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Purpose of Review: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for metastatic renal cell carcinoma (mRCC), significantly improving overall survival and achieving durable responses. This review is timely due to the increasing number of ICI-based regimens now considered standard care for RCC. There is an urgent need to identify reliable biomarkers that can predict therapeutic responses and resistance, a key challenge in current research., Recent Findings: While tumor-specific factors such as pathological characteristics, genomic mutations, and transcriptional profiles have been extensively studied, no definitive predictive biomarker has yet emerged. Additionally, advanced technologies are being explored to address tumor heterogeneity. Recent research has focused on novel areas such as the microbiome, radiomics, and spatial transcriptomics, which show promise as potential biomarkers., Summary: The translation of these emerging biomarker findings into clinical practice is essential to improving personalized treatment strategies for RCC. Until reliable biomarkers are clinically available, clinical factors may play a pivotal role in guiding individualized treatment decisions to optimize patient outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To compare the differential efficacy of first-line immune checkpoint inhibitor (ICI)-based combined therapies among patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC), as recently, the efficacy of triplet therapy comprising nivolumab plus ipilimumab plus cabozantinib has been published., Patients and Methods: Three databases were searched in December 2022 for randomised controlled trials (RCTs) analysing oncological outcomes in patients with mRCC treated with first-line ICI-based combined therapies. We performed network meta-analysis (NMA) to compare the outcomes, including progression-free survival (PFS) and objective response rates (ORRs), in patients with intermediate- and poor-risk mRCC; we also assessed treatment-related adverse events., Results: Overall, seven RCTs were included in the meta-analyses and NMAs. Treatment ranking analysis revealed that pembrolizumab + lenvatinib (99%) had the highest likelihood of improved PFS, followed by nivolumab + cabozantinib (79%), and nivolumab + ipilimumab + cabozantinib (77%). Notably, compared to nivolumab + cabozantinib, adding ipilimumab to nivolumab + cabozantinib did not improve PFS (hazard ratio 1.02, 95% confidence interval 0.72-1.43). Regarding ORRs, treatment ranking analysis also revealed that pembrolizumab + lenvatinib had the highest likelihood of providing better ORRs (99.7%). The likelihoods of improved PFS and ORRs of pembrolizumab + lenvatinib were true in both International Metastatic RCC Database Consortium (IMDC) risk groups., Conclusions: Our analyses confirmed the robust efficacy of pembrolizumab + lenvatinib as first-line treatment for patients with intermediate or poor IMDC risk mRCC. Triplet therapy did not result in superior efficacy. Considering both toxicity and the lack of mature overall survival data, triplet therapy should only be considered in selected patients., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

TFEB -altered renal cell carcinomas are rare tumours. Here, we report the exceptional case of such a tumour in the setting of solid organ transplantation and with already metastatic disease at the time of diagnosis. The primary tumour occurred in the native kidney and only focally showed biphasic morphology whereas the metastasis, among others to the transplant kidney, showed nonspecific, albeit different morphology, but both had consistent TFEB translocation. Treatment with the immune checkpoint inhibitor pembrolizumab together with the multi-kinase inhibitor lenvatinib achieved partial response 14 months after diagnosis., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We present the final prespecified overall survival (OS) analysis of the open-label, phase III CLEAR study in treatment-naïve patients with advanced renal cell carcinoma (aRCC). With an additional follow-up of 23 months from the primary analysis, we report results from the lenvatinib plus pembrolizumab versus sunitinib comparison of CLEAR. Treatment-naïve patients with aRCC were randomly assigned to receive lenvatinib (20 mg orally once daily in 21-day cycles) plus pembrolizumab (200 mg intravenously once every 3 weeks) or sunitinib (50 mg orally once daily [4 weeks on/2 weeks off]). At this data cutoff date (July 31, 2022), the OS hazard ratio (HR) was 0.79 (95% CI, 0.63 to 0.99). The median OS (95% CI) was 53.7 months (95% CI, 48.7 to not estimable [NE]) with lenvatinib plus pembrolizumab versus 54.3 months (95% CI, 40.9 to NE) with sunitinib; 36-month OS rates (95% CI) were 66.4% (95% CI, 61.1 to 71.2) and 60.2% (95% CI, 54.6 to 65.2), respectively. The median progression-free survival (95% CI) was 23.9 months (95% CI, 20.8 to 27.7) with lenvatinib plus pembrolizumab and 9.2 months (95% CI, 6.0 to 11.0) with sunitinib (HR, 0.47 [95% CI, 0.38 to 0.57]). Objective response rate also favored the combination over sunitinib (71.3% v 36.7%; relative risk 1.94 [95% CI, 1.67 to 2.26]). Treatment-emergent adverse events occurred in >90% of patients who received either treatment. In conclusion, lenvatinib plus pembrolizumab achieved consistent, durable benefit with a manageable safety profile in treatment-naïve patients with aRCC.

