Inclusion Criteria:

• The participant (or legally acceptable representative if applicable) provides written informed consent for the study.
• Must be ≥ 18 years of age on the day of signing the informed consent.
• Have a history of histologically or cytologically-confirmed diagnosis of squamous cell cancer of the head and neck (HNSCC) that is recurrent, metastatic, or persistent with:
  • Confirmed HPV16 infection;
  • Confirmed tumor PDL1 expression defined as a CPS ≥ 1 using the FDA-approved Dako PD-L1 IHC 22C3 PharmDx Assay.
• Subjects may not have received any immunological therapy for metastatic disease.
• Have recurrent and/or metastatic measurable disease based on RECIST 1.1 as assessed by the local PI/radiology. There must be confirmation that the subject's imaging shows at least 1 lesion that is appropriate for selection as a target lesion per RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have adequate organ function as defined below. Specimens must be collected within 10 days prior to the start of study combination treatment.
• If subject received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
• For female subjects defined as Women of childbearing potential (WOCBP) a negative urine pregnancy test must be obtained during screening. Women who are surgically sterile or at least 2 years postmenopausal do not require pregnancy testing.
  • Note: Female subjects of childbearing potential must be willing to use an effective method of contraception for the course of the study through 120 days after the last dose of study medication.
• Male subjects of childbearing potential must agree to use an effective method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

Exclusion Criteria:

• Pregnancy Exclusion:
  • A female subject defined as a WOCBP who has a positive serum pregnancy test (e.g., within 14 days) prior to treatment.
• Has received prior therapy with an anti-PD-1, anti-PD- L1, or anti-PD-L2 agent with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137) and was discontinued from that treatment due to a Grade 3 or higher AE.
• Has received prior systemic anti-cancer therapy including investigational agents within 30 days prior to treatment.
  • Note: Subjects must have recovered from all AEs due to previous therapies to < Grade 1 baseline.  Subjects with < 2 Grade neuropathy and < 2 Grade alopecia are an exception to this criterion  and may qualify for therapy.
  • Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting treatment.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Subjects must have recovered from all-radiation-related toxicities, not require corticosteroids and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (< 2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Received immunotherapy/immunomodulatory or immunosuppressive agents (e.g., IFNs, tumor necrosis factor, interleukins, immunoglobulins or other biological response modifiers [GM-CSF, granulocyte colony-stimulating factor, macrophage colonystimulating factor]) within 6 weeks prior to administration of the first study combination treatment.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 30 days prior to the first dose of study treatment.
  • Note: Subjects who entered the follow-up phase of an investigational study may participate as long as it has been 30 days after the last dose of the investigational agent.
• Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of graftversus-host disease (GVHD).
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. Current or recent use of physiologic doses of intra-articular, topical, or inhaled corticosteroids is acceptable.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
  • Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• Has known active central nervous system (CNS) metastases and/or carcinomatosis meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable; i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that repeat imaging should be performed during study screening clinical stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment).
• Has severe hypersensitivity (> Grade 3) to pembrolizumab and/or any of its excipients.
• Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g.,thyroxine, insulin or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not consider a form of systemic treatment and is allowed.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.