Pembrolizumab improves survival in locally advanced head and neck cancer

1. Among patients with locally advanced head and neck squamous-cell carcinoma (HNSCC), neoadjuvant and adjuvant pembrolizumab improved event-free survival compared to standard care alone.

2. Pembrolizumab was associated with immune-mediated adverse events, including those of grade 3 or higher.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Resectable locally advanced HNSCC is a disease with high morbidity, with few treatment advances in recent times. Adjuvant radiotherapy is the standard of care, yet the five-year survival rates remained low due to disease recurrence. The immunotherapy agent pembrolizumab is first-line for recurrent and metastatic HNSCC, and it has shown promise in improving outcomes in prior phase two trials for locally advanced HNSCC compared to historical controls. This study assessed neoadjuvant and adjuvant pembrolizumab in patients with resectable, nonmetastatic HNSCC. Compared to standard care alone, pembrolizumab significantly improved 36-month event-free survival across the combined positive score (CPS) range, corresponding to the proportion of cells that express program death ligand 1 (PD-L1). Although the incidence of adverse events was similar between pembrolizumab and standard care, pembrolizumab was associated with a higher rate of immune-mediated adverse events, most commonly hypothyroidism. The study was limited by difficulty in delineating the contribution of specific trials and standard therapies and the small size of certain subgroups, including those with CPS less than one. Overall, these results showed that pembrolizumab improved event-free survival in patients with locally advanced HNSCC.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This was an open-label, randomized, active-controlled, multicenter trial investigating the efficacy and safety of neoadjuvant and adjuvant pembrolizumab to standard care for patients with locally advanced HNSCC. Eligible patients were 18 years of age or older with newly diagnosed, nonmetastatic, resectable locally advanced HNSCC. A total of 714 participants were randomized in a 1:1 ratio to the pembrolizumab plus standard of care group or the standard of care group, which consisted of surgery and adjuvant radiotherapy with or without concomitant cisplatin. The primary outcome was event-free survival (EFS), stratified into three populations: PD-L1 CPS ≥10 (CPS-10 population), PD-L1 CPS ≥1 (CPS-1 population), and the total population (irrespective of CPS), where a higher CPS corresponds with a higher proportion of tumor cells expressing PD-L1. Within the CPS-10 subgroup, the EFS at 36 months was 59.8% in the pembrolizumab group vs. 45.9% in the control group (Hazard Ratio [HR], 0.66; 95% Confidence Interval [CI], 0.49-0.88, p=0.004). For the CPS-1 subgroup, EFS at 36 months was 58.2% in the pembrolizumab group vs. 44.9% in the control group (HR, 0.70; 95% CI, 0.55-0.89; p=0.003). For the combined population, EFS at 36 months was 57.6% in the pembrolizumab group vs. 46.4% in the control group (HR, 0.73; 95% CI 0.58-0.92; p=0.008). Overall, the median EFS was 51.8 months in the pembrolizumab group vs. 30.4 months in the control group. Three-year OS was 68.2% in the pembrolizumab group vs. 59.2% in the control group in the CPS-10 population (HR, 0.72; 95% CI, 0.52-0.98; p=0.04), which did not meet the prespecified statistical significance. Treatment-related adverse events occurred in 81.4% of patients in the pembrolizumab group and 81.9% in the control group. In summary, these results showed that the addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced HNSCC.

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