Nivolumab-Ipilimumab Combination Shows Clinical Gains but Cost-Effectiveness Concerns in HCC

The combination of nivolumab and ipilimumab is unlikely to be considered cost-effective from a US healthcare payer perspective at current pricing, despite demonstrating a significant survival advantage in the first-line treatment of unresectable hepatocellular carcinoma (HCC), according to a new cost-effectiveness study in Cancer.

Clinical efficacy data for the analysis were derived from the phase 3 CheckMate 9DW trial (NCT04039607), a randomized trial that evaluated nivolumab plus ipilimumab vs tyrosine kinase inhibitors (TKIs) lenvatinib or sorafenib in 668 previously untreated patients with unresectable HCC. The positive outcomes from this study ultimately supported the April 2025 regulatory approval.

The analysis revealed that nivolumab plus ipilimumab produced an incremental gain of 0.66 quality-adjusted life years (QALYs) compared with TKI therapy. However, this clinical gain came at an additional cost of $132,652, resulting in an incremental cost-effectiveness ratio (ICER) of $200,409 per QALY. This figure significantly exceeds standard US willingness-to-pay thresholds of $100,000 and $150,000 per QALY, suggesting that the combination may not be financially sustainable for routine use in the US healthcare system.

Probabilistic sensitivity analysis further underscored the financial challenge, indicating only a 4.6% to 20% probability of the regimen being cost-effective at current market prices. The high cost of immunotherapy agents and the extended duration of maintenance nivolumab were identified as the primary drivers of the unfavorable ICER.

Researchers conducted scenario analyses to identify conditions under which the regimen could meet cost-effectiveness standards. One notable strategy involved extending the maintenance dosing of nivolumab from every 4 weeks to every 8 weeks. This adjustment reduced the ICER to $82,202 per QALY, bringing the treatment within the $100,000 WTP threshold. Additionally, the study suggested that moderate price reductions of the immunotherapy agents would substantially increase the likelihood of the regimen achieving cost-effectiveness.

From a payer perspective, the regimen's failure to meet conventional US cost-effectiveness thresholds raises important questions about formulary placement, reimbursement restrictions, and prior authorization requirements. In an increasingly value-conscious oncology landscape, therapies that exceed accepted willingness-to-pay thresholds may face delayed uptake or restricted access, even when clinically advantageous.

At the patient level, high-cost regimens contribute to financial toxicity, which has been associated with decreased treatment adherence, diminished quality of life, and worse overall outcomes. Even insured patients may experience substantial out-of-pocket expenses, particularly under high-deductible or coinsurance-based plans. The economic burden of high-cost therapies may exacerbate disparities in access, disproportionately affecting socioeconomically vulnerable populations.

"Nivolumab plus ipilimumab is unlikely to be cost-effective as first-line therapy for unresectable HCC from US health care payer perspective. However, extended dosing interval or price reductions may render the regimen economically viable," the study authors concluded.