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Oxaliplatin and 5-FU/Folinic Acid (Modified FOLFOX6) with Or Without Aflibercept in First-Line Treatment of Patients with Metast

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Oxaliplatin and 5-FU/Folinic Acid (Modified FOLFOX6) with Or Without Aflibercept in First-Line Treatment of Patients with Metast Annals of Oncology original articles Annals of Oncology 27: 1273–1279, 2016 doi:10.1093/annonc/mdw176 Published online 18 April 2016 Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study G. Folprecht1*, C. Pericay2, M. P. Saunders3, A. Thomas4, R. Lopez Lopez5,J.K.Roh6, V. Chistyakov7, T. Höhler8, J.-S. Kim9, R.-D. Hofheinz10, S. P. Ackland11,12, D. Swinson13, M. Kopp14, D. Udovitsa15, M. Hall16, T. Iveson17, A. Vogel18 & J. R. Zalcberg19 1Medical Department I, University Cancer Center, University Hospital Carl Gustav Carus, Dresden, Germany; 2Hospital de Sabadell, Corporació Sanitaria Parc Taulí-Institut Universitari, Sabadell, Spain; 3Department of Radiotherapy and Oncology, The Christie NHS Foundation Trust, Manchester; 4Department of Cancer Studies, University of Leicester, Leicester, UK; 5Department of Medical Oncology, Hospital Clinico Universitario e Instituto de Investigación, Santiago de Compostela, Spain; 6Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 7Pyatigorsk Cancer Dispensary, Stavropol, Russia; 8Department I of Internal Medicine, Prosper Hospital, Recklinghausen, Germany; 9Department of Oncology and Hematology, Korea University Guro Hospital, Seoul, Republic of Korea; 10Department III of Internal Medicine, University Hospital, Mannheim, Germany; 11Department of Medical Oncology, Calvary Mater Hospital, Newcastle; 12Hunter Medical Research Institute and University of Newcastle, Callaghan, Australia; 13Department of Oncology, St James’ Hospital, Leeds, UK; 14Samara Regional Oncology Dispensary, Samara; 15Oncological Dispensary #2, Sochi, Russia; 16Cancer Services Division, Mount Vernon Cancer Centre, Middlesex; 17Department of Medical Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK; 18Clinic of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany; 19School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia Received 19 August 2015; revised 12 February 2016 and 25 March 2016; accepted 10 April 2016 Background: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. Patients and methods: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus afliber- cept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. Results: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2– 34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2–30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89–9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62–9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74–1.36). The re- sponse rates were 49.1% (95% CI 39.7–58.6) and 45.9% (95% CI 36.4–55.7) for patients treated with and without afli- bercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diar- rhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endo- thelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmon- ary embolism (5.9% versus 5.2%). Conclusion: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. Clinical Trial Number: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41. Key words: aflibercept, mFOLFOX6, angiogenesis, oxaliplatin, colorectal cancer *Correspondence to: Dr Gunnar Folprecht, Medical Department I, University Cancer Center, University Hospital Carl Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany. Tel: +49-351-458-4794; E-mail: [email protected] © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]. Downloaded from https://academic.oup.com/annonc/article-abstract/27/7/1273/1741921 by guest on 12 February 2018 original articles Annals of Oncology introduction Imaging for tumor assessments was carried out every 8 weeks until disease progression (according to investigator assessment) and centrally fi In patients with metastatic colorectal cancer (mCRC), rst-line reviewed by an Independent Review Committee (IRC) blinded to study treat- treatment options usually involve combination chemotherapy ment and carried out according to RECIST 1.0. All time-dependent events regimens comprising infusional fluorouracil (5-FU) and leucov- were calculated from randomization. Adverse events (AEs) were reported orin plus either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) using the Medical Dictionary for Regulatory Activities (MedDRA) version [1]. The addition of an anti-angiogenic agent is noted to mod- 14.0 and toxicity was graded according to NCI common toxicity criteria estly improve treatment outcome in the first-line setting. The (NCI-CTC) version 3.0. anti-VEGF-A (vascular endothelial growth factor-A) antibody The primary objective of the study was to estimate the PFS rate at 12 bevacizumab improves overall survival (OS) when combined months according to central review. The trial was not powered to demonstrate first line with either the irinotecan/bolus 5-FU/folinic acid IFL superiority of one treatment arm over the other. As a pre-planned exploratory regimen [2] or 5-FU/folinic acid [3]. The combination of bevaci- analysis, the Kaplan–Meier estimates for PFS and OS were computed for each zumab with an oxaliplatin-based regimen was associated with treatment group. The hazard ratios (aflibercept versus control) and 95% confi- longer progression-free survival (PFS) in the first-line setting, dence interval (CI) were estimated using the Cox proportional hazards model, fi but OS differences did not reach statistical significance, and re- after adjusting according to the above-mentioned strati cation factors. Overall sponse rate was not improved by the addition of bevacizumab response rate (ORR) was estimated in each treatment group. [4]. In the treatment of second-line mCRC, the addition of bev- The anticipated median PFS in the mFOLFOX6 arm was 8.5 months. A risk reduction of 23% was expected in the aflibercept/mFOLFOX6 arm, cor- acizumab to FOLFOX4 has been shown to improve OS in a bev- responding to a median PFS of 11 months or a PFS rate of 46.9% at 12 acizumab-naïve population previously treated with irinotecan/ months for aflibercept/mFOLFOX6 and 37.6% for mFOLFOX6. Considering 5-FU [5]. The ML18147 study has demonstrated the benefitof 9.4% precision for the 95% CI, 110 patients per arm were required. The total continuing bevacizumab, with a concomitant switch in the number of patients required was estimated to be 230 allowing for 10 patients chemotherapy backbone, in mCRC patients who had progressed being lost to follow-up. With this precision, the lower limit of the 95% CI of on a prior combination of an alternative chemotherapy back- the estimated PFS at 12 months in the aflibercept/mFOLFOX6 group was to bone plus bevacizumab [6]. be at least equal to the PFS at 12 months expected in the mFOLFOX6 arm. The fl fl A ibercept (VEGF-trap, US: ziv-a ibercept) is a recombi- final analysis was planned 1 year after the randomization of the last patient. nantly produced, fusion protein binding all isoforms of human The study was approved by each recruiting center’s ethics committee and the VEGF-A, VEGF-B and the placental growth factor (PlGF). It corresponding health authority. All patients provided signed informed consent interferes with the biological actions of VEGF by complexing to participate in the study before any study procedures were carried out. VEGF and preventing it from interacting with its receptors on endothelial cells [7]. Furthermore, clinical data from the multi- center, randomized, placebo-controlled, phase III VELOUR results trial, demonstrated a significant benefit from the addition of afli- patient population bercept to FOLFIRI in terms of median OS, PFS and response rate in patients with mCRC who had progressed on prior oxali- Between March 2009 and April 2010, 236 patients were enrolled platin-based therapy [8]. Moreover, this survival benefitwas from 36 centers in Australia, Germany, Italy, Republic of Korea, noted both in patients who were bevacizumab-naïve and those Russian Federation, Spain and UK. One hundred and nineteen fl who were previously treated with bevacizumab [8, 9]. patients were randomized to receive a ibercept/mFOLFOX6, The present randomized,
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