Renal cell carcinoma (RCC) represents 2% of all diagnosed malignancies worldwide, with disease recurrence affecting 20% to 40% of patients. Existing prognostic recurrence models based on clinicopathological features continue to be a subject of controversy. In this meta-analysis, we summarized research findings that explored the correlation between clinicopathological characteristics and post-surgery survival outcomes in non-metastatic RCC patients. Our analysis incorporates 99 publications spanning 140 568 patients. The study's main findings indicate that the following clinicopathological characteristics were associated with unfavorable survival outcomes: T stage, tumor grade, tumor size, lymph node involvement, tumor necrosis, sarcomatoid features, positive surgical margins (PSM), lymphovascular invasion (LVI), early recurrence, constitutional symptoms, poor performance status (PS), low hemoglobin level, high body-mass index (BMI), diabetes mellitus (DM) and hypertension. All of which emerged as predictors for poor recurrence-free survival (RFS) and cancer-specific survival. Clear cell (CC) subtype, urinary collecting system invasion (UCSI), capsular penetration, perinephric fat invasion, renal vein invasion (RVI) and increased C-reactive protein (CRP) were all associated with poor RFS. In contrast, age, sex, tumor laterality, nephrectomy type and approach had no impact on survival outcomes. As part of an additional analysis, we attempted to assess the association between these characteristics and late recurrences (relapses occurring more than 5 years after surgery). Nevertheless, we did not find any prediction capabilities for late disease recurrences among any of the features examined. Our findings highlight the prognostic significance of various clinicopathological characteristics potentially aiding in the identification of high-risk RCC patients and enhancing the development of more precise prediction models., (© 2023 UICC.)

Background: The multikinase-inhibitor Cabozantinib is a widely used treatment strategy in metastatic renal cell carcinoma (mRCC), either in combination with the programmed cell death protein-1 (PD-1) inhibitor nivolumab or as monotherapy. Cabozantinib is given continuously at a dose of 60 mg once daily when used as a single agent and at 40 mg when combined with nivolumab. Treatment-related adverse events (TRAE's) were shown to occur frequently., Objective: We aimed to assess the safety and efficacy of cabozantinib in patients with mRCC. Patients were treated in various lines. Furthermore, we analyzed the impact of an alternative treatment schedule in patients not able to maintain continuous dosing., Patients: This is a single center retrospective study from the Medical University of Vienna., Outcome Measurements and Statistical Analysis: Overall response rates (ORR), progression free survival (PFS) and overall survival (OS) were evaluated for the entire cohort, by treatment line and by treatment schedule., Results: Between January 2014 until April 2021, 71 patients received cabozantinib. Sixty-seven patients were eligible for full evaluation. By IMDC criteria, 32.4%, 59.2%, and 8.5% were classified as favorable, intermediate and poor risk respectively. Cabozantinib was offered as a 2nd-line or 3rd-line treatment in 38.0% and 32.4% of patients, respectively. An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 months (95% CI: 5.5-16.2). When compared to continuous dosing, an alternative treatment schedule was associated with longer PFS (12.2 months (95% CI: 0-25.5) vs. 6.1 months (95% CI: 0.37-11.8) (P = .014, HR 0.46 (95% CI: 0.24-0.86), respectively) and a lower frequency and severity of TRAE's., Conclusions: Safety and efficacy of cabozantinib in real world is comparable to what has been observed in the pivotal trials, irrespective of the treatment line. An alternative schedule may further improve efficacy and safety., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

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/aim: Patients with advanced renal cell carcinoma (aRCC) treated with immune-oncology (IO) drugs may need to discontinue the treatment when severe immune-related adverse events (irAE) occur; however, the impact of discontinuation on survival remains unknown., Patients and Methods: This is a retrospective multicenter analysis using a database of 183 aRCC patients treated with first-line IO drugs combination. The patients were divided into two groups according to the necessity of discontinuation due to irAEs. The primary endpoint was overall survival (OS). Cox proportional hazard models determined the predictive factors on OS., Results: Among a total of 135 patients who experienced irAE, 38 patients had to discontinue and 52 continued the treatment while treating irAE. When compared to patients who were able to continue treatment, discontinuation was associated with significantly higher rates of IO-IO doublet use, severe irAE (grade ≥3), steroid use, and the occurrence of immune-related pneumonitis (p=0.03, p<0.001, p<0.001, and p=0.02, respectively). The objective response rates were comparable between the two groups (discontinuation 55.6% vs. no discontinuation 56.0%, p=0.7). On univariate analysis, patients who discontinued had a significantly worse OS when compared to those who continued treatment (p=0.02). On the contrary, on multivariate analysis treatment discontinuation was not associated with poor OS (HR=1.1, p=0.9)., Conclusion: Treatment discontinuation due to irAE was not associated with poor prognosis in aRCC patients treated with ICI-based combination therapy. Treatment discontinuation may be a reasonable treatment option for well-selected patients, specifically for those who experienced good treatment responses., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Data on the effects of prior cytoreductive nephrectomy (CN) in patients with renal cell carcinoma (RCC) with synchronous metastases (M1 disease) before immune checkpoint inhibitor (ICI) treatment are limited. In this post hoc analysis of treatment-naive patients with advanced RCC from the phase 3 JAVELIN Renal 101 trial, we assessed efficacy outcomes in the avelumab + axitinib and sunitinib arms in patients who were initially diagnosed with M1 disease (n = 412) grouped by prior CN (yes vs no). Progression-free survival (PFS) and overall survival (OS) were analyzed using multivariable Cox regression, and objective response rates (ORRs) were analyzed using logistic regression. After adjusting for imbalances in baseline variables, the hazard ratio (HR) for PFS in the prior CN versus no prior CN subgroup was 0.79 (95% confidence interval [CI] 0.53-1.16) in the avelumab + axitinib arm, and 1.15 (95% CI 0.77-1.70) in the sunitinib arm. The corresponding HRs for OS were 0.59 (95% CI 0.38-0.93) and 0.86 (95% CI, 0.55-1.34), and the odds ratios for ORR were 2.67 (95% CI 1.32-5.41) and 2.02 (95% CI 0.82-4.94), respectively. Prospective studies of the potential benefits of CN and its appropriate timing in patients receiving first-line treatment with ICI-containing combinations are warranted. PATIENT SUMMARY: This study looked at patients with kidney cancer whose disease had already spread outside the kidneys when it was first detected. We found that patients whose kidney had been removed before starting treatment with avelumab + axitinib had better outcomes than those whose kidney had not been removed. For patients treated with sunitinib, the results were more similar between the groups with and without prior kidney removal. However, statistical tests did not find any significant differences. The JAVELIN Renal 101 trial is registered on ClinicalTrials.gov as NCT02684006., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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.)

