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Stéphane Oudard - One of the best experts on this subject based on the ideXlab platform.
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ima901 a multipeptide cancer vaccine plus Sunitinib versus Sunitinib alone as first line therapy for advanced or metastatic renal cell carcinoma imprint a multicentre open label randomised controlled phase 3 trial
Lancet Oncology, 2016Co-Authors: Brian I Rini, Stéphane Oudard, Arnulf Stenzl, Romauld Zdrojowy, M I Kogan, Mikhail Shkolnik, Steffen Weikert, Sergio Bracarda, Simon J Crabb, Jens BedkeAbstract:Summary Background In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to Sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects. Methods The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries. HLA-A*02 -positive patients (aged ≥18 years) with treatment-naive, histologically confirmed metastatic or locally advanced (or both) clear-cell renal cell carcinoma were randomly assigned (3:2) to receive Sunitinib plus up to ten intradermal vaccinations of IMA901 (4·13 mg) and granulocyte macrophage colony-stimulating factor (75 μg), with one dose of cyclophosphamide (300 mg/m 2 ) 3 days before the first vaccination, or to receive Sunitinib alone. Sunitinib (50 mg) was given orally once daily, with each cycle defined as 4 weeks on treatment followed by 2 weeks off treatment, until progression of disease as determined by the investigator, death, or withdrawal of consent. Block randomisation (block size five) was done centrally using an interactive web response system, stratified by prognostic risk, geographical region, and previous nephrectomy. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival from randomisation until death of any cause as determined by the investigator, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01265901. Findings Between Dec 22, 2010, and Dec 15, 2012, we screened 1171 patients, of whom 339 were randomly assigned to receive Sunitinib plus IMA901 (n=204) or Sunitinib monotherapy (n=135). Patients had a median follow-up of 33·27 months (IQR 29·92–35·64). Median overall survival did not differ significantly between the groups (33·17 months [95% CI 27·81–41·36] in the Sunitinib plus IMA901 group vs not reached [33·67–not reached] in the Sunitinib monotherapy group; hazard ratio 1·34 [0·96–1·86]; p=0·087). 116 (57%) of 202 patients in the Sunitinib plus IMA901 group and 62 (47%) of 132 in the Sunitinib group had grade 3 or worse adverse events, the most common of which were hypertension, neutropenia, and anaemia in both groups, and mild-to-moderate transient injection-site reactions (eg, erythema, pruritus) were the most frequent IMA901-related side-effect in the Sunitinib plus IMA901 group. Serious adverse events leading to death occurred in four (2%) patients (one respiratory failure and circulatory collapse [possibly related to Sunitinib], one oesophageal varices haemorrhage [possibly related to Sunitinib], one cardiac arrest [possibly related to Sunitinib], and one myocardial infarction) and eight (6%) patients in the Sunitinib group (one case each of renal failure, oesophageal varices haemorrhage, circulatory collapse, wound infection, ileus, cerebrovascular accident [possibly treatment related], and sepsis). Interpretation IMA901 did not improve overall survival when added to Sunitinib as first-line treatment in patients with metastatic renal cell carcinoma. The magnitude of immune responses needs to be improved before further development of IMA901 in this disease is indicated. Funding Immatics Biotechnologies.
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Clinical activity of Sunitinib rechallenge in metastatic renal cell carcinoma-Results of the REchallenge with Sunitinib in MEtastatic RCC (RESUME) Study.
