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Renal cell carcinoma is the predominant histological type of kidney cancer with historically poor patient outcomes. Lenvatinib in combination with pembrolizumab is an approved first-line regimen for people with advanced renal cell carcinoma that showed clinically meaningful improvements in efficacy over sunitinib in the CLEAR trial; however, reduced patient exposure to treatment (often stemming from adverse reactions) is a potential therapeutic barrier that must be addressed. Here, we present management strategies for adverse reactions associated with this treatment combination: fatigue, diarrhea, musculoskeletal pain, hypertension, stomatitis, decreased appetite, rash, nausea, and proteinuria. Dosing modification of lenvatinib and pembrolizumab should be made according to the prescribing information for each medication. Clinicians should consider that some adverse reactions, such as diarrhea, may be attributable to lenvatinib, or may be a symptom of immune-related adverse reactions to pembrolizumab (such as colitis). Adverse reactions can generally be managed by: (1) advising the patient on precautionary measures (eg, for stomatitis, practice dental hygiene, avoid irritating foods, and maintain adequate hydration), (2) monitoring for changes in symptoms from baseline (eg, changes in bowel movements, blood pressure or level of fatigue), (3) interrupting/dose reducing lenvatinib or interrupting pembrolizumab, if warranted, and advising the patient to manage their current symptoms via self-care (managing diarrhea with antidiarrheal agents and hydration), and (4) implementing medical interventions (eg, thyroid replacement or antihypertensive therapy) when needed. Through successful management of adverse reactions, oncology clinicians can improve the well-being of their patients and likely enhance adherence rates to treatment with lenvatinib and pembrolizumab. [ABSTRACT FROM AUTHOR]

The treatment of metastatic renal cell carcinoma has evolved on last years. Nowadays immune-combinations are the standard treatment in first-line setting. There is no prognostic biomarker for metastatic renal cell carcinoma in the systemic immunotherapy treatment era. Systemic Immune-Inflammation Index is a cheap and readily available prognostic tool to be used in daily clinical practice. Background: Systemic treatment with immune combinations is the gold standard for metastatic renal cell carcinoma (mRCC) worldwide. The systemic immune-inflammation index (SII) is a prognostic marker for several types of malignant neoplasms, including mRCC, in the era of tyrosine kinase inhibitor (TKI) treatment. Data regarding the prognostic value of the SII in patients with mRCC treated with immunotherapy are scarce and controversial. Methods: We retrospectively collected the data of patients with mRCC from 56 centers in 18 countries. SII (Platelet × Neutrophil/Lymphocyte count) was calculated prior to the first systemic treatment and cut-off was defined by a survival receiver operating characteristic (ROC) analysis. The primary objective of our retrospective study was to assess the outcomes of patients treated with first-line immunotherapy. Results: Data from 1034 mRCC patients was collected and included in this analysis. The SII cut-off value was 1265. After a follow-up of 26.7 months, and the overall survival (OS) and progression-free survival (PFS) were 39.8 and 15.7 months, respectively. According to SII (low vs. high), patients with low-SII had longer OS (55.7 vs. 22.2 months, P < .001), better PFS (20.8 vs. 8.5 months, P < .001), and higher overall response rate (52 vs. 37%, P = .033). Conclusion: A high SII is associated with poor oncological outcomes in patients with mRCC. SII could be an easily accessible prognostic indicator for use in clinical practice. [ABSTRACT FROM AUTHOR]

Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib. Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as "no concomitant PPIs" or "concomitant PPIs"; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice. A total of 128 patients were consecutively enrolled in the study; 78 belonged to the "no concomitant PPIs" group and 50 to the "concomitant PPIs" group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities. The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting. • Changes of gastric pH by PPIs may significantly affect the bioavailability of tyrosine kinase inhibitors. • Our findings support the hypothesis that long-term treatment with PPI does not compromise the efficacy of ribociclib. • Consistent with our results, data from the literature show no effect of gastric pH changes on ribociclib pharmacokinetics. [ABSTRACT FROM AUTHOR]