Background: Nivolumab plus ipilimumab is approved as first-line regimen for intermediate-risk or poor-risk metastatic renal cell carcinoma, and nivolumab monotherapy as second-line therapy for all risk groups. We aimed to examine the efficacy and safety of nivolumab monotherapy and nivolumab plus ipilimumab combination as an immunotherapeutic boost after no response to nivolumab monotherapy in patients with intermediate-risk and poor-risk clear-cell metastatic renal cell carcinoma., Methods: TITAN-RCC is a multicentre, single-arm, phase 2 trial, done at 28 hospitals and cancer centres across Europe (Austria, Belgium, Czech Republic, France, Germany, Italy, Spain, and the UK). Adults (aged ≥18 years) with histologically confirmed intermediate-risk or poor-risk clear-cell metastatic renal cell carcinoma who were formerly untreated (first-line population) or pretreated with one previous systemic therapy (anti-angiogenic or temsirolimus; second-line population) were eligible. Patients had to have a Karnofsky Performance Status score of at least 70 and measurable disease per Response Evaluation Criteria in Solid Tumours (version 1.1). Patients started with intravenous nivolumab 240 mg once every 2 weeks. On early progressive disease (week 8) or non-response at week 16, patients received two or four doses of intravenous nivolumab (3 mg/kg) and ipilimumab (1 mg/kg) boosts (once every 3 weeks), whereas responders continued with intravenous nivolumab (240 mg, once every 2 weeks), but could receive two to four boost doses of nivolumab plus ipilimumab for subsequent progressive disease. The primary endpoint was confirmed investigator-assessed objective response rate in the full analysis set, which included all patients who received at least one dose of study medication; safety was also assessed in this population. An objective response rate of more than 25% was required to reject the null hypothesis and show improvement, on the basis of results from the pivotal phase 3 CheckMate-025 trial. This study is registered with ClinicalTrials.gov, NCT02917772, and is complete., Findings: Between Oct 28, 2016, and Nov 30, 2018, 207 patients were enrolled and all received nivolumab induction (109 patients in the first-line group; 98 patients in the second-line group). 60 (29%) of 207 patients were female and 147 (71%) were male. 147 (71%) of 207 patients had intermediate-risk metastatic renal cell carcinoma and 51 (25%) had poor-risk disease. After median follow-up of 27·6 months (IQR 10·5-34·8), 39 (36%, 90% CI 28-44; p=0·0080) of 109 patients in the first-line group and 31 (32%, 24-40; p=0·083) of 98 patients in the second-line group had a confirmed objective response for nivolumab with and without nivolumab plus ipilimumab. Confirmed response to nivolumab at week 8 or 16 was observed in 31 (28%) of 109 patients in the first-line group and 18 (18%) of 98 patients in the second-line group. The most frequent grade 3-4 treatment-related adverse events (reported in ≥5% of patients) were increased lipase (15 [7%] of 207 patients), colitis (13 [6%]), and diarrhoea (13 [6%]). Three deaths were reported that were deemed to be treatment-related: one due to possible ischaemic stroke, one due to respiratory failure, and one due to pneumonia., Interpretation: In treatment-naive patients, nivolumab induction with or without nivolumab plus ipilimumab boosts significantly improved the objective response rate compared with that reported for nivolumab monotherapy in the CheckMate-025 trial. However, overall efficacy seemed inferior when compared with approved upfront nivolumab plus ipilimumab. For second-line treatment, nivolumab plus ipilimumab could be a rescue strategy on progression with approved nivolumab monotherapy., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MOG reports institutional research grants from Bristol Myers Squibb, Intuitive Surgical, and Bayer Vital; personal consulting fees from AstraZeneca, Bristol Myers Squibb, Ipsen, MSD, Pfizer, Astellas Pharma, EUSA Pharma, Merck Serono, Roche Pharma, Eisai, Bayer Vital, Janssen, Gilead, and Novartis; personal honoria from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Ipsen, Merck Serono, EUSA Pharma, Janssen, Astellas Pharma, and Takeda; and travel expenses from Merck Serono, Bristol Myers Squibb, Bayer, Pfizer, and AstraZeneca. PB reports grants from Bristol Myers Squibb, Ipsen, MSD, Pfizer, Merck, AstraZeneca, Janssen, and Gilead; consulting fees from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, AAA Pharma, Novartis, Gilead, and Bayer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Suibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas Pharma, Bayer, AAA Pharma, and Novartis; and travel expenses Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, and Astellas Pharma. ManS reports personal consulting fees for advisory boards from Bristol Myers Squibb, MSD, Eisai, Ipsen, and Exelixis; personal honoria for lectures from Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca; and personal participation on advisory boards for Bristol Myers Squibb, MSD, Merck, Eisai, Ipsen, Exelixis, EUSA Pharma, and AstraZeneca. JB reports an educational grant from Astellas Pharma; consulting fees from Bristol Myers Squibb, MSD, Merck, Ipsen, and Pfizer; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Ipsen and Merck; travel expenses from Ipsen and Merck; and participation on a data safety monitoring board or advisory board for MSD, Pfizer, and Ipsen. BPV reports consulting fees from Bristol Myers Squibb, MSD Oncology, Astellas Pharma, AstraZeneca, Novartis, Bayer, and Advanced Accelerator Applications-Novartis; payment or honoria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Ipsen, Roche, EUSA Pharma, Pfizer, Merck, Astellas Pharma, AstraZeneca, and Bayer; and travel expenses from Merck, Pfizer, Advanced Accelerator Applications-Novartis, and Roche. KL payment for medical writing (to their institution) for manuscript writing from Bristol Myers Squibb and Intuitive Surgical; and travel expenses from Ipsen. ID reports institutional research grants from Roche and AstraZeneca; honoria for lectures, presentations, or educational events from Bristol Myers Squibb, MSD, Ipsen, Roche Genentech, Janssen, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Gilead, and Bayer; travel expenses from Merck-Pfizer, Ipsen, Janssen, Bayer, and AstraZeneca; participation on an advisory board for Bristol Myers Sqibb, MSD, Ipsen, Roche Genentech, Astellas Pharma, EUSA Pharma, Bayer, Novartis, Eisai, Debio Pharma, Pharmacyclics, and Gilead; is the cofounder of GO NORTE (GU cooperative group, unpaid); is Vice President of Germ Cell Spanish Group (unpaid); is an executive board member of the GUARD consortium (GU cooperative group, unpaid); has received institutional medical writing support from Roche Genentech; and has procured substances for preclinical research purposes from Jansen (institutional research group). GdV reports consulting fees from Bristol Myers Squibb, Astellas Pharma, MSD, Merck, and Eisai; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer, Bristol Myers Squibb, Roche, Novartis, Ipse, Pfizer, Astellas Pharma, Pierre Fabre, MSD, Merck, and Janssen; travel expenses from Roche and MSD; and participation on a data safety monitoring board or advisory board for AstraZeneca. FP reports participation on a data safety monitoring board or advisory board for Daiichi and Novartis. PM reports payment or honoria for lectures, presentation, speaker bureaus, manuscript writing or educational events from Bayer; payments for expert testimony from Amgen; travel expenses from Bayer; and reports participation on a data safety monitoring board or advisory board for Pfizer, Novartis, and Astellas Pharma. LA reports consulting fees, paid to their institution, from Bristol Myers Squibb, Ipsen, Roche, Novartis, Pfizer, Astellas Pharma, Merck, MSD, AstraZeneca, Janssen, and Eisai; and travel expenses from Bristol Myers Squibb, MSD, Ipsen, and Pfizer. EE, NC, MarS, US, SF, and GB declare no competing interests., (Copyright © 2023 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.

