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FOLFOX Alone Or Combined with Rilotumumab Or Panitumumab As European Journal of Cancer 115 (2019) 97e106 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.ejcancer.com Clinical Trial FOLFOX alone or combined with rilotumumab or panitumumab as first-line treatment for patients with advanced gastroesophageal adenocarcinoma (PRODIGE 17-ACCORD 20-MEGA): a randomised, open-label, three-arm phase II trial David Malka a,*, Eric Franc¸ois b, Fre´de´rique Penault-Llorca c, Florence Castan d, Olivier Bouche´ e, Jaafar Bennouna f, Franc¸ois Ghiringhelli g, Christelle de la Fouchardie`re h, Christophe Borg i, Emmanuelle Samalin j, Jean-Baptiste Bachet k, Jean-Luc Raoul l, Laurent Miglianico m, Leila Bengrine-Lefe`vre n, Laetitia Dahan o, Ce´dric Lecaille p, Thomas Aparicio q, Trevor Stanbury r, Herve´ Perrier s, Anne Cayre t, Pierre Laurent-Puig u, Sophie Gourgou d, Jean-Franc¸ois Emile v, Julien Taı¨eb w a Department of Cancer Medicine, Gustave Roussy, Universite´ Paris-Saclay, Villejuif, France b Department of Medical Oncology, Centre Antoine Lacassagne, Nice, France c Pathology Unit, Centre Jean Perrin, UMR 1240 INSERM IMoST, Universite´ Clermont Auvergne, Clermont-Ferrand, France d Biometrics Unit, Institut du Cancer de Montpellier-Val d’Aurelle, Universite´ de Montpellier, Montpellier, France e Department of Hepatogastroenterology and Digestive Oncology, Hoˆpital Robert Debre´, Reims, France f Department of Medical Oncology, Institut de Cance´rologie de l’Ouest Rene´ Gauducheau, Saint-Herblain, France g Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon, France h Department of Medical Oncology, Centre Le´on Be´rard, Lyon, France i Cancer Immunotherapy, INSERM U1098 EFS/BFC, Besanc¸on, France j Digestive Oncology Unit, Institut du Cancer de Montpellier-Val d’Aurelle, Montpellier, Universite´ de Montpellier, France k Sorbonne Universite´,Hoˆpitaux Universitaires Pitie´-Salpe´trie`re, Department of Hepatogastroenterology, APHP, Paris, France l Department of Medical Oncology, Institut Paoli Calmettes, Marseille, France m Department of Radiotherapy, Centre Hospitalier Prive´ Saint Gre´goire, Saint Gre´goire, France n Department of Medical Oncology, Hoˆpital Saint Antoine, Paris, France o Department of Digestive Oncology, Centre Hospitalier La Timone, Marseille, France p Department of Hepatogastroenterology, Polyclinique Bordeaux Nord Aquitaine, Bordeaux, France q Department of Gastroenterology and Digestive Cancerology, Hoˆpital Avicenne, HUPSSD, Bobigny, Paris 13 University, Sorbonne, Paris Cite´, France r R&D Unicancer, Paris, France * Corresponding author: Department of Cancer Medicine, Gustave Roussy, 114 rue Edouard Vaillant, F-94805 Villejuif, France. E-mail address: [email protected] (D. Malka). https://doi.org/10.1016/j.ejca.2019.04.020 0959-8049/ª 2019 Elsevier Ltd. All rights reserved. 98 D. Malka et al. / European Journal of Cancer 115 (2019) 97e106 s Department of Medical Oncology, Hoˆpital Saint Joseph, Marseille, France t Department of Pathology, LBM OncoGenAuvergne, Clermont Ferrand, France u Universite´ Paris Descartes, Centre de Ressources Biologiques EPIGENETEC, Unite´ INSERM U775U1147, Paris, France v Department of Pathology & EA4340, Hoˆpital Ambroise Pare´ & Versailles University, Boulogne Billancourt, France w Department of Hepatogastroenterology and Gastrointestinal Oncology, Hoˆpital Europe´en Georges Pompidou, Paris, Sorbonne Paris Cite´, Paris Descartes University, France Received 19 December 2018; received in revised form 7 April 2019; accepted 12 April 2019 Available online 23 May 2019 KEYWORDS Abstract Background: Epidermal growth factor receptor (EGFR) and hepatocyte growth Advanced factor (HGF)/mesenchymaleepithelial transition (MET) pathways, which promote tumour gastroesophageal growth and proliferation, are often deregulated in advanced gastroesophageal adenocarci- adenocarcinoma; nomas. We assessed whether adding panitumumab (an EGFR inhibitor) or rilotumumab (a First-line treatment; HGF inhibitor) to first-line fluoropyrimidine-based and platinum-based chemotherapy (modi- Panitumumab; fied oxaliplatin, leucovorin and fluorouracil [mFOLFOX6]) benefits to patients with advanced Rilotumumab; gastroesophageal adenocarcinoma. mFOLFOX6 Patients and methods: This phase II, open-label, randomised, three-arm study enrolled pa- tients 18 years, with advanced gastroesophageal adenocarcinoma, Eastern Cooperative Oncology Group performance status 0e1 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 panitumu- mab (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 sur- vival (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 Z 16.4e29.0). The 4-month PFS rate was 71% (95% confidence interval [CI] Z 57e82) with chemotherapy alone, 57% (95% CI Z 42e71) combined with pa- nitumumab and 61% (95% CI Z 47e74) combined with rilotumumab. Median OS was 13.1 months (95% CI Z 8.7e16.9) with chemotherapy alone, 8.3 months (95% CI Z 6.2e13.2) combined with panitumumab and 11.5 months (95% CI Z 7.9e17.1) combined with rilotumu- mab. 