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Toni K. Choueiri - One of the best experts on this subject based on the ideXlab platform.
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Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk alliance a031203 cabosun randomised trial progression free survival by independent review and overall survival update
European Journal of Cancer, 2018Co-Authors: Toni K. Choueiri, Susan Halabi, Ben Sanford, Olwen Hahn, Dror M Michaelson, Meghara K Walsh, Thomas Olencki, Joel Picus, Colin Hessel, Eric J SmallAbstract:Abstract Background The randomised phase 2 CABOSUN trial comparing Cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). Patients and methods Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to Cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases. Results A total of 157 patients were randomised 1:1 to Cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8–14.0) versus 5.3 months (95% CI 3.0–8.2) for Cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31–0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0–30.8) versus 9% (95% CI 3.7–17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6–not estimable) with Cabozantinib and 21.2 months (95% CI 16.3–27.4) with sunitinib (HR 0.80 [95% CI 0.53–1.21]. The incidence of grade 3 or 4 adverse events was 68% for Cabozantinib and 65% for sunitinib. Conclusions In this phase 2 trial, Cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk. Trial Registration Number NCT01835158 .
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Long-term follow-up of overall survival for Cabozantinib versus everolimus in advanced renal cell carcinoma
British journal of cancer, 2018Co-Authors: Robert J. Motzer, Bernard Escudier, Thomas Powles, Christian Scheffold, Toni K. ChoueiriAbstract:In the phase 3 METEOR trial (NCT01865747), Cabozantinib significantly improved progression-free survival, overall survival, and objective response rate compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy. A statistically significant improvement in overall survival was observed at a second interim analysis with 320 recorded deaths. 658 patients with advanced RCC who had received at least one prior VEGFR tyrosine kinase inhibitor were randomised 1:1 to Cabozantinib (60 mg daily) or everolimus (10 mg daily). Survival follow-up continued to reach the 408 deaths that were pre-specified for the final analysis. With 430 deaths (198 for Cabozantinib and 232 for everolimus), median overall survival was 21.4 months with Cabozantinib and 17.1 months with everolimus (HR 0.70, 95% CI 0.58–0.85; P = 0.0002). Safety profiles of Cabozantinib and everolimus were consistent with those reported previously. Cabozantinib significantly improved overall survival compared with everolimus in previously treated patients with advanced RCC with consistent results after long-term follow-up.
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Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk the alliance a031203 cabosun trial
Journal of Clinical Oncology, 2017Co-Authors: Toni K. Choueiri, Susan Halabi, Ben Sanford, Olwen Hahn, Dror M Michaelson, Meghara K Walsh, Darren R Feldman, Thomas Olencki, Joel Picus, Eric J SmallAbstract:Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated Cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to Cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (Cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, Cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23 to 44) for Cabozantinib versus 12% (95% CI, 5.4 to 21) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for Cabozantinib and 68% for sunitinib and included diarrhea (Cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.
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Cabozantinib versus everolimus in advanced renal cell carcinoma meteor final results from a randomised open label phase 3 trial
Lancet Oncology, 2016Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Frede Donskov, Nizar M. Tannir, Paul N Mainwaring, Hans J Hammers, Brian I Rini, Bruce J Roth, Katriina PeltolaAbstract:Summary Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of Cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg Cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive Cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the Cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with Cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p vs 3% [2–6] with everolimus; p vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the Cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the Cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with Cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, Cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.
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Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma
The New England journal of medicine, 2015Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Frede Donskov, Paul N Mainwaring, Hans J Hammers, Brian I Rini, Thomas E. Hutson, Jae Lyun Lee, Katriina PeltolaAbstract:BackgroundCabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of Cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. MethodsWe randomly assigned 658 patients to receive Cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. ResultsMedian progression-free survival was 7.4 months with Cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with Cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] ...
Dale Miles - One of the best experts on this subject based on the ideXlab platform.
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A population pharmacokinetic model of Cabozantinib in healthy volunteers and patients with various cancer types.
