor OS (LDH ( p =.001) and CRP ( p  < .001))., Conclusion: The results of this analysis suggest that serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.Key messagesIn this retrospective analysis, 114 patients with solid tumours were included. The results of this analysis point out that pre-treatment LDH, CRP and albumin levels are strongly prognostic for a poor 6-month OS.In addition to that, a high GRIm-score and poor GPS were associated with a worse OS (GRIm: HR = 2.84, 95% CI 1.72-4.69; p  < .001 for high vs. low; GPS HR = 3.57, 95% CI 1.76-7.25; p  < .001 for poor vs. good).Pre-treatment serum parameters might have prognostic value for the outcome of cancer patients treated with ICI, regardless of the tumour type.

(1) Background: The incidence of psychological distress and its impact on renal cell carcinoma (RCC) patients is unclear. Our aim was to analyze the literature regarding the prevalence of psychological distress and its impact on patients with non-metastatic or metastatic RCC; (2) Methods: A systematic search of five databases was performed. Studies were considered eligible if they included patients with RCC, had a prospective or retrospective design, and assessed anxiety, depression, or psychological distress at any time during treatment or follow-up. Exclusion criteria: no treatment for RCC, or not providing data for RCC patients; (3) Results: A total of 15 studies were included. Reported psychological distress was up to 77% and the prevalence of depressive and anxiety symptoms were up to 77.6% and 68.3% in patients with non-metastatic RCC. There was no association of depression with overall survival (OS) in patients with non-metastatic RCC treated by radical nephrectomy; on the contrary, in patients with metastatic disease, depression had an impact on OS. Limitations are related to the quality of the included studies; (4) Conclusions: Patients with RCC reported a high level of psychological distress like other cancer patients. It seems that for patients with localized disease, psychological distress does not impact OS, while it does in those with metastatic disease.

Aim: We aimed to assess the prognostic value of pretreatment hematological biomarkers in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (ICIs). Methods: PubMed, Web of Science and Scopus databases were searched for articles according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Results: Fifteen studies comprising 1530 patients were eligible for meta-analysis. High levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein and lactate dehydrogenase were significantly associated with worse progression-free survival. High NLR and PLR were significantly associated with worse overall survival. Conclusion: High pretreatment NLR and PLR appear to be hematological prognostic factors of progression and overall mortality in mRCC patients treated with ICIs. These findings might help in the design of correlative biomarker studies to guide the clinical decision-making in the immune checkpoint inhibitor era.

