David Malka1, Eric François2, Frédérique Penault-Llorca3, Florence Castan4, Olivier Bouché5, Jaafar Bennouna6, François Ghiringhelli7, Christelle de la Fouchardière8, Christophe Borg9, Emmanuelle Samalin10, Jean-Baptiste Bachet11, Jean-Luc Raoul12, Laurent Miglianico13, Leila Bengrine-Lefèvre14, Laetitia Dahan15, Cédric Lecaille16, Thomas Aparicio17, Trevor Stanbury18, Hervé Perrier19, Anne Cayre20, Pierre Laurent-Puig21, Sophie Gourgou4, Jean-François Emile22, Julien Taïeb23. 1. Department of Cancer Medicine, Gustave Roussy, Université Paris-Saclay, Villejuif, France. Electronic address: david.malka@gustaveroussy.fr. 2. Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France. 3. Pathology Unit, Centre Jean Perrin, UMR 1240 INSERM IMoST, Université Clermont Auvergne, Clermont-Ferrand, France. 4. Biometrics Unit, Institut du Cancer de Montpellier-Val d'Aurelle, Université de Montpellier, Montpellier, France. 5. Department of Hepatogastroenterology and Digestive Oncology, Hôpital Robert Debré, Reims, France. 6. Department of Medical Oncology, Institut de Cancérologie de l'Ouest René Gauducheau, Saint-Herblain, France. 7. Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon, France. 8. Department of Medical Oncology, Centre Léon Bérard, Lyon, France. 9. Cancer Immunotherapy, INSERM U1098 EFS/BFC, Besançon, France. 10. Digestive Oncology Unit, Institut du Cancer de Montpellier-Val d'Aurelle, Montpellier, Université de Montpellier, France. 11. Sorbonne Université, Hôpitaux Universitaires Pitié-Salpétrière, Department of Hepatogastroenterology, APHP, Paris, France. 12. Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France. 13. Department of Radiotherapy, Centre Hospitalier Privé Saint Grégoire, Saint Grégoire, France. 14. Department of Medical Oncology, Hôpital Saint Antoine, Paris, France. 15. Department of Digestive Oncology, Centre Hospitalier La Timone, Marseille, France. 16. Department of Hepatogastroenterology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France. 17. Department of Gastroenterology and Digestive Cancerology, Hôpital Avicenne, HUPSSD, Bobigny, Paris 13 University, Sorbonne, Paris Cité, France. 18. R&D Unicancer, Paris, France. 19. Department of Medical Oncology, Hôpital Saint Joseph, Marseille, France. 20. Department of Pathology, LBM OncoGenAuvergne, Clermont Ferrand, France. 21. Université Paris Descartes, Centre de Ressources Biologiques EPIGENETEC, Unité INSERM U775U1147, Paris, France. 22. Department of Pathology & EA4340, Hôpital Ambroise Paré & Versailles University, Boulogne Billancourt, France. 23. Department of Hepatogastroenterology and Gastrointestinal Oncology, Hôpital Européen Georges Pompidou, Paris, Sorbonne Paris Cité, Paris Descartes University, France.
Abstract
BACKGROUND: Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS: This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance. RESULTS: The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%). CONCLUSIONS: We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinoma patients. TRIAL REGISTRATION: European Clinical Trials Database, number 2009-012797-12.
RCT Entities:
BACKGROUND:Epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathways, which promote tumour growth and proliferation, are often deregulated in advanced gastroesophageal adenocarcinomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modified oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced gastroesophageal adenocarcinoma. PATIENTS AND METHODS: This phase II, open-label, randomised, three-arm study enrolled patients ≥18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0-1 and no known HER2 overexpression. Patients were randomly assigned (1:1:1) mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h) alone or combined with panitumumab (6 mg/kg) or rilotumumab (10 mg/kg) every 2 weeks until limiting toxicity, patient's refusal or disease progression. The primary end-point was the 4-month progression-free survival (PFS) rate. Secondary end-points included overall survival (OS) and tolerance. RESULTS: The study enrolled 162 patients in 29 French centres. The median follow-up was 23.6 months (interquartile range = 16.4-29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] = 57-82) with chemotherapy alone, 57% (95% CI = 42-71) combined with panitumumab and 61% (95% CI = 47-74) combined with rilotumumab. Median OS was 13.1 months (95% CI = 8.7-16.9) with chemotherapy alone, 8.3 months (95% CI = 6.2-13.2) combined with panitumumab and 11.5 months (95% CI = 7.9-17.1) combined with rilotumumab. Adverse events grade ≥III occurred less frequently with chemotherapy alone (62%) than with panitumumab (83%) and rilotumumab (89%). CONCLUSIONS: We found no benefit in adding panitumumab or rilotumumab to mFOLFOX6 first-line chemotherapy to treat advanced gastroesophageal adenocarcinomapatients. TRIAL REGISTRATION: European Clinical Trials Database, number 2009-012797-12.