Cancer chemotherapy and pharmacology, 2018Co-Authors: Steven Lacy, Linh Nguyen, Dale Miles, Bei Yang, Jace Nielsen, Matt HutmacherAbstract:An integrated population pharmacokinetic (popPK) model was developed to describe the pharmacokinetics (PK) of tyrosine kinase inhibitor Cabozantinib in healthy volunteers (HVs) and patients with various cancer types and to identify any differences in Cabozantinib PK across these populations. Plasma concentration data used to develop the popPK model were obtained from nine clinical trials (8072 concentrations from 1534 HVs or patients) of Cabozantinib in HVs and patients with renal cell carcinoma (RCC), medullary thyroid carcinoma (MTC), glioblastoma multiforme, castration-resistant prostate cancer, or other advanced malignancies. PK data across studies were adequately characterized by a two-compartment disposition model with dual first- and zero-order absorption processes and first-order elimination. Baseline demographic covariates (age, weight, gender, race, and cancer type) were generally predicted to have a small-to-moderate impact on apparent clearance (CL/F). However, MTC cancer type did show an approximately 93% higher CL/F relative to HVs following chronic dosing, resulting in approximately 40–50% lower predicted steady-state Cabozantinib plasma concentrations. This popPK analysis showed Cabozantinib CL/F values to be higher for patients with MTC and may account for the higher dosage required in this patient population (140-mg) to achieve plasma exposures comparable to those in patients with RCC and other tumor types administered a 60-mg Cabozantinib tablet dose. Possible factors that may underlie the higher Cabozantinib clearance observed in MTC patients are discussed.
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a phase ib ii study of Cabozantinib xl184 with or without erlotinib in patients with non small cell lung cancer
Cancer Chemotherapy and Pharmacology, 2017Co-Authors: Heather A. Wakelee, Scott N Gettinger, Jeffrey A Engelman, Pasi A Janne, Howard J West, Deepa S Subramaniam, Joseph Leach, Michael Wax, Yifah Yaron, Dale MilesAbstract:Purpose Cabozantinib is a multi-kinase inhibitor that targets MET, AXL, and VEGFR2, and may synergize with EGFR inhibition in NSCLC. Cabozantinib was assessed alone or in combination with erlotinib in patients with progressive NSCLC and EGFR mutations who had previously received erlotinib.
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Clinical Pharmacokinetics and Pharmacodynamics of Cabozantinib.
Clinical pharmacokinetics, 2016Co-Authors: Steven Lacy, Dale Miles, Linh NguyenAbstract:Cabozantinib inhibits receptor tyrosine kinases involved in tumor angiogenesis and metastasis. The capsule formulation (Cometriq®) is approved for the treatment of progressive metastatic medullary thyroid cancer at a 140-mg free base equivalent dose. The tablet formulation (Cabometyx™, 60-mg free base equivalent dose) is approved for the treatment of renal cell carcinoma following anti-angiogenic therapy. Cabozantinib displays a long terminal plasma half-life (~120 h) and accumulates ~fivefold by day 15 following daily dosing based on area under the plasma concentration-time curve (AUC). Four identified inactive metabolites constitute >65 % of total Cabozantinib-related AUC following a single 140-mg free base equivalent dose. Cabozantinib AUC was increased by 63–81 % or 7–30 % in subjects with mild/moderate hepatic or renal impairment, respectively; by 34–38 % with concomitant cytochrome P450 3A4 inhibitor ketoconazole; and by 57 % following a high-fat meal. Cabozantinib AUC was decreased by 76–77 % with concomitant cytochrome P450 3A4 inducer rifampin, and was unaffected following administration of proton pump inhibitor esomeprazole. Cabozantinib is a potent in vitro inhibitor of P-glycoprotein, and multidrug and toxin extrusion transporter 1 and 2-K, and is a substrate for multidrug resistance protein 2. No clinically significant covariates affecting Cabozantinib pharmacokinetics were identified in a population pharmacokinetic analysis. Patients with medullary thyroid cancer with low model-predicted apparent clearance were more likely to dose hold/reduce Cabozantinib early, and had a lower average dose through day 85. However, longitudinal tumor modeling suggests that Cabozantinib dose reductions from 140 to 60 mg/day did not markedly reduce tumor growth inhibition in medullary thyroid cancer patients.
