Background: In platinum-resistant RM-HNSCC, the efficacy of cetuximab is modest with a tumor response rate of 13%, median time to progression of 2.3 months and median overall survival (OS) of 6 months (Vermorken JCO 2007). In HPV (-) HNSCC, p16 inactivation and/or CCND1 (cyclin D1) amplification are ubiquitous events that result in hyperactivation of the CDK/cyclin D regulatory complex and Rb inactivation. Deregulated cyclin D1 expression is a mechanism of resistance to EGFR inhibitors. In a phase I trial, palbociclib, a potent CDK4/6 inhibitor, given with cetuximab, was safe and tumor responses were observed in RM HNSCC (Adkins Oral Oncology 2016). Methods: In a phase II trial, patients with platinum-resistant, cetuximab-naive HPV (-) RM HNSCC were treated with palbociclib 125 mg po/d Days 1-21 of 28 day cycles and weekly cetuximab. Platinum-resistance was defined as: progression on platinum in the RM setting; cetuximab-naïve was defined as: no prior cetuximab for RM disease. HPV (-) disease was defined as SCC of the oral cavity, larynx, hypopharynx or p16 negative SCC of the oropharynx. Tumor response assessments (RECIST 1.1) were performed every 2 cycles. We hypothesized that palbociclib and cetuximab would increase the tumor response rate from 13% (historical data with cetuximab) to > 26%. Futility assessments of response and toxicity occurred after every 6 patients (sample size: 30) using a Bayesian monitoring method. Results: 30 patients were enrolled. Median age 67 years (range: 26-84). Sites of recurrence: local/regional (6), distant (8), or both (16). Tumor response occurred in 35% (8 of 23 evaluable to date). Decrease in target lesions occurred in 57% (13 of 23 evaluable). Median progression free survival (PFS) was 6.4 months and median OS was 12.1 months. Immunotherapy was given to three patients before and eight after study participation. Conclusions: Palbociclib and cetuximab resulted in a robust tumor response rate and prolongation of PFS and OS in platinum-resistant HPV (-) RM-HNSCC. The median OS of 12.1 months is the longest reported for patients with platinum-resistant RM HNSCC. Clinical trial information: NCT02101034