- Has histologically confirmed diagnosis of R/M HNSCC that is considered incurable by
Note: Participants with newly-diagnosed HNSCC must be M1/Stage IV.
- Has a primary tumor location of oropharynx, oral cavity, hypopharynx, or larynx.
Note: Primary tumor site of nasopharynx (any histology) or unknown primary tumor (including
p16+ unknown primary) are not eligible.
Contraceptive use by men should be consistent with local regulations regarding the methods
of contraception for those participating in clinical studies. If the contraception
requirements in the local label for any of the study interventions is more stringent than
the requirements above, the local label requirements are to be followed.
- Male participants agree to use approved contraception during the treatment period for
at least 7 days after the last dose of lenvatinib/placebo, or refrain from
heterosexual intercourse during this period
- Female participants are not pregnant or breastfeeding, and are not a woman of
childbearing potential (WOCBP), OR are a WOCBP that agrees to use contraception during
the treatment period (or 14 days prior to the initiation of study treatment for oral
contraception) and for at least 120 days post pembrolizumab, or 30 days post
lenvatinib/placebo, whichever occurs last
- Has measurable disease per RECIST 1.1 as assessed by BICR. Note: Lesions situated in a
previously irradiated area are considered measurable if progression has been showed in
- Participants with oropharyngeal cancer must have results from testing of human
papillomavirus HPV status.
- Has an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
- Has adequately controlled blood pressure with or without antihypertensive medications.
- Has adequate organ function.
- Has a history of any contraindication or has a severe hypersensitivity to any
components of pembrolizumab (≥Grade 3) or lenvatinib.
- Has pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
- Has a history of a gastrointestinal condition or procedure that, in the opinion of the
investigator, may affect oral study drug absorption.
- Has clinically significant cardiovascular impairment within 12 months of the first
dose of study intervention, such as history of congestive heart failure greater than
New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or
cerebrovascular accident/transient ischemic attack (TIA)/stroke, cardiac
revascularization, or cardiac arrhythmia associated with hemodynamic instability.
- Has disease that is suitable for local therapy administered with curative intent.
- Had PD within 6 months of completion of curatively intended systemic treatment for
locoregionally advanced HNSCC.
- Has had major surgery within 3 weeks before to first dose of study interventions.
- Has difficulty swallowing capsules or ingesting a suspension orally or by a feeding
- Has received prior therapy with lenvatinib or pembrolizumab.
- Received last dose of systemic therapy for locoregionally advanced disease less than 6
months before signing consent.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
CTLA-4, OX-40, CD137).
- Has received prior systemic anticancer therapy including investigational agents within
4 weeks before randomization.
- Has received prior radiotherapy within 2 weeks of start of study intervention.
- Has received a live vaccine within 30 days before the first dose of study
intervention. Administration of killed vaccines is allowed.
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks before the first dose of
- 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 the first dose of study intervention.
- Has a known additional malignancy that is progressing or has required active treatment
within the past 3 years.
Note: Participants 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 carcinomatous
- Has an active autoimmune disease that has required systemic treatment in 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 considered a form
of systemic treatment and is allowed.
- Has a history of (non-infectious) pneumonitis that required steroids or has current
- Has an active infection requiring systemic therapy. (e.g., tuberculosis, known viral
or bacterial infections, etc.).
- Has a known history of human immunodeficiency virus (HIV) infection.
- Has a known history of hepatitis B (defined as HBsAg reactive) or known active
hepatitis C virus (defined as HCV ribonucleic acid (RNA) [qualitative] is detected)
- Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study, starting with the screening visit through 120 days
after the last dose of study intervention.
- Has had an allogenic tissue/solid organ transplant.
- Has a known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study.