c-Met inhibitors are a class of drugs that include nonselective and selective molecules. These drugs can differ in terms of pharmacodynamic and pharmacokinetic properties that may be clinically relevant. c-Met inhibitors with high potency and selectivity may allow achieving optimal c-Met inhibition in c-Met-driven tumors while reducing unwanted off-target toxicities due to activation of multiple kinases. Nonselective drugs can instead be considered in tumors that also recognize other drivers (e.g., ALK, ROS, VEGF). Improved understanding of the clinical pharmacokinetics of c-Met inhibitors can help avoid drug-drug interactions and optimize schedules for continuous in vivo inhibition of c-Met phosphorylation. The current review article provides a detailed overview of the clinical pharmacology of molecules used in c-Met-driven tumors., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: In the phase III JAVELIN Renal 101 trial, first-line avelumab plus axitinib demonstrated a progression-free survival (PFS) and objective response rate (ORR) benefit versus sunitinib in patients with advanced renal cell carcinoma (aRCC). However, efficacy in elderly patients remains unclear. We report efficacy and safety by age group from the second interim analysis of overall survival (OS)., Patients and Methods: PFS and ORR as per blinded independent central review (RECIST 1.1), OS, and safety were assessed in patient groups aged <65, ≥65 to <75, and ≥75 years., Results: In the avelumab plus axitinib and sunitinib arms, 271/138/33 and 275/128/41 patients aged <65, ≥65 to <75, and ≥75 years, respectively, were randomized. At data cut-off (January 2019), median PFS [95% confidence interval (CI)] with avelumab plus axitinib versus sunitinib in these respective age groups was 11.6 (8.4-19.4) versus 6.9 (5.6-8.4) months [hazard ratio (HR), 0.63; 95% CI 0.501-0.786], 13.8 (11.1-18.0) versus 11.0 (7.8-16.6) months (HR, 0.88; 95% CI 0.627-1.231), and 13.8 [7.0-not estimable (NE)] versus 9.8 (4.3-NE) months (HR, 0.76; 95% CI 0.378-1.511). Median OS (95% CI) in the respective age groups was not reached (NR) (NE-NE) versus 28.6 (25.5-NE) months (HR, 0.74; 95% CI 0.541-1.022), 30.0 (30.0-NE) versus NR (NE-NE) months (HR, 0.89; 95% CI 0.546-1.467), and 25.3 (19.9-NE) versus NR (19.4-NE) months (HR, 0.87; 95% CI 0.359-2.106). ORR (95% CI) in the respective age groups was 49.4% (43.3% to 55.6%) versus 27.3% (22.1% to 32.9%), 60.9% (52.2% to 69.1%) versus 28.9% (21.2% to 37.6%), and 42.4% (25.5% to 60.8%) versus 22.0% (10.6% to 37.6%). In the avelumab plus axitinib arm, grade ≥3 adverse events (AEs) and immune-related AEs occurred in 76.9%/81.2%/72.7% and 45.5%/48.1%/36.4% in the respective age groups., Conclusions: First-line avelumab plus axitinib demonstrated favorable efficacy across age groups, including patients aged ≥75 years. OS data were still immature; follow-up is ongoing. The safety profile was generally consistent across age groups., Competing Interests: Disclosure YT has received honoraria from Pfizer, Astellas Pharma, Novartis, Ono Pharmaceutical, Bristol Myers Squibb, and Chugai Pharma; has served in a consulting or advisory role for Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; and has received research funding paid to his institution from Pfizer, Ono Pharmaceutical, Takeda, Astellas Pharma, AstraZeneca, Novartis, Chugai Pharma, MSD, and Eisai. RJM has served in a consulting or advisory role for AstraZeneca, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, Genentech/Roche, Incyte, Lilly, MSD, Novartis, and Pfizer; has received research funding paid to his institution, from Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, MSD, Novartis, and Pfizer; and has received travel, accommodations, and expenses from Bristol Myers Squibb. TKC owns stock and additional ownership interests in Pionyr and Tempest Therapeutics; has received honoraria from Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, Exelixis, Foundation Medicine, Genentech/Roche, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Sanofi/Aventis, New England Journal of Medicine, and UpToDate; has served in a consulting or advisory role for Alexion Pharmaceuticals, Alligent, Analysis Group, ASCO, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, New England Journal of Medicine, and UpToDate; has received research funding paid to his institution, from Agensys, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Cerulean Pharma, Congressionally Directed Medical Research Programs (DOD), Corvus Pharmaceuticals, Eisai, Exelixis, Foundation Medicine, Gateway for Cancer Research, GlaxoSmithKline, Ipsen, MSD, NCI, Novartis, Peloton Therapeutics, Pfizer, Prometheus, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharmaceuticals; owns patents, royalties, or other intellectual property for international patent application no. PCT/US2018/058430, entitled ‘Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy’ and international patent application no. PCT/US2018/12209, entitled ‘PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response’; and has received travel, accommodations, and expenses from Alexion Pharmaceuticals, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, MSD, Michael J. Hennessy Associates, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, New England Journal of Medicine, and UpToDate. BIR owns stock and other ownership interests in PTC Therapeutics; has served in a consulting or advisory role for Bristol Myers Squibb, Pfizer, Genentech/Roche, Aveo, Synthorx, Compugen, MSD, Corvus, Surface Oncology, 3D Medicines, Aravive, Alkermes, Arrowhead, GSK, and Shionogi; has received research funding paid to his institution, from Pfizer, MSD, Genentech/Roche, Aveo, AstraZeneca, Bristol Myers Squibb, and Exelixis; and has received travel, accommodations, and expenses from MSD, Pfizer, and Bristol Myers Squibb. HM has received honoraria; served in a consulting or advisory role for; and has received research funding paid to his institution from Pfizer. HU has received speakers’ bureau fees from Pfizer, Bayer, MSD, Bristol Myers Squibb, and Janssen; and has received research funding paid to his institution from Takeda, Daiichi Sankyo, Astellas Pharma, Ono Pharmaceutical, AstraZeneca, Sanofi, and Kissei Pharmaceutical. LA has served in a consulting or advisory role for Amgen, Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Exelixis, Corvus, Peloton Therapeutics, Exelixis, and Janssen; has received research funding paid to her institution, from Bristol Myers Squibb; and has received travel, accommodations, and expenses from Bristol Myers Squibb and MSD. YF is an employee of Pfizer R&D Japan. YU is an employee of Pfizer R&D Japan and owns stock in Pfizer. JW is an employee of Pfizer and owns stock in Pfizer. MM is an employee of Pfizer. MS has received honoraria from Pfizer, Merck, Bristol Myers Squibb, MSD, Ipsen, Exelixis, Eisai, EUSA, and Alkermes; has served in a consulting or advisory role for Pfizer, Merck, Bristol Myers Squibb, MSD, Ipsen, Exelixis, Eisai, EUSA, and Alkermes; and has received travel, accommodations, and expenses from Pfizer, Roche, and Ipsen. Data sharing Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Cabozantinib is an inhibitor of multiple tyrosine kinases, including AXL, MET and VEGF receptors. Here, we describe the rationale and design for the phase II CaboPoint trial (ClinicalTrials.gov identifier: NCT03945773), which will evaluate the efficacy and safety of cabozantinib as a second-line treatment in patients with unresectable, locally advanced or metastatic renal cell carcinoma whose disease has progressed despite checkpoint inhibitor therapy. Patients will be recruited into two cohorts: prior ipilimumab plus nivolumab (cohort A) or prior checkpoint inhibitor-VEGF-targeted therapy (cohort B). All patients will receive once-daily oral cabozantinib 60 mg for up to 18 months. The primary end point is objective response rate. Secondary end points include overall survival, progression-free survival and safety.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of renal cell carcinoma was published in 2019 with an update planned for 2021. It was therefore decided by both the ESMO and the Singapore Society of Oncology (SSO) to convene a special, virtual guidelines meeting in May 2021 to adapt the ESMO 2019 guidelines to take into account the ethnic differences associated with the treatment of renal cell carcinomas in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with renal cell carcinoma representing the oncological societies of China (CSCO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence and was independent of the current treatment practices and drug access restrictions in the different Asian countries. The latter were discussed when appropriate., Competing Interests: Disclosure RK declares institutional payments from Pfizer, Merck Sharp & Dohme (MSD), Bristol Myers Squibb (BMS), Eisai, Amgen, Astellas, Johnson & Johnson (J&J), Novartis and Merck, support for meeting attendance or travel from Pfizer, MSD, BMS, Eisai, Amgen, Astellas, J&J, Novartis and Merck. CP declares consulting fees from AstraZeneca, BMS, Eisai, EUSA Pharma, Ipsen, Merck, MSD, Novartis and Pfizer, payment or honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, MSD, Novartis and Pfizer, support for attending meetings and/or travel from Roche. AW declares personal fees from MS, MSD, Pfizer, EISAI and IPSEN, participation on a data safety monitoring or advisory board for BMS, MSD, Pfizer, EISAI, IPSEN. TP declares research funding from Merck Serono, MSD, Roche, BMS, AstraZeneca, Astellas, Novartis, J&J, Seattle Genetics, Pfizer, Exelixis and Eisai, honoraria from Merck Serono, MSD, Roche, BMS, AstraZeneca, Astellas, Novartis, J&J, Seattle Genetics, Pfizer, Exelixis and Eisai. QSN declares support for attending meetings and/or travel from BMS, Boehringer Ingelheim, MSD and Astellas, participation on a data safety monitoring or advisory board for MSD and Boehringer Ingelheim. MSc declares honoraria from BMS, MSD, Merck, Roche, Pfizer, EUSA, EISAI, EXELIXIS and Ipsen, consulting fees from BMS, MSD, Merck, Roche, Pfizer, EUSA, EISAI, EXELIXIS and Ipsen, support for attending meetings and/or travel from BMS, Roche, Pfizer and Ipsen, participation on a data or safety monitoring board for BMS, MSD, Merck, Roche, Pfizer, EUSA, EISAI, EXELIXIS and Ipsen. YM declares payments or honoraria from BMS, MSD and Takeda, participation on an advisory board for Chugai Pharmaceutical and Takeda, local PI, institutional, financial interest from MSD. JL declares grants or contracts from Pfizer, Ipsen, BMS, MSD, Merck, Roche, AstraZeneca, Seattle Genetics, participation on a data safety monitoring or advisory board from Pfizer Korea, Astella Korea, BMS, Merck, MSD, AstraZeneca, stocks or stock options from Myovant Sciences, Amgen, J&J and Merck. FC declares payment for educational events from Eisai and Pfizer, receipt of equipment for a patient sampling programme from Pfizer. Y-SP declares honoraria and consulting fees from MSD, Roche, Merck, Ipsen, BMS/ONO, Novartis, Pfizer, Astellas, Janssen and GlaxoSmithKline (GSK), support for attending meetings and/or travel from Ipsen, BMS/ONO, Novartis, Pfizer, Astellas and Janssen. MSa declares research grants from Roche and MSD, payments or honoraria from MSD, Novartis, Roche, Pfizer, Eisai, Novartis, AstraZeneca, Amgen and Ipsen, receipt of equipment/materials for a compassionate programme for drugs/drug samples from Pfizer, AstraZeneca, Novartis, Ipsen, Eisai and MSD. HL declares payment or honoraria from MSD, Amgen, Astellas and IPSEN, participation on a data safety monitoring or advisory board for MSD and Astellas. HK declares payment or honoraria from BMS, MSD, Merck Biopharma, Takeda and Pfizer. GSB (deceased). GC declares institutional grants from Merck, consulting fees from BMS, Pfizer, MSD, AstraZeneca, Daichii Sankyo, Lilly, Novartis and Seattle Genetics, payment or honoraria from AstraZeneca, Roche and Daichii Sankyo. SC declares consulting fees from BMS, AstraZeneca, MSD, Roche and Servier, payment or honoraria from BMS, AstraZeneca, Roche, Ipsen, MSD Eisai and Bayer, consulting fees from BMS, AstraZeneca, MSD, Roche and Servier and stock or stock options in BMS and Agenus Oncology. SP declares fees for consultancy/advisory roles from AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Imedex, Incyte, Janssen, Medscape, MSD, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, speaker roles for AstraZeneca, Boehringer Ingelheim, BMS, ecancer, Eli Lilly, Illumina, Imedex, Medscape, MSD, Novartis, PER, Pfizer, Prime, Roche/Genentech, RTP, Sanofi, Takeda and the receipt of grants/research support: (Sub) investigator in trials (institutional financial support for trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, BMS, Clovis, GSK, Illumina, Lilly, MSD, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics, Roche/Genentech. TY declares institutional grants or contracts from Taiho Pharmaceuticals, Sumitomo Dainippon, Ono Pharmaceuticals, Chugai Pharmaceuticals, Amgen, Parexel International, MSD, Daiichi Sankyo, and Sanofi. All other authors have declared no conflicts of interest. See also ICMJE forms., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure TP reports research funding from Merck Serono, Merck Sharp & Dohme (MSD), Roche, Bristol Myers Squibb (BMS), AstraZeneca, Astellas, Novartis, Johnson and Johnson, Seattle Genetics, Pfizer, Exelixis and Eisai and honoraria from Merck Serono, MSD, Roche, BMS, AstraZeneca, Astellas, Novartis, Johnson and Johnson, Seattle Genetics, Pfizer, Exelixis and Eisai; LA reports research funding from BMS (Institution) and advisory roles (Institution) for Astellas, AstraZeneca, BMS, Corvus Pharmaceuticals, Ipsen, Janssen, Merck & Co, MSD, Novartis, Pfizer and Eisai; AB has reported restricted educational grant for an investigator-initiated trial of neoadjuvant therapy in high-risk renal cancer from Pfizer, steering committee member and local investigator in an adjuvant trial for BMS, steering committee member and principal investigator in an adjuvant trial for Roche/Genentech, medical steering committee member to advise the patient advocacy group on medical topics and strategy for the International Kidney Cancer Coalition and medical steering committee member to advise the patient advocacy group on medical topics and strategy for the Kidney Cancer Association; VG has reported advisory roles for BMS, MSD, EISAI, EUSA Pharma, Merck-Serono, Nanobiotix, Pfizer and Roche, speaker's honoraria for AstraZeneca, BMS, MSD, EISAI, Ipsen, Janssen-Cilag, Merck-Serono, Pfizer and Roche, stocks in AstraZeneca, BMS, MSD and Seattle Genetics, steering committee member for BMS, EISAI, Ipsen, Novartis and PharmaMar and research grants from AstraZeneca, BMS, MSD, Ipsen and Pfizer; CP reports consultant/speaker honoraria from Angelini Pharma, AstraZeneca, BMS, Eisai, EUSA Pharma, General Electric, Ipsen, Janssen, Merck, MSD, Novartis and Pfizer, expert testimony for EUSA Pharma and Pfizer and travel support from Roche and Protocol Steering Committee member for BMS, Eisai and EUSA Pharma; GP reports honoraria for advisory board/consultant/speaker from AstraZeneca, Bayer, BMS, Eisai, Janssen, Ipsen, Merck, MSD, Novartis and Pfizer and research grants from Ipsen and Novartis; MS reports consultant/speaker honoraria from Pfizer, BMS, Merck, MSD, EISAI, EUSA Pharma, Ipsen and Alkermes, travel support from Pfizer and Roche and Protocol Steering Committee member for Pfizer and Merck; CSR reports honoraria for advisory board for Astellas Pharma, Bayer, BMS, EUSA Pharma, Ipsen, Novartis, Pfizer, Sanofi-Aventis, MSD and Hoffman-La Roche Ltd and speaker fees for Astellas, BMS, Ipsen, Pfizer and Hoffman-La Roche and research grant from Ipsen; GdV reports advisory boards for Astellas, Bayer, BMS, EUSA Pharma, Ipsen, MSD, Pfizer and Merck, invited speaker for Astellas, BMS, Ipsen, MSD, Pfizer, Roche and Merck and institutional research grant from Roche.