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Pharmacokinetic (PK) drug interaction studies of Cabozantinib: Effect of CYP3A inducer rifampin and inhibitor ketoconazole on Cabozantinib plasma PK and effect of Cabozantinib on CYP2C8 probe substrate rosiglitazone plasma PK.
Journal of clinical pharmacology, 2015Co-Authors: Linh Nguyen, Jaymes Holland, Natacha Benrimoh, Dale Miles, Caroline Engel, Terry E. O'reilly, Steven LacyAbstract:Cabozantinib is a small-molecule tyrosine kinase inhibitor that has been approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. In vitro data indicate that (1) cytochrome P450 (CYP) 3A4 is the primary CYP isoenzyme involved in the metabolism of Cabozantinib, and (2) CYP2C8 is the CYP isoenzyme most potently inhibited by Cabozantinib with potential for in vivo inhibition at clinically relevant plasma exposures. Pharmacokinetic (PK) drug–drug interactions (DDIs) were evaluated clinically between Cabozantinib and (1) a CYP3A inducer (rifampin) in healthy volunteers, (2) a CYP3A inhibitor (ketoconazole) in healthy volunteers, and (3) a CYP2C8 substrate (rosiglitazone) in patients with solid tumors. Compared with Cabozantinib given alone, coadministration with rifampin resulted in a 4.3-fold higher plasma clearance (CL/F) of Cabozantinib and a 77% decrease in Cabozantinib plasma AUC0–inf, whereas coadministration with ketoconazole decreased Cabozantinib CL/F by 29% and increased Cabozantinib AUC0–inf by 38%. Chronic coadministration with Cabozantinib resulted in no significant effect on rosiglitazone plasma Cmax, AUC0–24, or AUC0–inf. In summary, chronic use of strong CYP3A inducers and inhibitors should be avoided when Cabozantinib is administered, and Cabozantinib at clinically relevant exposures is not anticipated to markedly affect the PK of concomitant medications via CYP enzyme inhibition.
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Metabolism and Disposition of Cabozantinib in Healthy Male Volunteers and Pharmacologic Characterization of Its Major Metabolites
Drug metabolism and disposition: the biological fate of chemicals, 2015Co-Authors: Steven Lacy, Dale Miles, Bih Hsu, Dana T. Aftab, Ronghua Wang, Linh NguyenAbstract:Metabolism and excretion of Cabozantinib, an oral inhibitor of receptor tyrosine kinases, was studied in 8 healthy male volunteers after a single oral dose of 175 mg Cabozantinib l-malate containing 14C-Cabozantinib (100 µ Ci/subject). Total mean radioactivity recovery within 48 days was 81.09%; radioactivity was eliminated in feces (53.79%) and urine (27.29%). Cabozantinib was extensively metabolized with 17 individual metabolites identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in plasma, urine, and feces. Relative plasma radioactivity exposures (analyte AUC0-t/total AUC0-t for Cabozantinib+major metabolites) were 27.2, 25.2, 32.3, 7, and 6% for Cabozantinib and major metabolites monohydroxy sulfate (EXEL-1646), 6-desmethyl amide cleavage product sulfate (EXEL-1644), N -oxide (EXEL-5162), and amide cleavage product (EXEL-5366), respectively. Comparable relative plasma exposures determined by LC-MS/MS analysis were 32.4, 13.8, 45.9, 4.9, and 3.1%, respectively. These major metabolites each possess in vitro inhibition potencies ≤1/10th of parent Cabozantinib against the targeted kinases MET, RET, and VEGFR2/KDR. In an in vitro cytochrome P450 (CYP) panel, Cabozantinib and EXEL-1644 both inhibited most potently CYP2C8 ( K iapp = 4.6 and 1.1 µ M, respectively). In an in vitro drug transporter panel, Cabozantinib inhibited most potently MATE1 and MATE2-K (IC50 = 5.94 and 3.12 µ M, respectively) and was a MRP2 substrate; EXEL-1644 inhibited most potently OAT1, OAT3, OATP1B1, MATE1, and OATP1B3 (IC50 = 4.3, 4.3, 6.1, 16.7, and 20.6 µ M, respectively) and was a substrate of MRP2, OAT3, OATP1B1, OATP1B3, and possibly P-gp. Therefore, Cabozantinib appears to be the primary pharmacologically active circulating analyte, whereas both Cabozantinib and EXEL-1644 may represent potential for drug-drug interactions.
