⁃ \- Informed consent

• Signed written and voluntary informed consent.

• Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.

• Age \> 18 years old. Disease characteristics

• Have histologically confirmed diagnosis of head and neck squamous cell carcinoma.

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

• Known Human papillomavirus (HPV) status in oropharyngeal primaries and tested by p16 and/or HPV DNA testing by ISH or PCR. Local testing is acceptable.

• Have confirmed disease progression per RECIST 1.1 on or after receiving platinum / 5-FU and pembrolizumab as first-line therapy for recurrent/metastatic disease. Patients must have measurable disease assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI) based on RECIST 1.1 as assessed by the local site investigator/radiology. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• All patients must provide a tumor biopsy obtained prior to the start of cetuximab +/- paclitaxel. A newly obtained biopsy -after progression to pembrolizumab + platinum-based chemotherapy - of a tumor lesion not previously irradiated for central biomarker analysis prior to start of study treatment is strongly preferred, but an archival sample may be acceptable upon discussion with the sponsor, if obtained in the prior 12 months.

• Note: Fine needle aspirate \[FNA\] is not adequate. Repeat samples may be required if adequate (quality and quantity) tissue is not provided. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides

• Patient characteristics

• Have a performance status of 0 or 1 on the ECOG Performance Scale

⁃ Patients must have adequate organ function as determined by the following. Screening labs should be performed within -7 days of treatment initiation:

⁃ a. Hematology

‣ Absolute neutrophils \> 1.5 x 109/L

‣ Platelets \> 100 x 109/L

‣ Hemoglobin \> 90 g/L

‣ Biochemistry

‣ Bilirubin \< 1.5 x upper limit of normal (ULN)

‣ AST and ALT \< 2.5 x ULN

‣ Creatinine or measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤ 1.5xULN or ≥ 60 mL/min, respectively.

⁃ Note: Hematology test should be obtained without transfusion or receipt of colony stimulating factors within 4 weeks prior to obtaining the sample.

⁃ Evidence of post-menopausal status, or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

• Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

∙ Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

⁃ Female subjects of childbearing potential should have a negative blood pregnancy test within 72 hours prior to receiving the first dose of study medication. A urine test can be considered if a blood test is not appropriate.

⁃ Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 180 days after the last dose of study medication (6 months for paclitaxel). Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \>1 year.

⁃ Note: Abstinence is acceptable if this is the usual lifestyle and preferred method of contraception for the subject.

⁃ Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 180 days after the last dose of study therapy (6 months for paclitaxel).

⁃ Note: Abstinence is acceptable if this is the usual lifestyle and preferred method of contraception for the subject.