Colorectal cancer is the third most commonly diagnosed cancer worldwide, accounting for roughly 9.6 percent of cancer cases and 9.3 percent of cancer deaths in 2022. Around 22 percent of patients already have metastatic disease at diagnosis, and about 70 percent will eventually relapse with metastatic spread, making metastatic colorectal cancer the leading cause of death from the disease. Within this population, an estimated 4 to 5 percent harbor microsatellite instability-high or mismatch repair deficient tumors, a molecular signature associated with worse outcomes than microsatellite stable disease but also with striking sensitivity to immune checkpoint inhibitors, because the defective DNA repair machinery generates abundant mutations that the immune system can recognize.

Until recently, pembrolizumab was the recommended first-line treatment for these patients, a position supported by the pivotal phase III KEYNOTE-177 trial, in which median progression-free survival reached 16.5 months with pembrolizumab compared with 8.2 months with chemotherapy at five years of follow-up. The efficacy of nivolumab plus ipilimumab in the same setting has been demonstrated in the ongoing phase III CheckMate-8HW trial, in which patients were randomized to the combination, nivolumab monotherapy, or investigator’s choice of chemotherapy. At a median follow-up of 31.5 months, 79 percent of first-line patients receiving the combination were progression-free at 12 months, compared with just 21 percent of those on chemotherapy, and median progression-free survival was not reached in the combination arm.

What has been missing is direct comparative evidence between the two immunotherapy regimens, since no trial has yet pitted nivolumab plus ipilimumab against pembrolizumab. To bridge that gap, the research team, led by investigators at OPEN Health with colleagues at Bristol Myers Squibb, constructed a three-state semi-Markov model simulating patients’ movement between progression-free health, progressed disease, and death over a lifetime horizon of approximately 33 years, from the perspective of a United States healthcare payer. A semi-Markov structure was chosen deliberately: because mature overall survival data for first-line patients in CheckMate-8HW were not yet available, the model needed to capture the dependency of post-progression survival on the time a patient spends before progressing, an approach previously accepted in multiple health technology assessments for metastatic colorectal cancer.

The technical heart of the study lies in its indirect treatment comparisons. Since pembrolizumab was not studied in CheckMate-8HW, the researchers anchored their comparison on chemotherapy, the common comparator in both CheckMate-8HW and KEYNOTE-177. Because the proportional hazards assumption was violated, a constant hazard ratio would have biased the results, so the base case used time-varying hazard ratios derived from parametric survival extrapolations fitted independently to each trial arm, with a generalized gamma distribution providing the best statistical fit. Published Kaplan-Meier curves from KEYNOTE-177 were digitized and reconstructed into pseudo-individual patient data using validated methodology. To test robustness, the team also applied three alternative methods: a fractional polynomial network meta-analysis, an anchored matching-adjusted indirect comparison adjusting for differences in age, performance status, mutation status, tumor sidedness, and metastatic sites, and an unanchored version of the same technique.

The base case results were striking. Nivolumab plus ipilimumab dominated pembrolizumab, meaning it produced both lower total costs and greater quality-adjusted life years, with cost savings of 58,819 dollars and a gain of 2.32 quality-adjusted life years. Compared with chemotherapy, the combination added 3.49 quality-adjusted life years at an incremental cost of 58,783 dollars, yielding an incremental cost-effectiveness ratio of 16,849 dollars per quality-adjusted life year, far below commonly accepted United States willingness-to-pay thresholds of 50,000 and 100,000 dollars per quality-adjusted life year. In the model, patients on the combination accrued 7.04 discounted quality-adjusted life years and 7.80 life years, versus 4.72 and 3.58 for pembrolizumab and 3.55 and 1.48 for chemotherapy. Total costs were 517,548 dollars for the combination, 576,367 dollars for pembrolizumab, and 458,765 dollars for chemotherapy, with the combination’s higher drug acquisition costs offset by lower disease management and monitoring costs, driven by its substantially reduced risk of progression.

The findings proved robust across the alternative comparison methods, with quality-adjusted life year gains for nivolumab plus ipilimumab over pembrolizumab ranging from 1.65 to 2.35 depending on the methodology employed. Scenario analyses varied survival distributions, patient populations, drug dosing assumptions, and cost inputs, and while dominance over pembrolizumab was not maintained in every cost variation, all resulting incremental cost-effectiveness ratios remained below accepted United States thresholds. In the probabilistic sensitivity analysis of 1,000 iterations, nivolumab plus ipilimumab had an 88 percent probability of being the most cost-effective option at a 50,000 dollar threshold. The parameters most influential on the results were the frequency of inpatient admissions with progressed disease, drug dosing, age at model onset, and the hazard ratio between the two immunotherapies.

The authors acknowledge important limitations. Mature overall survival data for first-line patients in CheckMate-8HW were unavailable, so post-progression survival was modeled using overall survival data from the phase II CheckMate-142 trial, which enrolled second-line patients and may have slightly overestimated mortality; assuming equal post-progression survival across treatments was a deliberately conservative choice that attributes all benefit to prolonged time to progression. Drug prices were based on list prices from the Redbook database, which do not reflect confidential discounts or rebates, and background mortality was age- and sex-adjusted from United States life tables, potentially underestimating deaths in the progression-free state. The model was nevertheless validated against external survival data and prior health technology assessment submissions, and its structure was recently accepted by the United Kingdom’s National Institute for Health and Care Excellence, which approved nivolumab plus ipilimumab as a first-line treatment for this population. Similar positive reimbursement decisions followed in Canada and the Netherlands.

The economic context amplifies the significance of these findings. Colorectal cancer carries the second highest global economic burden of all cancers, with total annual treatment costs in the United States of 10.5 billion dollars, and spending projected to rise by more than one billion dollars between 2017 and 2030 as the population ages and novel therapies enter practice. The study was funded by Bristol Myers Squibb, whose employees co-authored the work alongside OPEN Health researchers, a common arrangement in pharmacoeconomic research that readers should weigh when interpreting results. Nonetheless, the analysis concludes that first-line nivolumab plus ipilimumab represents a compelling and potentially cost-saving option for patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer, and the authors call for further research into comparative effectiveness against pembrolizumab and the costs of progressive disease as longer-term trial data mature.

Subject of Research: Cost-effectiveness of nivolumab plus ipilimumab versus pembrolizumab and chemotherapy as first-line treatment for microsatellite instability-high metastatic colorectal cancer

Article Title: 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

Article References: 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. (n.d.). https://doi.org/10.1007/s12325-026-03787-x

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03787-x

Keywords: metastatic colorectal cancer, microsatellite instability-high, mismatch repair deficiency, nivolumab, ipilimumab, pembrolizumab, immunotherapy, cost-effectiveness, indirect treatment comparison, semi-Markov model, quality-adjusted life years, CheckMate-8HW