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.
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 with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (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.



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 response 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 aflibercept, 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 diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial 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 pulmonary embolism (5.9% versus 5.2%).



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.



NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41.
Medical Department I, University Cancer Center, University Hospital Carl Gustav Carus, Dresden, Germany gunnar.folprecht@uniklinikum-dresden.de.
G
G
Folprecht
Hospital de Sabadell, Corporació Sanitaria Parc Taulí-Institut Universitari, Sabadell, Spain.
C
C
Pericay
Department of Radiotherapy and Oncology, The Christie NHS Foundation Trust, Manchester.
M P
MP
Saunders
Department of Cancer Studies, University of Leicester, Leicester, UK.
A
A
Thomas
Department of Medical Oncology, Hospital Clinico Universitario e Instituto de Investigación, Santiago de Compostela, Spain.
R
R
Lopez Lopez
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
J K
JK
Roh
Pyatigorsk Cancer Dispensary, Stavropol, Russia.
V
V
Chistyakov
Department I of Internal Medicine, Prosper Hospital, Recklinghausen, Germany.
T
T
Höhler
Department of Oncology and Hematology, Korea University Guro Hospital, Seoul, Republic of Korea.
J-S
JS
Kim
Department III of Internal Medicine, University Hospital, Mannheim, Germany.
R-D
RD
Hofheinz
Department of Medical Oncology, Calvary Mater Hospital, Newcastle Hunter Medical Research Institute and University of Newcastle, Callaghan, Australia.
S P
SP
Ackland
Department of Oncology, St James' Hospital, Leeds, UK.
D
D
Swinson
Samara Regional Oncology Dispensary, Samara.
M
M
Kopp
Oncological Dispensary #2, Sochi, Russia.
D
D
Udovitsa
Cancer Services Division, Mount Vernon Cancer Centre, Middlesex.
M
M
Hall
Department of Medical Oncology, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
T
T
Iveson
Clinic of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
A
A
Vogel
School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia.
J R
JR
Zalcberg
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D000077150:Oxaliplatin; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*
D009944:Organoplatinum Compounds; D011993:Recombinant Fusion Proteins; D000077150:Oxaliplatin; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil
aflibercept; angiogenesis; colorectal cancer; mFOLFOX6; oxaliplatin