Background: The treatment landscape for metastatic renal cell carcinoma (mRCC) has significantly evolved in recent years. Without direct comparator trials, factors such as cost effectiveness (CE) are important to guide decision-making.

Objective: To assess the CE of guideline-recommended approved first- and second-line treatment regimens.

Design, setting, and participants: A comprehensive Markov model was developed to analyze the CE of the five current National Comprehensive Cancer Network-recommended first-line therapies with appropriate second-line therapy for patient cohorts with International Metastatic RCC Database Consortium favorable and intermediate/poor risk.

Outcome measurements and statistical analysis: Life years, quality-adjusted life years (QALYs), and total accumulated costs were estimated using a willingness-to-pay threshold of $150 000 per QALY. One-way and probabilistic sensitivity analyses were performed.

Results and limitations: In patients with favorable risk, pembrolizumab + lenvatinib followed by cabozantinib added $32 935 in costs and yielded 0.28 QALYs, resulting in an incremental CE ratio (ICER) of $117 625 per QALY in comparison to pembrolizumab + axitinib followed by cabozantinib. In patients with intermediate/poor risk, nivolumab + ipilimumab followed by cabozantinib added $2252 in costs and yielded 0.60 QALYs compared to cabozantinib followed by nivolumab, yielding an ICER of $4184. Limitations include differences in median follow-up duration between treatments.

Conclusions: Pembrolizumab + lenvatinib followed by cabozantinib, and pembrolizumab + axitinib followed by cabozantinib were cost-effective treatment sequences for patients with favorable-risk mRCC. Nivolumab +ipilimumab followed by cabozantinib was the most cost-effective treatment sequence for patients with intermediate-/poor-risk mRCC, dominating all preferred treatments.

Patient summary: Because new treatments for kidney cancer have not been compared head to head, comparison of their cost and efficacy can help in making decisions about the best treatments to use first. Our model showed that patients with a favorable risk profile are most likely to benefit from pembrolizumab and lenvatinib or axitinib followed by cabozantinib, while patients with an intermediate or poor risk profile will probably benefit most from nivolumab and ipilimumab followed by cabozantinib.