A randomized, placebo-controlled, phase II study of docetaxel and platinum with or without erlotinib in recurrent/metastatic head and neck squamous-cell carcinomas

PURPOSE: We conducted a randomized phase II trial to evaluate whether adding erlotinib to platinum/docetaxel improves clinical outcomes in the first-line treatment of recurrent or metastatic head and neck squamous-cell carcinomas, building on our previous single-arm phase II trial. PATIENTS AND METHODS: every 21 days for six cycles) with either erlotinib (150 mg/day orally until progression) or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rates, duration of response, and correlations of erlotinib-induced rash/biomarkers with outcomes. RESULTS: Median PFS was 6.1 months with erlotinib versus 4.4 months with placebo [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.42-0.95, P = 0.026]. Median overall survival was 17.0 months in the erlotinib arm compared with 13.7 months in the control arm (HR 0.67, 95% CI 0.43-1.04, P = 0.0718), meeting the prespecified type I error threshold. Subgroup analyses demonstrated numerically favorable PFS HRs across most clinical subgroups, with a more pronounced benefit observed in patients with oropharyngeal and human papillomavirus-related tumors. Development of grade ≥2 rash during the first cycle of erlotinib was associated with significantly improved overall survival (HR 0.40, 95% CI 0.19-0.87, P = 0.021). The addition of erlotinib increased the incidence of grade 2-4 adverse events, particularly gastrointestinal toxicity, rash, fatigue, and dehydration but no unexpected safety signals were observed. CONCLUSIONS: The study met its primary endpoint, supporting the continued relevance of epidermal growth factor receptor (EGFR) inhibition in this disease. Although contemporary immunotherapy-based standards limit direct adoption of this regimen, these results provide clinically meaningful insight into EGFR biology and support further development of modernized, tyrosine kinase inhibitor-based EGFR strategies, including rational combinations and biomarker-driven approaches, to improve outcomes.