Purpose: To analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex., Methods: Three databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting., Results: Overall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55-0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68-0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females., Conclusions: OS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making., (© 2023. The Author(s).)

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.)

Immune checkpoint inhibitors (ICIs) have led to substantial changes in systemic treatment for metastatic renal cell carcinoma (mRCC). For patients whose metastases respond to upfront ICI therapy, deferred cytoreductive nephrectomy (CN) may confer a survival advantage. Further data from ongoing trials are awaited regarding the role of deferred versus immediate CN for mRCC in the ICI era. PATIENT SUMMARY: The first-line treatment currently recommended for kidney cancer that has spread to other sites is immunotherapy. For patients who experience a good response to this treatment, surgical kidney removal to control the primary tumor may have a survival benefit. More evidence from clinical trials is needed to confirm the efficacy of this approach., (Copyright © 2023. Published by Elsevier B.V.)

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.

Background: Recently, immune checkpoint inhibitor (ICI)-combination therapies have radically altered the treatment landscape in metastatic renal cell carcinoma (mRCC). No phase 3 trials have assessed the impact of cytoreductive nephrectomy (CN) for efficacy in mRCC patients treated with ICI-combination therapy. We aimed to assess the role of ICI-combination therapy based on CN status., Methods: Multiple databases were searched for articles published until June 2021. Studies comparing overall and/or progression-free survival (OS/PFS) in mRCC patients treated with ICI combination-therapy were deemed eligible., Results: Six studies met the eligibility criteria. ICI-combination therapy was associated with significantly better OS/PFS than sunitinib in patients who had undergone CN (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.59-0.77/HR, 0.57; 95% CI, 0.44-0.74, respectively; both P < 0.001), and in those who had not (HR, 0.69; 95% CI, 0.57-0.85/HR, 0.63; 95% CI, 0.52-0.77, respectively; both P < 0.001). Although the OS and PFS benefits of ICI-combination therapy were larger in those undergoing CN, the HR for OS and PFS indicated that ICI-combination therapy's treatment effect did not differ substantially with or without CN. In network meta-analyses, nivolumab plus cabozantinib was the most effective regimen in those undergoing CN, and pembrolizumab plus lenvatinib for those not undergoing CN., Conclusion: The effect of ICI combination therapy did not differ between mRCC patients undergoing and not undergoing CN. As each ICI combination regimen varied widely in its effect in patients undergoing and not undergoing CN, CN may contribute to better treatment decision-making for ICI-combination therapy recipients., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Both immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor receptor (VEGFR) inhibitors are approved for advanced renal cell carcinoma treatment and can cause cardiovascular events (CVs); thus, combination therapy could lead to major adverse CV events (MACE). Cardiac serum biomarker assessment and imaging, including left ventricular ejection fraction (LVEF) monitoring, can be used to evaluate MACE., Methods: To our knowledge, the JAVELIN Renal 101 trial, assessing avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma, is the first randomized study of ICI plus VEGFR inhibitor treatment to include prospective serial cardiac monitoring of LVEF and serum cardiac biomarkers., Results: MACE (defined as grade ≥ 3 CV AEs) occurred in 31 patients (7.1%) in the combination arm and 17 patients (3.9%) in the sunitinib arm. Patients in the combination arm who had high baseline troponin T values were at higher risk of MACE versus patients with low values (MACE in 6/35 v 7/135, respectively; relative risk, 3.31; 95% CI, 1.19 to 9.22). This association was not observed in patients treated with sunitinib. Other CV baseline risk factors and serum cardiac biomarkers were not significantly predictive for MACE, although a