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. ª 2019 Elsevier Ltd. All rights reserved. 1. Introduction patients [9,11,12]. Similarly, abnormal HGF and MET upregulation occurs in gastric cancer [10,11,13,14], with Gastric cancer is the second leading cause of cancer MET overexpression in 18e82% of patients [14].Pan- death worldwide [1]. Doublet or triplet chemotherapy itumumab, a monoclonal antibody targeting EGFR, is with a platinum-fluoropyrimidine backbone remains the approved in advanced colorectal cancer [15]. First reports mainstay of treatment for fit patients with advanced of EGFR inhibitors combined with chemotherapy showed gastric cancer [2]. However, the prognosis of these tu- promising results in advanced gastric cancer [12,16].Rilo- mours remains dismal, with reported median overall tumumab, a monoclonal antibody targeting HGF, the survival (OS) times inferior to 1 year [3e8]. ligand of the MET receptor, was shown tolerable and Targeted therapies have been developed to counteract active in various advanced solid tumours [17,18]. the deregulation of signal transduction pathways, Our study assessed the efficacy and safety of pan- including epidermal growth factor receptor (EGFR) and itumumab or rilotumumab combined with 5- hepatocyte growth factor (HGF)/mesenchymaleepithelial fluorouracil-based and oxaliplatin-based chemotherapy transition (MET) pathways [9,10]. In advanced gastric as first-line therapy for advanced gastroesophageal cancer, EGFR overexpression occurs in up to 50% of adenocarcinomas. D. Malka et al. / European Journal of Cancer 115 (2019) 97e106 99 2. Methods duration of response, disease control rate and treatment toxicity. Adverse events were assessed by National 2.1. Study oversight Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, except peripheral neurop- MEGA (MET or EGFR inhibition in gastroesophageal athy which was graded with Levi’s scale [21]. adenocarcinoma) was designed as a phase II, open-label, randomised, three-arm study. Patients aged 18 years 2.5. Exploratory biomarker analysis with locally advanced (unresectable) or metastatic adenocarcinoma of the stomach, gastroesophageal Archival tumour samples were collected at inclusion, junction or oesophagus, an Eastern Cooperative and blood samples were collected at inclusion and on Oncology Group performance status of 0 or 1 and day 1 of cycle 3 before treatment administration. adequate organ functions were eligible. Non-inclusion Exploratory studies aimed to identify predictive and criteria included prior chemotherapy for advanced dis- prognostic biomarkers among functional or molecular ease, known HER2 overexpression (immunohisto- alterations of the EGFR/RAS/RAF, HER2 and HGF/ chemistry 3þ or 2 þ with positive in situ hybridisation), MET pathways. The circulating tumour cell analysis has known meningeal or brain metastases, and peripheral been reported [22] and the immune cell (myeloid-derived neuropathy grade II. Patients were randomly assigned suppressor cells, NK cells) analysis will be reported (1:1:1) modified oxaliplatin, leucovorin and fluorouracil separately. (mFOLFOX6) (chemotherapy alone group), mFOL- FOX6 with panitumumab (panitumumab group) or 2.6. Statistical considerations mFOLFOX6 with rilotumumab (rilotumumab group). Randomisation was stratified (minimisation method) by Based on a Fleming single-stage design, with a one-sided a Z extent of disease (metastatic or locally advanced), his- -level of 5% and a power of 90%, with H0 40% and Z tological subtype by Lauren classification [19] (diffuse, H1 60% of success (defined as a non-progression rate intestinal or mixed) and centre. All patients provided at 4 months), 51 evaluable patients per group were written informed consent before participating. The required [23]. In the experimental groups,
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