European journal of cancer (Oxford England : 1990), 2016Co-Authors: Stéphane Oudard, Lionnel Geoffrois, Aline Guillot, Christine Chevreau, Jean-laurent Deville, Sabrina Falkowski, Helen Boyle, Marjorie Baciuchka, P. Gimel, Brigitte LaguerreAbstract:Abstract Aim To assess the efficacy and tolerability of Sunitinib rechallenge in the third-line or later setting in patients with metastatic renal cell carcinoma (mRCC). Patients and methods This observational study comprised 61 mRCC patients at 19 centres in France who received Sunitinib rechallenge between January 2006 and May 2013. Patients received first-line Sunitinib, ≥1 different targeted therapies, and then Sunitinib rechallenge. Patient/disease characteristics, tolerability, treatment modalities, and outcomes of therapeutic lines were recorded. The primary end-point was progression-free survival (PFS) in Sunitinib rechallenge. Results Analyses included 52 patients; median age was 59 years, 75% were male, and 98% had clear-cell mRCC and prior nephrectomy. At Sunitinib rechallenge versus first-line, patients had poorer performance (Karnofsky performance status 90–100: 30% versus 81%) and Memorial Sloan Kettering Cancer Centre prognostic risk (poor risk: 18% versus 3%). Overall, 20%, 65%, 12%, and 4% received Sunitinib rechallenge as third-, fourth-, fifth-, and sixth-line therapy, respectively, at 14.6 months (median) after stopping initial treatment. With first-line Sunitinib and rechallenge, median PFS was 18.4 and 7.9 months, respectively; objective response rate was 54% and 15%. Two of eight rechallenge responders had not achieved first-line response. Median overall survival was 55.9 months. The Sunitinib rechallenge safety profile was as expected, with no new adverse events reported. Conclusions Sunitinib rechallenge is a feasible treatment option with potential clinical benefit for mRCC patients. Disease progression with first-line Sunitinib may not be associated with complete or irreversible resistance to therapy.
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Sunitinib for the treatment of metastatic renal cell carcinoma
Cancer treatment reviews, 2011Co-Authors: Stéphane Oudard, Benoit Beuselinck, Jasper Decoene, Peter AlbersAbstract:Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor approved multinationally for the first- and second-line treatment of metastatic renal cell carcinoma (mRCC). The recommended dose of Sunitinib is 50mg per day for 4 weeks followed by 2 weeks off-treatment (Schedule 4/2). In a phase III trial in 750 patients with mRCC who had not received prior treatment, Sunitinib demonstrated superior efficacy to interferon-α for the first-line treatment of mRCC. Sunitinib doubled progression-free survival compared with interferon-α; furthermore, median OS with Sunitinib was greater than 2 years. As a result, Sunitinib is now considered a reference standard of care for first-line mRCC treatment in patients at favourable or intermediate prognostic risk and is recommended in treatment guidelines. Additionally, results from an expanded-access programme, in a broad, heterogeneous patient population, confirmed the efficacy of Sunitinib. Sunitinib has a distinct and predictable profile of adverse events, most of which are manageable with standard medical interventions. Therapy management strategies, including optimisation of dose and treatment duration and adverse event management can help patients achieve optimal efficacy with Sunitinib in clinical practice. To further improve outcomes in patients with mRCC, current trials are evaluating sequencing or combination of targeted agents. The use of Sunitinib as adjuvant therapy after nephrectomy and as neoadjuvant therapy is also being assessed. This paper provides an in-depth critical review of Sunitinib, with particular focus on the data supporting the use of Sunitinib for mRCC.
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Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma
The Journal of urology, 2009Co-Authors: M. P. Sablin, Sylvie Négrier, Alain Ravaud, Stéphane Oudard, C. Balleyguier, J. Gautier, C. Celier, Jacques Medioni, Bernard EscudierAbstract:Purpose: Sorafenib and Sunitinib are 2 tyrosine kinase inhibitors that were recently approved for renal cell carcinoma. In many patients sequential administration of the 2 drugs occurs because of the lack of sustained efficacy of the first agent. We determined the efficacy and safety of sequential administration.Materials and Methods: To determine whether cross-resistance occurs between these 2 drugs we analyzed the outcome in 90 consecutive patients with renal cell carcinoma from 4 sites in France who had received the 2 drugs sequentially. All patients received sorafenib followed by Sunitinib or vice versa. From 2003 to 2006, 68 patients received sorafenib, while 22 received Sunitinib first.Results: In the sorafenib-Sunitinib group median progression-free survival was 26 weeks with sorafenib and 28 with Sunitinib. In the Sunitinib-sorafenib group median progression-free survival was 22 weeks with Sunitinib and 17 with sorafenib. Median overall survival was 135 weeks in the sorafenib-Sunitinib group and 8...