Background: Immune checkpoint inhibitors (ICIs) have led to a paradigm change in the management of metastatic renal cell carcinoma (mRCC). Prospective trials have focused on ICI treatment in the first or second line. The aim of this analysis is to evaluate the benefit of ICI across different treatment lines., Patients and Methods: This is a single-center retrospective study that included mRCC patients who received ICIs in various treatment lines. Objective response rates (ORR), progression-free survival (PFS) and overall survival (OS) were evaluated., Results: Ninety-four patients were eligible for full evaluation. Patients were classified as International mRCC Database Consortium (IMDC) risk group categorization as good, intermediate and poor risk in 26.8%, 61.6% and 14.8% of cases, respectively. They were treated with ICI monotherapy, dual ICI therapy and ICI + tyrosine kinase inhibitor in 59%, 20% and 21% of cases, respectively. ORR, median PFS and OS for the entire cohort was 39.4%, 9.67 months [95% confidence interval (CI) 6.9-12.4 months] and 23.6 months (95% CI 13.3-33.9 months), respectively. The ORR by treatment line was 33% in first, 40.4% in the second, 35% in the third and 43.5% in the fourth line and beyond. Median PFS by treatment line was 8.6, 10.3, 7.9 and 7.23 months, respectively. The median OS was not reached in first-line treatment and was 26.2, 18.1 and 20.7 months in the second, third and fourth line and beyond, respectively., Conclusions: ICIs or ICI combinations are active in all treatment lines and should also be offered in heavily pretreated patients. Patient selection based on tumor and patient factors allows for maximal benefit from ICI-based therapies., Competing Interests: Disclosure AB has received travel grants from Roche, Ipsen, Pfizer and EUSA and a research grant from Pfizer; MS has received honoraria for advisory boards or lectures from Pfizer, Ipsen, Exelixis, EUSA, EISAI, BMS, MSD, Merck, Alkermes; SFS has received honoraria from Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, SANOCHEMIA, Sanofi, Takeda, UroGen; had/having consulting or advisory roles in Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, SANOCHEMIA, Sanofi, Takeda, UroGen; member of speakers' bureau in Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, SANOCHEMIA, Sanofi, Takeda, UroGen, Movember Foundation; and has filed the following patents: method to determine prognosis after therapy for prostate cancer (granted 6 September 2002); methods to determine prognosis after therapy for bladder cancer (granted 19 June 2003); prognostic methods for patients with prostatic disease (granted 5 August 2004); soluble Fas urinary marker for the detection of bladder transitional cell carcinoma (granted 20 July 2010). All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tumor mutational burden (TMB) and density of tumor-infiltrating lymphocytes (TIL) have been postulated as predictive biomarkers for immunotherapy. Therefore, we investigated the concordance of TMB and TIL of primary/extracranial renal cell carcinoma (RCC) specimens and matched brain metastases (BM)., Patients and Methods: Twenty specimens from 10 patients were retrieved from the Vienna Brain Metastasis Registry (6/10 primary tumor, 4/10 lung metastasis, 10/10 matched BM). TMB was assessed using the TruSight Oncology 500 gene panel with libraries sequenced on a NextSeq instrument. TIL subsets (CD3+, CD8+, CD45RO+, FOXP3+, PD-L1+) were investigated using immunohistochemistry (Ventana Benchmark Ultra system) and automated tissue analysis (Definiens software)., Results: No significant difference in TMB, CD3+, CD8+, CD45RO+, FOXP3+ or PD-L1+ expression was observed between extracranial and matched intracranial specimens (P > 0.05). Higher CD8+ TIL (P = 0.053) and CD45RO+ TIL (P = 0.030) densities in the primary tumor compared with the intracranial samples were observed in specimens collected after exposure to systemic treatment. Neither extracranial sample origin (lung metastasis versus primary RCC) nor extracranial disease status at BM diagnosis (progressive versus stable disease) were significantly associated with TMB or TIL densities in extracranial and intracranial samples (P > 0.05). No significant correlation was found between the median differences of TMB or TIL densities from extracranial to intracranial samples and BM-free survival., Conclusion: The comparable immunological microenvironment of extra- and intracranial tumor samples in our study underscores the immunological activation also in BM from RCC, and therefore, supports the development of immune modulatory treatments also in patients with brain metastatic RCC., Competing Interests: Disclosure ASB has research support from Daiichi Sankyo (≤ €10 000), Roche (> €10 000) and honoraria for lectures, consultation or advisory board participation from Roche, Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all < €5000) as well as travel support from Roche, Amgen and AbbVie. GW received restricted travel grants from NX Development Corp. MS received honoraria for ad boards and lectures from Pfizer, Roche, Ipsen, Exelixis, EUSA, Eisai, Alkermes, BMS, MSD and Merck. MP has received research support from Böehringer-Ingelheim, GlaxoSmithKline, Merck Sharp & Dome and Roche and honoraria for lectures, consultation or advisory board participation from Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, AstraZeneca, AbbVie, Lilly, MEDahead, Daiichi Sankyo, Merck Sharp & Dome. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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: Management of metastatic renal cell cancer (mRCC) has undergone a paradigm shift with immune-checkpoint inhibitors (ICI) in the first-line setting. However, direct comparative data are inadequate to inform treatment decisions. Therefore, we aimed to assess first-line therapy for mRCC and indirectly compare the efficacy and safety of currently available treatments., Materials and Methods: Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or progression-free survival (OS/PFS) and/or adverse events (AEs) in mRCC patients were considered eligible., Results: Six studies matched our eligibility criteria. For OS, pembrolizumab plus axitinib [hazard ratio (HR) 0.85, 95% credible interval (CrI) 0.73-0.98] and nivolumab plus ipilimumab (HR 0.86, 95% CrI 0.75-0.99) were significantly more effective than sunitinib, and pembrolizumab plus axitinib was probably the best option based on analysis of the treatment ranking. For PFS, pembrolizumab plus axitinib (HR 0.86, 95% CrI 0.76-0.97) and avelumab plus axitinib (HR 0.85, 95% CrI 0.74-0.98) were statistically superior to sunitinib, and avelumab plus axitinib was likely to be the preferred option based on analysis of the treatment ranking, closely followed by pembrolizumab plus axitinib. Nivolumab plus ipilimumab had significantly lower rates of serious AEs than sunitinib., Conclusion: Pembrolizumab plus axitinib seemed to be the most efficacious first-line agents, while nivolumab plus ipilimumab had the most favorable efficacy-tolerability equilibrium. These findings may facilitate individualized treatment strategies and inform future direct comparative trials in an expanding treatment options without direct comparison between approved drugs.

