AUTHOR=Niewada Maciej , Macioch Tomasz , Konarska Magdalena , Mela Aneta , Goszczyński Adam , Przekopińska Bogusława , Rajkiewicz Karolina , Wysocki Piotr , Krzakowski Maciej 

TITLE=Immune checkpoint inhibitors combined with tyrosine kinase inhibitors or immunotherapy for treatment-naïve metastatic clear-cell renal cell carcinoma—A network meta-analysis. Focus on cabozantinib combined with nivolumab

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1063178

DOI=10.3389/fphar.2022.1063178

ISSN=1663-9812

ABSTRACT=The aim of this review is to compare the efficacy of combined cabozantinib + nivolumab therapy with other immune checkpoint inhibitors combined with tyrosine kinase inhibitors or monoclonal antibodies blocking the CTLA-4 antigen in the first-line treatment of metastatic clear-cell renal cell carcinoma (RCC).
Methodology: A systematic literature search was carried out in the PubMed and EMBASE databases. Randomized controlled trials (RCTs) on therapies recommended by the latest EAU and ESMO guidelines for treatment-naïve metastatic RCC (i.e., lenvatinib + pembrolizumab, axitinib + pembrolizumab and nivolumab + ipilimumab) were searched. A network meta-analysis was performed for data synthesis. The methodology of included RCTs was assessed using the Cochrane RoB 2 tool. The data were analyzed in the overall population as well as in risk subgroups defined according to the International Metastatic Database Consortium (IMDC) i.e., patients with a favorable and intermediate or poor prognoses. The most recent cut-off dates from included studies were analyzed.
Results: Four RCTs (CheckMate 9ER, KEYNOTE-426, CLEAR and CheckMate 214) were included in the review. No studies directly comparing cabozantinib + nivolumab with any of the drug combinations included in this review were available. NMA showed that cabozantinib + nivolumab was superior compared to axitinib + pembrolizumab and nivolumab + ipilimumab in all analyzed comparisons (overall population and IMDC risk subgroups), both in terms of OS and PFS. The advantage of cabozantinib + nivolumab was statistically significant only for PFS when compared to axitinib + pembrolizumab and nivolumab + ipilimumab in the overall population. The results for the comparison of cabozantinib + nivolumab with lenvatinib + pembrolizumab showed numerical superiority of lenvatinib + pembrolizumab combination, but none of the results were statistically significant.
Conclusions: Inclusion of the most recent cut-off data from CheckMate 9ER did not affect the role of the cabozantinib + nivolumab combination for treatment-naïve metastatic RCC. Cabozantinib + nivolumab is an effective therapeutic option for the first-line treatment of advanced renal cancer that is recommended both in the latest European and American guidelines for all IMDC risk groups.