Cost-Effectiveness of Perioperative Pembro in Head and Neck Cancer Hinges on PD-L1 Expression

A new cost-effectiveness analysis suggests that whether perioperative pembrolizumab represents good value for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) may depend on a PD-L1 biomarker result, according to a study published in JAMA Otolaryngology-Head & Neck Surgery.^1,2

The analysis builds on results from the phase 3 KEYNOTE-689 trial, which established that adding perioperative pembrolizumab, given both before and after surgery, to standard of care (SOC) improved event-free survival (EFS) among patients with resectable, locally advanced HNSCC.³

Using a partitioned survival model built on the KEYNOTE-689 cohort, investigators estimated that patients with a high PD-L1 expression level (combined positive score [CPS] >10) gained approximately 1.35 additional quality-adjusted life-years (QALYs) from the addition of perioperative pembrolizumab, at an incremental cost of $181,900. That translated to an incremental cost-effectiveness ratio (ICER) of $134,700, below the $150,000 willingness-to-pay (WTP) threshold commonly used to define good value in the United States.¹

By contrast, patients with a CPS of 1 to 10 gained only about 0.08 additional QALYs for an incremental cost of $166,500, yielding an ICER of $2,179,400, far above that threshold. A probabilistic sensitivity analysis (PSA) estimated a 57% likelihood that pembrolizumab was cost-effective at the $150,000 WTP threshold in the CPS greater than 10 group, compared with an 11% likelihood in the CPS 1 to 10 group.¹

"Perioperative pembrolizumab per the KEYNOTE-689 protocol can add nearly a year to the standard treatment of locally advanced head and neck squamous cell carcinoma, with each cycle of the drug costing an estimated $12,000 and an estimated additional $170,000 to $180,000 per patient," Pratyusha Yalamanchi, MD, MBA, the study's senior author and a clinical assistant professor of otolaryngology-head & neck surgery at the University of Michigan Medical School, stated in a news release.² "These results suggest that we need more data to give both patients and providers a clearer understanding of the costs and benefits of the added therapy in their individual cases."

Safety Considerations

The cost model incorporated Centers for Medicare & Medicaid Services (CMS)-derived costs for managing serious adverse events associated with pembrolizumab, reflecting the added toxicity burden of extending immunotherapy across both the neoadjuvant and adjuvant periods. In the underlying KEYNOTE-689 trial, grade 3 or higher treatment-related adverse events occurred in 44.6% of patients who received pembrolizumab plus SOC, compared with 42.9% of those who received SOC alone, and treatment-related death occurred in 1.1% and 0.3% of patients, respectively.³

The study authors noted that the added toxicity risk and extended treatment timeline also raise the likelihood that patients discontinue therapy before completing the full course, a factor that carries both clinical and financial consequences.²

Study Design and Data Sources for the Cost Analysis

The economic model simulated the KEYNOTE-689 cohort using a partitioned survival approach with 3 mutually exclusive health states: event-free survival, disease progression, and death. Kaplan-Meier survival curves from KEYNOTE-689 were digitized to generate model inputs, and outcomes for the CPS 1 to 10 subgroup were derived indirectly from the trial's previously reported CPS of 1 or greater and CPS of 10 or greater subgroup data.

Costs for drug acquisition (pembrolizumab and cisplatin), administration, surgery, radiation therapy, supportive care, and adverse event management were drawn from the Healthcare Cost and Utilization Project and CMS databases. QALY values for each health state were derived from published literature, including EuroQol 5-Dimension 3-Level health questionnaire data collected in the CheckMate 141 trial, weighted using a US population preference algorithm. The primary outcome was the ICER, stratified by PD-L1 CPS, with a PSA performed to account for parameter uncertainty.¹

More Background on KEYNOTE-689

KEYNOTE-689 itself enrolled patients with newly diagnosed, resectable, locally advanced HNSCC, who were randomly assigned to receive 2 cycles of neoadjuvant pembrolizumab followed by surgery and adjuvant radiotherapy, with or without cisplatin, and then 15 cycles of adjuvant pembrolizumab, or SOC consisting of surgery and adjuvant radiotherapy, with or without cisplatin, alone.³

In patients with a PD-L1 CPS of 1 or greater had a median event-free survival (EFS) of 59.7 months with pembrolizumab plus SOC compared with 29.6 months with SOC alone (HR, 0.70; 95% CI, 0.55-0.89; P = .0014), while those with a CPS of 10 or greater had a median EFS of 59.7 months with pembrolizumab plus SOC versus 26.9 months with SOC alone (hazard ratio, 0.66; 95% confidence interval, 0.49-0.88; P = .0022).³

Based on these data, the FDA approved perioperative pembrolizumab in 2025 for adults with resectable locally advanced HNSCC with a PD-L1 CPS of 1 or greater.⁴

Additional Perspective on the Cost Analysis

The study authors noted that HNSCC is often diagnosed at an advanced stage and already carries a substantial economic and therapeutic burden independent of immunotherapy. They added that the length of the pembrolizumab regimen and its potential for side effects increases the likelihood that patients do not complete the full treatment course because of treatment-related and financial toxicity, underscoring the importance of continued cost-benefit analysis as perioperative immunotherapy use expands.

"The ability of perioperative immunotherapy to improve outcomes for patients with advanced head and neck squamous cell carcinoma is incredibly exciting," Yalamanchi said.² "We believe a stronger biomarker-stratified approach is necessary for more personalized, informed decision making for patients with locally advanced head and neck cancer."

References

1. Coyle AH, Hutton DW, Buchakjian MR, et al. Combined positive score and cost-effectiveness of perioperative pembrolizumab for head and neck cancer. JAMA Otolaryngol Head Neck Surg. Published online August 6, 2026. doi:10.1001/jamaoto.2026.2124.

2. Page S. Biomarkers aid cost-benefit analysis of head and neck cancer immunotherapy. Michigan Medicine Health Lab. Published August 10, 2026. Accessed August 11, 2026. https://tinyurl.com/2hwxxjn9

3. Uppaluri R, Haddad RI, Tao Y, et al. Neoadjuvant and adjuvant pembrolizumab in locally advanced head and neck cancer. N Engl J Med. 2025;393(1):37-50. doi:10.1056/NEJMoa2415434

4. FDA approves neoadjuvant and adjuvant pembrolizumab for resectable locally advanced head and neck squamous cell carcinoma. FDA. June 12, 2025. Accessed June 13, 2025. https://tinyurl.com/47aztrcp