Cetuximab, Docetaxel and Cisplatin as First-Line Treatment in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Results of the GORTEC 2014-01 TPExtreme Randomized Trial

Background: After promising results from TPEx phase II trial in first line recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), this trial compared the TPEx regimen (docetaxel-platinum-cetuximab) to the standard EXTREME regimen. Methods: Patients with R/M HNSCC unsuitable for curative treatment were randomized between TPEx (four cycles docetaxel-cisplatin-cetuximab followed by cetuximab maintenance 500 mg/m² every two weeks) and EXTREME (six cycles 5FU-cisplatin-cetuximab followed by weekly cetuximab 250 mg/m² maintenance). Main inclusion criteria were patients fit for cisplatin, performance status (PS) ≤1, creatinine clearance >60ml/min, and age <70 years. The primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), toxicity, quality of life (qol). Findings: 539 patients were randomized: median age 60 years, 92% smokers, 68% PS1, 40% had oropharyngeal cancer (HPV-DNA positive in 19%). In the EXTREME arm, 44% of patients received all cycles of chemotherapy (CT) vs 72% in the TPEx arm (p<0.0001). OS was not significantly different between arms: HR=0.89 (95%CI: 0.74-1.08, p=0.23), median OS was 13.4 months in the EXTREME arm vs 14.5 in the TPEx arm. There was no significant difference between arms for PFS (HR=0.88 (95%CI 0.74-1.04, p=0.14), median PFS was 6.2 months in the EXTREME arm vs 6.0 in the TPEx arm. Toxicity was lower in the TPEx arm than in the EXTREME arm: 36% vs 52% of patients with grade ≥4 adverse events during CT (p<0.002). More patients started maintenance in the TPEx arm than in the EXTREME arm (72% vs 52%, p<0.0001). During the first six months, better qol was observed in the TPEx arm compared to the EXTREME arm for several QLQ-C30 scores including global health status (p=0.03). Interpretation: This trial confirmed the good survival results of the TPEx regimen. Despite lack of significant OS increase, TPEx regimen appeared superior than EXTREME for compliance, safety and qol.  Trial Registration: ClinicalTrials.gov identifier: NCT 02268695 Funding Statement: Merck Sante S.A.S., Lyon, France, an affiliate of Merck KGaA, Darmstadt, Germany, Chugai Pharma, Paris La Defense, France Declaration of Interests: JG has received research grant from Boehringer Ingelheim, BMS, Chugai, GSK, Merck Serono and Sanofi and has been an advisory board member for Astra Zeneca, BMS, Innate Pharma, Merck. AA has received grant support, paid to her institution, from the GORTEC for this study and has received grant support, paid to her institution, from F. Hoffmann–La Roche, outside this study. JF reports grants, personal fees and non-financial support from ASTRA ZENECA and BMS, personal fees and non-financial support from MSD, personal fees from MERCK and INNATE, outside the submitted work. UK Dr. Keilholz reports grants and personal fees from Merck KGaA. JB participated to advisory boards of MSD, BMS, Debiopharm, Merck, AstraZeneca. RM has received research grant from Merck-Serono and has been an advisory board member for Astra Zeneca, BMS, Rakuten, Merck-Serono, MSD, Nanobiotics, Bayer, Roche. PS reports personal fees from Merck Serono, outside the submitted work. CE reports personal fees from Astra Zeneca, BMS, Innate Pharma, Merck SD, Merck Serono. LG reports personal fees from BMS, IPSEN, Merck Serono, MSD, Pfizer. The remaining authors have no disclosure. Ethics Approval Statement: This study was approved by Competent authorities and ethics committees in July 2014 (France), October 2014 (Spain), and May 2015 (Germany). All patients gave written informed consent prior any study procedure.