{"entity":{"id":"recurrent-metastatic-hnscc","kind":"cancer","name":"Recurrent or metastatic head and neck squamous cell carcinoma","aka":["R/M HNSCC","Advanced head and neck cancer","Platinum-refractory head and neck cancer"],"tldr":"When head and neck cancer comes back where it cannot be removed, or spreads elsewhere, it is treated to extend life rather than cure: pembrolizumab, alone or with chemotherapy, is the first choice, cetuximab-based regimens and cheap oral chemotherapy are alternatives, and antibodies that hit two targets at once are in late-stage trials.","summary":"Recurrent or metastatic head and neck squamous cell carcinoma covers disease that returns in the head and neck after radiotherapy or surgery and cannot be salvaged, and disease that has spread to the lungs, bone or liver. A minority with locoregional recurrence are cured by salvage surgery or re-irradiation, and a few with a single metastasis are treated with stereotactic radiotherapy; for the rest treatment is systemic and palliative. Work-up includes biopsy, PD-L1 combined positive score, HPV status of oropharyngeal primaries and the interval since platinum, since progression within six months of platinum defines platinum-refractory disease.\n\nFirst-line treatment was defined for a decade by EXTREME (2008), in which cetuximab with platinum and fluorouracil gave median overall survival of 10.1 against 7.4 months. CheckMate 141 (2016) then showed that nivolumab extended survival after platinum failure (7.5 against 5.1 months), and KEYNOTE-048 (2019) moved immunotherapy to the front: pembrolizumab alone gave median survival of 14.9 against 10.7 months in tumours with a combined positive score of 20 or more, and pembrolizumab with chemotherapy gave 13.0 against 10.7 months in the whole population, with a durable tail at five years. Pembrolizumab-based treatment is now the standard, EXTREME or its docetaxel variant TPExtreme the option for rapidly progressing disease or after immunotherapy, and cetuximab sarotalocan photoimmunotherapy is approved in Japan for locoregional recurrence.\n\nThe frontier is combinations that lift response rates above the roughly one in five seen with pembrolizumab alone. Petosemtamab, a bispecific antibody against EGFR and LGR5, produced responses in about six in ten untreated patients with pembrolizumab in phase 2 and is in the phase 3 LiGeR-HN1 and LiGeR-HN2 trials; ficerafusp alfa, which blocks EGFR and traps TGF-beta, is in FORTIFI-HN01 for HPV-negative disease; HB-200, an arenavirus-based vaccine against HPV16 E6 and E7, has been tested with pembrolizumab in HPV16-positive disease; and the EGFR antibody-drug conjugate MRG003 is in phase 3 against cetuximab or methotrexate. In India, Tata Memorial trials showed that oral methotrexate with celecoxib beat intravenous cisplatin (median survival 7.5 against 6.1 months), that adding one-twentieth of the usual nivolumab dose raised one-year survival from 16.3 to 43.4 percent, and, in METRO PLUS, that adding metronomic tablets to paclitaxel-carboplatin doubled median survival from 5 to 10 months.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Head_and_neck_cancer","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Head_and_neck_cancer"}],"tags":["subtype-page","head-and-neck","state-page"],"related":["hpv-negative-head-and-neck-cancer","laryngeal-cancer","oral-cavity-cancer","oropharyngeal-cancer"],"cancers":[],"sections":[],"technologies":[],"targets":[],"drugs":["celecoxib","hb-200"],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":["tpextreme"],"people":[],"bottlenecks":[],"keyPapers":["paper-keynote-048-lancet-2019","paper-patil-low-dose-nivolumab-jco-2023","paper-extreme-vermorken-nejm-2008","paper-tpextreme-lancet-oncol-2021"],"journals":[],"dependsOn":[],"notes":[],"group":"head and neck","burden":"A large share of patients treated for locally advanced head and neck cancer relapse, most within two years; median survival was 7.4 months on platinum-fluorouracil in the EXTREME control arm and 13.0 months with pembrolizumab and chemotherapy in KEYNOTE-048.","subtypes":["Locoregional recurrence after radiotherapy (candidates for