Tivozanib showed improved progression free survival compared to sorafenib with less toxicity and better tolerability in patients with previously treated metastatic renal cell carcinoma. In this study we looked at most commonly reported adverse events, duration of toxicity, and characteristics of dose modifications. Our analysis showed that treatment related adverse events were less frequent, had longer onset, and shorter duration in tivozanib arm leading to less frequent dose modifications. Introduction: Tivozanib, vascular endothelial growth factor receptor inhibitor, met the primary endpoint of improved progression free survival compared to sorafenib in the phase 3 TIVO-3 study in patients with previously treated metastatic renal cell carcinoma. In this study we sought to understand the temporal characteristics of treatment related adverse events (TRAEs) and frequency and timing of the dose modifications. Materials and Methods: In this open label, randomized, phase 3 TIVO-3 study, previously treated patients with a diagnosis of metastatic renal cell carcinoma and with measurable disease were included. Patients were randomized to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily continuously. Based on updated safety analysis data (cutoff date of August 15, 2019), time to onset of the most commonly reported TRAEs, duration of toxicity, rate of dose modifications was calculated for each treatment arm. Results: Overall, 350 patients were randomly assigned to receive tivozanib or sorafenib;173 patients from the tivozanib arm and 170 patients from the sorafenib arm were included in this analysis. Patients received a median of 11.9 cycles (336 days) and 6.7 cycles (192 days) of tivozanib and sorafenib, respectively. Dose reductions, interruptions and treatment discontinuations were 25%, 50%, and 21%, and 39%, 50%, and 30% in the tivozanib and sorafenib arms, respectively, with a longer time to onset of TRAEs in the tivozanib arm. Conclusion: Tivozanib was associated with less TRAEs, fewer dose modifications, a longer time to onset and a shorter duration of TRAEs compared to sorafenib. [ABSTRACT FROM AUTHOR]

Patients' self-reporting is increasingly considered essential to measure quality-of-life and treatment-related side-effects. However, if multiple patient-reported instruments are used, redundancy may represent an overload for patients. Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) are a tool allowing direct patients' reporting of side-effects. We tested psychometric properties of a selected list of PRO-CTCAE items, in a cohort of 303 breast cancer patients, using validated instruments for quality of life assessment as anchors. The analysis of convergent validity with HADS (Hospital Anxiety and Depression Scale) and EORTC BR-23 sub-scales, and the analysis of responsiveness with the PGIC (Patients Global Impression of Change) score supported that a selected list of PRO-CTCAE symptoms might represent a standardized, agile tool for both research and practice settings to reduce patient burden without missing relevant information on patient perceptions. Among patients using digital devices, those with a higher education levels required shorter time to fulfil questionnaires. In conclusion, a selected list of PRO-CTCAE items can be considered as a standardized, agile tool for capturing crucial domains of side-effects and quality of life in patients with breast cancer. The study is registered on clinicaltrials.gov (NCT04416672). [Display omitted] • PRO-CTCAE allow patients' self-reporting of adverse events. • Convergent validity of selected PRO-CTCAE items with HADS and BR-23 was good. • Responsiveness to patients' impression of change was good. [ABSTRACT FROM AUTHOR]

• The extensive use of PPIs can interfere with the efficacy of oral therapies. • PPIs affect the survival of mRCC patients treated with pazopanib and cabozantinib. • The concomitant use of PPIs and TKIs requires an evaluation of benefits and risks. The administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC). Total 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as "no concomitant PPIs (PPI−)" if no PPIs were administered during TKIs, and as "concomitant PPIs (PPI+)" if the administration of PPIs was at least 75% of the time during which TKIs were given. Eighty patients administered pazopanib were PPI− and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P =.79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI− (n = 30) in long responders, being 24.7 versus 38 months (P =.04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI− (n = 131) was found, being 11.3 versus 18.1 months, respectively (P =0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI− (6 months vs. not reached, P =.04). No correlation with adverse events was found. This study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use. The extensive use of proton pump inhibitors (PPIs) poses the problem of their interference on the absorption of oral therapies and on the efficacy of the therapy. This study demonstrates an association between administration of PPIs and impaired PFS in mRCC patients treated with pazopanib and cabozantinib. It is recommended caution when prescribing PPIs and TKIs. [ABSTRACT FROM AUTHOR]

