Assessment of the Value of Nivolumab Plus Ipilimumab for Treating Microsatellite Instability-High/Mismatch Repair Deficiency Metastatic Colorectal Cancer: Indirect Treatment Comparison and Cost-Effectiveness Analysis.

INTRODUCTION: Colorectal cancer (CRC) is the third most common cancer and has the second highest global economic burden of all cancers. Among metastatic CRC (mCRC) cases, 4-5% are microsatellite instability-high/mismatch repair deficiency (MSI-H/dMMR) for which, up until recently, pembrolizumab was the recommended first-line treatment. This study has evaluated the cost-effectiveness of nivolumab plus ipilimumab versus pembrolizumab and chemotherapy in previously untreated, MSI-H/dMMR mCRC patients. METHODS: A three-state semi-Markov model with a lifetime horizon was developed adopting a United States (US) healthcare payer perspective. Effectiveness data for nivolumab plus ipilimumab and chemotherapy were sourced from Checkmate-8HW (NCT04008030). Indirect treatment comparisons (ITCs) using Checkmate-8HW and KEYNOTE-177 informed comparisons with pembrolizumab. Methods included time-varying parametric analysis, fractional polynomials and matching adjusted indirect comparison. Utilities, resource use and costs were derived from trial data, US databases and literature. RESULTS: Nivolumab plus ipilimumab dominated pembrolizumab in the base case analysis, as a first-line MSI-H/dMMR mCRC treatment yielding lower costs and greater quality-adjusted life years (QALYs) (Δ-US$58,819; Δ2.32). Compared with chemotherapy, costs and QALYs increased (Δ$58,783; Δ3.49) resulting in an incremental cost-effectiveness ratio (ICER) of $16,849. Across ITC methods, QALY gains versus pembrolizumab ranged from 1.65 to 2.35. Dominance over pembrolizumab was not maintained across all cost variations in scenario analyses, although resulting ICERs remained below commonly accepted US willingness-to-pay thresholds. The parameters most impactful of the ICER include the frequency of inpatient admissions with progressed disease and variations in drug dosing. CONCLUSIONS: This is the first study demonstrating that first-line treatment with nivolumab plus ipilimumab may offer significant health economic benefits over pembrolizumab when used to treat first-line MSI-H/dMMR mCRC patients. With QALY gains ranging from 1.65 to 2.35 across various ITC methodologies, nivolumab plus ipilimumab seems a compelling treatment option for first-line MSI-H/dMMR mCRC.