First-line Treatment of Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis - Beyond the Abstract

In many treatment choices in medicine, there are a dearth of randomized data to inform treatment decision. However, in the first-line treatment of metastatic renal cell carcinoma, there are a myriad of trials. However, nearly all have been designed as two-armed studies comparing a novel treatment approach to the current standard of care, beginning with placebo and moving to interferon and subsequently sunitinib. Thus, there is no direct comparative data for most of the agents currently available today.

In contrast to qualitative synthesis that informs most guidelines, network meta-analysis offers a quantitative approach to cross-trial comparisons. Network meta-analysis utilizes linked direct meta-analyses with a common comparator to allow for quantitative estimates of comparative treatment effects for agents that have not been directly compared in clinical trials. While direct evidence, and even more so meta-analysis of direct evidence, has typically been preferred in guideline writing, the World Health Organization has adopted network meta-analysis to inform clinical guidelines. Some have even suggested that network meta-analysis should supplant direct meta-analysis of randomize trials as the highest level of medical evidence to inform clinical decision making.1 With this in mind, we undertook a network meta-analysis of agents in common clinical use for the first-line treatment of patients with metastatic kidney cancer.

We first assessed this in a paper initially electronically published April 13, 2018, finding that cabozantinib was the preferred option for progression-free survival (PFS) and nivolumab plus ipilimumab for OS.2 Subsequently, JAVELIN Renal 1013 and KEYNOTE-4264  were published demonstrating significant benefits to the use of avelumab and axitinib and pembrolizumab plus axitinib, compared to sunitinib, respectively. Thus, we updated our analysis accounting for this new data.

We identified 12 relevant trials: 12 reported outcomes for PFS, 9 for OS, 10 FOR ORR, and 9 for AEs. In the ITT population, cabozantinib (SUCRA 84%), avelumab plus axitinib (SUCRA 68%), and pembrolizumab plus axitinib (SUCRA 82%) were superior to the other agents for PFS; pembrolizumab plus axitinib appeared superior for OS (SUCRA 95%); and atezolizumab demonstrated the lowest likelihood of AEs (SUCRA 100%). Findings were similar in the intermediate/poor-risk subgroup. There was a paucity of data to inform conclusions regarding favorable-risk mRCC and those with PD-L1 positive mRCC. Based on available data, avelumab plus axitinib may be a preferred choice in favorable-risk disease while nivolumab plus ipilimumab may be preferable in patients with PD-L1 positive disease.

Written by: Christopher JD Wallis, MD, PhD, FRCSC, Fellow in Urologic Oncology, Department of Urology, Vanderbilt University, Nashville, Tennessee, USA, and Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor, Augusta University, Georgia Cancer Center, Augusta, Georgia, USA.

References:
  1. Faltinsen EG, Storebo OJ, Jakobsen JC, Boesen K, Lange T, Gluud C. Network meta-analysis: the highest level of medical evidence? BMJ Evid Based Med. 2018;23(2):56-59.
  2. Wallis CJD, Klaassen Z, Bhindi B, et al. First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis. European urology. 2018;74(3):309-321.
  3. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2019;380(12):1103-1115.
  4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2019;380(12):1116-1127.
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