Head and neck squamous cell carcinoma (HNSCC) is one of the more challenging cancers to treat, particularly in the recurrent or metastatic setting where curative intent is rarely achievable. Pembrolizumab has established itself as a standard first-line option for eligible patients, changing the treatment approach in this disease area meaningfully.
The disease and its characteristics
HNSCC encompasses cancers of the oral cavity, oropharynx, hypopharynx, and larynx. The two main risk factors are tobacco and alcohol exposure (more common in older patients) and human papillomavirus (HPV) infection (more common in younger patients, particularly in oropharyngeal cancer). HPV-positive HNSCC generally has a better prognosis than HPV-negative disease.
Most patients with HNSCC present with locally advanced disease, where the primary treatment is surgery or chemoradiotherapy with curative intent. The recurrent or metastatic setting - where pembrolizumab is most commonly used - affects patients whose disease has spread beyond local control.
KEYNOTE-048 and first-line pembrolizumab
The pivotal trial establishing pembrolizumab in HNSCC was KEYNOTE-048, which enrolled patients with previously untreated recurrent or metastatic disease. It compared three approaches: pembrolizumab alone, pembrolizumab plus platinum-based chemotherapy, and the previous standard (cetuximab plus chemotherapy).
For patients with a Combined Positive Score (CPS) of 20 or higher, pembrolizumab monotherapy produced a median overall survival of 14.9 months versus 10.7 months with cetuximab-chemotherapy - a statistically significant and clinically meaningful improvement. For CPS 1 or higher (a broader population), both pembrolizumab monotherapy and the combination outperformed the control. Pembrolizumab is now a standard first-line option for eligible patients in this setting.
CPS scoring in head and neck cancer
Unlike in lung cancer - where the Tumour Proportion Score (TPS) is used - HNSCC eligibility is assessed using the Combined Positive Score (CPS). CPS counts PD-L1-positive tumour cells, lymphocytes, and macrophages together, divided by the total number of viable tumour cells, multiplied by 100. A CPS of 1 is a relatively low threshold, and the majority of HNSCC patients meet it. CPS 20 identifies patients most likely to benefit from monotherapy.
Quality of life considerations
HNSCC and its treatment can have significant impacts on swallowing, speech, and nutrition. Patients managing these challenges alongside active treatment face a considerable burden. The home-based administration option - where treatment can be delivered to the patient at home by a qualified nurse rather than requiring regular oncology unit visits - can meaningfully reduce the logistical and physical demands on patients who are already managing complex symptoms.
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