Inclusion Criteria:
- Histologically confirmed recurrent (not amenable to curative treatment with local
and/or systemic therapies) or metastatic (disseminated) HNSCC of the oral cavity,
oropharynx, hypopharynx, and/or larynx that is considered incurable by local
therapies.
- Disease progression at any time during or after treatment with a platinum-containing
(e.g., carboplatin or cisplatin) regimen.
- Disease progression on or after treatment with an anti-PD-1/PD-L1 mAb (programmed cell
death protein 1/programmed death-ligand 1 monoclonal antibody).
- Pre-study imaging that demonstrates evidence of disease progression based on
investigator review of at least 2 pre-study images per RECIST 1.1, following
initiation of treatment with a PD-1/PD-L1 inhibitor.
- Measurable disease by CT or MRI based on Response Criteria in Solid Tumors Version 1.1
(RECIST 1.1) as verified by blinded independent central review (BICR). Tumor lesions
situated in a previously irradiated area are considered measurable if progression has
been demonstrated in such lesions.
- ECOG performance status of 0 or 1 assessed within 7 days of the first dose of study
intervention.
- Male participants are eligible to participate if they agree to the following during
the intervention period and for at least 1 week after the last dose of lenvatinib, 3
months after the last dose of capecitabine and paclitaxel, and and 6 months after the
last dose of docetaxel:
- Refrain from donating sperm
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
(abstinent on a long term and persistent basis) and agree to remain abstinent; or
must agree to use contraception unless confirmed to be azoospermic.
- Contraceptive use by men should be consistent with local regulations regarding
the methods of contraception for those participating in clinical studies.
- A female participant is eligible to participate if she is not pregnant or
breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
- Is a WOCBP and using a contraceptive method that is highly effective (with a
failure rate of <1% per year), with low user dependency or be abstinent from
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a
long term and persistent basis), during the intervention period and for at least
120 days post pembrolizumab or 1 month post lenvatinib, whichever occurs last
(Arms 1 and 3), or during the intervention period and for at least 6 months after
the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last
dose of cetuximab (Arm 2).
- Female participants who randomize to Arm 2 must also agree not to donate or
freeze/store eggs during the intervention period and for at least 6 months after
the last dose of capecitabine, docetaxel, paclitaxel; and 2 months after the last
dose of cetuximab.
- Contraceptive use by women should be consistent with local regulations regarding
the methods of contraception for those participating in clinical studies.
- Adequately controlled blood pressure (BP) with or without antihypertensive
medications.
- Adequate organ function.
Exclusion Criteria:
- Carcinoma of the nasopharynx, salivary gland, unknown primary origin, or nonsquamous
histologies as primary tumors.
- Disease that is suitable for local therapy administered with curative intent.
- Life expectancy of less than 3 months and/or has rapidly progressing disease in the
opinion of the treating investigator.
- History of (noninfectious) pneumonitis/interstitial lung disease that required
steroids, or has current pneumonitis/interstitial lung disease.
- Active infection requiring systemic therapy.
- 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.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Known additional malignancy that is progressing or has required active systemic
treatment within the past 3 years, except basal cell carcinoma of the skin, squamous
cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ that have
undergone potentially curative therapy.
- Active autoimmune disease that has required systemic treatment in the past 2 years.
- Had an allogeneic tissue/solid organ transplant.
- Known history of human immunodeficiency virus (HIV) infection.
- History of hepatitis B or known active hepatitis C virus.
- History of any contraindication or has a severe hypersensitivity to any components of
pembrolizumab, lenvatinib or SOC chemotherapy.
- Pre-existing ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
- History of a gastrointestinal malabsorption or any other condition or procedure that
may affect oral study drug absorption.
- Had major surgery within 3 weeks prior to first dose of study interventions.
- Clinically significant cardiovascular impairment within 12 months of the first dose of
study drug.
- Active tuberculosis.
- Has difficulty swallowing capsules or ingesting a suspension orally, or by a feeding
tube.
- Prior treatment with lenvatinib.
- Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
weeks prior to Study Day 1 or has not recovered from adverse events (AEs) due to a
previously administered agent.
- Has received a live or live attenuated vaccine within 30 days prior to the first dose
of study intervention. Note: Administration of killed vaccines is allowed.
- Previously treated with 4 or more systemic regimens given for recurrent/metastatic
disease.
- Currently participating in or has participated in a study of an investigational agent
and received study therapy or used an investigational device within 4 weeks prior to
the first dose of study intervention.
- Known psychiatric or substance abuse disorder that would interfere with the
participant's ability to cooperate with the requirements of the study.
