• Signed ICF before initiation of any study procedures.

• Age ≥ 18 years at signing of ICF.

• Histologically previously confirmed HNSCC with evidence of metastatic or locally advanced disease not amenable to standard therapy with curative intent.

• HNSCC patients progressed on or after anti-PD-1 therapy and platinum-containing therapy.

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

• Documentation of p16 status (positive or negative) by local laboratory IHC for patients with primary oropharyngeal cancer.

• A baseline new tumor sample unless the patient has an available tumor sample as an FFPE block with sufficient material.

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

• ECOG PS of 0 or 1

• Life expectancy ≥ 12 weeks, as per investigator

• Adequate organ function (as per protocol)