• Signed ICF before initiation of any study procedures

• Age ≥ 18 years at signing of ICF

• Histologically confirmed HNSCC with evidence of metastatic or locally recurrent disease not amenable to local therapy with curative intent.

• The eligible HNSCC primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx.

• HNSCC patients eligible to receive pembrolizumab as 1L monotherapy with tumors expressing PD-L1, CPS ≥1.

• HNSCC patients should not have had previous systemic therapy administered in the incurable recurrent or metastatic setting

• A new tumor biopsy, unless the patient has an available archival tumor sample with sufficient material

• Measurable disease per Investigator assessment as defined by RECIST v1.1 by radiologic methods

• ECOG Performance Status (PS) of 0-1

⁃ Life expectancy ≥ 12 weeks, as per investigator assessment.

⁃ Left ventricular ejection fraction (LVEF) ≥50% or ≥ institutional normal limit, whichever is higher, by echocardiogram (ECHO) or multigated acquisition (MUGA) scan

⁃ Adequate organ function as defined per protocol.

⁃ HIV-positive patients are eligible only if the cluster of differentiation 4 (CD4+) count is ≥ 300/µl, viral load is undetectable, and the patient is currently receiving highly active antiretroviral therapy