HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer)
Head and neck cancers caused by tobacco and alcohol rather than HPV are harder to cure: surgery or cisplatin chemoradiation is the mainstay, immunotherapy given around surgery (KEYNOTE-689) or after it (NIVOPOSTOP) has begun to help, and pembrolizumab is the first treatment once the disease has spread.
Overview
HPV-negative head and neck squamous cell carcinoma is the classical, tobacco and alcohol driven disease of the oral cavity, larynx, hypopharynx and oropharynx, with areca nut and chewed tobacco the cause in South Asia. Tumours almost always carry TP53 mutation and CDKN2A loss, often EGFR overexpression, and arise from a field of damaged mucosa that produces second primaries; HPV-negative oropharyngeal cancer had three-year survival of 57.1 percent in the RTOG 0129 analysis against 82.4 percent for HPV-positive disease, and it is staged and treated with the other HPV-negative sites rather than with HPV-positive oropharyngeal cancer.
Curative treatment is surgery followed by radiotherapy, with cisplatin added when there is extranodal extension or a positive margin (the Bernier and Cooper trials of 2004), or definitive cisplatin chemoradiation, which the MACH-NC meta-analysis showed adds about 6.5 percentage points to five-year survival over radiotherapy alone; cetuximab with radiotherapy (Bonner) is the option for patients who cannot have cisplatin. Adding PD-1 or PD-L1 antibodies during chemoradiation failed in JAVELIN Head and Neck 100 and KEYNOTE-412, and the radiosensitiser xevinapant made outcomes worse in TrilynX, but immunotherapy around surgery has succeeded: KEYNOTE-689 gave median event-free survival of 59.7 against 29.6 months with perioperative pembrolizumab in tumours with a PD-L1 combined positive score of 1 or more, and NIVOPOSTOP raised three-year disease-free survival from 52.5 to 63.1 percent with nivolumab added to postoperative chemoradiation.
Recurrent or metastatic disease is treated as for all head and neck squamous cell carcinoma: pembrolizumab alone or with platinum and fluorouracil (KEYNOTE-048) replaced the cetuximab-based EXTREME regimen, though HPV-negative tumours respond less often to PD-1 blockade than HPV-positive ones. Trials now target this group specifically: FORTIFI-HN01 tests the EGFR and TGF-beta antibody ficerafusp alfa with pembrolizumab only in HPV-negative disease, and a phase 3 of ficlatuzumab with cetuximab is restricted to HPV-negative tumours. In India, oral metronomic methotrexate-celecoxib and low-dose nivolumab from Tata Memorial have set low-cost standards, and smoking cessation and alcohol reduction remain the interventions with the largest effect.
State of the art
- Cisplatin chemoradiation and surgery with postoperative treatment remain the curative backbone, essentially unchanged since 2004 until KEYNOTE-689 and NIVOPOSTOP.
- Immunotherapy helps when given around surgery, not during radiotherapy, a lesson from JAVELIN Head and Neck 100 and KEYNOTE-412.
- Two decades of radiosensitisers and EGFR inhibitors added to chemoradiation have not improved on cisplatin.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
- Check before combiningKidneys: Cisplatin
Dose reduce or avoid for CrCl below 60 (carboplatin is the alternative).
- Check before combiningKidneys: Methotrexate
High-dose methotrexate requires normal renal function, hydration, urine alkalinisation and leucovorin rescue with level monitoring.
- Good to knowImmune-related endocrinopathies (thyroiditis, hypophysitis)
Immunotherapy can attack hormone-producing glands: most often the thyroid (usually ending in an under-active thyroid needing lifelong tablets), and less often the pituitary (hypophysitis) or adrenal glands, which can be life-threatening if missed.
See all on the product pages:CisplatinMethotrexateNivolumabPembrolizumab·Printable cards in the navigator
Anatomy and lymph node drainage
- Oral cavity and tongue
- Oropharynx: tonsil, base of tongue (HPV)
- Nasopharynx (EBV)
- Larynx and hypopharynx
- Parotid and other salivary glands
- Thyroid
- Nodes: level I (submandibular)
- Nodes: level II (upper jugular)
- Nodes: level III-IV (jugular)
- Nodes: level V (posterior)
- Nodes: level VI (central, thyroid)
- Nodes: retropharyngeal (nasopharynx)
Site decides cause and behaviour: HPV drives oropharyngeal cancer, EBV drives nasopharyngeal cancer, tobacco drives oral and laryngeal cancer; all drain into the neck node levels that surgeons and radiotherapists map.