salvage surgery or re-irradiation)","Distant metastatic disease (lung, bone, liver)","Platinum-sensitive versus platinum-refractory disease (progression within six months of platinum)","PD-L1 combined positive score 20 or more, 1 to 19, and under 1","HPV-positive versus HPV-negative recurrent disease","Oligometastatic disease treated with stereotactic radiotherapy"],"biomarkers":["PD-L1 combined positive score (22C3 assay)","HPV and p16 status of oropharyngeal primaries","Platinum-free interval","EGFR expression (near universal, not predictive)","Circulating tumour DNA and HPV DNA (emerging)","Tumour mutational burden (pembrolizumab for 10 or more mutations per megabase)"],"standardOfCare":[{"setting":"First line, combined positive score 1 or more","approach":"Pembrolizumab alone for indolent disease, especially with a score of 20 or more; pembrolizumab with platinum and fluorouracil for bulky or symptomatic disease (KEYNOTE-048).","refs":["pembrolizumab","keynote-048","pd-l1-testing","cps"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"First line, combined positive score under 1 or immunotherapy unsuitable","approach":"Pembrolizumab with platinum-fluorouracil, or cetuximab with platinum-fluorouracil (EXTREME) or with docetaxel and platinum (TPExtreme).","refs":["pembrolizumab","cisplatin","carboplatin","fluorouracil","cetuximab","docetaxel","extreme","keynote-048"],"guideline":{"nccn":"Category 1","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"After platinum and immunotherapy","approach":"Cetuximab, docetaxel, paclitaxel or methotrexate as single agents; nivolumab or pembrolizumab if not given before (CheckMate 141); clinical trials.","refs":["nivolumab","checkmate-141","cetuximab","docetaxel","paclitaxel","methotrexate"],"guideline":{"nccn":"Category 1 (nivolumab, pembrolizumab)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Locoregional recurrence","approach":"Salvage surgery where resectable; re-irradiation with intensity-modulated or stereotactic techniques in selected patients; cetuximab sarotalocan photoimmunotherapy in Japan.","refs":["imrt-igrt","sbrt","cetuximab-sarotalocan","photoimmunotherapy"],"guideline":{"esmoMcbs":"2 (cetuximab sarotalocan, single-arm)","version":"NCCN Guidelines: Head and Neck Cancers","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1437"}},{"setting":"Resource-limited settings","approach":"Oral metronomic methotrexate with celecoxib; low-dose nivolumab added where affordable; metronomic tablets with paclitaxel-carboplatin (METRO PLUS).","refs":["methotrexate","metronomic-vs-cisplatin-tmh","low-dose-nivolumab-tmh","metro-plus-varanasi"]},{"setting":"Symptom control","approach":"Palliative radiotherapy for bleeding, pain or airway compromise; early involvement of palliative care, nutrition and speech and swallowing teams.","refs":["palliative-radiotherapy"]}],"stateOfArt":["Pembrolizumab-based first-line treatment gives a minority of patients survival measured in years, something no chemotherapy regimen did.","Response rates to immunotherapy alone remain low, so the field is racing to add a second antibody, an antibody-drug conjugate or a vaccine.","India has shown that cheap oral chemotherapy and fractional immunotherapy doses extend life at a small fraction of Western cost."],"history":[{"year":2006,"title":"Cetuximab approved for head and neck cancer","refs":["cetuximab","bonner-cetuximab-rt"]},{"year":2008,"title":"EXTREME: first survival gain in recurrent disease","refs":["extreme"]},{"year":2016,"title":"CheckMate 141: nivolumab after platinum","refs":["checkmate-141"]},{"year":2019,"title":"KEYNOTE-048: pembrolizumab first line","refs":["keynote-048"]},{"year":2020,"title":"Tata Memorial: oral metronomic chemotherapy beats cisplatin","refs":["metronomic-vs-cisplatin-tmh"]},{"year":2023,"title":"Tata Memorial: low-dose nivolumab nearly triples one-year survival","refs":["low-dose-nivolumab-tmh"]},{"year":2025,"title":"Petosemtamab with pembrolizumab: phase 2 responses in about six in ten; phase 3 under