Supervisors info:
Μαρκαντώνη-Κυρούδη Σοφία, Καθηγήτρια, Τμήμα Φαρμακευτικής, ΕΚΠΑ
Summary:
Background
Combination regimens with immune checkpoint inhibitors (ICIs), such as pembrolizumab plus axitinib (recommended for good, intermediate and poor- risk patients in accordance with the International Metastatic renal cell carcinoma Database Consortium (IMDC) score) and nivolumab plus ipilimumab (recommended for intermediate- and poor-risk group), are currently first-line treatment options for clear cell renal cell carcinoma (ccRCC) and seem to be preferred to other first-line alternative therapies such as sunitinib, pazopanib, cabozantinib, etc. Moreover, ICI drugs are considered to be a second-line treatment option for metastatic platinum-refractory urothelial cancer. ICI drugs have been associated with a new type of toxicity, known as immune-related adverse events (irAEs). Optimal management of adverse events is primarily based on early detection to reduce the requirement for treatment interruptions, maintain quality of life and avoid or minimize the risk of rare fatal events.
Objective
The aim of the present study was to evaluate and compare the safety of i) all first-line treatments for metastatic ccRCC, and ii) immunotherapy compared to conventional chemotherapy as second-line treatment for urothelial cancer. Furthermore, we aimed to assess and compare the economic impact of pembrolizumab plus axitinib and nivolumab plus ipilimumab, as first line-treatments for patients with metastatic ccRCC, from the perspective of the National Health System of Greece.
Methods
A search strategy was developed to conduct a comprehensive literature search on the Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Furthermore, additional research was conducted on the database https://clinicaltrials.gov. Two independent researchers selected the studies and extracted the data. Selected studies were evaluated for risk of bias by two researchers working independently of each other according to the revised Cochrane criteria (Cochrane Handbook for Systematic Reviews of Interventions Version 6.1). Review Manager software was used for statistical analysis. The quality of the meta-analysis results was evaluated by two independent researchers according to the GRADE criteria. For the economic analysis, data were collected from the revised Price Bulletin of Medicines for Human Use of the Greek Ministry of Health and the State Tariff. In addition, to calculate the cost of managing adverse events data were collected from the CheckMate 214 and KEYNOTE-426 clinical trials, and the Closed Consolidated Hospitals (ΚΕΝ) prices were used.
Results
Nine studies were selected for the systematic review of ccRCC and two for the systematic review of urothelial carcinoma. All selected studies were phase II and phase III parallel group randomized controlled trials with two interventions.
The meta-analysis of first-line treatments for ccRCC suggest that first-line treatment with ICI combinations have a lower risk of producing “treatment-related adverse events” than sunitinib (Odds Ratio (OR) 0.53 [95% CI 0.38-0.73]). No statistically significant difference was observed between first-line treatments and sunitinib with respect to the risk of producing “adverse events” (OR 0.70 [95% CI 0.45-1.09]) and “death from a treatment-related adverse event” (OR 0.98 [95% CI 0.56-1.71]). No statistically significant difference was observed between treatments compared with bevacizumab-INF-a for the outcome “adverse events” (OR 0.82 [95% CI 0.50-1.35]).
The meta-analysis of second-line treatments for urothelial carcinoma suggest that chemotherapy is associated with a higher risk of “adverse events” than ICI drugs (OR 0.32 [95% CI 0.17-0.60]). No statistically significant difference was observed, between immunotherapy and chemotherapy drugs, for the outcome “death from a treatment-related adverse event” (OR 0,59 [95% CI 0.24-1.43]).
The economic analysis estimated that the pembrolizumab plus axitinib (Keytruda / Inlyta) combination included an additional cost of 55.154,74 € per patient per year compared with the nivolumab plus ipilimumab (Opdivo / Yervoy) combination, for the first- line treatment of patients with metastatic ccRCC. The total financial burden for one treatment year was estimated to be 12.605.291 € and 7.089.817 € respectively, for a total of 100 patients. Whereas, the Keytruda / Inlyta combination had an additional cost of 64.575,65 € per patient compared to the Opdivo / Yervoy combination for the median PFS period of each treatment for the intermediate- and poor-risk population, with total costs per patient of 133.306,96 € (PFS=12,7 months) and 68.731,31 € (PFS=11,6 months), respectively.
Discussion-Conclusions
From the findings of the present study, it appears that regimens that include ICI inhibitors have a lower risk of adverse events than sunitinib alone, which until recently has been considered to be the gold standard for first-line treatment of patients with metastatic ccRCC. Furthermore, the incidence of toxicity appears to be lower with the ICIs, atezolizumab, pembrolizumab, than with the chemotherapy regimens in patients with platinum-resistant metastatic urothelial carcinoma. Clearly, more studies need to be conducted for safer conclusions, but these inhibitors seem to offer the added benefit of a lower risk of adverse events for the patient. The cost of ICIs is a challenge for health systems. From the perspective of the National Health System of Greece, the expenditure is estimated to be smaller for the nivolumab plus ipilimumab combination compared with the pembrolizumab plus axitinib combination for patients with metastatic ccRCC.
Keywords:
Meta-analysis, carcinoma, metastatic, renal cell, urothelial
