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A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Network meta-analysis of second line and beyond treatment options in metastatic clear cell renal cell carcinoma
Mavis Obeng-Kusi1, Jordyn J Kreutzfeldt2, Ricardo J Estrada-Mendizabal3
1Center for Health Outcomes and Pharmacoeconomic Research, Department of Pharmacy Practice and Science, University of Arizona R. Ken Coit College of Pharmacy, Tucson, AZ.
Introduction:
Deciding on the optimal second-line (2L) treatment for metastatic clear-cell renal cell carcinoma (ccRCC) remains challenging due to the limited information comparing each of the available options and the influence of the newly expanding first-line (1L) agents.
Patients And Methods:
We identified phase II/III randomized controlled trials (RCTs) evaluating 2L treatments in metastatic ccRCC. This Network Meta-analysis (NMA) evaluates the overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE). We used normal likelihood model to incorporate log hazard ratios (HRs), odds ratios (OR), and 95%-confidence-intervals (CI). Treatment p-scores were used for ranking. Data was analyzed in a fixed-effects model using the netmeta package in R v.1.5-0.
Results:
All therapies demonstrated some benefits over placebo. Lenvatinib + everolimus ranked first for OS (HR = 0.44; 95%CI = 0.24-0.82; p-score = 0.92), PFS (HR = 0.13; 95%CI = 0.07-0.24, p-score = 0.98), and ORR (OR = 35.95; 95%CI = 11.55-111.87; p-score = 0.93) compared to placebo, though with a higher SAE (OR = 5.27; p-score = 0.23). Cabozantinib ranked second for OS (HR = 0.57, p-score = 0.80), PFS (HR = 0.19; p-score = 0.86), and ORR (OR = 27.24, p-score = 0.84). Nivolumab was third for ORR (p-score = 0.79), fourth for OS (p-score = 0.69), fifth for PFS (p-score = 0.61), and last for SAE (p-score = 0.83). Lenvatinib monotherapy ranked worst SAE (OR = 5.89, p-score = 0.17) and third for OS and PFS. The latest drug, tivozanib, was sixth for PFS, OS, and ORR. The NMA matrix revealed no differential OS benefit between cabozantinib, lenvatinib + everolimus, and nivolumab. Other regimens had no significant OS benefit when compared to placebo.
Conclusion:
Based on OS and PFS, the lenvtatinib + everolimus combination yielded superior, followed by cabozantinib and Lenvatinib monotherapies; all were limited by a worse SAE profile. Nivolumab and pazopanib had the lowest odds of SAEs.
Insights
Lenvatinib plus everolimus showed superior overall survival and progression-free survival for metastatic clear-cell renal cell carcinoma. However, this combination and other effective treatments were associated with increased severe adverse events compared to placebo.
Area of Science:
- Oncology
- Medical Research
- Pharmacology
Background:
- Optimal second-line (2L) treatment selection for metastatic clear-cell renal cell carcinoma (ccRCC) is complex.
- Limited comparative data exists for available 2L therapies, especially considering evolving first-line (1L) options.
Purpose of the Study:
- To conduct a network meta-analysis (NMA) comparing second-line treatments for metastatic ccRCC.
- To evaluate overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and severe adverse events (SAE) of various 2L therapies.
Main Methods:
- Systematic identification of Phase II/III randomized controlled trials (RCTs) for 2L metastatic ccRCC treatments.
- Network meta-analysis utilizing a normal likelihood model to compare outcomes including OS, PFS, ORR, and SAEs.
- Ranking of treatments based on p-scores derived from hazard ratios (HRs) and odds ratios (ORs) within a fixed-effects model.
Main Results:
- Lenvatinib plus everolimus demonstrated superior efficacy for OS, PFS, and ORR compared to placebo, but with increased SAEs.
- Cabozantinib showed the second-best outcomes for OS, PFS, and ORR.
- Nivolumab and pazopanib had the lowest incidence of severe adverse events, while lenvatinib monotherapy was associated with the highest SAEs.
Conclusions:
- The combination of lenvatinib plus everolimus, followed by cabozantinib and lenvatinib monotherapy, offered superior OS and PFS.
- All effective treatments were associated with a higher risk of severe adverse events.
- Nivolumab and pazopanib presented the most favorable safety profiles regarding severe adverse events.
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