Background: Novel treatment modalities like targeted therapy and immunotherapy are currently changing treatment strategies and protocols in the field of medical oncology., Methods: Numbers of patients and patient contacts admitted to medical oncology day clinics of a large European academic cancer centre in the period from 2006 to 2018 were analysed using our patient administration system., Results: A patient cohort of 9.870 consecutive individual patients with 125.679 patient contacts was descriptively and retrospectively characterised. Mean age was 59.9 years. A substantial increase in both individual patients treated per year (+45.4%; 2006: 1.100; 2018: 1.599) and annual patient contacts (+63.3%; 2006: 8.857; 2018: 14.467) between 2006 and 2018 was detected. Hence and most interestingly, the ratio of visits per patient increased by approximately one visit per patient per year over the last 12 years (+12.4%; 2006: 8.0; 2018: 9.0). Further, a decrease of patient contacts in more prevalent entities like breast cancer was found, while contacts for orphan diseases like myeloma and sarcoma increased substantially. Interestingly, female patients showed more per patient contacts as compared with men (13.5 vs 11.9). Lastly, short-term safety data of outpatient day clinic admissions are reported., Conclusions: We present a representative and large set of patient contacts over time that indicates an increasing load in routine clinical work of outpatient cancer care. Increases observed were highest for orphan diseases, likely attributed to centralisation effects and increased treatment complexity., Competing Interests: Competing interests: MM has received honoraria for lectures and consultation from Roche, Novartis, Eli-Lilly and Medmedia and travel support from Amgen, Roche, Novartis, Pierre Fabre, Daiichi Sankyo and Eisai. RB was an advisor for Astra-Zeneca, Celgene, Daiichi, Eisai, Eli-Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche and Samsung and received lecture honoraria from Accord, Astra-Zeneca, BMS, Celgene, Eli-Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, Sandoz as well as research support from Daiichi, Novartis and Roche. MP has received honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen. The following for-profit companies have supported clinical trials and contracted research conducted by MP with payments made to his institution: Böhringer-Ingelheim, Bristol-Myers Squibb, Roche, Daiichi Sankyo, Merck Sharp & Dome, Novocure, GlaxoSmithKline, AbbVie. ASB has research support from Daiichi Sankyo (≤ €10 000), Roche (> €10 000) and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all <€5000) as well as travel support from Roche, Amgen and AbbVie. TB reports personal fees from Bayer (lecture fee, advisory board), personal fees from PharmaMar (lecture fee, advisory board), personal fees from Eli-Lilly (lecture fee, advisory board) outside the submitted work. SZ-M received honoraria for advisory boards and/or lectures from Boehringer Ingelheim, Merck Sharp & Dohme, Bristol Myers Squibb, Roche, AstraZeneca, Takeda and Pfizer. Research support to her was granted by Merck Sharp & Dohme. TF hast received honoraria from MSD, Merck Darmstadt, Roche, BMS, Accord, Sanofi, Boehringer Ingelheim, Novartis and was and advisor or consultant for MSD; Merck Darmstadt, Amgen, Pfizer, Sanofi and Boehringer Ingelheim. He has further received travel expenses, including accommodations, from Roche, MS and BMS as well as research grants or funding from MSD, Merck Darmstadt. AI-M announces following COIs: Participation at advisory boards of MSD, Servier and BMS, lecture honoraria from Eli Lilly and Servier and travel support from Roche and BMS. She has also served as local PI for clinical trials sponsored by BMS and Astellas. All other authors report no relevant conflicts of interest., (© 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.)

Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis., Patients and Methods: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population., Results: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]., Conclusion: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature., Clinical Trial Number: NCT02684006., Competing Interests: Disclosure TKC reports the following: Research (institutional and personal): AstraZeneca, Alexion, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda. Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OncLive, PeerView, and PER), Research to Practice, Lpath, Kidney Cancer Journal, Clinical Care Options, PlatformQ, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, New England Journal of Medicine, The Lancet Oncology, Heron Therapeutics, Lilly. Consulting or Advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol-Myers Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest. Stock ownership: Pionyr, Tempest. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of Medical Staff at Dana-Farber, member of NCCN Kidney Panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee. Patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled ‘PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response’, filed 3 January 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed 11 January 2017; International Patent Application No. PCT/US2018/058430, entitled ‘Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy’, filed 31 October 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed 3 November 2017. Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack). RJM reports personal fees and other from Pfizer during the conduct of the study; personal fees and other from Genentech/Roche, personal fees from Incyte, other from Bristol-Myers Squibb, personal fees and other from Novartis, personal fees and other from Exelixis, personal fees and other from Eisai, personal fees from Merck, outside the submitted work. BIR reports grants and personal fees from Pfizer during the conduct of the study, grants and personal fees from Merck (MSD), grants and personal fees from Bristol-Myers Squibb, personal fees from Novartis, grants and personal fees from GNE/Roche, personal fees from Exelixis, personal fees from Peloton, outside the submitted work. JH reports grants and personal fees from Bristol-Myers Squibb, MSD, Novartis, and Neon Therapeutics; personal fees from Pfizer, Roche/Genentech, Bayer, Immunocore, Seattle Genetics, Gadeta B.V., Celsius Therapeutics, and AstraZeneca/MedImmune, outside the submitted work. MTC reports personal fees from Eisai, grants and personal fees from EMD Serono, grants from Pfizer, personal fees from Genentech and AstraZeneca, grants from Exelixis and Janssen, other from Bristol-Myers Squibb, Roche, and Merck, outside the submitted work. BV reports personal fees from Bristol-Myers Squibb, personal fees and nonfinancial support from Merck Serono Dohme (MSD), personal fees from EUSA Pharma, personal fees and nonfinancial support from Ipsen, during the conduct of the study. CK reports personal fees from Pfizer, Bristol-Myers Squibb, Eisai, Ipsen, Astellas, and EMD Serono, outside the submitted work. GG-M and MU have nothing to disclose. JLL reports grants, personal fees, and other from Pfizer Korea and Ipsen Korea, personal fees and other from Janssen and Sanofi Aventis, personal fees from Novartis Korea, and personal fees and other from Astellas Korea and Bristol-Myers Squibb Korea, outside the submitted work. M-OG reports grants and personal fees from Novartis and Bristol-Myers Squibb, personal fees from Pfizer, Bayer HealthCare, Astellas, Intuitive Surgical, Sanofi Aventis, Hexal, APOGEPHA, Amgen, AstraZeneca, MSD, Janssen Cilag, Ono Pharma, Ipsen Pharma, Medac, and Merck, outside the submitted work. HG reports personal fees from Bristol-Myers Squibb, Astellas, Pfizer, AstraZeneca, Ipsen, Roche, and MSD, outside the submitted work. MS reports grants, personal fees, and nonfinancial support from Pfizer; personal fees and nonfinancial support from Roche; and personal fees from Novartis, Bristol-Myers Squibb, Ipsen, Exelixis, Eisai, Astellas, and EUSA Pharma, outside the submitted work. JL reports grants and personal fees from Achilles Therapeutics, MSD, Bristol-Myers Squibb, Nektar, Novartis, Pfizer, Roche/Genentech, and Immunocore; personal fees from AstraZeneca, Boston Biomedical, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Pierre Fabre, Secarna, Vitaccess, and Covance; and grants from Aveo and Pharmacyclics, outside the submitted work. MBA reports personal fees from Pfizer, Bristol-Myers Squibb, Merck, Roche, Exelixis, Eisai, Novartis, Alexion, Boehringer Ingelheim, Nektar, and X4 Pharmaceuticals, outside the submitted work. SKP has received honoraria from Astellas Pharma, Medivation, and Novartis; and fees for a consulting or advisory role from Aveo, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, Novartis, and Pfizer. JW, MM, SK, PC, AC, CF, BH, and AdP are employees of Pfizer. LA reports personal fees from Bristol-Myers Squibb, Pfizer, Ipsen, Peloton Therapeutics, Roche, MSD, and Novartis, outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Chemotherapy is the reference treatment for patients with advanced urothelial carcinoma, both in the neo-adjuvant and adjuvant settings; however, the overall outcome remains poor in this patient population. In the last few years, the addition of immune checkpoint inhibitors into the therapeutic armamentarium has changed the therapeutic landscape of several tumor types, including urothelial carcinoma. Many different molecules have been introduced on the market and several questions about immunotherapies are currently open and deserve a critical analysis. The current review article is aimed at describing the clinical pharmacology of monoclonal antibodies targeting PD-1 axis in urothelial malignancies to underline possible pharmacodynamic and pharmacokinetic differences among them., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Real-world data are essential to accurately assessing efficacy and toxicity of approved agents in everyday practice. PRINCIPAL, a prospective, observational study, was designed to confirm the real-world safety and efficacy of pazopanib in patients with advanced renal cell carcinoma (RCC)., Subjects, Materials, and Methods: Patients with clear cell advanced/metastatic RCC and a clinical decision to initiate pazopanib treatment within 30 days of enrollment were eligible. Primary objectives included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), relative dose intensity (RDI) and its effect on treatment outcomes, change in health-related quality of life (HRQoL), and safety. We also compared characteristics and outcomes of clinical-trial-eligible (CTE) patients, defined using COMPARZ trial eligibility criteria, with those of non-clinical-trial-eligible (NCTE) patients. Secondary study objectives were to evaluate clinical efficacy, safety, and RDI in patient subgroups., Results: Six hundred fifty-seven patients were enrolled and received ≥1 dose of pazopanib. Median PFS and OS were 10.3 months (95% confidence interval [CI], 9.2-12.0) and 29.9 months (95% CI, 24.7 to not reached), respectively, and the ORR was 30.3%. HRQoL showed no or little deterioration over time. Treatment-related serious adverse events (AEs) and AEs of special interest occurred in 64 (9.7%), and 399 (60.7%) patients, respectively. More patients were classified NCTE than CTE (85.2% vs. 14.8%). Efficacy of pazopanib was similar between the two groups., Conclusion: PRINCIPAL confirms the efficacy and safety of pazopanib in patients with advanced/metastatic RCC in a real-world clinical setting., Implications for Practice: PRINCIPAL is the largest ( n  = 657) prospective, observational study of pazopanib in patients with advanced/metastatic renal cell carcinoma, to the authors' knowledge. Consistent with clinical trial results that often contain specific patient types, the PRINCIPAL study demonstrated that the effectiveness and safety of pazopanib is similarly safe and effective in patients with advanced kidney cancer in a real-world clinical setting. The PRINCIPAL study showed that patients with advanced kidney cancer who are treated with first-line pazopanib generally do not show disease progression for approximately 10 months and generally survive for nearly 30 months., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Renal cell carcinoma (RCC) with sarcomatoid differentiation belongs to the most aggressive clinicopathologic phenotypes of RCC. It is characterized by a high propensity for primary metastasis and limited therapeutic options due to its relative resistance to established systemic targeted therapy. Most trials report on a poor median overall survival of 5 to 12 months. Sarcomatoid RCC can show the typical features of epithelial-mesenchymal transition (EMT) and may contain epithelial and mesenchymal features on both the morphological and immunhistochemical level. On the molecular level, next-generation sequencing confirmed differences in driver mutations between sarcomatoid RCC and non-sarcomatoid RCC. In contrast, mutational profiles within the epithelial and sarcomatoid components of sarcomatoid RCC were shown to be identical, with TP53 being the most frequently altered gene. These data suggest that both epithelial and sarcomatoid components of RCC originate from the same progenitor cell, segregating primarily according to the underlying histologic epithelial subtype of RCC (clear cell, papillary or chromophobe). Current studies have shown that sarcomatoid RCC express programmed death 1 (PD-1) and its ligand (PD-L1) at a much higher level than non-sarcomatoid RCC, suggesting that blockade of the PD-1/PD-L1 axis may be an attractive new therapeutic strategy. Preliminary results of clinical trials evaluating checkpoint inhibitors in patients with sarcomatoid RCC showed encouraging survival data and objective response and complete response rates of up to 62% and 18%, respectively. These findings may establish a new standard of care in the management of patients with sarcomatoid RCC.

