Background: Cetuximab (C) improves outcomes when added to chemotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN). C resistance is associated with nuclear localization of the epidermal growth factor receptor (EGFR). We hypothesized that an EGFR tyrosine kinase inhibitor (TKI) would improve response to C through inhibition of nuclear translocation of EGFR and undertook a Phase II study of total EGFR blockade, adding Erlotinib (E) to chemotherapy and C in patients with recurrent/metastatic SCCHN. Methods: 24 patients were enrolled. Following baseline tumor assessment and biopsy, they were treated with carboplatin (AUC 2 weekly)/paclitaxel (80mg/m² weekly) and C (400mg/m² loading, then 250mg/m²weekly thereafter). After the first 21-day cycle, biopsy was repeated, then therapy resumed with the addition of E (150mg daily x 2 days followed by 100mg daily) then a repeat biopsy after cycle 2. Treatment continued until disease progression or unacceptable toxicity. Restaging was done prior to cycles 2 and 4 and every 9 weeks thereafter. Primary end point was objective response rate (ORR) by RECIST v 1.1 – complete (CR) and partial (PR) responses. Secondary end points: toxicity, overall survival (OS) and laboratory correlates. Results: Median age for the group was 65.5 years. Patients received a median of 6 (range 1-17) cycles. 12/24 (50%) had objective responses (12 PR, 0 CR). 1 patient had a pathological complete response and 2 were consolidated with definitive radiation with no recurrence at 9 and 41 months. 7/24 (29%) had stable disease. For intent to treat population, median progression-free survival (PFS) and OS were 5.8 and 8.1 months, while for per protocol population, median OS was 10.6 months. 5 patients are alive at the time of analysis. Dose modification for toxicity was required in 50% of patients. Main toxicities were cytopenia, diarrhea, neuropathy, hypomagnesemia and rash. Conclusions: Total EGFR blockade demonstrated excellent efficacy and tolerability in this small sample. ORR, PFS, OS are comparable to historical controls treated with the EXTREME regimen. Correlative analyses are ongoing. Clinical trial information: NCT01316757