Comparative Effectiveness of Second-Line Targeted Therapies for Metastatic Renal Cell Carcinoma: A Systematic Review and Meta-Analysis of Real-World Observational Studies

<div><p>Objective</p><p>The optimal sequencing of targeted therapies for metastatic renal cell carcinoma (mRCC) is unknown. Observational studies with a variety of designs have reported differing results. The objective of this study is to systematically summarize and interpret the published real-world evidence comparing sequential treatment for mRCC.</p><p>Methods</p><p>A search was conducted in Medline and Embase (2009–2013), and conference proceedings from American Society of Clinical Oncology (ASCO), ASCO Genitourinary Cancers Symposium (ASCO-GU), and European Society for Medical Oncology (ESMO) (2011–2013). We systematically reviewed observational studies comparing second-line mRCC treatment with mammalian target of rapamycin inhibitors (mTORi) versus vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI). Studies were evaluated for 1) use of a retrospective cohort design after initiation of second-line therapy, 2) adjustment for patient characteristics, and 3) use of data from multiple centers. Meta-analyses were conducted for comparisons of overall survival (OS) and progression-free survival (PFS).</p><p>Results</p><p>Ten studies reported OS and exhibited significant heterogeneity in estimated second-line treatment effects (I² = 68%; P = 0.001). Four of these were adjusted, multicenter, retrospective cohort studies, and these showed no evidence of heterogeneity (I² = 0%; P = 0.61) and a significant association between second-line mTORi (>75% everolimus) and longer OS compared to VEGF TKI (>60% sorafenib) (HR = 0.82, 95% CI: 0.68 to 0.98) in a meta-analysis. Seven studies comparing PFS showed significant heterogeneity overall and among the adjusted, multicenter, retrospective cohort studies. Real-world observational data for axitinib outcomes was limited at the time of this study.</p><p>Conclusions</p><p>Real-world studies employed different designs and reported heterogeneous results comparing the effectiveness of second-line mTORi and VEGF TKI in the treatment of mRCC. Within the subset of adjusted, multicenter observational studies, second-line use of mTORi was associated with significantly prolonged survival compared with second-line use of VEGF TKI.</p></div

Studies comparing OS and PFS with VEGF TKI-mTORi versus VEGF TKI-VEGF TKI (HR<1 favors second-line mTORi versus VEGF TKI).

<p>CI, confidence interval; HR, hazard ratio; mTORi, mammalian target of rapamycin inhibitor; N/A, not available; OS, overall survival; PFS, progression-free survival; VEGF TKI, vascular endothelial growth factor tyrosine kinase inhibitor.</p>a<p>OS HRs and 95% CIs were imputed for Harrison et al. 2012, Gore et al. 2013, and Ruiz et al. 2013.</p>b<p>PFS HRs and 95% CIs were imputed for Heng et al. 2012 and Busch et al. 2013.</p>c<p>Heng et al. 2012 used prospective data collection. However, the comparative analysis was performed retrospectively.</p>d<p>The PFS results for Busch et al. 2011, Heng et al. 2012, Park et al. 2012, and Busch et al. 2013 were unadjusted. Y in column adjustment refers to the OS results.</p>e<p>Only one patient received axitinib in Elaidi et al. 2013. The number of patients who received axitinib was not reported in Ruiz et al. 2013. The number receiving axitinib was n = 10 in Signorovitch et al. 2013 (personal communication).</p><p>Studies comparing OS and PFS with VEGF TKI-mTORi versus VEGF TKI-VEGF TKI (HR<1 favors second-line mTORi versus VEGF TKI).</p

PRISMA diagram of selected records.

<p>PRISMA diagram of selected records.</p

Forest plots of 4 studies meeting all reliability criteria reporting comparative OS results.

<p>Forest plots of 4 studies meeting all reliability criteria reporting comparative OS results.</p

Funnel plots of 4 studies meeting all reliability criteria reporting comparative OS results.

<p>Funnel plots of 4 studies meeting all reliability criteria reporting comparative OS results.</p

Funnel plots of 10 studies reporting comparative OS results.

<p>Funnel plots of 10 studies reporting comparative OS results.</p

Forest plots of 10 studies reporting comparative OS results.

<p>Forest plots of 10 studies reporting comparative OS results.</p

Patient characteristics used for multivariable adjustment.

<p>Patient characteristics used for multivariable adjustment.</p