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MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.

Among men with nonmetastatic prostate cancer who had a rapid PSA doubling time and were receiving androgen-deprivation therapy, the median metastasis-free survival was 40.5 months with apalutamide versus 16.2 months with placebo. Rash occurred in 24% of men receiving apalutamide.

In the ongoing phase 3 CheckMate 214 trial, nivolumab plus ipilimumab showed superior efficacy over sunitinib in patients with previously untreated intermediate-risk or poor-risk advanced renal cell carcinoma, with a manageable safety profile. In this study, we aimed to assess efficacy and safety after extended follow-up to inform the long-term clinical benefit of nivolumab plus ipilimumab versus sunitinib in this setting. In the phase 3, randomised, controlled CheckMate 214 trial, patients aged 18 years and older with previously untreated, advanced, or metastatic histologically confirmed renal cell carcinoma with a clear-cell component were recruited from 175 hospitals and cancer centres in 28 countries. Patients were categorised by International Metastatic Renal Cell Carcinoma Database Consortium risk status into favourable-risk, intermediate-risk, and poor-risk subgroups and randomly assigned (1:1) to open-label nivolumab (3 mg/kg intravenously) plus ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, followed by nivolumab (3 mg/kg intravenously) every 2 weeks; or sunitinib (50 mg orally) once daily for 4 weeks (6-week cycle). Randomisation was done through an interactive voice response system, with a block size of four and stratified by risk status and geographical region. The co-primary endpoints for the trial were overall survival, progression-free survival per independent radiology review committee (IRRC), and objective responses per IRRC in intermediate-risk or poor-risk patients. Secondary endpoints were overall survival, progression-free survival per IRRC, and objective responses per IRRC in the intention-to-treat population, and adverse events in all treated patients. In this Article, we report overall survival, investigator-assessed progression-free survival, investigator-assessed objective response, characterisation of response, and safety after extended follow-up. Efficacy outcomes were assessed in all randomly assigned patients; safety was assessed in all treated patients. This study is registered with ClinicalTrials.gov, number NCT02231749, and is ongoing but now closed to recruitment. Between Oct 16, 2014, and Feb 23, 2016, of 1390 patients screened, 1096 (79%) eligible patients were randomly assigned to nivolumab plus ipilimumab or sunitinib (550 vs 546 in the intention-to-treat population; 425 vs 422 intermediate-risk or poor-risk patients, and 125 vs 124 favourable-risk patients). With extended follow-up (median follow-up 32·4 months [IQR 13·4–36·3]), in intermediate-risk or poor-risk patients, results for the three co-primary efficacy endpoints showed that nivolumab plus ipilimumab continued to be superior to sunitinib in terms of overall survival (median not reached [95% CI 35·6–not estimable] vs 26·6 months [22·1–33·4]; hazard ratio [HR] 0·66 [95% CI 0·54–0·80], p<0·0001), progression-free survival (median 8·2 months [95% CI 6·9–10·0] vs 8·3 months [7·0–8·8]; HR 0·77 [95% CI 0·65–0·90], p=0·0014), and the proportion of patients achieving an objective response (178 [42%] of 425 vs 124 [29%] of 422; p=0·0001). Similarly, in intention-to-treat patients, nivolumab and ipilimumab showed improved efficacy compared with sunitinib in terms of overall survival (median not reached [95% CI not estimable] vs 37·9 months [32·2–not estimable]; HR 0·71 [95% CI 0·59–0·86], p=0·0003), progression-free survival (median 9·7 months [95% CI 8·1–11·1] vs 9·7 months [8·3–11·1]; HR 0·85 [95% CI 0·73–0·98], p=0·027), and the proportion of patients achieving an objective response (227 [41%] of 550 vs 186 [34%] of 546 p=0·015). In all treated patients, the most common grade 3–4 treatment-related adverse events in the nivolumab and ipilimumab group were increased lipase (57 [10%] of 547), increased amylase (31 [6%]), and increased alanine aminotransferase (28 [5%]), whereas in the sunitinib group they were hypertension (90 [17%] of 535), fatigue (51 [10%]), and palmar-plantar erythrodysaesthesia (49 [9%]). Eight deaths in the nivolumab plus ipilimumab group and four deaths in the sunitinib group were reported as treatment-related. The results suggest that the superior efficacy of nivolumab plus ipilimumab over sunitinib was maintained in intermediate-risk or poor-risk and intention-to-treat patients with extended follow-up, and show the long-term benefits of nivolumab plus ipilimumab in patients with previously untreated advanced renal cell carcinoma across all risk categories. Bristol-Myers Squibb and ONO Pharmaceutical.