Bernard Escudier - One of the best experts on this subject based on the ideXlab platform.
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phase iii trial of adjuvant Sunitinib in patients with high risk renal cell carcinoma exploratory pharmacogenomic analysis
Clinical Cancer Research, 2019Co-Authors: Daniel J George, Robert J Motzer, Bernard Escudier, Jeanfrancois Martini, Michael Staehler, Ahmed Magheli, Frede Donskov, Michelle Casey, Olga Valota, Brigitte LaguerreAbstract:Purpose: In the S-TRAC trial, adjuvant Sunitinib prolonged disease-free survival (DFS) versus placebo in patients with loco-regional renal cell carcinoma at high risk of recurrence after nephrectomy. An exploratory analysis evaluated associations between single nucleotide polymorphisms (SNPs) in several angiogenesis- or hypoxia-related genes and clinical outcomes in S-TRAC. Experimental Design: Blood samples were genotyped for 10 SNPs and one insertion/deletion mutation using TaqMan assays. DFS was compared using log-rank tests for each genotype in Sunitinib versus placebo groups and between genotypes within each of three (Sunitinib, placebo, and combined Sunitinib plus placebo) treatment groups. P-values were unadjusted. Results: In all, 286 patients (Sunitinib, n=142; placebo, n=144) were genotyped. Longer DFS (HR [95% confidence interval]) was observed with Sunitinib versus placebo for VEGFR1 rs9554320 C/C (0.44 [0.21-0.91]; P=0.023), VEGFR2 rs2071559 T/T (0.46 [0.23-0.90]; P=0.020), and eNOS rs2070744 T/T (0.53 [0.30-0.94]; P=0.028). Shorter DFS was observed for VEGFR1 rs9582036 C/A versus C/C with Sunitinib, placebo, and combined therapies (P≤0.05), and A/A vs C/C with Sunitinib (P=0.022). VEGFR1 rs9554320 A/C versus A/A was associated with shorter DFS in the placebo (P=0.038) and combined (P=0.006) groups. Conclusions: Correlations between VEGFR1 and VEGFR2 SNPs and longer DFS with Sunitinib suggest germline SNPs are predictive of improved outcomes with adjuvant Sunitinib in patients with renal cell carcinoma. Independent validation studies are needed to confirm these findings.
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Sunitinib for the management of advanced renal cell carcinoma
Expert review of anticancer therapy, 2010Co-Authors: Bernard EscudierAbstract:Targeted agents, such as Sunitinib (SUTENT®) have become central to the management of advanced and/or metastatic renal cell carcinoma (mRCC). Sunitinib is an oral, multitargeted receptor tyrosine kinase inhibitor that has demonstrated efficacy for the treatment of mRCC in multiple clinical trials. In a Phase III trial in previously untreated patients with mRCC, Sunitinib was associated with median progression-free survival of 11 months, which was more than double that observed with interferon-α (5 months; p < 0.001). As a result, Sunitinib is recommended in international treatment guidelines and is considered a reference standard of care in the first-line setting for patients at favorable or intermediate prognostic risk. Sunitinib is generally well tolerated with a predictable adverse-event profile; the majority of adverse events can be managed with standard medical intervention. This paper presents an overview of data supporting the use of Sunitinib for mRCC, and considers the optimal management of sunit...
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Sequential Sorafenib and Sunitinib for Renal Cell Carcinoma
The Journal of urology, 2009Co-Authors: M. P. Sablin, Sylvie Négrier, Alain Ravaud, Stéphane Oudard, C. Balleyguier, J. Gautier, C. Celier, Jacques Medioni, Bernard EscudierAbstract:Purpose: Sorafenib and Sunitinib are 2 tyrosine kinase inhibitors that were recently approved for renal cell carcinoma. In many patients sequential administration of the 2 drugs occurs because of the lack of sustained efficacy of the first agent. We determined the efficacy and safety of sequential administration.Materials and Methods: To determine whether cross-resistance occurs between these 2 drugs we analyzed the outcome in 90 consecutive patients with renal cell carcinoma from 4 sites in France who had received the 2 drugs sequentially. All patients received sorafenib followed by Sunitinib or vice versa. From 2003 to 2006, 68 patients received sorafenib, while 22 received Sunitinib first.Results: In the sorafenib-Sunitinib group median progression-free survival was 26 weeks with sorafenib and 28 with Sunitinib. In the Sunitinib-sorafenib group median progression-free survival was 22 weeks with Sunitinib and 17 with sorafenib. Median overall survival was 135 weeks in the sorafenib-Sunitinib group and 8...