Bernard Escudier - One of the best experts on this subject based on the ideXlab platform.
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Long-term follow-up of overall survival for Cabozantinib versus everolimus in advanced renal cell carcinoma
British journal of cancer, 2018Co-Authors: Robert J. Motzer, Bernard Escudier, Thomas Powles, Christian Scheffold, Toni K. ChoueiriAbstract:In the phase 3 METEOR trial (NCT01865747), Cabozantinib significantly improved progression-free survival, overall survival, and objective response rate compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy. A statistically significant improvement in overall survival was observed at a second interim analysis with 320 recorded deaths. 658 patients with advanced RCC who had received at least one prior VEGFR tyrosine kinase inhibitor were randomised 1:1 to Cabozantinib (60 mg daily) or everolimus (10 mg daily). Survival follow-up continued to reach the 408 deaths that were pre-specified for the final analysis. With 430 deaths (198 for Cabozantinib and 232 for everolimus), median overall survival was 21.4 months with Cabozantinib and 17.1 months with everolimus (HR 0.70, 95% CI 0.58–0.85; P = 0.0002). Safety profiles of Cabozantinib and everolimus were consistent with those reported previously. Cabozantinib significantly improved overall survival compared with everolimus in previously treated patients with advanced RCC with consistent results after long-term follow-up.
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quality of life outcomes for Cabozantinib versus everolimus in patients with metastatic renal cell carcinoma meteor phase iii randomized trial
Journal of Clinical Oncology, 2018Co-Authors: David Cella, Bernard Escudier, Thomas Powles, Manuela Schmidinger, Frede Donskov, Nizar M. Tannir, Katriina Peltola, Daniel Yick Chin Heng, Paul N Mainwaring, Hans J HammersAbstract:Purpose In the phase III METEOR trial ( ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive Cabozantinib or everolimus. The Cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI-Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size ≥ 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or ≥ 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained ≥ 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the Cabozantinib and everolimus arms. Among the individual FKSI-19 items, Cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, Cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, Cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.
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Cabozantinib for the treatment of renal cell carcinoma
Expert opinion on pharmacotherapy, 2016Co-Authors: Bernard Escudier, Julie C. Lougheed, Laurence AlbigesAbstract:ABSTRACTIntroduction: Agents that target the vascular endothelial growth factor (VEGF) or mammalian target of rapamycin (mTOR) pathway as well as the PD-1 checkpoint inhibitor nivolumab are standard therapies for advanced renal cell carcinoma (RCC). Recently, Cabozantinib, an inhibitor of MET, VEGF receptors, and AXL, was approved by the FDA and European Commission based on improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to standard of care treatment with everolimus in a randomized phase 3 trial in advanced RCC after prior VEGFR-tyrosine kinase inhibitor (TKI) therapy.Areas covered:The preclinical development and scientific rationale, pharmacokinetics, and clinical efficacy and safety of Cabozantinib for the treatment of advanced RCC are reviewed. The use of Cabozantinib in clinical practice with the growing number of available treatments for advanced RCC is discussed.Expert opinion: Cabozantinib is the only therapy for advanced RCC that has impr...
