Highlights
- Pembrolizumab has achieved market dominance in the treatment of head and neck cancer (HNC), accounting for 87% of immunotherapy prescriptions by 2022.
- Despite FDA approvals for first-line use, overall immunotherapy uptake in patients under 65 remains relatively low, increasing from 2.3% in 2017 to only 2.8% in 2022.
- Immune-related adverse events (irAEs) are common, occurring in 41.2% of patients within 90 days, though severe irAEs are infrequent at 2.7%.
- Baseline hypothyroidism and liver disease are potent independent predictors of developing irAEs following treatment initiation.
Introduction: The Immunotherapy Revolution in HNC
The therapeutic landscape for recurrent or metastatic head and neck cancer (HNC) underwent a paradigm shift with the introduction of immune checkpoint inhibitors (ICIs). Specifically, monoclonal antibodies targeting the programmed cell death 1 (PD-1) receptor, such as pembrolizumab and nivolumab, have redefined survival expectations for a disease historically characterized by poor prognosis and limited treatment options. However, while clinical trials established the efficacy and safety of these agents, real-world prescribing patterns and the broad-spectrum incidence of immune-related adverse events (irAEs) in diverse patient populations have remained less clear.
Understanding how these drugs are utilized outside the controlled environment of clinical trials is essential for health policy experts and clinicians. This is particularly true for HNC, where patients often present with significant comorbidities and unique physiological challenges related to the primary site of disease. A recent retrospective cohort study published in JAMA Otolaryngology–Head & Neck Surgery provides critical insights into these dynamics, utilizing a robust claims-based database to track the evolution of HNC care from 2016 to 2022.
Study Design and Methodology
Researchers conducted a retrospective analysis using the MarketScan Commercial and multistate Medicaid databases. The study included 47,365 patients diagnosed with HNC between January 1, 2016, and December 31, 2022. To ensure data quality, inclusion required at least six months of insurance enrollment prior to diagnosis and at least one month of follow-up. Notably, the study focused on patients under the age of 65, excluding the Medicare-eligible population to maintain homogeneity in the commercial and Medicaid datasets.
The primary objectives were to measure the prescribing rates of immunotherapeutic agents overall and per year, and to analyze the market share of specific drugs. Secondary outcomes focused on the safety profile, specifically the incidence of irAEs and severe irAEs within 90 days of starting therapy, as well as the identification of risk factors associated with these toxicities through univariate and multivariate regression models.
Results: Market Dominance and Longitudinal Trends
Slow Growth in Utilization
Of the 47,365 patients identified with HNC, only 2,254 (4.8%) received immunotherapy within 12 months of diagnosis. While this number reflects the specific subset of patients with advanced or recurrent disease, the growth rate was surprisingly modest. The prescription rate increased from 2.3% in 2017 to 2.8% in 2022. This suggests that while ICIs are a cornerstone of modern oncology, their penetration into the broader HNC patient population—including those with early-stage disease where ICIs are not yet standard—remains limited.
The Rise of Pembrolizumab
Perhaps the most striking finding was the divergence in the use of pembrolizumab versus nivolumab. In the early years of the study (2016–2018), both agents shared a similar portion of the market. However, following key regulatory approvals and the publication of the KEYNOTE-048 trial results, pembrolizumab began to dominate. By 2022, pembrolizumab accounted for 87% of the immunotherapy market for HNC. This shift likely reflects the broader indications for pembrolizumab as a first-line monotherapy or in combination with chemotherapy, whereas nivolumab’s primary indication remained in the platinum-refractory setting.
Safety and Tolerability: Characterizing irAEs
Incidence of Toxicities
Safety remains a paramount concern when managing patients on ICIs. The study found that 41.2% of patients experienced at least one irAE within 90 days of treatment. These events are the result of an overactive immune system attacking healthy tissues. However, the rate of severe irAEs—those requiring intensive intervention or hospitalization—was low at 2.7%. This indicates that while the majority of toxicities are manageable, clinicians must remain vigilant for the minority of cases that escalate into life-threatening conditions.
Predictors of Adverse Events
The research identified specific baseline characteristics that significantly increased the risk of developing irAEs. Patients with pre-existing hypothyroidism were at the highest risk, with an adjusted odds ratio (aOR) of 6.7 (95% CI, 5.0-9.0). This is biologically plausible, as the thyroid gland is a frequent target of PD-1-mediated autoimmunity. Additionally, baseline liver disease was associated with a higher risk of irAEs (aOR, 1.7; 95% CI, 1.1-2.7). Interestingly, the overall comorbidity score was a significant predictor for the development of severe irAEs (OR, 1.02; 95% CI, 1.02-1.03), suggesting that the most fragile patients are at the highest risk for the most serious complications.
Expert Commentary: Interpreting the Data
The findings of this study underscore the importance of personalized medicine in HNC. The overwhelming market preference for pembrolizumab highlights how pivotal clinical trial data (like KEYNOTE-048) translates directly into clinical practice patterns. However, the modest overall increase in immunotherapy use suggests that many patients may still be treated with traditional cytotoxic or targeted therapies, or perhaps the transition to ICI-based care for the recurrent/metastatic population is already reaching a plateau in the under-65 demographic.
From a safety perspective, the high incidence of irAEs (41.2%) confirms that these drugs are not without cost to the patient’s quality of life. The strong association with baseline hypothyroidism suggests that patients with endocrine dysfunction require closer monitoring and potentially more aggressive hormone replacement therapy during treatment. The association between liver disease and irAEs also warrants caution, particularly in HNC populations where alcohol use history may contribute to baseline hepatic impairment.
One limitation of this study is its reliance on claims data, which may under-report mild toxicities that do not result in a specific billing code. Furthermore, the exclusion of patients over 65 means these results may not be fully generalizable to the elderly population, who often represent a significant portion of HNC cases and may have different toxicity profiles due to immunosenescence.
Conclusion
This comprehensive cohort study clarifies the real-world application of immunotherapy in HNC, demonstrating a clear preference for pembrolizumab and a manageable but frequent toxicity profile. As the oncology community continues to refine the use of ICIs, these data provide a vital benchmark for understanding which patients are most likely to receive these therapies and which are most at risk for complications. Future research should focus on the over-65 population and the long-term outcomes of patients who experience mild versus severe irAEs.
References
1. Peterson AM, Stwalley D, Kallogjeri D, et al. Immunotherapy Prescribing Patterns and Immune-Related Adverse Events in Patients With Head and Neck Cancer. JAMA Otolaryngol Head Neck Surg. Published online February 19, 2026. doi:10.1001/jamaoto.2025.5513
2. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-1928.
3. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016;375(19):1856-1867.