Optimizing targeted drug selection in combination therapy for patients with advanced or metastatic renal cell carcinoma: A systematic review and network meta-analysis of safety

Abstract

Objective: For patients with advanced or metastatic renal cell carcinoma (RCC), the dose of targeted agents was recommended in combination with immune checkpoint inhibitors. We performed a network meta-analysis to describe a categorized safety ranking profile and assess the adaptability of the combination options of targeted agents.

Methods: The targeted agents refer to vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) and mammalian target of rapamycin (mTOR) inhibitors. Randomized controlled trials comparing these drugs were enrolled in a Bayesian model network meta-analysis.

Results: Nineteen clinical trials with 11 treatments and 10,615 patients were included. For grade ≥ 3 adverse events (AEs), compared with placebo, lenvatinib plus everolimus showed worse safety than all other treatments except for lenvatinib (placebo vs. OR 0.23, 95% CI 0.07-0.78). Everolimus was generally the safest agent (OR 1.23, 95% CI 0.50-3.14). Sorafenib arose the least renal AEs (placebo vs. OR 0.85, 95% CI 0.06-11.64), whereas lenvatinib plus everolimus had the highest risk of renal toxicity (placebo vs. 0.17 95% CI 0.01-1.02). For gastrointestinal symptoms, everolimus was related to much lower toxicity than other agents. In the respiratory safety analysis, tivozanib (placebo vs. OR 0.15, 95% CI 0.07-0.31) and axitinib (OR 5.43, 95% CI 3.26-9.22) were the riskiest agents. In terms of hepatobiliary (placebo vs. OR 0.44, 95% CI 0.09-2.10) and hemotoxicity (placebo vs. OR 1.03, 95% CI 0.14-7.68) related AEs, lenvatinib was found to be the safest treatment compared to placebo.

Conclusions: Everolimus, with the best safety of grade ≥ 3, gastrointestinal, and respiratory AEs, was more likely to be considered for combination therapies. Lenvatinib appears to be the safest for blood/lymphatic and hepatobiliary AEs. For patients with renal disorders, sorafenib arises the least renal toxicity AEs. This study will guide treatment options and optimize the trial design for advanced or metastatic RCC.

Keywords: VEGF-TKI; mTOR inhibitor; renal cell carcinoma; targeted agents.

FIGURE 1

Study selection.

FIGURE 2

Network plots of comparisons on toxicity‐related adverse events (AEs) of treatments in patients with advanced or metastatic RCC. (A) Comparisons on grade ≥ 3 AEs and renal and urinary‐related AEs of any grade (B) Comparisons on gastrointestinal‐related adverse events and respiratory disorders‐related AEs of any grade (C) Comparisons on blood and lymphatic system‐related AEs and hepatobiliary of any grade. Each round node represents one single treatment. The total quantity of patients or AEs were shown in brackets. Each line represents a type of head‐to‐head comparison. The width of the lines is proportional to the number of trials comparing the connected treatments.

FIGURE 3

Pooled estimates of the network meta‐analysis. (A) Odds ratios (95% credible intervals) for grade ≥ 3 adverse events (AEs) (upper triangle) and renal and urinary‐related AEs (lower triangle). (B) Odds ratios (95% credible intervals) for gastrointestinal‐related AEs (upper triangle) and respiratory‐related AEs (lower triangle). (C) Odds ratios (95% credible intervals) for blood and lymphatic system‐related AEs (upper triangle) and hepatobiliary‐related AEs (lower triangle). Data in each cell are odds ratios (95% credible intervals) for the comparison of row‐defining treatment versus column‐defining treatment. Significant results are shown in bold.

FIGURE 4

Bayesian ranking probabilities of comparable treatments on safety for patients with advanced or metastatic RCC. Profiles indicate the probability of each comparable treatment being ranked from worst to best on grade ≥ 3 AEs, renal and urinary, gastrointestinal, respiratory, blood and lymphatic system, and hepatobiliary in any grade. Ranking sources are described in Table S3.