Background: Results from the phase 3 CLEAR study showed that lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell carcinoma. We aimed to assess the health-related quality-of-life (HRQOL) outcomes from the CLEAR study.Methods: This open-label, randomised, phase 3 study was done across 200 hospitals and cancer centres in 20 countries. Patients were required to be 18 years or older, with advanced clear-cell renal cell carcinoma, and a Karnofsky performance status of 70% or higher. Patients who had received previous systemic anticancer therapy for renal cell carcinoma were not eligible. Patients were randomly assigned (1:1:1) to lenvatinib (oral 20 mg per day) plus pembrolizumab (intravenous 200 mg every 21 days), lenvatinib (oral 18 mg per day) plus everolimus (oral 5 mg per day) in 21-day cycles, or sunitinib (oral 50 mg per day, 4 weeks on followed by 2 weeks off). Patients were assigned to treatments with a computer-generated randomisation scheme and were stratified by geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint, previously reported, was progression-free survival, and HRQOL was a secondary endpoint. Most HRQOL analyses were done in patients who underwent randomisation, received at least one dose of study treatment, and had any HRQOL data. Completion and compliance analyses were done in the full analysis set. Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the EQ-5D-3 Level (EQ-5D-3L) preference questionnaire were administered at baseline and on day 1 of each subsequent 21-day cycle. This study is registered with ClinicalTrials.gov, NCT02811861, and is closed to new participants.Findings: Between Oct 13, 2016, and July 24, 2019, 355 patients were randomly assigned to the lenvatinib plus pembrolizumab group, 357 to the lenvatinib plus everolimus group, and 357 to the sunitinib group. Median follow-up for HRQOL analyses was 12·9 months (IQR 5·6-22·3). Because of the promising efficacy and safety results of lenvatinib plus pembrolizumab in the first-line setting, we focus the HRQOL results in this report on that combination versus sunitinib. Mean change from baseline in the lenvatinib plus pembrolizumab group compared with the sunitinib group was -1·75 (SE 0·59) versus -2·19 (0·66) for FKSI-DRS, -5·93 (0·86) versus -6·73 (0·94) for EORTC QLQ-C30 global health status/quality of life (GHS/QOL), and -4·96 (0·85) versus -6·64 (0·94) for the EQ-5D visual analogue scale (VAS). Median time to first deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 9·14 weeks (95% CI 6·43-12·14) versus 12·14 weeks (9·14-15·29; HR 1·13 [95% CI 0·94-1·35], log-rank p=0·20) for FKSI-DRS, 12·00 weeks (7·29-15·14) versus 9·14 weeks (6·29-12·14; 0·88 [0·74-1·05], log-rank p=0·17) for EORTC QLQ-C30 GHS/QOL, and 9·43 weeks (6·43-12·29) versus 9·14 weeks (6·29-12·00; 0·83 [0·70-0·99], log-rank p=0·041) for the EQ-5D VAS. Median time to definitive deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 134·14 weeks (95% CI 120·00-not estimable) versus 117·43 weeks (90·14-131·29; HR 0·70 [95% CI 0·53-0·92], log-rank p=0·0081) for FKSI-DRS, 114·29 weeks (102·14-153·29) versus 75·14 weeks (57·29-105·14; 0·60 [0·47-0·77], log-rank p<0·0001) for EORTC QLQ-C30 GHS/QOL, and 124·86 weeks (94·71-134·57) versus 74·86 weeks (54·14-96·00; 0·67 [0·53-0·85], log-rank p=0·0012) for the EQ-5D VAS. No outcomes on any of the instruments significantly favoured sunitinib over lenvatinib plus pembrolizumab. Most HRQOL comparisons of lenvatinib plus everolimus versus sunitinib were similar or favoured sunitinib.Interpretation: These HRQOL results demonstrate that patients given lenvatinib plus pembrolizumab treatment had similar or favourable scores compared with patients given sunitinib, particularly with respect to time to definitive deterioration. These results support the efficacy and safety profile of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma.Funding: Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA). [ABSTRACT FROM AUTHOR]