- Oral cavity and tongueHPV-negative oropharyngeal cancer · Oral cavity squamous cell carcinoma (almost always HPV-negative) · TP53-mutant, CDKN2A-deleted tumours (the commonest genotype) · Tobacco and alcohol related, and areca-nut related, disease
- Oropharynx: tonsil, base of tongue (HPV)HPV-negative oropharyngeal cancer · Oral cavity squamous cell carcinoma (almost always HPV-negative)
- Nasopharynx (EBV)
- Larynx and hypopharynxLaryngeal and hypopharyngeal squamous cell carcinoma
- Parotid and other salivary glands
- Thyroid
- level I (submandibular)
- level II (upper jugular)
- level III-IV (jugular)
- level V (posterior)
- level VI (central, thyroid)
- retropharyngeal (nasopharynx)
Same organ: Oropharyngeal cancer (tonsil and base of tongue), Laryngeal and hypopharyngeal cancer, Oral cavity cancer (mouth and tongue), Head and neck squamous cell carcinoma, Nasopharyngeal carcinoma, Salivary gland cancers, Papillary thyroid cancer, Follicular thyroid cancer, Medullary thyroid cancer, Anaplastic thyroid cancer, Thyroid cancer, Nasal cavity and paranasal sinus cancers (including esthesioneuroblastoma), NUT carcinoma (midline carcinoma with NUTM1 rearrangement), Parathyroid carcinoma, Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4), HPV-positive oropharyngeal cancer, Recurrent or metastatic head and neck squamous cell carcinoma, Hypopharyngeal cancer, Adenoid cystic carcinoma, Salivary duct carcinoma, Mucoepidermoid carcinoma, Oral tongue and floor of mouth cancer, Buccal mucosa and gingivobuccal cancer (oral cancer in India), Lip cancer
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Most of the close to 900,000 head and neck cancers diagnosed each year worldwide are HPV-negative: oral cavity, laryngeal and hypopharyngeal cancers in smokers and drinkers, and areca-nut related oral cancer in South Asia; in the RTOG 0129 analysis three-year survival for HPV-negative oropharyngeal cancer was 57 percent.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Biopsy with p16 (and HPV testing for oropharyngeal primaries), PD-L1 combined positive score, panendoscopy for second primaries, CT or MRI and PET-CT for stage III to IV.
Surgery with neck dissection; perioperative pembrolizumab for tumours with a combined positive score of 1 or more (KEYNOTE-689), then radiotherapy or chemoradiation by pathology.
Postoperative cisplatin chemoradiation for extranodal extension or positive margins; nivolumab added on the basis of NIVOPOSTOP.
Definitive cisplatin chemoradiation to 70 Gy; cetuximab with radiotherapy for patients who cannot have cisplatin (Bonner).
Pembrolizumab alone (combined positive score 1 or more) or with platinum-fluorouracil (KEYNOTE-048); cetuximab-based EXTREME for rapid disease or PD-1 failure.
Oral metronomic methotrexate with celecoxib, with or without low-dose nivolumab (Tata Memorial trials).
Smoking cessation, alcohol reduction and betel quid cessation; second primaries make cessation after diagnosis worthwhile.
Subtypes & biomarkers
top- HPV-negative oropharyngeal cancer
- Oral cavity squamous cell carcinoma (almost always HPV-negative)
- Laryngeal and hypopharyngeal squamous cell carcinoma
- TP53-mutant, CDKN2A-deleted tumours (the commonest genotype)
- Tobacco and alcohol related, and areca-nut related, disease
- p16 negative and HPV DNA negative
- PD-L1 combined positive score (perioperative and recurrent treatment)
- TP53 mutation and CDKN2A loss
- EGFR expression (a target, not a predictive marker)
- Extranodal extension and margin status (postoperative treatment)
- Smoking and alcohol exposure
How often this target appears
- 2004Bernier and Cooper trials: postoperative cisplatin chemoradiation for extranodal extension or positive margins
- 2006Cetuximab with radiotherapy improves survival (Bonner)
- 2008EXTREME: cetuximab with platinum-fluorouracil first line
- 2009MACH-NC update: concomitant chemotherapy adds about 6.5 points to five-year survival
- 2019KEYNOTE-048: pembrolizumab first line in recurrent disease
- 2020JAVELIN Head and Neck 100: PD-L1 blockade with chemoradiation fails
- 2024TrilynX stopped: xevinapant worsens outcomes
- 2025KEYNOTE-689 approval and NIVOPOSTOP: immunotherapy around surgery
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 18 changes by month →- 2026-09-17This recordHPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer)Facts on this page last checked
When this page itself was last checked or edited.
