Overview of Head & Neck Cancer Treatment

Head and neck squamous cell carcinoma (HNSCC) treatment has been transformed by immunotherapy. Pembrolizumab alone or with chemotherapy is first-line for recurrent/metastatic disease (KEYNOTE-048). Cetuximab remains important in platinum-based combinations. HPV status is a key prognostic and predictive biomarker, with PD-L1 CPS guiding immunotherapy selection.

Treatment Selection for R/M HNSCC

First-Line (PD-L1 CPS ≥1)

  • Pembrolizumab + platinum + 5-FU (KEYNOTE-048)
  • Pembrolizumab monotherapy (CPS ≥20)

First-Line (PD-L1 CPS <1)

  • Cetuximab + platinum + 5-FU (EXTREME)

Second-Line

  • Nivolumab (CheckMate-141)
  • Cetuximab-based regimens

Epidemiology & Impact

Head and neck squamous cell carcinoma encompasses cancers of the oral cavity, oropharynx, hypopharynx, and larynx, with approximately 59,370 new cases and 12,470 deaths expected in 2025. Two distinct epidemiologic patterns exist: HPV-negative tumors from tobacco/alcohol (declining) and HPV-positive oropharyngeal cancers (rising sharply, now 70-80% of US oropharyngeal cases). HPV-positive HNSCC occurs in younger non-smokers with significantly better prognosis (3-year survival over 80% versus approximately 50% for HPV-negative). Men are affected 3 times more often than women.

Molecular Biology & Biomarkers

HPV-positive and HPV-negative HNSCC are molecularly distinct. HPV-positive tumors are driven by E6/E7 oncoproteins, typically have wild-type TP53 and fewer mutations. HPV-negative tumors harbor TP53 mutations in over 80% of cases, frequent CDKN2A loss, and CCND1 amplification. PD-L1 CPS is the key biomarker for pembrolizumab eligibility. EGFR amplification (15-20%) is therapeutically relevant via cetuximab.

Evolving Treatment Landscape

KEYNOTE-048 established pembrolizumab as the cornerstone: monotherapy for PD-L1 CPS 20 or higher, with platinum-5-FU for CPS 1 or higher. For locally advanced disease, concurrent cisplatin-chemoradiation is standard. Active de-escalation trials for HPV-positive disease investigate reduced radiation doses. Neoadjuvant checkpoint inhibitors show pathological response rates of 20-30%.

Approved Head & Neck Cancer Therapies

Keytruda
pembrolizumab
FDA Approved 2016 First-line (combo/mono) / R/R
Approved Indications (US/FDA)
First-line treatment of patients with metastatic or unresectable recurrent HNSCC in combination with platinum and 5-FU; as single agent for patients with PD-L1 CPS ≥1; for recurrent or metastatic HNSCC after platinum-based chemotherapy. Also approved as neoadjuvant/adjuvant for resectable locally advanced HNSCC (2025).
Dosing Schedule
200 mg IV Q3W or 400 mg IV Q6W
Drug Class
Checkpoint Inhibitor (Anti-PD-1)
Manufacturer
Merck
Approval Year
2016
Pivotal Trial
NCT02358031 ↗
Key Publication
Burtness et al. Lancet 2019 (KEYNOTE-048) ↗
Opdivo
nivolumab
FDA Approved 2016 Second-line
Approved Indications (US/FDA)
Treatment of patients with recurrent or metastatic HNSCC with disease progression on or after a platinum-based therapy.
Dosing Schedule
240 mg IV Q2W or 480 mg IV Q4W
Drug Class
Checkpoint Inhibitor (Anti-PD-1)
Manufacturer
Bristol-Myers Squibb
Approval Year
2016
Pivotal Trial
NCT02105636 ↗
Key Publication
Ferris et al. NEJM 2016 (CheckMate 141) ↗
Erbitux
cetuximab
FDA Approved 2006 First-line (with RT or chemo)
Approved Indications (US/FDA)
In combination with radiation therapy for locally or regionally advanced HNSCC; with platinum-based therapy and 5-FU for recurrent locoregional or metastatic HNSCC; single agent after prior platinum-based therapy failure.
Dosing Schedule
Loading dose 400 mg/m² IV, then 250 mg/m² IV weekly
Drug Class
Anti-EGFR Monoclonal Antibody
Manufacturer
Eli Lilly
Approval Year
2006
Key Publication
Bonner et al. NEJM 2006 ↗