Results from clinical trials have established sunitinib as a standard of care for first-line treatment of advanced or metastatic renal-cell carcinoma (RCC); however, many patients, particularly those with a poorer prognosis, do not meet inclusion criteria and little is known about the activity of sunitinib in these subgroups. The primary objective of this trial was to provide sunitinib on a compassionate-use basis to trial-ineligible patients with RCC from countries where regulatory approval had not been granted. Previously treated and treatment-naive patients at least 18 years of age with metastatic RCC were eligible. All patients received open-label sunitinib 50 mg orally once daily on schedule 4-2 (4 weeks on treatment, 2 weeks off). Safety was assessed regularly, tumour measurements done per local practice, and survival data collected where possible. Analyses were done in the modified intention-to-treat (ITT) population, which consisted of all patients who received at least one dose of sunitinib. This study is registered with ClinicalTrials.gov, NCT00130897. As of December, 2007, 4564 patients were enrolled in 52 countries. 4371 patients were included in the modified ITT population. This population included 321 (7%) patients with brain metastases, 582 (13%) with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher, 588 (13%) non-clear-cell RCC, and 1418 (32%) aged 65 years or more. Patients received a median of five treatment cycles (range 1–25). Reasons for discontinuation included lack of efficacy (n=1168 [27%]) and adverse events (n=362 [8%]). The most common treatment-related adverse events were diarrhoea (n=1936 [44%]) and fatigue (n=1606 [37%]). The most common grade 3–4 adverse events were fatigue (n=344 [8%]) and thrombocytopenia (n=338 [8%]) with incidences of grade 3–4 adverse events similar across subgroups. In 3464 evaluable patients, the objective response rate (ORR) was 17% (n=603), with subgroup ORR as follows: brain metastases (26 of 213 [12%]), ECOG performance status 2 or higher (29 of 319 [9%]), non-clear-cell RCC (48 of 437 [11%]) and age 65 years or more (176 of 1056 [17%]). Median progression-free survival was 10·9 months (95% CI 10·3–11·2) and overall survival was 18·4 months (17·4–19·2). In a broad population of patients with metastatic RCC, the safety profile of sunitinib 50 mg once-daily (initial dose) on schedule 4-2 was manageable and efficacy results were encouraging, particularly in subgroups associated with poor prognosis who are not usually entered into clinical trials. Pfizer Inc.

This study assessed the prognostic value of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic solid tumors. Clinical and biological data for patients with metastatic solid tumors treated in an oncology outpatient department and prospectively followed by a call center (PROCHE program) between January 2008 and December 2011 were analyzed. All patients with an NLR value within 28 days before the first cycle of first-line of chemotherapy were included (cohort 1). To assess influence of chemotherapy line on NLR prognostic value, data from patients treated with later chemotherapy lines were also analyzed (cohort 2). Adjusted multivariate Cox regressions with or without non-linear and time-dependent effects were performed. Optimal NLR cut-off was investigated by time-dependent sensitivity analysis using several indices. There were 317 and 134 patients in cohorts 1 and 2, respectively. Elevated NLR was associated with worse survival (hazard ratio [HR] for death, 1.35 [95% confidence interval 1.19-1.54]; p<0.0001). The optimal NLR cut-off in cohort 1 was dependent on index used and time of assessment: HR values were non-significant at a cut-off of 3.0 (1.34 [0.99-1.32], but significant when the cut-off was 4.0 (1.53 [1.11-2.10]). NLR was linearly related to mortality risk; in subgroup analysis, no significant interaction was found with co-variables or tumor localization overall (cohorts 1+2). Pre-treatment NLR is a useful prognostic tool in patients with metastatic solid tumors, irrespective of primary tumor site, chemotherapy line, age, gender and performance status. However, using an NLR cut-off value for clinical decision-making requires extreme caution.

