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Many patients in the favorable International Metastatic renal cell carcinoma (RCC) Data Base Consortium group (F-MRC) may have a relatively indolent disease course. Surveillance and delay of systemic therapy could be an option in this specific population. However, the question whether this delay could alter patients' outcome remains unanswered. Our objective was to determine if delaying first-line treatment influences the survival of F-MRC patients.We performed a retrospective multicenter national study involving the French Network for Research on Kidney Cancer UroCCR (NCT03293563). We included treatment naive F-MRC patients. We compared the overall survival of patients with immediate medical treatment (IMT) (started less than 3 months after metastatic diagnosis) to those with delayed medical treatment (DMT).We included 90 patients treated between 2009 and 2018. The median time before occurrence of metastases from diagnosis was 28 (12-137) months. The two groups (IMT vs. DMT) were comparable for follow-up, age, sarcomatoid feature, number, and localization of metastatic sites and ECOG performance status. IMT was given in 25 (27.8 %) patients. Local treatment of metastasis (LTM) was performed in 47 (52%) patients. Patients with DMT had more LTM (63% vs. 24%, P = .001). Among patients with DMT (n = 65); 27 (41%) received a systemic treatment and median systemic treatment-free survival was 39 months (95% CI, 26.3-51.6). Median overall survival from metastasis disease diagnosis was 55 months (95% CI, 42.4-67.5) in the IMT group and 88 months (95%CI, 64-111.9) in the DMT group (P = .028). In multivariable analysis LTM was the only prognostic factor associated to survival improvement (HR: 0.33; P = .024).Selected Patients with F-MRC may safely undergo DMT. LTM positively impacted survival in this population and should be considered whenever possible. Prospective trial with a larger population is needed to confirm these results.

In the current era of immune checkpoint inhibitors (ICIs), the role and optimal timing of a nephrectomy in patients with metastatic renal cell carcinoma (mRCC) remain unknown.To assess the oncological outcomes of patients who responded to ICI-based treatments and were subsequently treated with a delayed nephrectomy.This national retrospective evaluation included 30 patients with mRCC who underwent a nephrectomy after a complete response (CR) or a major partial response (80%) to ICI treatment at metastatic sites.Partial or radical nephrectomy after a favorable response to ICI treatment.Disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and potential discontinuation of systemic treatment were assessed.ICI-based treatments included ipilimumab-nivolumab (40%), ICI + tyrosine kinase inhibitor (10%), and nivolumab (50%). A delayed nephrectomy was performed after a median ICI treatment duration of 10 mo. In 19 cases (63.3%), surgeons faced difficulties due to adhesions or inflammatory changes. A complete pathological response was observed in 16.7% of patients. After a median follow-up of 19.5 mo after nephrectomy, 76.7% of patients achieved DFS. At 1 yr, 66.7% of patients were free from systemic treatment. The PFS and OS rates were, respectively, 96.7% and 100% at 1 yr, and 78.3% and 86.1% at 2 yr. Patients with a CR at metastatic sites had a better prognosis than those with a major partial response, in terms of DFS (p = 0.022) and PFS (p = 0.014).Despite potentially challenging surgery, a delayed nephrectomy for patients who responded to ICI treatment provided promising oncological outcomes, and the majority of patients could discontinue systemic treatment.In this study, we evaluated the clinical outcome in patients who responded well to immunotherapy, and subsequently underwent kidney ablation surgery. Three-quarters of patients experienced no recurrence, and in most cases, medical treatment could be discontinued.