trend toward an association with dyslipidemia was seen in the combination arm. No clinical value of on-treatment routine monitoring of LVEF in relation to MACE was observed. Although LVEF decline was significantly more frequent in the combination arm, most patients recovered, and decline was not associated with other significant cardiac events or symptoms., Conclusion: Patients with high baseline troponin T levels receiving ICI and VEGFR combinations may need to be monitored more closely for MACE. Routine monitoring of LVEF in asymptomatic patients is not recommended., Competing Interests: Brian I. RiniLeadership: MJH Life SciencesStock and Other Ownership Interests: PTC TherapeuticsConsulting or Advisory Role: Pfizer, Merck & Co (Kenilworth, NJ), Synthorx, Bristol Myers Squibb, AVEO, Surface Oncology, 3D Medicines, Corvus Pharmaceuticals, Aravive, Arrowhead Pharmaceuticals, Shionogi, Eisai, GlaxoSmithKlineResearch Funding: Pfizer (Inst), Roche/Genentech (Inst), Bristol Myers Squibb (Inst), Merck & Co (Kenilworth, NJ) (Inst), AstraZeneca/MedImmune (Inst), Incyte (Inst), Arrowhead Pharmaceuticals (Inst), Taris (Inst), Seattle Genetics (Inst), Immunomedics (Inst), Surface Oncology (Inst), Dragonfly Therapeutics (Inst), Aravive (Inst), Exelixis (Inst)Travel, Accommodations, Expenses: Pfizer, Bristol Myers Squibb, Merck & Co (Kenilworth, NJ) Javid J. MoslehiConsulting or Advisory Role: Aerovate Therapeutics, AstraZeneca, Audentes Pharmaceuticals, Boehringer, Bristol Myers Squibb, Cytokinetics, Deciphera, GlaxoSmithKline, Kurome Therapeutics, Mallinckrodt Pharmaceuticals, Myokardia, Myovant, Novartis, Pfizer, Pharmacyclics, ProteinCure, Takeda, Silverback Therapeutics, Star Therapeutics Marc BonacaResearch Funding: ARCA BioPahrma (Inst), AstraZeneca/MedImmune (Inst), Bayer (Inst), Better Therapeutics (Inst), CellResearch (Inst), EverlyWell (Inst), Janssen (Inst), Novo Nordisk (Inst), Osiris Medical (Inst), Amgen (Inst), HDL Therapeutics (Inst) Manuela SchmidingerHonoraria: Pfizer, Bristol Myers Squibb, Ipsen, Roche/Genentech, Merck & Co (Kenilworth, NJ), EISAI, EUSA Pharma, ALKERMESConsulting or Advisory Role: Pfizer, Bristol Myers Squibb, Roche, Ipsen, Merck & Co (Kenilworth, NJ), EUSA Pharma, EisaiTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche, Ipsen Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck & Co (Kenilworth, NJ) (Inst), AstraZeneca (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Bellerophon Theraeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck & Co (Kenilworth, NJ) Toni K. ChoueiriEmployment: Dana Farber Cancer HospitalLeadership: Dana Farber Cancer Hospital, NCCN, KidneyCan, ASCOStock and Other Ownership Interests: Pionyr, Tempest TherapeuticsHonoraria: NCCN, UpToDate, Michael J. Hennessy Associates, ASCO, Harborside Press, Analysis Group, AstraZeneca, Alexion Pharmaceuticals, Sanofi/Aventis, Bayer, Bristol Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck & Co (Kenilworth, NJ), Novartis, Peloton Therapeutics, Pfizer, Corvus Pharmaceuticals, Ipsen, Foundation Medicine, Eisai, PlatformQ Health, Clinical Care Options, Navinata Health, Kidney Cancer Association, Exelixis, Prometheus, Lpath, The New England Journal of Medicine, Lancet Oncology, Cerulean Pharma, alligent, the healthcare business of Merck KGaA (Darmstadt, Germany), HERON, Lilly, Janssen Oncology, IQvia, Aveo, NCI Genitourinary Cancers Steering CommitteeConsulting or Advisory Role: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck & Co (Kenilworth, NJ), Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, Peloton Therapeutics, UpToDate, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Navinata Health, Harborside Press, ASCO, The New England Journal of Medicine, Lancet Oncology, the healthcare business of Merck KGaA (Darmstadt, Germany), HERON, Lilly, ESMO, NiKang Therapeutics, Kanaph Therapeutics, Infinity Pharmaceuticals, AraviveResearch Funding: Pfizer (Inst), Novartis (Inst), Merck & Co (Kenilworth, NJ) (Inst), Exelixis (Inst), TRACON Pharma (Inst), GlaxoSmithKline (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Peloton Therapeutics (Inst), Roche/Genentech (Inst), Celldex (Inst), Agensys (Inst), Eisai (Inst), Takeda (Inst), Prometheus (Inst), Ipsen (Inst), Corvus Pharmaceuticals (Inst), Cerulean Pharma (Inst), Seattle Genetics/Astellas (Inst), Bayer (Inst), Foundation Medicine (Inst), Roche (Inst), Calithera Biosciences (Inst), Analysis Group (Inst), NCI (Inst), Gateway for Cancer Research (Inst), Congressionally Directed Medical Research Programs (DOD) (Inst)Patents, Royalties, Other Intellectual Property: International Patent Application No. PCT/US2018/058430, titled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy (Inst), International Patent Application No. PCT/US2018/12209, titled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response (Inst)Travel, Accommodations, Expenses: Pfizer, Bayer, Novartis, GlaxoSmithKline, Merck & Co (Kenilworth, NJ), Bristol Myers Squibb, Roche/Genentech, Eisai, Foundation Medicine, Cerulean Pharma, AstraZeneca, Exelixis, Prometheus, alligent, Ipsen, Corvus Pharmaceuticals, Lpath, Alexion Pharmaceuticals, Sanofi/Aventis, UpToDate, Peloton Therapeutics, NCCN, Michael J. Hennessy Associates, Analysis Group, Kidney Cancer Association, Clinical Care Options, PlatformQ Health, Harborside Press, Navinata Health, The New England Journal of Medicine, Lancet Oncology, the healthcare business of Merck KGaA (Darmstadt, Germany), HERON, Lilly, ESMOOther Relationship: Medical writing and editorial assistance support may have been funded by communications companies funded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, Parexel Robert J. MotzerConsulting or Advisory Role: Novartis, Eisai, Exelixis, Merck & Co (Kenilworth, NJ), Genentech/Roche, Incyte, Lilly, Pfizer, AstraZeneca, the healthcare business of Merck KGaA (Darmstadt, Germany), Calithera Biosciences, AveoResearch Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), Eisai (Inst), Novartis (Inst), Genentech/Roche (Inst), Exelixis (Inst), Merck & Co (Kenilworth, NJ) (Inst), Aveo (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb Michael B. AtkinsStock and Other Ownership Interests: Werewolf Pharma, PyxisConsulting or Advisory Role: Genentech, Novartis, Bristol Myers Squibb, Merck & Co (Kenilworth, NJ), Exelixis, Eisai, Agenus, Arrowhead Pharmaceuticals, Werewolf Pharma, Surface Oncology, Iovance Biotherapeutics, Pyxis, Pneuma Respiratory, Leads Biolabs, Fathom Biotechnology, Aveo, Cota Healthcare, Neoleukin Therapeutics, Adagene, Idera, Ellipses Pharma, AstraZeneca, PACT Pharma, Seattle Genetics, Pfizer, Scholar Rock, Asher Biotherapeutics, Calithera Biosciences, Takeda, Sanofi, Simcha TherapeuticsResearch Funding: Bristol Myers Squibb (Inst) John HaanenStock and Other Ownership Interests: Neogene TherapeuticsConsulting or Advisory Role: Merck & Co (Kenilworth, NJ) (Inst), Pfizer (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Roche/Genentech (Inst), Ipsen (Inst), Achilles Therapeutics (Inst), Immunocore (Inst), Sanofi (Inst), Third Rock Ventures (Inst), Neogene Therapeutics, Molecular Partners (Inst), bioNTech (Inst), T-Knife (Inst), PokeAcel (Inst), Instil Bio (Inst), Iovance Biotherapeutics (Inst)Research Funding: Merck & Co (Kenilworth, NJ) (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Neon Therapeutics (Inst), Amgen (Inst), BioNTech (Inst), Asher Biotherapeutics (Inst) Mariangela MarianiStock and Other Ownership Interests: Pfizer Jing WangEmployment: PfizerStock and Other Ownership Interests: Pfizer Subramanian HariharanEmployment: PfizerStock and Other Ownership Interests: Pfizer James LarkinHonoraria: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Roche/Genentech, Incyte, iOnctura, the healthcare business of Merck KGaA (Darmstadt, Germany), Eisai, Dynavax Technologies, Cancer Research UK, touchIME, touchEXPERTSConsulting or Advisory Role: Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Novartis, Boston Biomedical, Incyte, iOnctura, Iovance Biotherapeutics, Immunocore, YKT Corporation, Apple Tree PartnersResearch Funding: Pfizer (Inst), Novartis (Inst), Merck & Co (Kenilworth, NJ) (Inst), Bristol Myers Squibb (Inst), Achilles Therapeutics (Inst), Roche (Inst), Nektar (Inst), Covance (Inst), Immunocore (Inst), AVEO (Inst), Pharmacyclics (Inst)Travel, Accommodations, Expenses: Bristol Myers Squibb, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Incyte, GlaxoSmithKline, Pierre Fabre, the healthcare business of Merck KGaA (Darmstadt, Germany), iOnctura, British Uro-Oncology Group (BUG), ESMO, National Cancer Research Institute (NCRI), EUSA Pharma, Syneos Health, Kidney Cancer Association, Bioevents, MedConcept, RV MaisNo other potential conflicts of interest were reported.