Tyrosine-kinase inhibitors still represent a first-line option for selected patients with metastatic Renal Cell Carcinoma (mRCC). Our study aimed to compare the real-world efficacy of nivolumab or cabozantinib as second-line therapy in 343 patients with mRCC. We reported significant differences in terms of overall survival and progression-free survival between nivolumab and cabozantinib in specific mRCC subpopulations. Background: Tyrosine-kinase inhibitors (TKIs) still represent a first-line option for selected patients with metastatic Renal Cell Carcinoma (mRCC). We aimed to compare the real-world efficacy of nivolumab or cabozantinib as secondline therapy in specific mRCC subpopulations. Patients and Methods: We retrospectively collected data from 11 centers from Italy, Spain and US. Overall Survival (OS) and Progression-Free Survival (PFS) were analyzed using Kaplan-Meier curves. Cox proportional models were used at univariate and multivariate analyses. Results: We collected data from 343 patients with mRCC, 123 (36%) treated with cabozantinib and 220 (64%) with nivolumab. The median OS resulted longer, but not statistically significant, with nivolumab in patients aged > 70 years (21.4 vs. 15.4 months, P = .746), treated with first-line pazopanib (26.8 vs. 11.6 months, P = .450), or with good (47.0 vs. 15.5 months, P = .285) or intermediate-r isk cr iter ia (14.4 vs. 11.0 months, P = .357), while it was longer, but even not statistically significant, for cabozantinib in patients who received previous sunitinib (25.7 vs. 21.7 months, P = .638) or with bone metastases (28.4 vs. 24.4 months, P = .871). The median PFS was significantly longer with cabozantinib in patients with clear cell histology (7.8 vs. 5.4 months, P = .026) and in patients with good risk features (12.3 vs. 5.7 months, P = .022). Conclusions: Nivolumab and cabozantinib resulted active in mRCC patients, showing distinct results when stratified into clinico-pathological features. [ABSTRACT FROM AUTHOR]

Renal-cell carcinoma (RCC) incidence is increasing. Our aim was to implement an artificial neural network in order to predict the new cases of RCC in the population starting from population rate, obesity, smoking incidence, uncontrolled hypertension, and life expectancy data in the United States. Preventing risk factors, and in particular hypertension, could help greatly reduce the incidence of RCC. Introduction: The incidence of kidney cancer is increasing; it could be counteracted with new ways to predict and detect it. We aimed to implement an artificial neural network in order to predict new cases of renal-cell carcinoma (RCC) in the population using population rate, obesity, smoking incidence, uncontrolled hypertension, and life expectancy data in the United States. Patients and Methods: Statistics were collected on US population numbers, life expectancy, obesity, smoking, and hypertension. We used MATLAB R2018 (MathWorks) software to implement an artificial neural network. Data were repeatedly and randomly divided into training (70%) and validation (30%) subsets. Results: The number of new RCC cases will grow from 44,400 (2020) to 55,400 (2050), an increase of þ24.7%. Our data show that preventing hypertension would have the greatest impact on reduction of the incidence, estimated at -775 and -575 cases per year in 2020 and in 2030, respectively. The prevention of obesity and smoking would have a more limited impact, estimated at -64 and -180 cases per year in 2020 and in 2030, respectively, for obesity, and -173 and -21 cases per year in 2020 and in 2030, respectively, for smoking. Conclusions: Our predictions underline the need for accurate studies on RCC-related risk factors to reduce the incidence. [ABSTRACT FROM AUTHOR]

Background: Recently, immune checkpoint inhibitors against PD-1/PD-L1 or CTLA4 have emerged as new treatments for metastatic renal cell carcinoma (mRCC), despite discrepancy between their effects on OS and PFS. We performed a meta-analysis of randomized trials comparing immunotherapy to standard of care (SOC) in mRCC.Methods: Searching the MEDLINE/PubMed, Cochrane Library and ASCO Meeting abstracts prospective studies were identified. Data extraction was conducted according to the PRISMA statement. The measured outcomes were OS, PFS, and ORR.Results: A total of 2832 patients were available for evaluation of OS, and 3033 for PFS and ORR. Compared to SOC, immunotherapy improved OS (HR = 0.75; 95%CI 0.66-0.85; p < 0.001), and PFS (HR = 0.88; 95%CI 0.80-0.97; p = 0.009). The PFS benefit was not confirmed when considering patients treated in first-line only (p = 0.10). Conversely, significant ORR improvement was found in patients treated in first-line only (HR = 1.14; 95%CI 1.02-1.28; p = 0.03) but not in the overall population.Conclusions: Immunotherapy improved OS compared to SOC in mRCC, irrespective of treatment line. In first-line, immunotherapy also increased the ORR compared to sunitinib. A lack of correlation between OS and PFS was confirmed, the latter to be used cautiously for the design and interpretation of trials involving immunotherapy in mRCC. [ABSTRACT FROM AUTHOR]

Several drugs have demonstrated clinical activity in metastatic renal cell carcinoma (mRCC). The identification of key metabolic pathways has led to the development of novel targeted therapies which have drastically changed the treatment paradigm of mRCC. Moreover, immune-checkpoint inhibitors have recently shown significant activity in advanced disease. Despite these advancements, the role of adjuvant therapy in localized, non-metastatic RCC remains unclear. The utility of many of these agents in the adjuvant setting is currently being actively explored. In this review, we will summarize the main clinical trials investigating adjuvant therapy in renal cell carcinoma, focusing primarily on immunotherapy and targeted agents. [ABSTRACT FROM AUTHOR]