The prognostic impact of renal cell carcinoma (RCC) morphotype remains unclear in patients who undergo partial nephrectomy (PN). Our objective was to determine the risk factors for recurrence after PN, including RCC morphotype.Patients with RCC who had undergone PN were extracted from the prospective, national French database, UroCCR. Patients with genetic predisposition, bilateral or multiple tumours, and those who had undergone secondary totalization were excluded. Primary endpoint was 5-year, recurrence-free survival (RFS), and secondary endpoint was overall survival (OS). Risk factors for recurrence were assessed by multivariable Cox regression analysis.Overall, 2,767 patients were included (70% male; median age: 61 years [interquartile range (IQR) 51-69]). Most (71.5%) of the PN procedures were robot-assisted. Overall, 2,573 (93.0%) patients were recurrence free, and 74 died (2.7%). Five-year RFS was 84.9% (IQR 82.4-87.4). A significant difference in RFS was observed between RCC morphotypes (p0.001). Surgical margins (hazard ratio [HR] = 2.0 [95% confidence interval (CI): 1.3-3.2], p0.01), pT stage1 (HR = 2.6 [95% CI: 1.8-3.7], p0.01]) and Fuhrmann grade2 (HR = 1.9 [95% CI: 1.4-2.6], p0.001) were risk factors for recurrence, whereas chromophobe subtype was a protective factor (HR = 0.08 [95% CI: 0.01-0.6], p = 0.02). Five-year OS was 94.0% [92.4-95.7], and there were no significant differences between RCC subgroups (p = 0.06). The main study limitation was its design (multicentre national database), which may be responsible for declarative bias.Chromophobe morphotype was significantly associated with better RFS in RCC patients who underwent PN. Conversely, pT stage, Fuhrman group and positive surgical margins were risk factors for recurrence.

Robot-assisted partial nephrectomy (RAPN) reduces morbidity, enabling development of Enhanced Recovery After Surgery (ERAS) and day-case protocols. Additional financial costs limit its integration into clinical practice. We evaluated the medico-economic impact of RAPN using a nurse-led coordinated pathway of care (NLC-RAPN).All tumor RAPNs performed in 2017 were prospectively included in nurse-led protocols: NP-RAAC (ERAS) or Ambu-Rein (day case). Clinico-biological and pathological data were prospectively collected within the French Research Network for Kidney Cancer database (NCT03293563). Estimated costs were compared to "average" patients at the national level operated by open partial nephrectomy (OPN) or RAPN, using data from the 2017 French hospital discharge database and the national cost scale.The NLC-RAPN cohort (n = 151) included 27 (18%) outpatients and the average hospital length of stay (LOS) was 2.4 days. In the national control cohorts for OPN (n = 2475) and RAPN (n = 3529), the average LOS were 8.0 and 5.2 days, respectively. The mean incomes per group were €7607 for NLC-RAPN, €9813 for OPN, and €8215 for RAPN. The mean daily cost of stay was €659 for NLC-RAPN, €838 for OPN, and €725 for RAPN. The overall cost for NLC-RAPN was €6594, €8733 for OPN, and €8763 for RAPN. The best operational margin was obtained for day-case NLC-RAPN (€1967).Combining RAPN with nurse-led coordinated pathways of care led to a shorter hospital stay and reduced costs versus OPN. This may facilitate the economic sustainability of robotic assistance for hospitals where the extra cost is not covered by the healthcare system.

The management of solitary kidney tumors is a surgical challenge, requiring irreproachable results on both oncological and functional outcomes. The goal of our study was to compare the perioperative results of robotic-assisted partial nephrectomy (RAPN) to open surgery in this indication.We led a multicentric study based on the prospectively maintained French national database UroCCR. Patients who underwent partial nephrectomy on a solitary kidney between 1988 and 2020 were included. Clinical and pathological data were retrospectively analyzed. The main outcome of the study was the analysis of the variation of the estimated glomerular filtration rate (eGFR) calculated according to MDRD at 3, 6, 12, and 24 months depending on the chosen surgical approach. The secondary outcomes were the comparison of Trifecta success, perioperative complications, and length of hospital stay.In total, 150 patients were included; 68 (45%) in the RAPN group and 82 (55%) in the open surgery group. The two groups were comparable for all data. The variation of eGFR at 3, 6, 12, or 24 months was comparable without any significant difference between the 2 groups (p = 0.45). Trifecta was achieved in 40% of the patients in the RAPN group and 33% in the open group (p = 0.42). A significant difference was observed for the length of stay, 5 days for the robot group versus 9 days for the open surgery group (p 0.0001).In our study, the surgical approach did not modify functional results and we noted a significant decrease in hospital stay and complications in the RAPN group. RAPN is a safe and efficient method for management of kidney tumors in solitary kidneys.

