• Incurable RM-HNSCC, defined as RM disease or second or subsequent primary HNSCC not amenable to cure by surgery and/or radiation therapy or patient declines or is ineligible for curative therapy. Eligible primary tumor sub-sites include oral cavity, oropharynx, larynx and hypopharynx only.

• PD-L1 positive (CPS ≥1) disease, based on local IHC assay using 22C3 antibody.

• Measurable disease per RECIST 1.1.

• No prior systemic therapy for RM-HNSCC. RM disease developing within 6 months of completion of either a) systemic platinum or cetuximab therapy given as a component of a curative-intent multi-modality regimen or b) radiation therapy and/or surgery is eligible.

• At least 18 years of age.

• ECOG performance status 0-1.

• Normal bone marrow and organ function as defined below:

‣ Absolute neutrophil count ≥ 1.5 K/cumm

⁃ Platelets ≥ 100 K/cumm

⁃ Hemoglobin ≥ 9.0 g/dL

⁃ Total bilirubin ≤ 1.5 x IULN

⁃ AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN. In the setting of liver metastases, AST(SGOT)/ALT(SGPT) ≤ 5.0 x IULN

⁃ Creatinine ≤ 1.5 x ULN. If patient has creatinine \> 1.5 x ULN, then 24 hour urine collection must be performed and creatinine clearance must be ≥ 40 mL/min by Cockcroft-Gault

⁃ Urine protein to creatinine ratio (UPC) ≤ 1; if UPC \> 1, then a 24-hour urine protein must be assessed and patient must have a 24-hour urine protein value \< 1 g to be eligible

⁃ INR ≤ 1.5 (≤ 3.0 if on warfarin) and PTT ≤ 1.5 x ULN (Patients are allowed to be on anticoagulation)

• The effects of Ramucirumab on the developing human fetus are unknown. For this reason and because VEGFR2 inhibiting agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of the study, and 28 days after completion of the study.

• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).