In contrast to venous thromboembolism, little is known about arterial thromboembolism in patients with cancer. The aim of this study was to quantify the risk and explore clinical risk factors of arterial thromboembolism in patients with cancer, and investigate its potential impact on mortality. Patients with newly-diagnosed cancer or progression of disease after remission were included in a prospective observational cohort study and followed for two years. Between October 2003 and October 2013, 1880 patients (54.3% male; median age 61 years) were included. During a median follow up of 723 days, 48 (2.6%) patients developed arterial thromboembolism [20 (41.7%) myocardial infarction, 16 (33.3%) stroke and 12 (25.0%) peripheral arterial events], 157 (8.4%) developed venous thromboembolism, and 754 (40.1%) patients died. The cumulative 3-, 6-, 12-, and 24-month risks of arterial thromboembolism were 0.9%, 1.1%, 1.7%, and 2.6%, respectively. Male sex (subdistribution hazard ratio=2.9, 95%CI: 1.5-5.6; P =0.002), age (subdistribution hazard ratio per 10 year increase=1.5, 1.2-1.7; P <0.001), hypertension (3.1, 1.7-5.5; P <0.001), smoking (2.0, 1.1-3.7; P =0.022), lung cancer (2.3, 1.2-4.2; P =0.009), and kidney cancer (3.8, 1.4-10.5; P =0.012) were associated with a higher arterial thromboembolism risk. Furthermore, the occurrence of arterial thromboembolism was associated with a 3.2-fold increased risk of all-cause mortality (hazard ratio=3.2, 95%CI: 2.2-4.8; P <0.001). Arterial thromboembolism is a less common complication in patients with cancer than venous thromboembolism. The risk of arterial thromboembolism is high in patients with lung and kidney cancer. Patients with cancer who develop arterial thromboembolism are at a 3-fold increased risk of mortality., (Copyright© 2018 Ferrata Storti Foundation.)

HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC. Immunohistochemistry and chromogenic in-situ hybridization was performed on formalin-fixed, paraffin-embedded samples. HER2 protein expression was observed in 27/81 (33%) cases, of which 8 cases exhibited amplification of HER2. One of them had an additional polysomy 17, whereas 6/67 HER2 non-amplified cases revealed a polysomy 17. Coamplification of HER2 and TOP2A was found in 4 cases, whereas 3 cases showed only HER2 amplification and 20 cases only TOP2A amplification. HER2 IHC overexpression was associated with higher-grade tumors (p = 0.001), non-organ confined carcinomas (p = 0.017), HER2 amplification (p < 0.00001) and TOP2A amplification (p = 0.016). HER2 amplification was association with higher tumor grade (p = 0.001) and lymphnode metastasis (p = 0.003). TOP2A IHC positivity was significantly associated with higher tumor grade (p = 0.0004), TOP2A amplification (p = 0.0003), polysomy 17 (p = 0.035) and HER2 IHC overexpression (p = 0.28), whereas all categories of tumor stage and HER2 amplification remained not related. TOP2A amplification was significantly more frequent in tumors with higher grade, higher tumor stage, polysomy 17 and distant metastasis (p = 0.015; p = 0.042; p = 0.032; p = 0.011), respectively. In univariate analyses HER2 IHC positivity, TOP2A amplification, and polysomy 17 were associated with poor clinical outcome after surgery. HER2 IHC overexpression and TOP2A amplification are associated with features of biologically aggressive UTUC. Overexpression and/or amplification of HER2 and TOP2A could help identify patients who may benefit from targeted therapy.

Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety.

Cabozantinib was recently approved for the treatment of advanced renal cell carcinoma (RCC) after treatment with vascular endothelial growth factor (VEGF)-targeted therapy. Cabozantinib is a multikinase inhibitor targeting VEGF receptor (VEGFR) 2, mesenchymal-epithelial transition receptor, and "anexelekto" receptor tyrosine kinase. A 60-mg daily dose led to improved overall survival and progression-free survival (PFS) versus everolimus in advanced RCC patients as a second- or later-line treatment in the METEOR trial. Improved PFS with cabozantinib versus sunitinib has also been demonstrated in the first-line setting in CABOSUN. However, cabozantinib, like other VEGFR inhibitors, is associated with toxicity that may affect the patient's quality of life. The most frequent adverse events (AEs) are diarrhea, fatigue, hypertension, hand-foot syndrome, weight loss, nausea, and stomatitis. This article summarizes the safety profile of cabozantinib in RCC patients and offers guidance for the management of these AEs. We discuss the underlying mechanisms of these AEs and, based on our experiences with cabozantinib and other multikinase inhibitors, we present approaches to manage toxicity. Prophylactic and therapeutic solutions are available to help with the management of toxicity associated with cabozantinib, and adequate interventions can ensure optimum adherence and maximize patient outcomes., Implications for Practice: Cabozantinib leads to improved survival outcomes in renal cell carcinoma patients compared with everolimus. However, management of the adverse event profile is crucial to achieve optimum adherence and outcomes with the use of cabozantinib. This review aims to provide appropriate guidance that will minimize the impact of adverse events and help to maximize the utility of this agent in patients with advanced renal cell carcinoma., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

A number of treatments targeting VEGF or mTOR pathways have been approved for metastatic clear cell Renal Cell Carcinoma (ccRCC), but the majority of patients show disease progression after first line therapy with a very low rate of complete or long-term responders. It has been shown that miRs may play a role in prediction of treatment response in various cancer types. The aim of our study was to identify a miR signature predictive for RCC patients' response to antiangiogenic tyrosine kinase inhibitor (TKI) treatment in the first line therapy. Sequencing of 40 paired normal/tumor formalin fixed and paraffin embedded ccRCC tissues revealed separate clustering via unsupervised dendrograms. With supervised analysis, the strongest differential expression was obtained with miR-99b-5p, which was significantly lower in patients with short progression free survival (<8 months) and TKI non-responders (progressive disease patients according to RECIST) (p<0.0001, each). Validation using RTqPCR and a second patient cohort compiled from three different hospitals (n=65) showed higher expression of miR-99b-5p in complete responders, but this trend did not reach statistical significance. It is concluded that low miR-99b-5p expression analyzed with sequencing methodology may correlate with tumor progression in TKI-treated ccRCC patients.

Background: The VHL protein (pVHL) is a multiadaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes. About 70 % of clear cell renal cell carcinoma (ccRCC) have VHL mutations with varying impact on pVHL function. Loss of pVHL function leads to the accumulation of Hypoxia Inducible Factor (HIF), which is targeted by current targeted treatments. In contrast to nonsense and frameshift mutations that highly likely nullify pVHL multipurpose functions, missense mutations may rather specifically influence the binding capability of pVHL to its partners. The affected pathways may offer predictive clues to therapy and response to treatment. In this study we focused on the VHL missense mutation pattern in ccRCC, and studied their potential effects on pVHL protein stability and binding partners and discussed treatment options., Methods: We sequenced VHL in 360 sporadic ccRCC FFPE samples and compared observed and expected frequency of missense mutations in 32 different binding domains. The prediction of the impact of those mutations on protein stability and function was assessed in silico. The response to HIF-related, anti-angiogenic treatment of 30 patients with known VHL mutation status was also investigated., Results: We identified 254 VHL mutations (68.3 % of the cases) including 89 missense mutations (35 %). Codons Ser65, Asn78, Ser80, Trp117 and Leu184 represented hotspots and missense mutations in Trp117 and Leu 184 were predicted to highly destabilize pVHL. About 40 % of VHL missense mutations were predicted to cause severe protein malfunction. The pVHL binding domains for HIF1AN, BCL2L11, HIF1/2α, RPB1, PRKCZ, aPKC-λ/ι, EEF1A1, CCT-ζ-2, and Cullin2 were preferentially affected. These binding partners are mainly acting in transcriptional regulation, apoptosis and ubiquitin ligation. There was no correlation between VHL mutation status and response to treatment., Conclusions: VHL missense mutations may exert mild, moderate or strong impact on pVHL stability. Besides the HIF binding domain, other pVHL binding sites seem to be non-randomly altered by missense mutations. In contrast to LOF mutations that affect all the different pathways normally controlled by pVHL, missense mutations may be rather appropriate for designing tailor-made treatment strategies for ccRCC.

Background: The European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) has been designed to stratify the therapeutic benefit of a certain drug registered for the treatment of cancer. However, though internally validated, this tool has not yet been evaluated for its feasibility in the daily practice of a major center of medical oncology., Methods: The practicability of the MCBS for advanced oncological diseases at the Clinical Division of Oncology, Medical University of Vienna, which constitutes one of the largest oncological centres in Europe, was analysed in a three-step approach. First, retrospectively collected data were analysed to gain an overview of treatments in regular use. Second, data were scored by using the MCBS. Third, the ensuing results were evaluated within corresponding programme directorships to assess feasibility in a real-life clinical context., Results: In the majority of tumour entities, the MCBS results reported earlier are consistent with daily clinical practice. Thus, in metastatic breast cancer or advanced lung cancer, there was a high level of clinical benefit for first-line treatment standards, and these results reflected well real-life experience. However, analyses based on the first version of the MCBS are limited if it comes to salvage treatment in tumour entities in which optimal sequencing of potential treatment options is of major importance, as in metastatic colorectal or renal cell cancer. In contrast to this, it is remarkable that certain novel therapies such as nivolumab assessed for heavily pretreated advanced renal cancer reached the highest level of clinical benefit due to prolongation in survival and a favourable toxicity profile. The MCBS clearly underlines the potential benefit of these compounds., Conclusions: The MCBS is an excellent tool for daily clinical practice of a tertiary referral centre. It supports treatment decisions based on the clinical benefit to be expected from a novel approach such as immunotherapy in as yet untested indications., Competing Interests: Competing interests: GP has received honoraria for lectures by Merck Serono, Amgen, Bayer, Servier, Lilly, Celgene, Roche and Sanofi Aventis. RP has received honoraria for lectures or advisory boards by AstraZeneca, Böhringer Ingelheim, Lilly, MSD, Pfizer, Roche and Synta. MP has received research support by Böhringer Ingelheim, GSK, MSD, Roche and honoraria by BMS, Novartis, CMC Contrast, GSK, Mundipharma and Roche. MS has received honoraria for lectures by Pfizer, BMS, Novartis, Roche and Astellas. CCZ has received honoraria for advisory boards by Bristol Myers-Squibb, AstraZeneca, Imugene and Roche. All remaining authors have declared no conflict of interest.