Cabozantinib is an oral tyrosine kinase inhibitor (TKI) with activity against several receptors involved in the angiogenesis pathway, including vascular endothelial growth factor receptor (VEGFR), c-MET and AXL. The antiangiogenic properties of cabozantinib led to its use as a monotherapy for the treatment of metastatic renal cell cancer (RCC), and quickly resulted in this treatment becoming part of the standard of care for these tumors. Since the advent of immune checkpoint inhibitors (ICIs), new standards of care have emerged in first-line settings, involving dual ICI or ICI-VEGF-TKI (including ICI-cabozantinib) combination treatments, and leading to a more complex algorithm of care. Cabozantinib remains an option in second-line settings and is still a first-line standard of care treatment in cases where the use of ICIs is contraindicated. This review focuses on the selection of patients who may benefit most from cabozantinib therapy, including those with bone and brain metastases and those with a non-clear cell RCC histology. The need to consider disease-related symptoms, comorbidities, age, drug interactions and biomarker analyses in the choice of therapeutic strategy is also highlighted. Finally, the perspectives for the use of cabozantinib in RCC treatment are discussed.

Supplementary Table S1. A, Patient characteristics included in the study (Fig. 7, A and B). B, Patient characteristics included in the study (Fig. 7, C and D).

Supplementary Figure S7: Recapitulated schema.

PDF file - 50KB, Correlation between copy number alteration (blue - gain/amplification, red - loss) and gene expression profiling. Gene expression level is represented (in grey box plot), according to copy number alteration (each blue circle representing a CGH array results, diameter of circle depicts amplitude of gain).

PDF file - 153KB, Correlation analysis of the expression level of 36 genes - involved in MET pathway - between the patients harboring a MET mutations, the 6 ccRCC samples, and normal kidney tissue samples.

Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, VEGFC. In this study, we found that sunitinib can stimulate vegfc gene transcription and increase VEGFC mRNA half-life. In addition, sunitinib activated p38 MAPK, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich element–binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary, a therapy dedicated to destroying tumor blood vessels induced the development of lymphatic vessels, which may have contributed to the treatment failure. Cancer Res; 77(5); 1212–26. ©2017 AACR.

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Thyroid-like follicular renal cell carcinoma (TFRCC) is rare, with

Immune checkpoint inhibitors used for metastatic clear cell renal cell carcinoma treatment show significant rates of complete response on metastatic sites. Feasibility of delayed surgery on primitive tumors remains questionable, especially regarding conservative procedures. We present here the first reported case of robotic-assisted partial nephrectomy (RAPN) and concomitant metastasectomy after long exposure to immunotherapy. We performed an imperative salvage RAPN and metastasectomy in a 79-year-old woman with history of right radical nephrectomy for oligometastatic clear cell renal cell carcinoma, previous open partial nephrectomy and ablative treatment on the remaining left kidney. In fact, after complete response on the metastatic sites, the patient experienced progression on the solitary kidney despite immunotherapy. This limited experience of RAPN and metastasectomy after long exposure to immunotherapy appears to be feasible safe and efficient both on the oncological and functional point of view.