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Cabozantinib versus everolimus in advanced renal cell carcinoma meteor final results from a randomised open label phase 3 trial
Lancet Oncology, 2016Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Frede Donskov, Nizar M. Tannir, Paul N Mainwaring, Hans J Hammers, Brian I Rini, Bruce J Roth, Katriina PeltolaAbstract:Summary Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of Cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg Cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive Cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the Cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with Cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p vs 3% [2–6] with everolimus; p vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the Cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the Cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with Cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, Cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.
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Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma
The New England journal of medicine, 2015Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Frede Donskov, Paul N Mainwaring, Hans J Hammers, Brian I Rini, Thomas E. Hutson, Jae Lyun Lee, Katriina PeltolaAbstract:BackgroundCabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of Cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. MethodsWe randomly assigned 658 patients to receive Cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. ResultsMedian progression-free survival was 7.4 months with Cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with Cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] ...
Carol Aghajanian - One of the best experts on this subject based on the ideXlab platform.
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a randomized phase ii study of Cabozantinib versus weekly paclitaxel in the treatment of persistent or recurrent epithelial ovarian fallopian tube or primary peritoneal cancer an nrg oncology gynecologic oncology group study
Gynecologic Oncology, 2019Co-Authors: Ursula A Matulonis, Michael W Sill, Vicky Makker, David G Mutch, Jay W Carlson, Christopher J Darus, Robert S Mannel, David P Bender, Erin K Crane, Carol AghajanianAbstract:Abstract Introduction Cabozantinib is a receptor tyrosine kinases inhibitor that targets MET (c-MET), VEGF receptor 2 (VEGFR2), RET, AXL, KIT, FLT-3, and TIE-2 and previously showed promising single agent activity in recurrent ovarian cancer. Methods This was an open label, 1:1 randomized study of Cabozantinib 60 mg orally (PO) daily versus weekly paclitaxel 80 mg/m2 given 3 out of 4 weeks (NCT01716715); 111 patients were enrolled. Eligibility included persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma and at least one but no >3 prior chemotherapy regimens. Results Median PFS was similar for both treatment groups and was 5.3 months for Cabozantinib and 5.5 months for weekly paclitaxel (HR 1.11 (90% CI 0.77–1.61, p = 0.64)). Secondary analyses of overall survival (OS) and event free survival (EFS) showed that Cabozantinib did not perform as well as weekly paclitaxel. Median OS for Cabozantinib was 19.4 months and was not reached for weekly paclitaxel (HR 2.27 (90% CI 1.17–4.41, p = 0.04). EFS was also worse in the Cabozantinib arm, 3.5 months, compared to weekly paclitaxel at 5.0 months (HR 1.81 (90% CI 1.24–2.63, p = 0.01). Overall response rate (ORR) was less for Cabozantinib compared to weekly paclitaxel (7% versus 24.1%). Gastrointestinal toxicities, specifically nausea, diarrhea, and abdominal pain were worse in the Cabozantinib arm. Conclusions Median PFS was similar for Cabozantinib and weekly paclitaxel. However, OS, EFS, and ORR were worse for Cabozantinib compared to weekly paclitaxel. Cabozantinib given at this dose and schedule cannot be recommended as a treatment for recurrent ovarian cancer.
Thomas Powles - One of the best experts on this subject based on the ideXlab platform.
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Long-term follow-up of overall survival for Cabozantinib versus everolimus in advanced renal cell carcinoma
British journal of cancer, 2018Co-Authors: Robert J. Motzer, Bernard Escudier, Thomas Powles, Christian Scheffold, Toni K. ChoueiriAbstract:In the phase 3 METEOR trial (NCT01865747), Cabozantinib significantly improved progression-free survival, overall survival, and objective response rate compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy. A statistically significant improvement in overall survival was observed at a second interim analysis with 320 recorded deaths. 658 patients with advanced RCC who had received at least one prior VEGFR tyrosine kinase inhibitor were randomised 1:1 to Cabozantinib (60 mg daily) or everolimus (10 mg daily). Survival follow-up continued to reach the 408 deaths that were pre-specified for the final analysis. With 430 deaths (198 for Cabozantinib and 232 for everolimus), median overall survival was 21.4 months with Cabozantinib and 17.1 months with everolimus (HR 0.70, 95% CI 0.58–0.85; P = 0.0002). Safety profiles of Cabozantinib and everolimus were consistent with those reported previously. Cabozantinib significantly improved overall survival compared with everolimus in previously treated patients with advanced RCC with consistent results after long-term follow-up.
