H Karcher

Nivolumab versus Cabozantinib: Comparing Overall Survival in Metastatic Renal Cell Carcinoma

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.

Cabozantinib versus everolimus, nivolumab, axitinib, sorafenib and best supportive care: A network meta-analysis of progression-free survival and overall survival in second line treatment of advanced renal cell carcinoma

Background Relative 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 & findings Systematic 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. Conclusion With 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.

Second-line cabozantinib versus nivolumab in advanced renal cell carcinoma: Systematic review and indirect treatment comparison

BACKGROUND Nivolumab and cabozantinib, two new treatment options for previously-treated advanced/metastatic renal cell carcinoma (aRCC), have recently been approved. METHODS Two independent reviewers performed study selection, data extraction, and risk of bias assessment. Indirect treatment comparisons were carried out by directly assessing HR differences and statistical modeling of Kaplan-Meier curves from these two trials. RESULTS Publications identified showed that no head-to-head comparisons had been carried out. Two indirect treatment comparisons used agreed that there was no significant difference in OS between cabozantinib and nivolumab and that cabozantinib significantly improved PFS compared to nivolumab. CONCLUSIONS The field of aRCC treatments is evolving rapidly, creating opportunities for individualized treatments and challenges for clinicians to keep up with the evidence. In lieu of availability of direct comparisons of all options, advanced modeling results presented herein can help to inform and improve personalized treatments.

A Practical Guide To Adding Patient Heterogeneity Into Phase Iii Trials: Results from Imi Getreal Wp2

We used mean CGI-S at 3 months (change from baseline) as outcome. This outcome was evaluated in patients taking the most frequently used drug (blinded). CGI-S score (Clinical Global Impression-Severity): • Assesses severity of patient’s mental illness at time of rating with one question • 7-point scale: from 1 (not at all ill) to 7 (extremely ill) • In SOHO cohort study, most patients have CGI-S values of 4 or 5

Efficacy, Effectiveness and the "Efficacy-To-Effectiveness Gap": Review of the Current State of Play and Perspectives. First Results From the Imi Getreal Consortium.

The GetReal consortium aims to improve the efficiency of the medicine development process by better incorporating estimates of relative effectiveness into drug development and to enrich decision-making by regulatory authorities and HTA bodies. This work has received support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement n°[115546], resources of which are composed of financial contribution from the European Union (FP7/2007‐ 2013) and EFPIA companies’ in kind contribution. About IMI GetReal & funding Results