way","refs":["petosemtamab","liger-hn1"]}],"pipeline":["petosemtamab","liger-hn1","nct06496178","ficerafusp-alfa","fortifi-hn01","nct07807163","mrg003","nct05751512","nct06601335","nct07276399","bnt113","monalizumab","cetuximab-sarotalocan","nct06699212"],"openProblems":["Most patients still die within two years.","No test yet identifies the minority who gain years from immunotherapy.","Salvage surgery and re-irradiation carry high complication rates.","Access to pembrolizumab and cetuximab in the countries with the most cases."],"parent":"head-and-neck"},"route":"/cancers/recurrent-metastatic-hnscc/","neighbours":{"cancer":[{"id":"head-and-neck","kind":"cancer","name":"Head and neck squamous cell carcinoma","route":"/cancers/head-and-neck/"},{"id":"hpv-negative-head-and-neck-cancer","kind":"cancer","name":"HPV-negative head and neck squamous cell carcinoma (including HPV-negative oropharyngeal cancer)","route":"/cancers/hpv-negative-head-and-neck-cancer/"},{"id":"hpv-positive-oropharyngeal-cancer","kind":"cancer","name":"HPV-positive oropharyngeal cancer","route":"/cancers/hpv-positive-oropharyngeal-cancer/"},{"id":"hypopharyngeal-cancer","kind":"cancer","name":"Hypopharyngeal cancer","route":"/cancers/hypopharyngeal-cancer/"},{"id":"laryngeal-cancer","kind":"cancer","name":"Laryngeal and hypopharyngeal cancer","route":"/cancers/laryngeal-cancer/"},{"id":"oral-cavity-cancer","kind":"cancer","name":"Oral cavity cancer (mouth and tongue)","route":"/cancers/oral-cavity-cancer/"},{"id":"oral-tongue-cancer","kind":"cancer","name":"Oral tongue and floor of mouth cancer","route":"/cancers/oral-tongue-cancer/"},{"id":"oropharyngeal-cancer","kind":"cancer","name":"Oropharyngeal cancer (tonsil and base of tongue)","route":"/cancers/oropharyngeal-cancer/"},{"id":"recurrent-metastatic-nasopharyngeal-carcinoma","kind":"cancer","name":"Recurrent and metastatic nasopharyngeal carcinoma","route":"/cancers/recurrent-metastatic-nasopharyngeal-carcinoma/"}],"drug":[{"id":"bnt113","kind":"drug","name":"BNT113","route":"/drugs/bnt113/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"celecoxib","kind":"drug","name":"Celecoxib","route":"/drugs/celecoxib/"},{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"cetuximab-sarotalocan","kind":"drug","name":"Cetuximab sarotalocan","route":"/drugs/cetuximab-sarotalocan/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"docetaxel","kind":"drug","name":"Docetaxel","route":"/drugs/docetaxel/"},{"id":"ficerafusp-alfa","kind":"drug","name":"Ficerafusp alfa","route":"/drugs/ficerafusp-alfa/"},{"id":"fluorouracil","kind":"drug","name":"Fluorouracil (5-FU)","route":"/drugs/fluorouracil/"},{"id":"hb-200","kind":"drug","name":"HB-200","route":"/drugs/hb-200/"},{"id":"methotrexate","kind":"drug","name":"Methotrexate","route":"/drugs/methotrexate/"},{"id":"monalizumab","kind":"drug","name":"Monalizumab","route":"/drugs/monalizumab/"},{"id":"mrg003","kind":"drug","name":"MRG003","route":"/drugs/mrg003/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"paclitaxel","kind":"drug","name":"Paclitaxel / nab-paclitaxel","route":"/drugs/paclitaxel/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"petosemtamab","kind":"drug","name":"Petosemtamab","route":"/drugs/petosemtamab/"}],"trial":[{"id":"nct05054439","kind":"trial","name":"A Clinical Study of SI-B001 in Combination With Paclitaxel/Docetaxel in the Treatment of Recurrent and Metastatic HNSCC","route":"/trials/nct05054439/"},{"id":"nct05044897","kind":"trial","name":"A Clinical Study to Evaluate the Efficacy and Safety of SI-B001 in the Treatment of Recurrent and Metastatic HNSCC","route":"/trials/nct05044897/"},{"id":"nct04534205","kind":"trial","name":"A Clinical Trial Investigating the Safety, Tolerability, and Therapeutic Effects of BNT113 in Combination With Pembrolizumab Versus Pembrolizumab Alone for Patients With a Form of Head and Neck Cancer Positive for Human Papilloma Virus 16 and Expressing the Protein PD-L1","route":"/trials/nct04534205/"},{"id":"nct06601335","kind":"trial","name":"A Phase 3 Study of AK112 Plus AK117 Versus Pembrolizumab in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)","route":"/trials/nct06601335/"},{"id":"nct06496178","kind":"trial","name":"A Phase 3 Study to Evaluate Petosemtamab Compared With Investigator's Choice