A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

  • End date
    Jul 30, 2026
  • participants needed
  • sponsor
    Merck Sharp & Dohme LLC
Updated on 19 August 2022
ct scan
squamous cell carcinoma
dental caries
squamous cell carcinoma of head and neck
human papillomavirus
intensity-modulated radiation therapy
carcinoma of oropharynx
advanced head and neck squamous cell carcinoma


This is a randomized, active-controlled, open-label study of pembrolizumab (Pembro) given prior to surgery and pembrolizumab in combination with standard of care radiotherapy (with or without cisplatin), as post-surgical therapy in treatment naïve participants with newly diagnosed Stage III/IVA, resectable, locoregionally advanced, head and neck squamous cell carcinoma (LA-HNSCC). Efficacy outcomes will be stratified by programmed cell death ligand 1 (PD-L1) combined positive score (CPS) status. The primary hypothesis is that pembrolizumab given before surgery and after surgery in combination with radiotherapy (with or without cisplatin) improves major pathological response and event-free survival compared to radiotherapy (with or without cisplatin) given after surgery alone.

Condition Head and Neck Neoplasms
Treatment Pembrolizumab 200 mg, Radiotherapy 60 Gray/day, Radiotherapy 66 Gray/day, Radiotherapy 70 Gray/day, Cisplatin 100 mg/m^2
Clinical Study IdentifierNCT03765918
SponsorMerck Sharp & Dohme LLC
Last Modified on19 August 2022


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Inclusion Criteria

Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries
Is eligible for primary surgery based on investigator decision and per local practice
Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy
Male participants must refrain from donating sperm throughout the study period and for up to 180 days after the last dose of study therapy
Female participant that is not pregnant or breastfeeding
Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST version 1.1
Has provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
Has results from testing of HPV status for oropharyngeal cancer defined as p16
Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of randomization

Exclusion Criteria

Has Stage T4B and/or N3 LA HNSCC and/or distant metastases
Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity. such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer (HNC)
Female participant who has a positive urine pregnancy test within 72 hours prior to study start or within 24 hours prior to the start of radiotherapy with or without cisplatin
Has received prior therapy with an anti-programmed cell death receptor 1(PD-1), anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor
Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to study start
Has received a live vaccine within 30 days prior to randomization
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy
Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis
Has Grade ≥2 audiometric hearing loss
Has Grade ≥2 neuropathy
Has Grade 3-4 bleeding due to the underlying malignancy
Has received major surgery or has not recovered adequately from the toxicity and/or complications from the intervention prior to study start
Has had previous allogeneic tissue/solid organ transplant
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, radiotherapy, cisplatin or their analogs
Has an active autoimmune disease that has required systemic treatment in past 2 years
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
Has an active infection requiring systemic therapy
Has a known history of human immunodeficiency virus (HIV) infection
Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] ribonucleic acid is detected)
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator
Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
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