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Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, Fong L, Joseph RW, Pal SK, Reeves JA, Sznol M, Hainsworth J, Rathmell WK, Stadler WM, Hutson T, Gore ME, Ravaud A, Bracarda S, Suárez C, Danielli R, Gruenwald V, Choueiri TK, Nickles D, Jhunjhunwala S, Piault-Louis E, Thobhani A, Qiu J, Chen DS, Hegde PS, Schiff C, Fine GD, Powles T
(2018) Nat Med 24: 749-757
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Carcinoma, Renal Cell, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Kidney Neoplasms, Male, Middle Aged, Mutation, Sunitinib, Treatment Outcome
Show Abstract · Added October 30, 2019
We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.
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19 MeSH Terms
Phase II Study of Two Weeks on, One Week off Sunitinib Scheduling in Patients With Metastatic Renal Cell Carcinoma.
Jonasch E, Slack RS, Geynisman DM, Hasanov E, Milowsky MI, Rathmell WK, Stovall S, Juarez D, Gilchrist TR, Pruitt L, Ornstein MC, Plimack ER, Tannir NM, Rini BI
(2018) J Clin Oncol 36: 1588-1593
MeSH Terms: Administration, Oral, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Renal Cell, Drug Administration Schedule, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Sunitinib, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added October 30, 2019
Purpose Standard frontline treatment of patients with metastatic renal cell carcinoma currently includes sunitinib. A barrier to long-term treatment with sunitinib includes the development of significant adverse effects, including diarrhea, hand-foot syndrome (HFS), and fatigue. This trial assessed the effect of an alternate 2 weeks on, 1 week off (2/1) schedule of sunitinib on toxicity and efficacy in previously untreated patients with metastatic renal cell carcinoma. Methods Patients started with oral administration of 50 mg sunitinib on a 2/1 schedule and underwent schedule and dose alterations if toxicity developed. The primary end point was < 15% grade ≥ 3 fatigue, diarrhea, or HFS. With 60 patients, the upper bound of the CI would fall below the published 4/2 schedule grade ≥ 3 toxicity rate of 25% to 30%. Results Fifty-nine patients were treated between August 2014 and March 2016. Seventy-seven percent were intermediate or poor risk per Memorial Sloan Kettering Cancer Center criteria. With a median follow-up of 17 months, 25% of patients experienced grade 3 fatigue, HFS, or diarrhea; 37% required a dose reduction, and 10% discontinued because of toxicity. The overall response rate was 57%, median progression-free survival was 13.7 months, and median overall survival was not reached. At 12 weeks, Functional Assessment of Cancer Therapy-General scores dropped between 0% and 10% from baseline, with less reduction in patients who continued treatment longer. Conclusion The primary end point of decreased grade 3 toxicity was not met; however, treatment with a 2/1 sunitinib schedule is associated with a lack of grade 4 toxicity, a low patient discontinuation rate, and high efficacy.
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Cardio-oncology: it takes two to translate.
Moslehi J, Cheng S
(2013) Sci Transl Med 5: 187fs20
MeSH Terms: Angiogenesis Inhibitors, Animals, Coronary Vessels, Heart, Indoles, Microvessels, Pericytes, Pyrroles, Sunitinib
Added March 4, 2015
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9 MeSH Terms
Management of antiangiogenic therapy-induced hypertension.
de Jesus-Gonzalez N, Robinson E, Moslehi J, Humphreys BD
(2012) Hypertension 60: 607-15
MeSH Terms: Angiogenesis Inhibitors, Antihypertensive Agents, Carcinoma, Renal Cell, Combined Modality Therapy, Humans, Hypertension, Indoles, Kidney Neoplasms, Lisinopril, Male, Middle Aged, Nephrectomy, Pyrroles, Sunitinib, Treatment Outcome, Withholding Treatment
Added March 4, 2015
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16 MeSH Terms
Cardiac side effects of anticancer treatments: new mechanistic insights.
Geisberg C, Pentassuglia L, Sawyer DB
(2012) Curr Heart Fail Rep 9: 211-8
MeSH Terms: Anthracyclines, Antibiotics, Antineoplastic, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Benzenesulfonates, Daunorubicin, Doxorubicin, Heart Failure, Humans, Indoles, Myocardial Contraction, Myocytes, Cardiac, Niacinamide, Phenylurea Compounds, Pyridines, Pyrroles, Sorafenib, Sunitinib, Trastuzumab
Show Abstract · Added March 5, 2014
Damage to heart cells leading to heart failure is a known complication of well-established cancer therapies including anthracycline antibiotics and radiation therapy, and the cardiovascular complications of these therapies has been controlled in large part through dose limitations and modifications of delivery methods. Recent research into the cellular and molecular mechanisms for the cardiovascular effects of these therapies may lead to other cardioprotective strategies that improve effectiveness of cancer treatments. Newer cancer therapies that have been developed based upon specifically targeting oncogene signaling also have been associated with heart failure. Rapid development of a detailed understanding of how these agents cause cardiac dysfunction promises to improve outcomes in cancer patients, as well as stimulate concepts of cardiovascular homeostasis that will likely accelerate development of cardiovascular therapies.