Monotherapy in Previously Treated Head and Neck Squamous Cell Carcinoma P","route":"/trials/nct06496178/"},{"id":"nct06062420","kind":"trial","name":"A Platform Study of Novel Immunotherapy Combinations as First-Line Treatment in Participants With PD-L1 Positive Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck- GALAXIES H&N-202","route":"/trials/nct06062420/"},{"id":"nct07807163","kind":"trial","name":"A Study Evaluating Ficerafusp Alfa (BCA101) QW in Combination With Pembrolizumab vs Alternative Ficerafusp Alfa Dosing in 1L R or M HNSCC","route":"/trials/nct07807163/"},{"id":"nct07276399","kind":"trial","name":"A Study of Amivantamab in Addition to Standard of Care Agents (SOC) Compared With SOC Alone in Participants With Recurrent/Metastatic Head and Neck Cancer","route":"/trials/nct07276399/"},{"id":"nct06699212","kind":"trial","name":"A Study of ASP-1929 Photoimmunotherapy in Combination With Pembrolizumab in First-line Treatment of Locoregional Recurrent Squamous Cell Carcinoma of ","route":"/trials/nct06699212/"},{"id":"nct06006169","kind":"trial","name":"A Study of BL-B01D1, SI-B003 and BL-B01D1+SI-B003 in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma and Other Solid Tumor","route":"/trials/nct06006169/"},{"id":"nct06437522","kind":"trial","name":"A Study of BL-B01D1+PD-1 Monoclonal Antibody in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma and Other Solid Tumors","route":"/trials/nct06437522/"},{"id":"nct06064877","kind":"trial","name":"A Study of Ficlatuzumab in Combination With Cetuximab in Participants With Recurrent or Metastatic (R/M) HPV Negative Head and Neck Squamous Cell Carcinoma","route":"/trials/nct06064877/"},{"id":"nct06378177","kind":"trial","name":"A Study of LVGN6051 Combination Therapy in Patient With Head and Neck Squamous Cell Carcinoma (HNSCC)","route":"/trials/nct06378177/"},{"id":"nct06668961","kind":"trial","name":"A Study of SI-B001+SI-B003 Combined With Platinum-based Chemotherapy as First-line Treatment in Patients With Recurrent or Metastatic Head and Neck Sq","route":"/trials/nct06668961/"},{"id":"nct05751512","kind":"trial","name":"A Study to Evaluate MRG003 vs Cetuximab/Methotrexate in in the Treatment of Patients With RM-SCCHN","route":"/trials/nct05751512/"},{"id":"nct06769698","kind":"trial","name":"A Study to See if Giving Fianlimab and Cemiplimab Together is Better Than Cemiplimab Alone at Treating Recurrent or Metastatic Head and Neck Squamous ","route":"/trials/nct06769698/"},{"id":"nct07059221","kind":"trial","name":"A Trial of SHR-A2102 With Adebrelimab With or Without Other Anti-tumor Therapies in Recurrent/MetastaticHead and Neck Squamous Cell Carcinoma Cancer","route":"/trials/nct07059221/"},{"id":"nct03769506","kind":"trial","name":"ASP-1929 Photoimmunotherapy (PIT) Study in Recurrent Head/Neck Cancer for Patients Who Have Failed at Least Two Lines of Therapy","route":"/trials/nct03769506/"},{"id":"nct04590963","kind":"trial","name":"Assessment of Efficacy and Safety of Monalizumab Plus Cetuximab Compared to Placebo Plus Cetuximab in Recurrent or Metastatic Head and Neck Cancer","route":"/trials/nct04590963/"},{"id":"bonner-cetuximab-rt","kind":"trial","name":"Bonner trial (cetuximab plus radiotherapy)","route":"/trials/bonner-cetuximab-rt/"},{"id":"checkmate-141","kind":"trial","name":"CheckMate 141","route":"/trials/checkmate-141/"},{"id":"nct06194656","kind":"trial","name":"Clinical Trial of SIBP-03 in Patients With Head and Neck Squamous Cell Carcinoma","route":"/trials/nct06194656/"},{"id":"nct07617805","kind":"trial","name":"EGFR/HER2 Dual-Target CAR-NK Cells for Recurrent or Metastatic HNSCC","route":"/trials/nct07617805/"},{"id":"extreme","kind":"trial","name":"EXTREME","route":"/trials/extreme/"},{"id":"fortifi-hn01","kind":"trial","name":"FORTIFI-HN01","route":"/trials/fortifi-hn01/"},{"id":"nct06295731","kind":"trial","name":"INBRX-106 in Combination With Pembrolizumab in First-line PD-L1 CPS≥20 HNSCC","route":"/trials/nct06295731/"},{"id":"keynote-048","kind":"trial","name":"KEYNOTE-048","route":"/trials/keynote-048/"},{"id":"liger-hn1","kind":"trial","name":"LiGeR-HN1","route":"/trials/liger-hn1/"},{"id":"low-dose-nivolumab-tmh","kind":"trial","name":"Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial)","route":"/trials/low-dose-nivolumab-tmh/"},{"id":"metro-plus-varanasi","kind":"trial","name":"METRO