A Study of Pembrolizumab (MK-3475) for First Line Treatment of Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck (MK-3475-048/KEYNOTE-048)

A Phase 3 Clinical Trial of Pembrolizumab (MK-3475) in First Line Treatment of Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Participants with recurrent or metastatic (R/M) squamous cell cancer of the head and neck (HNSCC) will be randomly assigned to receive pembrolizumab monotherapy [pembro mono], pembrolizumab plus chemotherapy with a platinum-based drug (cisplatin or carboplatin) and 5-Fluorouracil (5-FU) [pembro combo], or cetuximab plus a platinum-based drug (cisplatin or carboplatin) and 5-FU [control]. The overall primary study hypotheses are as follows in all participants and in participants with Programmed Cell Death Ligand 1 (PD-L1) positive expression defined by Combined Positive Score (CPS) ≥1 and CPS ≥20: 1) pembrolizumab monotherapy prolongs progression free survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) assessed by Blinded Independent Central Review (BICR) and prolongs overall survival (OS) compared to standard treatment, and 2) pembrolizumab combination with chemotherapy prolongs PFS per RECIST 1.1 assessed by BICR and prolongs OS compared to standard treatment.

The 12 primary superiority hypotheses will be evaluated by comparing the pembro mono arm or pembro combo arm separately to the control arm, for PFS and OS in all first line (1L) R/M HNSCC participants and in 1L R/M HNSCC participants with positive PD-L1 expression (PD-L1 CPS ≥1 and CPS ≥20).

Per protocol, response/progression or adverse events (AEs) that occur during the second pembrolizumab course will not be counted towards efficacy outcome measures or safety outcome measures, respectively.

Inclusion Criteria:

• Histologically- or cytologically-confirmed recurrent or metastatic head and neck squamous cell carcinoma considered incurable by local therapies
• No prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy completed > 6 months prior if given as part of multimodal treatment for locally advanced disease)
• Primary tumor locations of oropharynx, oral cavity, hypopharynx, or larynx. Participants may not have a primary tumor site of nasopharynx (any histology)
• Measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Adequate organ function
• Can provide tissue for PD-L1 biomarker analysis from a core or excisional biopsy (fine needle aspirate is not sufficient): A newly obtained biopsy (within 90 days prior to start of study treatment) is preferred but an archival sample is acceptable.
• Have results from testing of human papillomavirus (HPV) status for oropharyngeal cancer
• Female participants of childbearing potential should have a negative pregnancy test and must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication
• Male participants must agree to use an adequate method of contraception starting with the first dose of study medication through 180 days after the last dose of study medication

Exclusion Criteria:

• Disease suitable for local therapy administered with curative intent
• Has progressive disease (PD) within six (6) months of completion of curatively intended systemic treatment for locoregionally advanced HNSCC
• Radiation therapy (or other non-systemic therapy) within 2 weeks prior to randomization or not fully recovered from adverse events due to a previously administered treatment
• Currently participating and receiving study therapy, or participated in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks of the first dose of study medication
• Life expectancy of <3 months and/or has rapidly progressing disease
• Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication (physiologic doses of corticosteroids may be approved after consultation with the Sponsor)
• Diagnosed and/or treated additional malignancy within 5 years prior to randomization with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cervical and/or breast cancers
• Has had an allogeneic tissue/solid organ transplant
• Active central nervous system metastases and/or carcinomatous meningitis
• Active autoimmune disease that has required systemic treatment in past 2 years; replacement therapy is not considered a form of systemic treatment
• History of (non-infectious) pneumonitis that required steroids or current pneumonitis
• Active infection requiring systemic therapy
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study medication
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or previously participated in Merck MK-3475 clinical trial
• Known history of human immunodeficiency virus (HIV)
• Known active Hepatitis B or C
• Received a live vaccine within 30 days of planned start of study medication