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Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naive Patients: a Systematic Review and Network Meta-Analysis.

ABSTRACT: BACKGROUND:Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC). OBJECTIVE:To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC. METHODS:We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC. The outcomes analyzed were overall survival (OS) and progression-free survival (PFS). A network meta-analysis (NMA) was conducted comparing OS and PFS hazard ratios (HRs). RESULTS:Thirteen studies were identified in the SLR to be eligible for inclusion in the NMA. The overall study populations were heterogeneous in terms of risk groups; some studies included favorable risk patients. In intermediate-risk patients, HRs (95% confidence interval) for PFS were 0.52 (0.33, 0.82), 0.46 (0.26, 0.80), 0.20 (0.12, 0.36), and 0.37 (0.20, 0.68) when cabozantinib was compared with sunitinib, sorafenib, interferon (IFN), or bevacizumab plus IFN, respectively. In poor-risk patients, the NMA also demonstrated significant superiority in terms of PFS for cabozantinib; HRs were 0.31 (0.11, 0.90), 0.22 (0.06, 0.87), 0.16 (0.04, 0.64), and 0.20 (0.05, 0.88), when cabozantinib was compared with sunitinib, temsirolimus, IFN, or bevacizumab plus IFN, respectively. When the overall study populations were compared, the results were similar to the subgroup analyses. OS HRs in all analyses favored cabozantinib, but were not statistically significant. CONCLUSIONS:The results suggest that cabozantinib significantly increases PFS in intermediate-, and poor-risk subgroups when compared to standard-of-care comparators. Although overall populations included favorable risk patients in some studies, the results seen were consistent with the subgroup analyses.

SUBMITTER: Schmidt E

PROVIDER: S-EPMC5887000 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naïve Patients: a Systematic Review and Network Meta-Analysis.

Schmidt Elvira E Lister Johanna J Neumann Monika M Wiecek Witold W Fu Shuai S Vataire Anne-Lise AL Sostar Jelena J Huang Shengnan S Marteau Florence F

Targeted oncology 20180401 2

<h4>Background</h4>Cabozantinib has recently been evaluated as a first-line treatment in advanced renal cell carcinoma (aRCC).<h4>Objective</h4>To indirectly assess efficacy of cabozantinib versus standard-of-care (SoC) comparators in the first-line treatment of aRCC.<h4>Methods</h4>We conducted a systematic literature review (SLR) to identify randomized controlled studies in the first-line setting for aRCC. The outcomes analyzed were overall survival (OS) and progression-free survival (PFS). A ...[more]

PMID: 29492762

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Project description:BackgroundThe efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known.MethodsIn this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point.ResultsOverall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib.ConclusionsNivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).

Project description:Renal-cell carcinoma (RCC) affects over 330,000 new patients every year, of whom 1/3 present with metastatic RCC (mRCC) at diagnosis. Most mRCC patients treated with a first-line agent relapse within 1 year and need second-line therapy. The present study aims to compare overall survival (OS) between nivolumab and cabozantinib from two recent pivotal studies comparing, respectively, each one of the two emerging treatments against everolimus in patients who relapse following first-line treatment. Comparison is traditionally carried out using the Bucher method, which assumes proportional hazard. Since OS curves intersected in one of the pivotal studies, models not assuming proportional hazards were also considered to refine the comparison. Four Bayesian parametric survival network meta-analysis models were implemented on overall survival (OS) data digitized from the Kaplan-Meier curves reported in the studies. Three models allowing hazard ratios (HR) to vary over time were assessed against a fixed-HR model. The Bucher method favored cabozantinib, with a fixed HR for OS vs. nivolumab of 1.09 (95% confidence interval: [0.77, 1.54]). However, all models with time-varying HR showed better fits than the fixed-HR model. The log-logistic model fitted the data best, exhibiting a HR for OS initially favoring cabozantinib, the trend inverting to favor nivolumab after month 5 (95% credible interval <1 from 10 months). The initial probability of cabozantinib conferring superior OS was 54%, falling to 41.5% by month 24. Numerical differences in study-adjusted OS estimates between the two treatments remained small. This study evidences that HR for OS of nivolumab vs. cabozantinib varies over time, favoring cabozantinib in the first months of treatment but nivolumab afterwards, a possible indication that patients with poor prognosis benefit more from cabozantinib in terms of survival, nivolumab benefiting patients with better prognosis. More evidence, including real-world observational data, is needed to compare effectiveness between cabozantinib and nivolumab.

Project description:BackgroundRelative effect of therapies indicated for the treatment of advanced renal cell carcinoma (aRCC) after failure of first line treatment is currently not known. The objective of the present study is to evaluate progression-free survival (PFS) and overall survival (OS) of cabozantinib compared to everolimus, nivolumab, axitinib, sorafenib, and best supportive care (BSC) in aRCC patients who progressed after previous VEGFR tyrosine-kinase inhibitor (TKI) treatment.Methodology & findingsSystematic literature search identified 5 studies for inclusion in this analysis. The assessment of the proportional hazard (PH) assumption between the survival curves for different treatment arms in the identified studies showed that survival curves in two of the studies did not fulfil the PH assumption, making comparisons of constant hazard ratios (HRs) inappropriate. Consequently, a parametric survival network meta-analysis model was implemented with five families of functions being jointly fitted in a Bayesian framework to PFS, then OS, data on all treatments. The comparison relied on data digitized from the Kaplan-Meier curves of published studies, except for cabozantinib and its comparator everolimus where patient level data were available. This analysis applied a Bayesian fixed-effects network meta-analysis model to compare PFS and OS of cabozantinib versus its comparators. The log-normal fixed-effects model displayed the best fit of data for both PFS and OS, and showed that patients on cabozantinib had a higher probability of longer PFS and OS than patients exposed to comparators. The survival advantage of cabozantinib increased over time for OS. For PFS the survival advantage reached its maximum at the end of the first year's treatment and then decreased over time to zero.ConclusionWith all five families of distributions, cabozantinib was superior to all its comparators with a higher probability of longer PFS and OS during the analyzed 3 years, except with the Gompertz model, where nivolumab was preferred after 24 months.

Dataset Information

Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naive Patients: a Systematic Review and Network Meta-Analysis.

Publications

Cabozantinib Versus Standard-of-Care Comparators in the Treatment of Advanced/Metastatic Renal Cell Carcinoma in Treatment-naïve Patients: a Systematic Review and Network Meta-Analysis.

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