Background The CARMENA trial in patients with metastatic renal cell carcinoma (mRCC) demonstrated that treatment with sunitinib alone was noninferior to cytoreductive nephrectomy (CN) followed by sunitinib (nephrectomy⬜sunitinib). Objective The objective of this study was to provide updated overall survival (OS) outcomes of CARMENA and assess whether some subgroups may still benefit from upfront CN. Design, setting, and participants CARMENA was a phase III trial in 450 patients with mRCC enrolled from 2009 to 2017. Intervention Patients in the intention-to-treat population received nephrectomy⬜sunitinib (standard of care [SOC]; n = 226) or sunitinib alone (n = 224). Outcome measurements and statistical analysis Primary endpoint was OS, assessed using an updated data cut-off (October 2018; median OS event-free follow-up, 36.6 mo). Patients were reclassified by risk using International Metastatic RCC Database Consortium (IMDC) criteria. Results and limitations Sunitinib alone was noninferior to nephrectomy⬜sunitinib (hazard ratio [HR], 0.97; 95% confidence interval, 0.79⬜1.19; p = 0.8) and demonstrated longer median OS (19.8 mo vs 15.6 mo, respectively). For patients with two or more IMDC risk factors, OS was significantly longer with sunitinib alone than with nephrectomy⬜sunitinib (31.2 mo vs 17.6 mo, respectively; HR, 0.65; p = 0.03). For patients with one IMDC risk factor, OS was longer for nephrectomy⬜sunitinib versus sunitinib alone although not significantly (31.4 mo vs 25.2 mo; HR, 1.30; p = 0.2). The post hoc nature of the subgroup analyses may limit their interpretation. Conclusions Sunitinib alone was noninferior compared with nephrectomy⬜sunitinib, suggesting that CN should not be considered SOC in patients with mRCC requiring systemic treatment. Certain subgroups, including patients with one IMDC risk factor, may still benefit from upfront CN. Patient summary We assessed the survival of patients with metastatic kidney cancer in a clinical trial. Patients treated with sunitinib on its own had the same survival as patients who had surgery before sunitinib treatment. We conclude that surgery may not be necessary for some patients with metastatic kidney cancer.

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

Background The efficacy of anti-VEGF/VEGF receptors in the treatment of metastatic clear cell renal cell carcinoma (ccRCC) varies from patient to patient. Discovering the reasons for this variability could lead to the identification of relevant therapeutic targets. We have investigated the possibility of splicing events leading to new forms of VEGF that are less efficiently inhibited by anti-VEGF/VEGFR targeting the conventional forms. Methods In silico analysis identified the presence of an unknown splice acceptor in the last intron of the VEGF gene resulting in an insertion of 23 bases in VEGF mRNA. Such an insertion can occur in previously described splice variants of VEGF (VEGFXXX) and shift the open reading frame, leading to a change in the c-terminal part of VEGF. We investigated the role of the resulting new major form of VEGF, VEGF222NF, in physiological and pathological angiogenesis. We analyzed the expression of these new alternatively spliced forms in normal tissue and in a series of RCC cells by qPCR and ELISA. We generated experimental RCC in mice by implanting ccRCC cells overexpressing VEGF222NF. The experimental RCC were also treated with polyclonal anti-VEGF/NF antibodies. The relationship between plasmatic VEGF/NF levels and resistance to anti-VEGFR and survival was also investigated in a cohort of patients from the NCT00943839 clinical trial. Results VEGF222/NF stimulated endothelial cell proliferation and vascular permeability through activation of VEGFR2. Overexpression of VEGF222/NF stimulated proliferation and metastatic properties of RCC cells, whereas its downregulation resulted in cell death. RCC cells overexpressing VEGF222/NF generated aggressive experimental tumors that developed functional blood and lymphatic vessels. Anti-VEGFXXX/NF antibodies slowed the growth of experimental RCC by inhibiting tumor cell proliferation and the development of blood and lymphatic vessels. High plasmatic VEGFXXX/NF levels correlated with shorter survival and lower efficacy of anti-angiogenic drugs. Conclusions The existence of new VEGF isoforms has shed new light on the VEGF field.

Robot-assisted partial nephrectomy (RAPN) is a difficult procedure with risk of significant perioperative complications. The objective was to evaluate the impact of preoperative planning and intraoperative guidance with 3D model reconstructions on perioperative outcomes of RAPN. We conducted a retrospective analysis of all patients who underwent RAPN for kidney tumor by three high-volume expert surgeons from academic centers. Clinical data were collected prospectively after written consent into the French kidney cancer network database UroCCR (CNIL-DR 2013-206; NCT03293563). Our cohort was divided into two groups: 3D-Image guided RAPN group (3D-IGRAPN) and control group. A propensity score according to age, pre-operative renal function and RENAL tumor complexity score was used. Both surgical techniques were compared in terms of perioperative outcomes. The initial study cohort included 230 3D-IGRAPN and 415 control RAPN. Before propensity-score matching, patients in the 3D-IGRAPN group had a larger tumor (4.3 cm vs. 3.5 cm, P

