Washington, DC (UroToday.com) At the second kidney cancer session at the 2019 Society for Urologic Oncology Annual Meeting, Dr. Sumanta Pal addressed the utility of observational data in driving treatment decisions for patients with metastatic renal cell carcinoma.
He began his talk by highlighting a high-profile paper published in the Journal of Clinical Oncology earlier this year by Dr. Soni et al. In this study, a total of 755 large population-based observational studies designed to compare two different oncologic treatments were matched with 350 randomized controlled trials, and the outcomes and observed effect sizes of these studies were compared. The analysis showed no correlation between the results of the observational trials and those of the randomized controlled trials (CCC 0.128, 95% CI 0.046-0.295), despite efforts on the parts of the authors of the observational studies to isolate the effect of the treatment choice by controlling for confounding using a number of different statistical methods. (Of note, 101 observational trials and 50 randomized controlled trials were for genitourinary cancers.) This seriously calls into question whether population-based trials like these have any significant utility in guiding treatment choice in oncology at all.
Dr. Pal went on to examine how this finding relates to kidney cancer specifically. He pointed out that for a significant number of patients with metastatic kidney cancer, there currently is equipoise between 3 first-line regimens: nivolumab + ipilimumab (as validated in CHECKMATE 214), axitinib + avelumab (JAVELIN 101), and axitinib + pembrolizumab (KEYNOTE 426). He then proposed a hypothetical straw-man trial, the cutely-named Overlooked By Very Intelligent Obtuse University Scholars (OBVIOUS) trial which would simply randomize patients for whom there is equipoise to one of these 3 therapies. This, of course, would be extremely expensive, would divert resources away from testing novel agents, and would run the risk of being rendered moot by new discoveries before it resulted. Thus this obvious solution to obtaining the desired information is certainly not a practical one.
As a result, his group attempted to answer this question of optimal first-line therapy with a systematic review and network meta-analysis of the existing randomized literature. (Hahn et al) 10 studies were included. Surface under the cumulative ranking curves (SUCRA) statistics were used to estimate the likelihood of superiority of one regimen over the others. Pembrolizumab/axitinib appeared to be superior to the other agents in terms of overall survival (SUCRA 95%). For progression-free survival, axitinib/avelumab (SUCRA 68%) and cabozantinib (SUCRA 84%) joined pembrolizumab/axitinib (SUCRA 82%) as the most likely best treatments. However, Dr. Pal pointed out, the small observed differences between groups, the variability in study endpoints, absence of patient-level data, immaturity of the underlying trials, and variable definitions of subgroups all limit the strength of the final conclusion. Thus, the analysis overall will likely do little to resolve the equipoise in clinical practice for most oncologists.
He then highlighted an effort using the International Metastatic Renal-cell Carcinoma Database to compared combinations of immune checkpoint inhibitors with VEGF-inhibitors (IOVEs) with nivolumab + ipilimumab (Dudani et al). The IMDC database contains relatively rich, granular, patient-level data but still this analysis was limited by modest sample size (188 patients total), limited follow up, absence of response rate data, limited toxicity data, etc. Regardless, no differences were noted between the treatment groups, so equipoise would remain even without these limitations.
The answer to “Can observational data help us choose between the available first line therapies for metastatic RCC” seems to be a simple “no” at this point, at least if that choice is to be made purely on efficacy. While observational data has its place, the differences between these treatments, if present at all, are just too small to be detected with any significant confidence, especially given the limitations of the research methods.
Presented by: Sumanta Kumar Pal, MD, Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research; Co-director, Kidney Cancer Program, City of Hope
Written by: Marshall Strother, MD, Society for Urologic Oncology Fellow, Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia PA @mcstroth at the 20th Annual Meeting of the Society of Urologic Oncology (SUO), December 4 - 6, 2019, Washington, DC
Soni PD, Hartman HE, Dess RT, et al. Comparison of Population-Based Observational Studies With Randomized Trials in Oncology. J Clin Oncol. 2019;37(14):1209-1216.
Dudani S, Graham J, Wells JC, Bakouny Z, Pal SK, Dizman N, Donskov F, Porta C, de Velasco G, Hansen A, Iafolla M, Beuselinck B, Vaishampayan UN, Wood LA, Liow E, Yan F, Yuasa T, Bjarnason GA, Choueiri TK, Heng DYC. First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Results from the International Metastatic Renal-cell Carcinoma Database Consortium. European urology 2019;76(6):861-7.