- 2025Trial resultKEYNOTE-689KEYNOTE-689 reported
Median EFS 59.
- 2025Trial resultNIVOPOSTOP (GORTEC 2018-01)NIVOPOSTOP (GORTEC 2018-01) reported
Three-year disease-free survival 63.
- 2025MilestoneKEYNOTE-689KEYNOTE-689 approval and NIVOPOSTOP: immunotherapy around surgery
A milestone in how this cancer is treated.
- 2024Trial resultTrilynXTrilynX reported
EFS 19.
- 2024MilestoneTrilynXTrilynX stopped: xevinapant worsens outcomes
A milestone in how this cancer is treated.
What is in development for HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer), drawn from the whole corpus: 11 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 3
Trials under way · 3
- FORTIFI-HN01 · phase 2/3 · Bicara Therapeutics
- A Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV Negative Head and Neck Squamous Cell Carcinoma · phase 3 · AVEO Pharmaceuticals
- A Study of Dostarlimab vs Placebo After Chemoradiation in Adult Participants With Locally Advanced Unresected Head and Neck Squamous Cell Carcinoma · phase 3 · GlaxoSmithKline
Trials reported · 5
- NIVOPOSTOP (GORTEC 2018-01) · phase 3 · 2025 · positive
- JAVELIN Head and Neck 100 · phase 3 · 2020 · negative
- KEYNOTE-048 · phase 3 · 2019 · positive
- KEYNOTE-689 · phase 3 · 2025 · positive
- TrilynX · phase 3 · 2024 · negative
Open problems and what is being done
Cure rates for locally advanced HPV-negative disease have barely moved in twenty years.
No predictive biomarker beyond PD-L1, which is imperfect.
Function after laryngectomy, glossectomy and high-dose radiotherapy.
Second primaries and continued smoking after treatment.
Incidence still rising where tobacco and areca nut use are common.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Mumbai · cancer center | India | none recorded | 2 | 665 | 4,926 | none recorded | #80 |
Bethesda, MD · government | United States | none recorded | 0 | 2,905 | 47,715 | - | |
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Tianjin · cancer center | China | none recorded | 0 | 1,219 | 11,455 | - | |
Hangzhou · cancer center | China | none recorded | 0 | 1,219 | 17,635 | - | |
Beijing · hospital | China | none recorded | 0 | 1,154 | 11,808 | - | |
Pittsburgh, PA · cancer center | United States | 0 | 1,078 | 21,539 | - | ||
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
Naples · cancer center | Italy | none recorded | 0 | 961 | 15,028 | - | |
Changsha · cancer center | China | none recorded | 0 | 930 | 14,477 | - | |
Jinan · cancer center | China | none recorded | 0 | 920 | 7,804 | - | |
Rotterdam · cancer center | Netherlands | none recorded | 0 | 852 | 12,180 | - | |
Dresden · cancer center | Germany | none recorded | 0 | 728 | 7,984 | - | |
| United Kingdom | none recorded | 0 | 693 | 7,168 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with HPV-negative head and neck squamous cell carcinoma but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about HPV-negative head and neck squamous cell carcinoma
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example p16 negative and HPV DNA negative, PD-L1 combined positive score, TP53 mutation and CDKN2A loss, EGFR expression, Extranodal extension and margin status), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include HPV-negative oropharyngeal cancer, Oral cavity squamous cell carcinoma, Laryngeal and hypopharyngeal squamous cell carcinoma.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Diagnosis and staging
- For my situation (diagnosis and staging), which of the standard options do you recommend and why?Why: Guideline options include: Biopsy with p16 (and HPV testing for oropharyngeal primaries), PD-L1 combined positive score, panendoscopy for second primaries, CT or MRI and PET-CT for stage III to IV.
Resectable stage III to IVA
- For my situation (resectable stage iii to iva), which of the standard options do you recommend and why?Why: Guideline options include: Surgery with neck dissection; perioperative pembrolizumab for tumours with a combined positive score of 1 or more (KEYNOTE-689), then radiotherapy or chemoradiation by pathology.
- Am I a candidate for Pembrolizumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-689 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
After surgery, high risk
- For my situation (after surgery, high risk), which of the standard options do you recommend and why?Why: Guideline options include: Postoperative cisplatin chemoradiation for extranodal extension or positive margins; nivolumab added on the basis of NIVOPOSTOP.
