Teaching pack: Head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma arises from the lining of the mouth, throat (oropharynx, hypopharynx), voice box, and nose, and includes the distinct Epstein-Barr-virus-driven nasopharyngeal carcinoma. Two epidemics coexist: tobacco- and alcohol-related cancers, declining in rich countries but common globally, and HPV-driven oropharyngeal cancer, rising among younger non-smokers and now the most common HPV cancer in the US. HPV-positive disease is far more curable (3-year survival >80%) and has its own staging system.

Curative treatment is surgery (increasingly transoral robotic surgery) and/or cisplatin-based chemoradiation with IMRT; both leave lasting effects on speech, swallowing, and salivation, which is why de-escalation for HPV-positive disease has been pursued so hard, and why its repeated failure (RTOG 1016, De-ESCALaTE, NRG-HN005) matters. Immunotherapy transformed recurrent and metastatic disease: nivolumab (CheckMate 141) and then pembrolizumab first line (KEYNOTE-048) replaced the cetuximab-chemotherapy EXTREME regimen, and in June 2025 KEYNOTE-689 delivered the first perioperative approval, doubling event-free survival by giving pembrolizumab before and after surgery. Immunotherapy given concurrently with chemoradiation, by contrast, has failed repeatedly. Nasopharyngeal carcinoma gained its first US approval with toripalimab plus chemotherapy in 2023.

• Perioperative IO.
• HPV vaccination reducing future incidence.
• Perioperative pembrolizumab (KEYNOTE-689) is the first curative-intent advance since cetuximab-radiation in 2006, with median event-free survival roughly doubled.
• Pembrolizumab-based first-line therapy for recurrent or metastatic disease produces a durable survival tail that chemotherapy never did.
• HPV-positive oropharyngeal cancer is recognised as a distinct, highly curable disease, but the standard dose of chemoradiation still stands because every de-escalation trial has fallen short.
• Nasopharyngeal carcinoma has immunotherapy-chemotherapy as first line in the US, EU, and China.

1. 1987Cisplatin-5-FU induction and larynx preservation trials begin
2. 2000Concurrent cisplatin chemoradiation becomes standard for locally advanced disease
3. 2006Cetuximab + RT
4. 2006Cetuximab + radiation improves survival (Bonner)
5. 2008EXTREME defines first-line therapy for recurrent/metastatic disease
6. 2009Transoral robotic surgery FDA-cleared
7. 2010RTOG 0129: HPV status is the dominant prognostic factor
8. 2016PD-1 approved second line
9. 2016Nivolumab (CheckMate 141) and pembrolizumab approved after platinum
10. 2018AJCC 8th edition gives HPV-positive oropharynx cancer its own staging

• Tilatamig samrotecan (product)
• Lifileucel (product)
• Petosemtamab (product)
• LiGeR-HN1 (trial)
• Ficerafusp alfa (product)
• FORTIFI-HN01 (trial)
• Cetuximab sarotalocan (product)
• Circulating tumour HPV DNA (ctHPV-DNA) (technology)
• ctHPV-DNA-adapted de-escalation of chemoradiation (idea)
• Photoimmunotherapy as an in situ vaccine with PD-1 blockade (idea)
• EGFR-directed bispecific + PD-1 blockade (pairing)
• Boron neutron capture therapy (technology)

• KEYNOTE-048 (phase 3, n=882): Overall survival, CPS ≥20, pembrolizumab monotherapy: 14.9 months vs 10.7 months, HR 0.61
• CheckMate 141 (phase 3, n=361): Overall survival: 7.5 months vs 5.1 months, HR 0.7
• EXTREME (phase 3, n=442): Overall survival: 10.1 months vs 7.4 months, HR 0.8
• JUPITER-02 (phase 3, n=289): Progression-free survival: pending
• KEN SHE (single-dose HPV vaccine) (phase 3, n=2,275): Vaccine efficacy against persistent HPV16/18 infection: 97.5%
• KEYNOTE-689 (phase 3, n=714): Event-free survival (CPS ≥1): 59.7 months vs 29.6 months

• Functional toxicity of chemoradiation.
• Few targets beyond EGFR/PD-1.
• HPV-negative, tobacco-related disease has 5-year survival around 50% and has seen little improvement in curative outcomes beyond KEYNOTE-689.
• De-escalation for HPV-positive disease has failed in every randomised trial; the field still lacks a validated way to identify who can receive less.
• Only two drug targets (EGFR and PD-1) have approved agents; PIK3CA, NOTCH, and CDKN2A alterations remain undrugged.
• Immunotherapy concurrent with chemoradiation has failed three times; the mechanism is not fully understood.

1. What is the standard treatment for stage II-III triple-negative breast cancer today?
   Answer

   Neoadjuvant pembrolizumab with carboplatin/paclitaxel then anthracycline chemotherapy, surgery, and adjuvant pembrolizumab (KEYNOTE-522); adjuvant olaparib for germline BRCA carriers with residual disease (OlympiA); capecitabine for residual disease without BRCA.
2. Which biomarkers must be tested at diagnosis of advanced non-small-cell lung cancer?
   Answer

   EGFR, ALK, ROS1, BRAF V600E, MET exon 14/amplification, RET, NTRK, KRAS G12C, HER2 mutations, and PD-L1 TPS.
3. What fraction of advanced melanoma patients on nivolumab plus ipilimumab are alive at ten years?
   Answer

   About 43% overall survival (CheckMate 067), with melanoma-specific survival around 52%.
4. What is the first approved TIL therapy and how well does it work?
   Answer

   Lifileucel (Amtagvi, Iovance), approved 2024 for anti-PD-1-refractory melanoma: response rate about 31%, with roughly a third of responders still responding at five years.
5. Which cooperative group ran the trial that put nivolumab into first-line Hodgkin lymphoma?
   Answer

   SWOG (S1826, nivolumab-AVD vs BV-AVD), leading to FDA approval in March 2026 for ages 12 and over.
6. What single change would most improve outcomes across all cancers, and what evidence supports it?
   Answer

   Prevention and early detection: HPV vaccination has driven cervical cancer toward elimination in vaccinated cohorts, tobacco control and screening (mammography, colonoscopy, low-dose CT) have proven mortality benefits, and early-stage disease is where surgery cures; MCED blood tests aim to extend this but are unproven.

• Wikipedia: https://en.wikipedia.org/wiki/Head_and_neck_cancer
• Guideline: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437
• Guideline: https://pmc.ncbi.nlm.nih.gov/articles/PMC11163648/