Few options exist for patients with locally advanced or metastatic urothelial carcinoma after progression with platinum-based chemotherapy. We aimed to assess the safety and efficacy of atezolizumab (anti-programmed death-ligand 1 [PD-L1]) versus chemotherapy in this patient population. We conducted this multicentre, open-label, phase 3 randomised controlled trial (IMvigor211) at 217 academic medical centres and community oncology practices mainly in Europe, North America, and the Asia-Pacific region. Patients (aged ≥18 years) with metastatic urothelial carcinoma who had progressed after platinum-based chemotherapy were randomly assigned (1:1), via an interactive voice and web response system with a permuted block design (block size of four), to receive atezolizumab 1200 mg or chemotherapy (physician's choice: vinflunine 320 mg/m2, paclitaxel 175 mg/m2, or 75 mg/m2 docetaxel) intravenously every 3 weeks. Randomisation was stratified by PD-L1 expression (expression on <1% [IC0] or 1% to <5% [IC1] of tumour-infiltrating immune cells vs ≥5% of tumour-infiltrating immune cells [IC2/3]), chemotherapy type (vinflunine vs taxanes), liver metastases (yes vs no), and number of prognostic factors (none vs one, two, or three). Patients and investigators were aware of group allocation. Patients, investigators, and the sponsor were masked to PD-L1 expression status. The primary endpoint of overall survival was tested hierarchically in prespecified populations: IC2/3, followed by IC1/2/3, followed by the intention-to-treat population. This study, which is ongoing but not recruiting participants, is registered with ClinicalTrials.gov, number NCT02302807. Between Jan 13, 2015, and Feb 15, 2016, we randomly assigned 931 patients from 198 sites to receive atezolizumab (n=467) or chemotherapy (n=464). In the IC2/3 population (n=234), overall survival did not differ significantly between patients in the atezolizumab group and those in the chemotherapy group (median 11·1 months [95% CI 8·6–15·5; n=116] vs 10·6 months [8·4–12·2; n=118]; stratified hazard ratio [HR] 0·87, 95% CI 0·63–1·21; p=0·41), thus precluding further formal statistical analysis. Confirmed objective response rates were similar between treatment groups in the IC2/3 population: 26 (23%) of 113 evaluable patients had an objective response in the atezolizumab group compared with 25 (22%) of 116 patients in the chemotherapy group. Duration of response was numerically longer in the atezolizumab group than in the chemotherapy group (median 15·9 months [95% CI 10·4 to not estimable] vs 8·3 months [5·6–13·2]; HR 0·57, 95% CI 0·26–1·26). In the intention-to-treat population, patients receiving atezolizumab had fewer grade 3–4 treatment-related adverse events than did those receiving chemotherapy (91 [20%] of 459 vs 189 [43%] of 443 patients), and fewer adverse events leading to treatment discontinuation (34 [7%] vs 78 [18%] patients). Atezolizumab was not associated with significantly longer overall survival than chemotherapy in patients with platinum-refractory metastatic urothelial carcinoma overexpressing PD-L1 (IC2/3). However, the safety profile for atezolizumab was favourable compared with chemotherapy, Exploratory analysis of the intention-to-treat population showed well-tolerated, durable responses in line with previous phase 2 data for atezolizumab in this setting. F Hoffmann-La Roche, Genentech.

Summary Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies—VEGF and mTOR inhibitors—are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib.

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy. Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system using a validated computer system, and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00410124. All randomised patients were included in efficacy analyses. The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0·30, 95% CI 0·22–0·40, p<0·0001; median progression-free survival 4·0 [95% CI 3·7–5·5] vs 1·9 [1·8–1·9] months). Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had pneumonitis of grade 3 severity. Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies. Novartis Oncology.

In the last few years, the standard of care for metastatic clear cell renal cell carcinoma (mccRCC) has changed dramatically with the emergence of the immune checkpoint inhibitors (ICI): anti-PD(L)-1 used as a monotherapy or as in combination either with an anti CTLA-4 or with an anti-angiogenic molecule (VEGFR tyrosine kinase inhibitor (TKI)). These combinations are now recommended in first line setting for mccRCC, according to the last European recommendations. In the face of these new therapeutic options, the question of selecting the best treatment arises as well as the optimal sequence. Predictive biomarkers are required to guide the therapeutic choice and provide a personalized treatment for each patient. This narrative review will provide an overview of the main predictive biomarkers assessed in mccRCC treatment, with a particular focus on mRNA panel signatures.

To the Editor: The use of sunitinib, an inhibitor of the split-kinase-domain family of receptor tyrosine kinases (including vascular endothelial growth factor receptor types 1 and 2 1 ), has been associated with a 15 to 25% incidence of hypertension in patients with advanced renal-cell carcinoma 2 , 3 ; a similar incidence has been associated with other antiangiogenic drugs. 3 , 4 We report on 14 consecutive patients with metastatic renal-cell carcinoma who were being treated with sunitinib and in whom home monitoring of blood pressure by teletransmission revealed a rapid, marked increase in blood pressure, an effect that was not detected by casual . . .