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 This was a placebo-controlled, double-blind, single-center phase II study. Patients ( N = 120) were randomly assigned (1 : 1) to receive platinum (carboplatin area under the curve 6 or cisplatin 75 mg/m 2 every 21 days for six cycles) plus docetaxel (75 mg/m 2 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.