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quality of life outcomes for Cabozantinib versus everolimus in patients with metastatic renal cell carcinoma meteor phase iii randomized trial
Journal of Clinical Oncology, 2018Co-Authors: David Cella, Bernard Escudier, Thomas Powles, Manuela Schmidinger, Frede Donskov, Nizar M. Tannir, Katriina Peltola, Daniel Yick Chin Heng, Paul N Mainwaring, Hans J HammersAbstract:Purpose In the phase III METEOR trial ( ClinicalTrials.gov identifier: NCT01865747), 658 previously treated patients with advanced renal cell carcinoma were randomly assigned 1:1 to receive Cabozantinib or everolimus. The Cabozantinib arm had improved progression-free survival, overall survival, and objective response rate compared with everolimus. Changes in quality of life (QoL), an exploratory end point, are reported here. Patients and Methods Patients completed the 19-item Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19) and the five-level EuroQol (EQ-5D-5L) questionnaires at baseline and throughout the study. The nine-item FKSI-Disease-Related Symptoms (FKSI-DRS), a subset of FKSI-19, was also investigated. Data were summarized descriptively and by repeated-measures analysis (for which a clinically relevant difference was an effect size ≥ 0.3). Time to deterioration (TTD) was defined as the earlier of date of death, radiographic progressive disease, or ≥ 4-point decrease from baseline in FKSI-DRS. Results The QoL questionnaire completion rates remained ≥ 75% through week 48 in each arm. There was no difference over time for FKSI-19 Total, FKSI-DRS, or EQ-5D data between the Cabozantinib and everolimus arms. Among the individual FKSI-19 items, Cabozantinib was associated with worse diarrhea and nausea; everolimus was associated with worse shortness of breath. These differences are consistent with the adverse event profile of each drug. Cabozantinib improved TTD overall, with a marked improvement in patients with bone metastases at baseline. Conclusion In patients with advanced renal cell carcinoma, relative to everolimus, Cabozantinib generally maintained QoL to a similar extent. Compared with everolimus, Cabozantinib extended TTD overall and markedly improved TTD in patients with bone metastases.
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Cabozantinib versus everolimus in advanced renal cell carcinoma meteor final results from a randomised open label phase 3 trial
Lancet Oncology, 2016Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Frede Donskov, Nizar M. Tannir, Paul N Mainwaring, Hans J Hammers, Brian I Rini, Bruce J Roth, Katriina PeltolaAbstract:Summary Background Cabozantinib is an oral inhibitor of tyrosine kinases including MET, VEGFR, and AXL. The randomised phase 3 METEOR trial compared the efficacy and safety of Cabozantinib versus the mTOR inhibitor everolimus in patients with advanced renal cell carcinoma who progressed after previous VEGFR tyrosine-kinase inhibitor treatment. Here, we report the final overall survival results from this study based on an unplanned second interim analysis. Methods In this open-label, randomised phase 3 trial, we randomly assigned (1:1) patients aged 18 years and older with advanced or metastatic clear-cell renal cell carcinoma, measurable disease, and previous treatment with one or more VEGFR tyrosine-kinase inhibitors to receive 60 mg Cabozantinib once a day or 10 mg everolimus once a day. Randomisation was done with an interactive voice and web response system. Stratification factors were Memorial Sloan Kettering Cancer Center risk group and the number of previous treatments with VEGFR tyrosine-kinase inhibitors. The primary endpoint was progression-free survival as assessed by an independent radiology review committee in the first 375 randomly assigned patients and has been previously reported. Secondary endpoints were overall survival and objective response in all randomly assigned patients assessed by intention-to-treat. Safety was assessed per protocol in