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19 MeSH Terms
Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study.
Poprach A, Pavlik T, Melichar B, Puzanov I, Dusek L, Bortlicek Z, Vyzula R, Abrahamova J, Buchler T, Czech Renal Cancer Cooperative Group
(2012) Ann Oncol 23: 3137-3143
MeSH Terms: Aged, Angiogenesis Inhibitors, Antineoplastic Agents, Carcinoma, Renal Cell, Disease-Free Survival, Exanthema, Female, Hand-Foot Syndrome, Humans, Indoles, Kidney Neoplasms, Male, Middle Aged, Neoplasm Metastasis, Niacinamide, Phenylurea Compounds, Protein Kinase Inhibitors, Pyrroles, Registries, Retrospective Studies, Skin, Sorafenib, Sunitinib, Treatment Outcome
Show Abstract · Added March 5, 2014
BACKGROUND - A retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed.
PATIENTS AND METHODS - Data on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand-foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash.
RESULTS - The cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort.
CONCLUSION - The presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib.
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24 MeSH Terms
Reversible cardiomyopathy associated with sunitinib and sorafenib.
Uraizee I, Cheng S, Moslehi J
(2011) N Engl J Med 365: 1649-50
MeSH Terms: Aged, Antineoplastic Agents, Benzenesulfonates, Cardiomyopathies, Female, Humans, Indoles, Male, Middle Aged, Niacinamide, Phenylurea Compounds, Protein-Tyrosine Kinases, Pyridines, Pyrroles, Sorafenib, Sunitinib, Vascular Endothelial Growth Factor A
Added March 4, 2015
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17 MeSH Terms
Incidence and risk of congestive heart failure in patients with renal and nonrenal cell carcinoma treated with sunitinib.
Richards CJ, Je Y, Schutz FA, Heng DY, Dallabrida SM, Moslehi JJ, Choueiri TK
(2011) J Clin Oncol 29: 3450-6
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Renal Cell, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Follow-Up Studies, Heart Failure, Humans, Incidence, Indoles, Kidney Neoplasms, Middle Aged, Pyrroles, Randomized Controlled Trials as Topic, Risk Factors, Sunitinib, Survival Rate, Treatment Outcome
Show Abstract · Added March 4, 2015
PURPOSE - Sunitinib is a multitargeted receptor tyrosine kinase inhibitor approved for treatment of renal cell carcinoma (RCC) and GI stromal tumor. Congestive heart failure (CHF) is an important adverse effect that has been reported with sunitinib, but overall incidence and relative risk (RR) remain undefined. We performed an up-to-date meta-analysis to determine the risk of developing CHF in patients with both RCC and non-RCC tumors treated with sunitinib.
METHODS - Medline databases were searched for articles published between January 1966 and February 2011. Eligible studies were limited to phase II and III trials of sunitinib with adequate safety reporting in patients with cancer of any tumor type. Summary incidence, RR, and 95% CIs were calculated using random- or fixed-effects models based on the heterogeneity of included studies.
RESULTS - A total of 6,935 patients were included. Overall incidence for all- and high-grade CHF in sunitinib-treated patients was 4.1% (95% CI, 1.5% to 10.6%) and 1.5% (95% CI, 0.8% to 3.0%), respectively. RR of all- and high-grade CHF in sunitinib-treated patients compared with placebo-treated patients was 1.81 (95% CI, 1.30 to 2.50; P < .001) and 3.30 (95% CI, 1.29 to 8.45; P = .01), respectively. On subgroup analysis, there was no difference observed in CHF incidence for patients with RCC versus non-RCC or in trials with or without cardiac monitoring. No evidence of publication bias was observed.
CONCLUSION - Sunitinib use is associated with increased risk of CHF in patients with cancer.
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20 MeSH Terms
The loss of radiographic enhancement in primary renal cell carcinoma tumors following multitargeted receptor tyrosine kinase therapy is an additional indicator of response.