Background: In clinical trials, the use of intermediate time-to-event end points (TEEs) is increasingly common, yet their choice and definitions are not standardized. This limits the usefulness for comparing treatment effects between studies. The aim of the DATECAN Kidney project is to clarify and recommend definitions of TEE in renal cell cancer (RCC) through a formal consensus method for end point definitions., Materials and Methods: A formal modified Delphi method was used for establishing consensus. From a 2006-2009 literature review, the Steering Committee (SC) selected 9 TEE and 15 events in the nonmetastatic (NM) and metastatic/advanced (MA) RCC disease settings. Events were scored on the range of 1 (totally disagree to include) to 9 (totally agree to include) in the definition of each end point. Rating Committee (RC) experts were contacted for the scoring rounds. From these results, final recommendations were established for selecting pertinent end points and the associated events., Results: Thirty-four experts scored 121 events for 9 end points. Consensus was reached for 31%, 43% and 85% events during the first, second and third rounds, respectively. The expert recommend the use of three and two endpoints in NM and MA setting, respectively. In the NM setting: disease-free survival (contralateral RCC, appearance of metastases, local or regional recurrence, death from RCC or protocol treatment), metastasis-free survival (appearance of metastases, regional recurrence, death from RCC); and local-regional-free survival (local or regional recurrence, death from RCC). In the MA setting: kidney cancer-specific survival (death from RCC or protocol treatment) and progression-free survival (death from RCC, local, regional, or metastatic progression)., Conclusions: The consensus method revealed that intermediate end points have not been well defined, because all of the selected end points had at least one event definition for which no consensus was obtained. These clarified definitions of TEE should become standard practice in all RCC clinical trials, thus facilitating reporting and increasing precision in between trial comparisons., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: With the advent of targeted therapies, many treatment options in the first-line setting of metastatic clear cell renal cell carcinoma (mccRCC) have emerged. Guidelines and randomized trial reports usually do not elucidate the decision criteria for the different treatment options. In order to extract the decision criteria for the optimal therapy for patients, we performed an analysis of treatment algorithms from experts in the field., Materials and Methods: Treatment algorithms for the treatment of mccRCC from experts of 11 institutions were obtained, and decision trees were deduced. Treatment options were identified and a list of unified decision criteria determined. The final decision trees were analyzed with a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees. The most common treatment recommendations were determined, and areas of discordance were identified., Results: The analysis revealed heterogeneity in most clinical scenarios. The recommendations selected for first-line treatment of mccRCC included sunitinib, pazopanib, temsirolimus, interferon-α combined with bevacizumab, high-dose interleukin-2, sorafenib, axitinib, everolimus, and best supportive care. The criteria relevant for treatment decisions were performance status, Memorial Sloan Kettering Cancer Center risk group, only or mainly lung metastases, cardiac insufficiency, hepatic insufficiency, age, and "zugzwang" (composite of multiple, related criteria)., Conclusion: In the present study, we used diagnostic nodes to compare treatment algorithms in the first-line treatment of mccRCC. The results illustrate the heterogeneity of the decision criteria and treatment strategies for mccRCC and how available data are interpreted and implemented differently among experts., Implications for Practice: The data provided in the present report should not be considered to serve as treatment recommendations for the management of treatment-naïve patients with multiple metastases from metastatic clear cell renal cell carcinoma outside a clinical trial; however, the data highlight the different treatment options and the criteria used to select them. The diversity in decision making and how results from phase III trials can be interpreted and implemented differently in daily practice are demonstrated., (©AlphaMed Press.)

There are now a range of effective targeted agents available for the first- and second-line treatment of advanced renal cell carcinoma (RCC). However, patients with advanced RCC have varied responses to therapy; some experience long-term responses while others may not respond, or even progress rapidly. Characteristics or markers that could be used to determine which patients will benefit most from which agent may enable us to select the optimal treatment of each individual patient, thereby improving efficacy and avoiding unnecessary toxic effects. These characteristics may be at the cellular or genetic level. Alternatively, the occurrence of adverse events may act as surrogate markers of a drug's on treatment activity, enabling prediction of outcomes during treatment. Recently, it has been suggested that during some targeted therapy for advanced RCC, the occurrence of specific adverse events, such as hypertension, hypothyroidism, hand-foot syndrome or fatigue/asthenia, may be associated with improved efficacy. This article reviews the evidence supporting clinical biomarkers in patients with advanced RCC receiving targeted agents. We also consider how these clinical biomarkers may affect the future management of patients with advanced RCC.

Background/aim: the ideal sequence of targeted agents for advanced kidney cancer is still unknown. In the present study we assessed the clinical benefit of two different sequential approaches, namely sorafenib, an inhibitor of mammalian target of rapamycin (mTORi) and sunitinib, or sunitinib (an mTORi) and sorafenib., Patients and Methods: we retrospectively reviewed the outcome of 40 advanced kidney cancer patients treated with one of the two above sequences., Results: a total of 26 patients were treated with the sequence sorafenib-mTORi-sunitinib and 14 with the sequence sunitinib-mTORi-sorafenib. The actuarial overall median progression-free survival (PFS) in the sorafenib-mTORi-sunitinib group and in the sunitinib-mTORi-sorafenib group were 21.9 and 22.8 months, respectively (log-rank test: p=0.928). In the sorafenib-mTORi-sunitinib group, patients in first-, second- and third-line therapy experienced PFS of 11.7, 5.1 and 9.1 months, respectively, while in the sunitinib-mTORi-sorafenib group PFS was 14.4, 4.3, and 3.9 months, respectively., Conclusion: Our results suggest there is no significant difference between the two sequence modalities.