PLUS (Tata Memorial Centre, Varanasi)","route":"/trials/metro-plus-varanasi/"},{"id":"metronomic-vs-cisplatin-tmh","kind":"trial","name":"Oral metronomic chemotherapy vs intravenous cisplatin (Tata Memorial)","route":"/trials/metronomic-vs-cisplatin-tmh/"},{"id":"nct06016920","kind":"trial","name":"Safety and Efficacy of VB10.16 and Pembrolizumab in Patients With Head-Neck Squamous Cell Carcinoma","route":"/trials/nct06016920/"},{"id":"nct06727565","kind":"trial","name":"Study of Novel Treatment Combination Therapies in Participants With Head and Neck Squamous Cell Carcinoma Regardless of PD-L1 Expression Status; Subst","route":"/trials/nct06727565/"},{"id":"nct05287113","kind":"trial","name":"Study of Retinfanlimab in Combination With INCAGN02385 and INCAGN02390 as First-Line Treatment in Participants With PD-L1-Positive (CPS ≥ 1) Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck","route":"/trials/nct05287113/"},{"id":"nct04843098","kind":"trial","name":"Study of TL117 in Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma","route":"/trials/nct04843098/"},{"id":"nct06082167","kind":"trial","name":"Study of Zanzalintinib (XL092) + Pembrolizumab vs Pembrolizumab in Subjects With PD-L1 Positive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma","route":"/trials/nct06082167/"},{"id":"nct05283226","kind":"trial","name":"Study to Evaluate the Safety and Efficacy of Oral NRC-2694-A in Combination With Paclitaxel in Patients With Recurrent and/or Metastatic Head and Neck","route":"/trials/nct05283226/"},{"id":"nct07254585","kind":"trial","name":"SYS6010 Combined With Enlonstobart In Recurrent Or Metastatic Head And Neck Squamous Cell Carcinoma","route":"/trials/nct07254585/"},{"id":"nct07795034","kind":"trial","name":"To Evaluate the Efficacy and Safety of Accelerator-Based Boron Neutron Capture Therapy (AB-BNCT) Combined With NBB-001 and NBB-002 for Patients With Recurrent Head and Neck Malignancies","route":"/trials/nct07795034/"},{"id":"tpextreme","kind":"trial","name":"TPExtreme (GORTEC 2014-01)","route":"/trials/tpextreme/"}],"paper":[{"id":"paper-checkmate-141-ferris-nejm-2016","kind":"paper","name":"CheckMate 141: nivolumab for recurrent head and neck squamous cell carcinoma after platinum","route":"/key-papers/paper-checkmate-141-ferris-nejm-2016/"},{"id":"paper-extreme-vermorken-nejm-2008","kind":"paper","name":"EXTREME: platinum-based chemotherapy plus cetuximab in recurrent or metastatic head and neck cancer","route":"/key-papers/paper-extreme-vermorken-nejm-2008/"},{"id":"paper-keynote-048-lancet-2019","kind":"paper","name":"KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer","route":"/key-papers/paper-keynote-048-lancet-2019/"},{"id":"paper-patil-low-dose-nivolumab-jco-2023","kind":"paper","name":"Low-dose immunotherapy in head and neck cancer: a randomised study (Tata Memorial)","route":"/key-papers/paper-patil-low-dose-nivolumab-jco-2023/"},{"id":"paper-tpextreme-lancet-oncol-2021","kind":"paper","name":"TPExtreme (GORTEC 2014-01): docetaxel, cisplatin and cetuximab versus the EXTREME regimen in recurrent or metastatic head and neck cancer","route":"/key-papers/paper-tpextreme-lancet-oncol-2021/"}],"term":[{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/"},{"id":"pd-l1-testing","kind":"term","name":"PD-L1 expression testing (22C3, SP142, SP263)","route":"/terms/pd-l1-testing/"}],"technology":[{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"palliative-radiotherapy","kind":"technology","name":"Palliative radiotherapy","route":"/technologies/palliative-radiotherapy/"},{"id":"photoimmunotherapy","kind":"technology","name":"Photoimmunotherapy & photodynamic therapy","route":"/technologies/photoimmunotherapy/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"}],"person":[{"id":"joel-guigay","kind":"person","name":"Joël Guigay","route":"/people/joel-guigay/"},{"id":"robert-ferris","kind":"person","name":"Robert L. Ferris","route":"/people/robert-ferris/"}]}}