Cowey CL, Fielding JR, Rathmell WK
(2010) Urology 75: 1108-13.e1
MeSH Terms: Antineoplastic Agents, Benzenesulfonates, Carcinoma, Renal Cell, Female, Humans, Indoles, Kidney Neoplasms, Male, Middle Aged, Niacinamide, Phenylurea Compounds, Protein Kinase Inhibitors, Pyridines, Pyrroles, Radiographic Image Enhancement, Retrospective Studies, Sorafenib, Sunitinib, Treatment Outcome
Show Abstract · Added October 17, 2015
OBJECTIVES - To characterize radiographic intratumoral contrast enhancement in the primary tumor of patients with renal cell carcinoma treated with either sorafenib or sunitinib, and to compare the relationship between primary tumor response and loss of enhancement. Use of the antiangiogenic multitargeted tyrosine kinase inhibitors sorafenib and sunitinib in renal cell carcinoma often results in stabilization of tumor size based on measurement of external tumor diameter; however, internal tumor changes in enhancement have been occasionally noted.
METHODS - Thirty patients who received sunitinib or sorafenib therapy were evaluated for primary tumor response with contrast-enhanced computed tomography images before and after at least 1 cycle of treatment. Evaluation of intratumoral contrast enhancement was quantified using a workstation that allowed for three-dimensional renderings of the kidney and measurement of density in Hounsfield units (HU). The relationship between loss of intratumoral enhancement and other outcome variables was examined.
RESULTS - A loss of enhancement within the primary tumor, following therapy with tyrosine kinase inhibitors, was positively associated with primary tumor response (P = .0053). Additionally, the degree of post-treatment tumor enhancement was positively associated with tumor response to tyrosine kinase inhibition (P = .045).
CONCLUSIONS - Intratumoral changes in computed tomography enhancement after receptor tyrosine kinase inhibition correlate with primary tumor response, and may be a useful adjunct to the standard response evaluation criteria in solid tumors (RECIST criteria) in assessing response to therapy. Prospective studies evaluating antiangiogenic agents should explore intratumoral changes in contrast enhancement as part of response criteria, and examine the effect of intratumoral changes on survival-based outcomes.
Copyright 2010 Elsevier Inc. All rights reserved.
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Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA
(2009) J Clin Oncol 27: 3584-90
MeSH Terms: Administration, Oral, Adult, Aged, Carcinoma, Renal Cell, Confidence Intervals, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Follow-Up Studies, Humans, Indoles, Injections, Subcutaneous, Interferon-alpha, Kaplan-Meier Estimate, Kidney Neoplasms, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Staging, Probability, Proportional Hazards Models, Pyrroles, Sunitinib, Survival Analysis, Treatment Outcome
Show Abstract · Added March 7, 2014
PURPOSE - A randomized, phase III trial demonstrated superiority of sunitinib over interferon alfa (IFN-alpha) in progression-free survival (primary end point) as first-line treatment for metastatic renal cell carcinoma (RCC). Final survival analyses and updated results are reported.
PATIENTS AND METHODS - Seven hundred fifty treatment-naïve patients with metastatic clear cell RCC were randomly assigned to sunitinib 50 mg orally once daily on a 4 weeks on, 2 weeks off dosing schedule or to IFN-alpha 9 MU subcutaneously thrice weekly. Overall survival was compared by two-sided log-rank and Wilcoxon tests. Progression-free survival, response, and safety end points were assessed with updated follow-up.
RESULTS - Median overall survival was greater in the sunitinib group than in the IFN-alpha group (26.4 v 21.8 months, respectively; hazard ratio [HR] = 0.821; 95% CI, 0.673 to 1.001; P = .051) per the primary analysis of unstratified log-rank test (P = .013 per unstratified Wilcoxon test). By stratified log-rank test, the HR was 0.818 (95% CI, 0.669 to 0.999; P = .049). Within the IFN-alpha group, 33% of patients received sunitinib, and 32% received other vascular endothelial growth factor-signaling inhibitors after discontinuation from the trial. Median progression-free survival was 11 months for sunitinib compared with 5 months for IFN-alpha (P < .001). Objective response rate was 47% for sunitinib compared with 12% for IFN-alpha (P < .001). The most commonly reported sunitinib-related grade 3 adverse events included hypertension (12%), fatigue (11%), diarrhea (9%), and hand-foot syndrome (9%).
CONCLUSION - Sunitinib demonstrates longer overall survival compared with IFN-alpha plus improvement in response and progression-free survival in the first-line treatment of patients with metastatic RCC. The overall survival highlights an improved prognosis in patients with RCC in the era of targeted therapy.
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28 MeSH Terms