To assess the oncological outcomes of renal cell carcinoma (RCC) associated with tumor thrombus and identify predictive factors of recurrence.Multi-institutional study that included patients with cT3-4N0-1M0 RCC with tumoral thrombus identified in the prospective UroCCR database (CNIL DR 2013-206; NCT03293563). pT3a without involvement of the renal vein were excluded. All patients underwent radical nephrectomy and a thrombectomy of the renal vein ± inferior vena cava ± right atrium. The primary endpoint was recurrence-free survival (RFS). Thirty-two patients who had adjuvant therapies (tyrosine kinase inhibitors or mTOR inhibitor) were compared to control group (surveillance) in a propensity score-matched 1:1 sub-analysis RESULTS: A total of 432 patients were included: 70.4% pT3a, 20.1% pT3b, 4.2% pT3c and 5.3% pT4. Tumor characteristics were: 90.7% clear cell RCC, 13.9% pN1, and 87.1% high Fuhrman grade. 173 patients (40%) had disease recurrence, and median RFS was 37.3 months (95% CI, 26.4-46.7). In a multivariate analysis (Cox model), predictive factors of recurrence were: pT4 (HR 2.66; 95% CI, 1.42-4.99; p = 0.002), pN1 (HR 2.53; 95% CI, 1.46-4.39; p 0.001), tumor necrosis (HR 2.92; 95% CI, 1.85-4.62; p 0.001), tumor size 10 cm (HR 1.56; 95% CI, 1.08-2.24; p = 0.018). Adjuvant therapy was a protective factor of cancer recurrence (HR 0.33; 95% CI, 0.17-0.66; p = 0.002). Propensity score-matched sub-analysis of adjuvant vs control (surveillance) confirmed adjuvant treatment as a protective factor of cancer recurrence (Log rank p = 0.015).In this contemporary multi-institutional cohort of RCC + tumor thrombus, we reported higher recurrence rate shortly after surgical excision and demonstrated an oncological benefit of adjuvant treatment.

Objectives: To describe the evolution of day-case success rate over the years and to identify predictive factors for prolonged hospitalization or readmissions. Methods: Retrospective review of all ...

Objective: To improve endoscopic recognition of the most frequently encountered kidney stone morphologies for a better etiological approach in lithiasis by urologists. Materials and methods: An expert urologist intra-operatively and prospectively (between June 2015 and June 2018) examined the surface, the section and the nucleus of all encountered kidney stones. Fragmented stones were subsequently analysed by a biologist based on both microscopic morphological (i.e. binocular magnifying glass) and infrared (i.e. FTIR) examinations (microscopists were blinded to the endoscopic data). Morphological criteria were collected and classified for the endoscopic and microscopic studies. The Wilcoxon–Mann–Whitney test was carried out to detect differences between the endoscopic and microscopic diagnoses. A diagnosis for a given urinary stone was considered "confirmed" for a non-statistically significant difference. Results: A total of 399 urinary stones were included in this study: 51.4% of the stones exhibited only one morphological type while 48.6% were mixed stones (41% had at least two morphologies and 7.6% had three morphologies). The overall matching rate was 81.6%. Diagnostics were confirmed for the following morphologies: whewellite (Ia or Ib), weddellite (IIa or IIb), uric acid (IIIa or IIIb), carbapatite-struvite association (IVb), brushite (IVd). Conclusions: Our preliminary study demonstrates the feasibility of using endoscopic morphology for the most frequently encountered urinary stones and didactic boards of confirmed endoscopic images are provided. The current study constitutes the first step toward endoscopic stone recognition, which is essential in lithiasis. We provide didactic boards of confirmed endoscopic images which paves the way for automatic computer-aided in-situ recognition.

International audience; Background: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.