Jayesh Desai - One of the best experts on this subject based on the ideXlab platform.
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Thyrotoxicosis during Sunitinib treatment for renal cell carcinoma.
Clinical endocrinology, 2008Co-Authors: Mathis Grossmann, Jayesh Desai, Erosha Premaratne, Ian D. DavisAbstract:Summary Context Sunitinib malate is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma (RCC) and gastrointestinal stromal tumours. Hypothyroidism has been observed in patients treated with Sunitinib, but the mechanism whereby Sunitinib induces hypothyroidism is unknown. Objective To describe a series of six patients who developed thyrotoxicosis while on Sunitinib for metastatic RCC. Setting The study was conducted at Austin Health, a tertiary teaching hospital in Melbourne, Australia. Results Two patients developed severe thyrotoxicosis within 10 weeks after commencing Sunitinib. In contrast, in the four patients who presented with later onset (16–30 weeks) thyrotoxicosis, the thyrotoxicosis was relatively mild, self-limiting and rapidly progressed to hypothyroidism. These patients experienced recurrent episodes of thyrotoxicosis in temporal relation to their cyclical Sunitinib treatment. One patient had cytological evidence of lymphocytic thyroiditis. Conclusions These findings suggest that Sunitinib-induced hypothyroidism may be a consequence of preceding thyroiditis with associated transient thyrotoxicosis. As predictive factors are currently unknown, we suggest regular monitoring of thyroid function in all patients commenced on Sunitinib. Clinicians treating patients with Sunitinib or other similar kinase inhibitors should to be alerted to thyroid dysfunction as a potential toxicity of these agents.
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cardiotoxicity associated with tyrosine kinase inhibitor Sunitinib
The Lancet, 2007Co-Authors: Risto Kerkela, Susan M Dallabrida, Flavia Cassiola, Maria Rupnick, Elke Pravda, Kathleen C Woulfe, David Zurakowski, Lisa Nguyen, Jayesh DesaiAbstract:Summary Background Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with Sunitinib in patients with metastatic gastrointestinal stromal tumours. Methods We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of Sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined Sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of Sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. Findings Eight of 75 (11%) patients given repeating cycles of Sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved Sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to Sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. Interpretation Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with Sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
Kanishka Sircar - One of the best experts on this subject based on the ideXlab platform.