Background Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr. Objective To analyze long-term safety with sunitinib in mRCC patients. Design, setting, and participants Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g. cytokine refractory or treatment-naïve). Outcome measurements and statistical analysis Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment. Results and limitations Among long-term patients ( n =807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0–<6 mo to 42% at 5–<6 yr and by cumulative analysis from 14% at 0–<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients. Conclusions Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative. Patient summary More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk. [ABSTRACT FROM AUTHOR]

Summary: Background: An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma. Methods: In this multicentre phase 3 study, patients with clear cell metastatic renal cell carcinoma who received one previous VEGF-targeted therapy and one previous mTOR inhibitor were randomly assigned through an interactive voice and web response system to receive open-label dovitinib (500 mg orally according to a 5-days-on and 2-days-off schedule) or sorafenib (400 mg orally twice daily) in a 1:1 ratio. Randomisation was stratified by risk group and region. The primary endpoint was progression-free survival (PFS) assessed by masked central review. Efficacy was assessed in all patients who were randomly assigned and safety was assessed in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01223027. Findings: 284 patients were randomly assigned to the dovitinib group and 286 to the sorafenib group. Median follow-up was 11·3 months (IQR 7·9–14·6). Median PFS was 3·7 months (95% CI 3·5–3·9) in the dovitinib group and 3·6 months (3·5–3·7) in the sorafenib group (hazard ratio 0·86, 95% CI 0·72–1·04; one-sided p=0·063). 280 patients in the dovitinib group and 284 in the sorafenib group received at least one dose of study drug. Common grade 3 or 4 adverse events included hypertriglyceridaemia (38 [14%]), fatigue (28 [10%]), hypertension (22 [8%]), and diarrhoea (20 [7%]) in the dovitinib group, and hypertension (47 [17%]), fatigue (24 [8%]), dyspnoea (21 [7%]), and palmar-plantar erythrodysaesthesia (18 [6%]) in the sorafenib group. The most common serious adverse event was dyspnoea (16 [6%] and 15 [5%] in the dovitinib and sorafenib groups, respectively). Interpretation: Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting. Funding: Novartis Pharmaceuticals Corporation. [ABSTRACT FROM AUTHOR]

The recent approval of immune checkpoint inhibitor (ICI)-based combinations has redefined the first-line standard of care of metastatic renal cell carcinoma (mRCC) patients. Although the undisputed advantage of these combinations, most patients progressed, requiring subsequent therapies. The change of first-line therapy inevitably led to modification of the all mRCC treatment algorithm; to date, the most appropriate second-line options remain still unclear. The aim of our review was to provide a useful summary of the available evidence in order to overcome the doubts about treatment sequences. Retrospectively, the efficacy of second-line VEGFR-TKIs seems to be greater after failure of a dual ICIs combination rather than after ICIs plus VEGFR-TKIs, nevertheless prospective data of second-line TKIs are limited. Moreover, ICI re-challenge could be an option but, again, most data derived from retrospective series emphasizing the identification of predictive factors of response to select mRCC patients that could benefit from this strategy. Novel molecules and different ICI-based combinations are under evaluation with the aim of implementing the second-line setting. In particular, belzutifan, ciforadenant (CPI-444), and talazoparib achieved encouraging objective response rates (ORR) in phase I/II trials. Phase III trials comparing these new molecules with the standard of care are currently ongoing. The first-line regimen, and the type and duration of response emerged as crucial factors that could influence the efficacy of second-line therapy. Prognostic models that integrate clinical features and molecular biomarkers with a predictive value are warranted to guide clinicians in the decision-making process with the ultimate goal of offering to the patients the most effective therapy in a personalized, precision medicine-based, therapeutic strategy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Sorafenib has proven efficacy in metastatic renal cell carcinoma (mRCC). Interferon (IFN) has antiangiogenic activity that is thought to be both dose- and administration-schedule dependent. Objective: To compare two different schedules of IFN combined with sorafenib. Design, setting, and participants: Single-stage, prospective, noncomparative, randomized, open-label, multicenter, phase 2 study on previously untreated patients with mRCC and Eastern Cooperative Oncology Group performance status 0–2. Intervention: Sorafenib 400mg twice daily plus subcutaneous IFN, 9 million units (MU) three times a week (Arm A) or 3 MU five times a week (Arm B). Outcome measurements and statistical analysis: Primary end points were progression-free survival (PFS) for each arm and safety. Data were evaluated according to an intent-to-treat analysis. Results and limitations: A total of 101 patients were evaluated. Median PFS was 7.9 mo in Arm A and 8.6 mo in Arm B (p =0.049) and the median duration of response was 8.5 and 19.2 mo, respectively (p =0.0013). Nine partial responses were observed in Arm A, and three complete and 14 partial responses were observed in Arm B (17.6% vs 34.0%; p =0.058); 24 and 21 patients (47% and 42%), respectively, achieved stable disease. The most common grade 3–4 toxicities were fatigue plus asthenia (28% vs 16%; p =0.32) and hand-foot skin reactions (20% vs 18%). Conclusions: Sorafenib plus frequent low-dose IFN showed good efficacy and tolerability. Further investigations should be warranted to identify a possible positioning of this intriguing regimen (6% complete response rate) in the treatment scenario of mRCC. [Copyright &y& Elsevier]

