Nivolumab/Ipilimumab in HCC Offers Clinical Gains but Carries Economic Burden

Despite demonstrating a significant survival advantage in the first-line treatment of unresectable hepatocellular carcinoma (HCC), the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) is unlikely to be considered cost-effective from a US healthcare payer perspective at current pricing, a new cost-effectiveness study in Cancer determined.¹

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 (Lenvima) or sorafenib (Nexavar) in 668 previously untreated patients with unresectable HCC.² As presented at the 2025 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, nivolumab plus ipilimumab demonstrated a significant overall survival benefit over either TKI (HR, 0.79; 95% CI, 0.65-0.96; P =.018), along with a manageable safety profile.³

The positive outcomes from this study ultimately supported the April 2025 FDA approval of nivolumab plus ipilimumab in this indication.

Results of the Cost-Effectiveness Analysis

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.

Potential Paths to Economic Viability

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. The investigators noted that while the clinical superiority of the dual-checkpoint blockade is established, its adoption into standard-of-care protocols may be hindered by these economic considerations unless pricing or dosing strategies are optimized.

The Cost of High-Cost Therapies

The study’s findings highlight the difficulty of reconciling clinical benefit with affordability in the era of high-cost immunotherapies, even for treatments that offer meaningful survival gains. While the combination in the CheckMate 9DW trial reported superior clinical outcomes compared with TKIs, the high cost of the regimen poses a burden for health systems, payers, and ultimately patients.

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. This tension between innovation and sustainability underscores the growing importance of cost-effectiveness analyses in shaping oncology treatment guidelines and coverage decisions.

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.

In a recent interview with Targeted Oncology, Lucio Gordan, MD of Florida Cancer Specialists & Research Institute elaborated on how such financial toxicity may manifest in patients.

“At the end of the day, the patients may be charged a higher fee or co-payment, especially at the beginning of the year, after out-of-pocket has not been maximized yet or has not happened,” he explained. Consequently, the economic burden of high-cost therapies may exacerbate disparities in access, disproportionately affecting socioeconomically vulnerable populations.

As summarized by authors Luo et al, “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.” This conclusion reinforces the need for collaborative efforts among clinicians, policymakers, manufacturers, and payers to ensure that advances in cancer therapy remain both clinically meaningful and financially accessible.

REFERENCES

1. Luo J, Li Z, Ge J, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first‐line treatment for unresectable hepatocellular carcinoma: A cost‐effectiveness analysis. Cancer. 2026;132(3). doi: 10.1002/cncr.70259

2. A study of nivolumab in combination with ipilimumab in participants with advanced hepatocellular carcinoma (CheckMate 9DW). ClinicalTrials.gov. Updated August 3, 2025. Accessed February 12, 2026. https://clinicaltrials.gov/study/NCT04039607

3. Yau T, Galle PR, Decaens T, et al. Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW): an open-label, randomised, phase 3 trial. The Lancet. 2025;405(10492):1851-1864. doi: 10.1016/s0140-6736(25)00403-9