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everolimus versus Sunitinib prospective evaluation in metastatic non clear cell renal cell carcinoma espn a randomized multicenter phase 2 trial
European Urology, 2016Co-Authors: Nizar M Tannir, Eric Jonasch, Laurence Albiges, Emre Altinmakas, Chaan S Ng, Surena F Matin, Xuemei Wang, Wei Qiao, Pheroze Tamboli, Kanishka SircarAbstract:Abstract Background Sunitinib and everolimus are standard first-line and second-line therapies, respectively, in clear cell renal cell carcinoma (ccRCC). Objective To conduct a randomized phase 2 trial comparing Sunitinib and everolimus in non–clear cell RCC (non-ccRCC). Design, setting, and participants Patients with metastatic, non-ccRCC, or ccRCC with >20% sarcomatoid features (ccSRCC) were randomized to receive Sunitinib or everolimus with crossover at disease progression. Outcome measurement and statistical analysis Primary end point was progression-free survival (PFS) in first-line therapy; 108 patients were needed to show improvement in median PFS (mPFS) from 12 wk with Sunitinib to 20 wk with everolimus. Results and limitations Interim analysis of 68 patients (papillary [27], chromophobe [12], unclassified [10], translocation [7], ccSRCC [12]) prompted early trial closure. The mPFS in first-line therapy was 6.1 mo with Sunitinib and 4.1 mo with everolimus ( p =0.6); median overall survival (mOS) was not reached with Sunitinib and was 10.5 mo with everolimus, respectively ( p =0.014). At final analysis, mOS was 16.2 and 14.9 mo with Sunitinib and everolimus, respectively ( p =0.18). There were four partial responses (PRs) in first-line therapy (Sunitinib: 3 of 33 [9%]; everolimus, 1 of 35 [2.8%]) and four PRs in second-line therapy (Sunitinib: 2 of 21 [9.5%]; everolimus, 2 of 23 [8.6%]), with mPFS of 1.8 mo and 2.8 mo, respectively. In patients without sarcomatoid features in their tumors ( n =49), mOS was 31.6 mo with Sunitinib and 10.5 mo with everolimus ( p =0.075). Genomic profiling of a chromophobe RCC from a patient with a PR to first-line everolimus revealed a somatic TSC2 mutation. Conclusions In this trial, everolimus was not superior to Sunitinib. Both agents demonstrated modest efficacy, underscoring the need for better therapies in non-ccRCC. Patient summary This randomized phase 2 trial provides the first head-to-head comparison of everolimus and Sunitinib in patients with metastatic non–clear cell renal cell carcinoma (non-ccRCC). The observed very modest efficacy underscores the need to develop more effective therapies for non-ccRCC.
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targeting met and axl overcomes resistance to Sunitinib therapy in renal cell carcinoma
Oncogene, 2016Co-Authors: Lijun Zhou, Nizar M Tannir, Surena F Matin, Pheroze Tamboli, Xuesong Zhang, Peter German, Zhiyong Ding, Christopher G Wood, Jose A Karam, Kanishka SircarAbstract:Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to Sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that Sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to Sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing Sunitinib treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line, 786-O, was chronically treated with Sunitinib, and assayed for AXL, MET, epithelial mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of Sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by shRNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets VEGFR, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue Sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic Sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT associated gene expression changes including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with Sunitinib enhanced angiogenesis in 786-0/HUVEC co-culture models. The suppression of AXL or MET expression, and the inhibition of AXL and MET activation using cabozantinib both impaired chronic Sunitinib treatment-induced prometastatic behavior in cell culture, and rescued acquired resistance to Sunitinib in xenograft models. In summary, chronic Sunitinib treatment induces the activation of AXL and MET signaling and promotes pro-metastatic behavior and angiogenesis. The inhibition of AXL and MET activity may overcome resistance induced by prolonged Sunitinib therapy in metastatic RCC.
Maria Rupnick - One of the best experts on this subject based on the ideXlab platform.
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cardiotoxicity associated with tyrosine kinase inhibitor Sunitinib
The Lancet, 2007Co-Authors: Risto Kerkela, Susan M Dallabrida, Flavia Cassiola, Maria Rupnick, Elke Pravda, Kathleen C Woulfe, David Zurakowski, Lisa Nguyen, Jayesh DesaiAbstract:Summary Background Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with Sunitinib in patients with metastatic gastrointestinal stromal tumours. Methods We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of Sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined Sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of Sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. Findings Eight of 75 (11%) patients given repeating cycles of Sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved Sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to Sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. Interpretation Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with Sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
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Cardiotoxicity associated with tyrosine kinase inhibitor Sunitinib. Commentary
The Lancet, 2007Co-Authors: Heikki Joensuu, Risto Kerkela, Susan M Dallabrida, Maria Rupnick, Elke Pravda, Kathleen C Woulfe, David Zurakowski, Lisa Nguyen, Tammy F. Chu, Flavia CassiolaAbstract:Background Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with Sunitinib in patients with metastatic gastrointestinal stromal tumours. Methods We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of Sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined Sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of Sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice. Findings Eight of 75 (11%) patients given repeating cycles of Sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved Sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to Sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes. Interpretation Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with Sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.