Abstract: The introduction of novel anti-angiogenic therapies has greatly improved the outcome of patients with metastatic renal cell carcinoma (mRCC). The use of these therapies in combination or sequentially is proposed to provide greater efficacy. We have reviewed completed and ongoing clinical trials in mRCC that have reported efficacy and/or safety data of novel therapies used in combination or sequentially. Bevacizumab appears to be a useful partner when combined with interferon (IFN), while controversial results have been reported when combined with temsirolimus and everolimus. Other combinations appear to have unacceptable tolerability or require dose or schedule optimization. Sequencing data provide a clear indication that multiple lines of treatment may extend survival. The ‘ideal’ sequence, however, is still unknown. In conclusion, novel therapies used in combination or sequentially have potential to provide optimised treatment and patient outcomes in mRCC. The results from ongoing/planned trials are expected to help shape future therapy. [Copyright &y& Elsevier]

Aims and scope: Over the last six years, the use of targeted agents has revolutionised the treatment of metastatic renal cell carcinoma (mRCC) and dramatically improved outcomes for patients. Multiple effective first-and second-line agents are now available or are in development, raising key questions and new challenges around the long-term management of mRCC. These topics were the focus of a Pfizer meeting held at the 7th European International Kidney Cancer Symposium (EIKCS) in Vienna (4–5 May 2012), where leading European oncology experts discussed recent advances and ongoing issues in mRCC clinical practice. ‘It is important for clinicians who see large numbers of patients with this rare disease to get together and share their experience and observations, for the benefit of those who only see few patients in their practice’, said Professor Manuela Schmidinger, Chair of the meeting. This report offers an overview of the critical evidence and the issues of long-term mRCC management debated at the meeting. It also presents key conclusions from the recently launched report ‘Europe 2012: is kidney cancer management at a crossroad?’, written by a selected panel of European kidney cancer experts to highlight current barriers to the optimal treatment of mRCC patients and the development of solutions to address these. [Copyright &y& Elsevier]

Abstract: Background: Elderly patients with metastatic renal cell carcinoma (mRCC) may require special treatment considerations, particularly when comorbidities are present. An understanding of the efficacy and safety of targeted agents in elderly patients with mRCC is essential to provide individualized therapy. Objective: To evaluate the efficacy and safety of everolimus in elderly patients (those ≥65 and ≥70 yr of age) enrolled in RECORD-1. Design, setting, and participants: The multicenter randomized RECORD-1 phase 3 trial (Clinicaltrials.gov identifier, NCT00410124; http://www.clinicaltrials.gov) enrolled patients with mRCC who progressed during or within 6 mo of stopping sunitinib and/or sorafenib treatment (n =416). Intervention: Everolimus 10mg once daily (n =277) or placebo (n =139) plus best supportive care. Treatment was continued until disease progression or unacceptable toxicity. Measurements: Median progression-free survival (PFS), median overall survival (OS), and time to deterioration in Karnofsky performance status (TTD-KPS) were assessed using the Kaplan-Meier method; the log-rank test was used to compare treatment arms. Other outcomes evaluated included reduction in tumor burden, overall response rate (ORR), and safety. Results and limitations: In RECORD-1, 36.8% of patients were ≥65 yr and 17.5% were ≥70 yr of age. PFS, OS, TTD-KPS, reduction in tumor burden, and ORR were similar in the elderly and the overall RECORD-1 population. Everolimus was generally well tolerated in elderly patients, and most adverse events were grade 1 or 2 in severity. The toxicity profile of everolimus was generally similar in older patients and the overall population; however, peripheral edema, cough, rash, and diarrhea were reported more frequently in the elderly regardless of treatment. The retrospective nature of the analyses was the major limitation. Conclusions: Everolimus is effective and tolerable in elderly patients with mRCC. When selecting targeted therapies in these patients, the specific toxicity profile of each agent and any patient comorbidities should be considered. [Copyright &y& Elsevier]