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.

Introduction: This study aimed to determine the prognostic value of a panel of SIR-biomarkers, relative to standard clinicopathological variables, to improve mRCC patient selection for cytoreductive nephrectomy (CN)., Material and Methods: A panel of preoperative SIR-biomarkers, including the albumin-globulin ratio (AGR), De Ritis ratio (DRR), and systemic immune-inflammation index (SII), was assessed in 613 patients treated with CN for mRCC. Patients were randomly divided into training and testing cohorts (65/35%). A machine learning-based variable selection approach (LASSO regression) was used for the fitting of the most informative, yet parsimonious multivariable models with respect to prognosis of cancer-specific survival (CSS). The discriminatory ability of the model was quantified using the C-index. After validation and calibration of the model, a nomogram was created, and decision curve analysis (DCA) was used to evaluate the clinical net benefit., Results: SIR-biomarkers were selected by the machine-learning process to be of high discriminatory power during the fitting of the model. Low AGR remained significantly associated with CSS in both training (HR 1.40, 95% CI 1.07-1.82, p = 0.01) and testing (HR 1.78, 95% CI 1.26-2.51, p = 0.01) cohorts. High levels of SII (HR 1.51, 95% CI 1.10-2.08, p = 0.01) and DRR (HR 1.41, 95% CI 1.01-1.96, p = 0.04) were associated with CSS only in the testing cohort. The exclusion of the SIR-biomarkers for the prognosis of CSS did not result in a significant decrease in C-index (- 0.9%) for the training cohort, while the exclusion of SIR-biomarkers led to a reduction in C-index in the testing cohort (- 5.8%). However, SIR-biomarkers only marginally increased the discriminatory ability of the respective model in comparison to the standard model., Conclusion: Despite the high discriminatory ability during the fitting of the model with machine-learning approach, the panel of readily available blood-based SIR-biomarkers failed to add a clinical benefit beyond the standard model., (© 2021. The Author(s).)