- Am I a candidate for Cisplatin, Nivolumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of NIVOPOSTOP (GORTEC 2018-01) apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Unresectable or organ-preserving
- For my situation (unresectable or organ-preserving), which of the standard options do you recommend and why?Why: Guideline options include: Definitive cisplatin chemoradiation to 70 Gy; cetuximab with radiotherapy for patients who cannot have cisplatin (Bonner).
- Am I a candidate for Cisplatin, Cetuximab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Bonner trial (cetuximab plus radiotherapy) apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Recurrent or metastatic
- For my situation (recurrent or metastatic), which of the standard options do you recommend and why?Why: Guideline options include: Pembrolizumab alone (combined positive score 1 or more) or with platinum-fluorouracil (KEYNOTE-048); cetuximab-based EXTREME for rapid disease or PD-1 failure.
- Am I a candidate for Pembrolizumab, Cetuximab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-048 and EXTREME apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Resource-limited settings
- For my situation (resource-limited settings), which of the standard options do you recommend and why?Why: Guideline options include: Oral metronomic methotrexate with celecoxib, with or without low-dose nivolumab (Tata Memorial trials).
- Am I a candidate for Methotrexate, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial) and Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial) apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Prevention
- For my situation (prevention), which of the standard options do you recommend and why?Why: Guideline options include: Smoking cessation, alcohol reduction and betel quid cessation; second primaries make cessation after diagnosis worthwhile.
Any stage
- Are there clinical trials I could join, for example of Ficerafusp alfa, FORTIFI-HN01, A Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV Negative Head and Neck Squamous Cell Carcinoma, A Study of Dostarlimab vs Placebo After Chemoradiation in Adult Participants With Locally Advanced Unresected Head and Neck Squamous Cell Carcinoma?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Cure rates for locally advanced HPV-negative disease have barely moved in twenty years”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “No predictive biomarker beyond PD-L1, which is imperfect”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with HPV-negative head and neck squamous cell carcinoma, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
10targets
2drugs
9companies
6terms
4trials
12Latest papers
topQuery for this cancer: (TITLE:"HPV-negative head and neck squamous cell carcinoma" OR ABSTRACT:"HPV-negative head and neck squamous cell carcinoma" OR TITLE:"including HPV-negative oropharyngeal cancer" OR ABSTRACT:"including HPV-negative oropharyngeal cancer" OR TITLE:"Tobacco-related head and neck cancer" OR ABSTRACT:"Tobacco-related head and neck cancer" OR TITLE:"HPV-negative oropharyngeal cancer" OR ABSTRACT:"HPV-negative oropharyngeal cancer" OR TITLE:"p16-negative head and neck cancer" OR ABSTRACT:"p16-negative head and neck cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer), not a curated reading list.
Similar pages
not linked directly; found by shared links- CancerOral tongue and floor of mouth cancer
Shares KEYNOTE-689, NIVOPOSTOP (GORTEC 2018-01), KEYNOTE-048, Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial) and the tags subtype-page, head-and-neck.
- CancerHypopharyngeal cancer
Shares Bonner trial (cetuximab plus radiotherapy), KEYNOTE-689, NIVOPOSTOP (GORTEC 2018-01), KEYNOTE-048 and the tags subtype-page, head-and-neck.
- CancerBuccal mucosa and gingivobuccal cancer (oral cancer in India)
Shares NIVOPOSTOP (GORTEC 2018-01), Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial), Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial), Smoking cessation in cancer patients and the tags subtype-page, head-and-neck.
- CancerLip cancer
Shares KEYNOTE-048, Smoking cessation in cancer patients, Chemoradiation (chemoradiotherapy, CRT), Cisplatin and the tags subtype-page, head-and-neck.
- CancerHPV-positive oropharyngeal cancer
Shares KEYNOTE-048, HPV-positive (p16) head and neck cancer, Chemoradiation (chemoradiotherapy, CRT), Recurrent or metastatic head and neck squamous cell carcinoma and the tags subtype-page, head-and-neck.
- CancerMucoepidermoid carcinoma
Shares PD-L1 expression testing (22C3, SP142, SP263), Chemoradiation (chemoradiotherapy, CRT), Cisplatin, IMRT / IGRT (modern external beam) and the tags subtype-page, head-and-neck.
- CancerSalivary duct carcinoma
Shares Chemoradiation (chemoradiotherapy, CRT), Cisplatin, IMRT / IGRT (modern external beam), Pembrolizumab and the tags subtype-page, head-and-neck.
- CancerAdenoid cystic carcinoma
Shares Cisplatin, IMRT / IGRT (modern external beam) and the tags subtype-page, head-and-neck.