Cisplatin and 5-Fluorouracil with or Without Epidermal Growth Factor Receptor Inhibition Panitumumab for Patients with Non-Resectable, Advanced or Metastatic Esophageal Squamous Cell Cancer: A Prospective, Open-Label, Randomised Phase 3 AIO/EORTC Trial (Power)

Abstract

Background: Advanced unresectable esophageal squamous cell cancer (ESCC) is treated with palliative chemotherapy of cisplatin and 5-fluorouracil (CF). Targeting epidermal growth factor receptor (EGFR) with antibodies panitumumab (P) or cetuximab with chemotherapy enhanced overall survival (OS) in metastatic colorectal cancer or squamous cell cancer of head and neck. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in confirmed advanced ESCC. Methods: 146 patients, not curatively resectable and not qualified for definitive radio-chemotherapy were randomised 1:1 to CF (cisplatin [100 mg/m² i.v., day 1] and 5-fluorouracil [1000 mg/m²/day i.v., days 1-4]), versus CF plus P [9 mg/kg, i.v., day 1], each q3-week cycle) until progressive disease or inacceptable toxicity. Safety was reviewed by a pre-planned Monitoring Board after 40, 70 and 100 patients completing at least one cycle. After 53 patients enrolled, cisplatin was amended from 100 to 80 mg/m². Findings: The academic phase 3 trial was terminated early for futility on an interim efficacy analysis: median OS favoured CF over CFP, regardless of cisplatin dose (HR 1·77, 95%CI 1·06-2·98; p=0·028). In the final analysis, median OS was 10·2 vs 9·4 months for CF vs CFP, respectively (HR 1·17, 95%CI 0·79-1·75; p=0·43). Most deaths were related to disease progression, 44 (56·4%) in CF and 34 (43·6%) in CFP. Objective responses (27/73 [37·0%]) were identical in both arms. Most common severe adverse events were kidney injury (3 [4·3%] vs 7 [9·7%]), general deterioration (5 [7·1%] vs 5 [6·9%]), and dysphagia (4 [5·7%] vs 4 [5·6%]) in CF vs CFP, respectively. High levels of soluble (s)EGFR were associated with worse PFS. sEGFR was induced under CFP. Interpretation: Cisplatin/5-fluorouracil is an established palliative regimen in unselected advanced or metastatic ESCC patients. EGFR inhibition added to CF did not improve survival. Biomarker results support further liquid biomarker studies. Trial Registration Number: The study is registered with ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15). Funding: The trial was funded by AIO-Studien-gGmbH. Partial financial support and panitumumab were provided by Amgen Inc. Declaration of Interest: MM has travel support and advisory role for Amgen. FL reports personal fees from Amgen. All other authors declare that they have no conflicts of interest during the conduct of the study. Ethical Approval: The clinical study protocol was reviewed and approved by the responsible ethics committees of all participating sites. The trial was conducted in accordance with the principles of the International Conference on Harmonisation on Good Clinical Practice. All patients gave written informed consent before enrolment and any trial-specific procedures.