A 65-year-old White male with a history of heavy smoking was initially diagnosed with squamous cell cancer (SCC) of the epiglottis in 2003 and treated with radiotherapy….CCND1 amplification was identified as the only targetable mutation for an off-label indication of CDK4/CDK6 inhibitors....Our case reporting an unexpectedly durable response to cetuximab following the failure of multiple lines of therapy, most recently nivolumab, aligns with several other retrospective case series and supports further investigation of the potential synergistic effects of sequential therapy with ICI followed by cetuximab in prospective studies.