Abstract: The use of targeted agents to treat metastatic renal cell carcinoma (mRCC) has significantly extended progression-free and overall survival but raises issues relating to the long-term delivery of care and the sustained monitoring of efficacy and toxicities, certain of which have not previously been experienced. In this paper, an expert group of medical oncologists, urologists and oncology nurses and pharmacists review and make informal recommendations on the multidisciplinary management of mRCC in the light of progress made and problems that have arisen. Decentralisation of care, with a shift in emphasis from large to small hospitals and possibly to the community, may offer advantages of cost and convenience. However, the major responsibility for care should continue to lie with clinicians (either medical oncologists or urologists) with extensive experience in mRCC, assisted by specialist nurses, and working in centres with facilities adequate to monitor efficacy and manage toxicities. That said, the extended survival of patients emphasises the importance of compliance and the long-term prevention, detection and management of side effects. Much of this will take place in the community. There is therefore a need for multidisciplinary working to extend beyond specialist centres to include general practitioners, community nurses and pharmacists. Although this paper focuses on mRCC, many of the considerations discussed are also relevant to the management of more common solid tumours in the era of targeted therapy. [Copyright &y& Elsevier]

Abstract: Purpose: In April 2009, an expert group of 11 physicians and clinical nurses met to discuss the management of selected adverse events associated with the use of everolimus for the treatment of metastatic renal cell carcinoma (mRCC). Everolimus is an orally administered inhibitor of the mammalian target of rapamycin that recently received approval from the European Medicines Agency for the treatment of advanced RCC that has progressed on or after treatment with vascular endothelial growth factor (VEGF)–targeted therapy, and from the United States Food and Drug Administration for treatment of advanced RCC after failure of sorafenib or sunitinib. Before the approval of everolimus, no standard therapy existed for the treatment of mRCC after failure of VEGF-targeted therapy. RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) was the pivotal multicenter, phase III, randomised, double-blind, placebo-controlled trial of everolimus that led to approval for patients with disease progression on or after treatment with VEGF-targeted agents. Safety data from RECORD-1 were reviewed by these clinicians, all of whom had experience using everolimus in patients with mRCC. Adverse events discussed were non-infectious pneumonitis, infections, stomatitis and metabolic abnormalities. Results: The outcome of this discussion is summarised here. Guidance for management of these adverse events is provided. Both clinicians and patients should be aware of the potential side-effects of everolimus and understand that these side-effects are manageable with standard care to optimise patient benefit. [Copyright &y& Elsevier]

Abstract: Context: The therapeutic scenario for metastatic renal cell carcinoma (mRCC) has been evolving rapidly, with sunitinib, sorafenib, bevacizumab, everolimus, pazopanib, and temsirolimus being successfully tested and approved in a short period of time. Oncologists must be familiar with the management of toxicity that these biologic agents cause, as such toxicity is different from that of conventional chemotherapeutic agents. Objective: To describe toxic effects associated with targeted therapy of mRCC and their proper management on the basis of currently available evidence. Evidence acquisition: We conducted a systematic analysis of the literature on 15th October 2010 by performing a search of Medical Subject Headings (MeSH) on PubMed using the words sorafenib, sunitinib, bevacizumab, everolimus, pazopanib, or temsirolimus combined with the MeSH term kidney neoplasms. Consideration for inclusion was given to articles providing data concerning (1) incidence and grading and (2) management of targeted therapy–related toxic effects. A separate search was conducted on PubMed to retrieve meta-analyses using each drug name and the word meta-analysis. Evidence synthesis: Hypertension, fatigue, bone marrow toxicity, skin toxicity, and gastrointestinal side-effects are common with the six targeted agents. Everolimus and temsirolimus are associated with immunosuppression, metabolic alterations, and interstitial pneumonitis, while sunitinib is associated with hypothyroidism. Recommendations for treating these conditions usually follow those for the general population because of the lack of experimental data in this setting (eg, for management of sunitinib-induced hypertension). Conclusions: The treating oncologist should try to manage side-effects associated with targeted therapy using supportive and pharmacologic interventions. Severe toxicity requires external specialist consultation and treatment suspension and/or dose reduction. Experimental data about the management of targeted therapy–related toxicity in mRCC is lacking and required in this setting. [Copyright &y& Elsevier]