all patients who received at least one dose of study drug. The study is closed for enrolment but treatment and follow-up of patients is ongoing for long-term safety evaluation. This trial is registered with ClinicalTrials.gov, number NCT01865747. Findings Between Aug 8, 2013, and Nov 24, 2014, 658 patients were randomly assigned to receive Cabozantinib (n=330) or everolimus (n=328). The median duration of follow-up for overall survival and safety was 18·7 months (IQR 16·1–21·1) in the Cabozantinib group and 18·8 months (16·0–21·2) in the everolimus group. Median overall survival was 21·4 months (95% CI 18·7–not estimable) with Cabozantinib and 16·5 months (14·7–18·8) with everolimus (hazard ratio [HR] 0·66 [95% CI 0·53–0·83]; p=0·00026). Cabozantinib treatment also resulted in improved progression-free survival (HR 0·51 [95% CI 0·41–0·62]; p vs 3% [2–6] with everolimus; p vs 12 [4%] in the everolimus group), diarrhoea (43 [13%] vs 7 [2%]), fatigue (36 [11%] vs 24 [7%]), palmar-plantar erythrodysaesthesia syndrome (27 [8%] vs 3 [1%]), anaemia (19 [6%] vs 53 [17%]), hyperglycaemia (3 [1%] vs 16 [5%]), and hypomagnesaemia (16 [5%] vs none). Serious adverse events grade 3 or worse occurred in 130 (39%) patients in the Cabozantinib group and in 129 (40%) in the everolimus group. One treatment-related death occurred in the Cabozantinib group (death; not otherwise specified) and two occurred in the everolimus group (one aspergillus infection and one pneumonia aspiration). Interpretation Treatment with Cabozantinib increased overall survival, delayed disease progression, and improved the objective response compared with everolimus. Based on these results, Cabozantinib should be considered as a new standard-of-care treatment option for previously treated patients with advanced renal cell carcinoma. Patients should be monitored for adverse events that might require dose modifications. Funding Exelixis Inc.
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Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma
The New England journal of medicine, 2015Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Frede Donskov, Paul N Mainwaring, Hans J Hammers, Brian I Rini, Thomas E. Hutson, Jae Lyun Lee, Katriina PeltolaAbstract:BackgroundCabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of Cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. MethodsWe randomly assigned 658 patients to receive Cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. ResultsMedian progression-free survival was 7.4 months with Cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with Cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] ...
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phase 3 randomized study of Cabozantinib xl184 versus everolimus in subjects with clear cell renal cell carcinoma meteor
Journal of Clinical Oncology, 2014Co-Authors: Toni K. Choueiri, Bernard Escudier, Thomas Powles, Christian Scheffold, David Cella, Robert J. MotzerAbstract:TPS4601 Background: Cabozantinib is an oral receptor tyrosine kinase inhibitor (TKI) with potent activity against MET and VEGFR2. Cabozantinib has demonstrated clinical activity in multiple solid tumor types, including heavily pretreated subjects with clear cell renal cell carcinoma (ccRCC) (Choueiri et al.; ASCO 2012, abstract 4504). In ccRCC, VHL tumor suppressor gene dysfunction results in impaired HIF degradation and consequent activation of MET and VEGF pathways. Moreover, MET has been implicated in adaptive resistance to VEGF-pathway targeted agents. Based on the clinical activity seen to date and the scientific rationale, there is strong interest in the evaluation of Cabozantinib in ccRCC. Methods: This Phase 3, open-label, multicenter study evaluates the efficacy and safety of Cabozantinib compared with everolimus in subjects with ccRCC (NCT01865747).The primary endpoint is progression-free survival (PFS) as evaluated by an independent radiology review committee (IRC). Secondary endpoints are over...