Introduction: Therapies combining either two immune check-point inhibitors (ICIs) or an ICI and a tyrosine kinase inhibitor (TKI) have been shown to improve overall survival (OS), progression-free survival (PFS) and objective response rates (ORR) in metastatic renal cell carcinoma (mRCC); moreover, unprecedented rates of complete remission (CR) have been reported., Areas Covered: Among six randomized trials of ICI combinations, four have outperformed the TKI sunitinib in terms of OS. The CheckMate 214 trial investigated the combination of nivolumab (a programmed cell death protein 1 [PD-1] inhibitor) and ipilimumab (a cytotoxic T-lymphocyte antigen-4 [CTLA-4)] inhibitor). Three other trials evaluated combinations of an ICI and a TKI. These combinations are: 1) pembrolizumab (PD-1 inhibitor) plus axitinib, 2) nivolumab plus cabozantinib, and 3) pembrolizumab plus lenvatinib. This short review addresses the findings of these trials, comparing outcomes and discussing the challenges of decision-making in clinical practice., Expert Opinion: Not all patients benefit from ICI combinations. Predictive biomarkers and new therapeutic approaches are urgently needed to overcome treatment failures. A growing understanding of immune escape mechanisms and the interplay between the immune response and the gut microbiota may offer additional rescue strategies beyond ICIs and TKIs.

We determined the oncologic outcomes and safety profiles of adjuvant immune checkpoint inhibitors (ICIs) compared to adjuvant tyrosine kinase inhibitors (TKIs) in patients at high risk after nephrectomy for clinically nonmetastatic renal cell carcinoma (RCC). Network meta-analyses were conducted for disease-free survival (DFS), overall survival (OS), and adverse events (AEs) with placebo as the common comparator arm. Six trials (KEYNOTE-564, S-TRAC, ASSURE, PROTECT, ATLAS, and SORCE) were included in our analysis. Compared to placebo, both pembrolizumab (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.51-0.92) and pazopanib 800 mg (HR 0.69, 95% CI 0.49-0.97) were significantly associated with better DFS. Adjuvant pembrolizumab (HR 0.54, 95% CI 0.30-0.97) was significantly associated with better OS compared to TKIs (HR 0.93, 95% CI 0.83-1.04). Analysis of treatment ranking revealed that pembrolizumab was the best treatment with regard to both DFS and OS and had the lowest likelihood of any-grade and high-grade AEs in comparison to TKIs. The superior oncologic benefit of pembrolizumab and its better toxicity profile support it as the new standard of care in the adjuvant setting for nephrectomy patients at high risk of RCC relapse. PATIENT SUMMARY: For patients with kidney cancer at high risk of relapse after surgical removal of their kidney, postoperative therapy with the immune checkpoint inhibitor pembrolizumab offers the best risk/benefit ratio., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: METEOR was a phase 3 trial (NCT01865747) of cabozantinib versus everolimus in adults with advanced or metastatic clear cell RCC previously treated with VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs). This post hoc analysis of METEOR compared outcomes for patients recruited from European and non-European countries., Material and Methods: Adults with advanced/metastatic clear cell RCC who had received ≥ 1 prior VEGFR-TKI treatment were randomized 1:1 to receive cabozantinib or everolimus. Patients were categorized by recruitment region: Europe or outside of Europe (rest of world [RoW]). Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events (AEs) were compared between regional subgroups., Results: In total, there were 320 eligible patients from Europe (cabozantinib, 167; everolimus, 153) and 338 from RoW (North America, 240 patients; Asia-Pacific, 86; Latin America, 12; randomized as cabozantinib, 163; everolimus, 175). PFS and OS were longer with cabozantinib than with everolimus and similar for the Europe and RoW subgroups. For PFS, the hazard ratio (HR) for cabozantinib versus everolimus was 0.54 for the Europe subgroup ( p < .001) and 0.50 for the RoW subgroup ( p < .001). For OS, the HR was 0.75 for the Europe subgroup ( p = .034) and 0.69 for the RoW subgroup ( p = .006). ORR in the Europe subgroup was 15% for cabozantinib and 3.9% for everolimus ( p < .001). For the RoW subgroup, ORR was 20% for cabozantinib and 2.9% for everolimus ( p < .001). Incidence of grade 3/4 AEs were similar for the Europe (cabozantinib, 74%; everolimus, 58%) and RoW subgroups (cabozantinib, 69%; everolimus, 64%)., Conclusion: In the METEOR trial, efficacy outcomes for patients recruited from European and non-European countries favored cabozantinib over everolimus. The efficacy and safety results for the regional subgroups were consistent with those of the overall METEOR population.

Purpose of Review: To perform indirect comparisons of efficacy and safety of first-line immune checkpoint inhibitor (ICI)-based combination therapies for renal cell carcinoma with sarcomatoid features (sRCC)., Recent Findings: Five trials were included in our network meta-analyses comprising 568 patients. The combinations nivolumab plus ipilimumab and nivolumab plus cabozantinib achieved significant improvement of progression-free survival (PFS), overall survival (OS), and objective response rates (ORR). Nivolumab plus ipilimumab was associated with the highest likelihood of achieving a complete response. All the included combinations significantly improved PFS and ORR. The combinations of pembrolizumab plus axitinib did not show a statistically significant association with OS. Nivolumab plus cabozantinib had the highest likelihood of improving PFS and OS., Summary: Our network meta-analysis demonstrates that sRCC are responsive to immune-based combinations. The dual ICI with nivolumab plus ipilimumab improved all efficacy outcomes and achieved the highest complete response rates (CRR). Although the association of nivolumab plus cabozantinib with CRR was not statistically significant, this combination demonstrated the highest likelihood of PFS and OS improvements., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)