To identify factors that might predict response to sunitinib in patients with renal cell carcinoma, we measured serum vascular endothelial growth factor (VEGF) and neutrophil gelatinase-associated lipocalin (NGAL) levels. A total of 85 patients were selected and, using the Motzer classification, 46 were assigned to the good- and 38 to the intermediate-risk groups. With univariate Cox analysis, both baseline serum VEGF and NGAL titers, determined by enzyme-linked immunosorbent assay, significantly predicted progression-free survival. For each biomarker, a threshold value was identified, which proved useful to classify patients into groups having titers above or below the thresholds. We then stratified patients according to the two dichotomous variables into good-, intermediate-, and poor-risk groups, and found significantly different progression-free survival rates ranging from 3.5 to 11.6 months. Both VEGF and NGAL maintained their predictive significance at bivariate analysis. Our study shows that serum levels of VEGF and NGAL are significant predictors of progression-free survival in patients with renal cell carcinoma treated with sunitinib. [ABSTRACT FROM AUTHOR]

Summary: Five targeted agents have shown efficacy in advanced renal cell carcinoma. These agents were evaluated in pivotal phase III clinical trials using different treatment settings and different patient populations. As patients encountered in ‘real life’ clinical practice are frequently under-represented in phase III trials, making treatment decisions based on phase III data alone may have limitations. In order to support treatment decisions for patients who do not fit within the inclusion criteria of many phase III trials, physicians must consider additional data sources such as expanded access programmes, sub- and retrospective analyses, and also clinical experience. The suitability of a specific targeted agent for a given patient group, e.g. elderly, will depend on a number of factors, including disease-, patient- and treatment-related characteristics. Here, we identify the need for an individualised patient-focused approach to the management of advanced renal cell carcinoma in clinical practice. In order to optimise therapy for individual patients, we present a schema providing guidance on the wide range of parameters that should be considered when making treatment decisions. We recommend the integration of this approach into everyday clinical practice. [Copyright &y& Elsevier]

Summary: The treatment options for metastatic renal cell carcinoma have expanded rapidly over the past 3 years, with four new agents available and others in late-stage development. This has resulted in a change of the standard of first-line care, with sunitinib or bevacizumab plus interferon the treatments of choice for patients with good or intermediate-risk renal cell carcinoma and temsirolimus treatment of choice for poor-risk disease. Sunitinib and bevacizumab plus interferon have similar efficacy, meaning that treatment choice is influenced by other factors: disease-related factors such as clear cell versus non-clear cell histology; patient factors such as co-morbidities, Memorial Sloan-Kettering Cancer Center risk and patient preference; and drug-related factors such as tolerability profile. The aim of this review is to describe the tolerability of the first-line treatment options for clear cell renal cell carcinoma, giving consideration to how tolerability profiles relate to drug mechanism of action. Thus, the incidence and aetiology of side effects related to vascular endothelial growth factor and vascular endothelial growth factor receptor inhibition using sunitinib and bevacizumab, as well as those of the non-specific side effects observed with sunitinib, are described. In addition, the potential patient impact and management of these side effects, as well as those of interferon and temsirolimus, are considered. Finally, the implications of the tolerability profiles of these agents for combination therapy and use in broader populations than those enrolled in trials are assessed. [Copyright &y& Elsevier]

Summary: Within a single-institution phase II trial, we investigated the antitumor activity of the Raltitrexed–Oxaliplatin combination as second-line therapy for malignant pleural mesothelioma (MPM). Fourteen patients were enrolled and all were assessable for response. The trial was then closed because chemotherapy, though well tolerated, yielded no objective responses. The best response observed was disease stabilization in 4 patients only (28.57%), while the other 10 patients (71.42%) progressed despite treatment. Median time to progression (TTP) was 8 weeks (average: 9.85, range: 7–20), while median overall survival was just 14 weeks (average: 21.69, range: 9–66+). [Copyright &y& Elsevier]