FOLFOXIRI plus bevacizumab versus FOLFIRI plus bevacizumab as first-line treatment of patients with metastatic colorectal cancer: updated overall survival and molecular subgroup analyses of the open-label, phase 3 TRIBE study.
BACKGROUND
In the TRIBE study, FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab significantly improved progression-free survival of patients with metastatic colorectal cancer compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. In this updated analysis, we aimed to provide mature results for overall survival-a secondary endpoint-and report treatment efficacy in RAS and BRAF molecular subgroups.


METHODS
TRIBE was an open-label, multicentre, phase 3 randomised study of patients (aged 18-70 years with Eastern Cooperative Oncology Group [ECOG] performance status of 2 or less and aged 71-75 years with an ECOG performance status of 0) with unresectable metastatic colorectal cancer who were recruited from 34 Italian oncology units. Patients were randomly assigned (1:1) via a web-based procedure to receive FOLFIRI plus bevacizumab or FOLFOXIRI plus bevacizumab. Bevacizumab was given as a 5 mg/kg intravenous dose. FOLFIRI consisted of a 180 mg/m(2) intravenous infusion of irinotecan for 60 min followed by a 200 mg/m(2) intravenous infusion of leucovorin for 120 min, a 400 mg/m(2) intravenous bolus of fluorouracil, and a 2400 mg/m(2) continuous infusion of fluorouracil for 46 h. FOLFOXIRI consisted of a 165 mg/m(2) intravenous infusion of irinotecan for 60 min, followed by an 85 mg/m(2) intravenous infusion of oxaliplatin given concurrently with 200 mg/m(2) leucovorin for 120 min, followed by a 3200 mg/m(2) continuous infusion of fluorouracil for 48 h. Tissue samples for RAS and BRAF mutational status analyses were centrally collected. In this updated analysis, we assessed the secondary endpoint of overall survival in the main cohort and treatment efficacy in RAS and BRAF molecular subgroups. All analyses were by intention to treat. TRIBE was concluded on Nov 30, 2014. The trial is registered with ClinicalTrials.gov, number NCT00719797.


RESULTS
Between July 17, 2008, and May 31, 2011, 508 patients were randomly assigned. At a median follow-up of 48·1 months (IQR 41·7-55·6), median overall survival was 29·8 months (95% CI 26·0-34·3) in the FOLFOXIRI plus bevacizumab group compared with 25·8 months (22·5-29·1) in the FOLFIRI plus bevacizumab group (hazard ratio [HR] 0·80, 95% CI 0·65-0·98; p=0·03). Median overall survival was 37·1 months (95% CI 29·7-42·7) in the RAS and BRAF wild-type subgroup compared with 25·6 months (22·4-28·6) in the RAS-mutation-positive subgroup (HR 1·49, 95% CI 1·11-1·99) and 13·4 months (8·2-24·1) in the BRAF-mutation-positive subgroup (HR 2·79, 95% CI 1·75-4·46; likelihood-ratio test p<0·0001). Treatment effect was not significantly different across molecular subgroups (pinteraction=0·52).


CONCLUSIONS
FOLFOXIRI plus bevacizumab is a feasible treatment option for those patients who meet the inclusion criteria of the present study, irrespective of baseline clinical characteristics and RAS or BRAF mutational status.
Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
Chiara
C
Cremolini
Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
Fotios
F
Loupakis
Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy.
Carlotta
C
Antoniotti
Department of Surgical Pathology, Medical, Molecular, and Critical Area, University of Pisa, Pisa, Italy.
Cristiana
C
Lupi
Department of Surgical Pathology, Medical, Molecular, and Critical Area, University of Pisa, Pisa, Italy.
Elisa
E
Sensi
Medical Oncology 1, Oncology Institute IRCCS Veneto, Padua, Italy.
Sara
S
Lonardi
Day Hospital of Oncology, Policlinico Umberto I, Rome, Italy.
Silvia
S
Mezi
Division of Medicine and Medical Oncology, Hospital of Cremona, Cremona, Italy.
Gianluca
G
Tomasello
Department of Oncology, Hospital San Raffaele IRCSS, Milan, Italy.
Monica
M
Ronzoni
Department of Medical Oncology, Poliambulanza Foundation, Brescia, Italy.
Alberto
A
Zaniboni
Medical Oncology, University Biomedical Campus, Rome, Italy.
Giuseppe
G
Tonini
Department of Clinical Medicine and Surgery, University Hospital Federico II, Naples, Italy.
Chiara
C
Carlomagno
Unit of Medical Oncology, Hospital Felice Lotti, Pontedera, Italy.
Giacomo
G
Allegrini
Medical Oncology 2, IRCCS University Hospital San Martino, Genoa, Italy.
Silvana
S
Chiara
Unit of Medical Oncology, Galliera Hospital, Genoa, Italy.
Mauro
M
D'Amico
Unit of Medical Oncology, Medical Centre Hospital Santa Croce and Carle, Cuneo, Italy.
Cristina
C
Granetto
Unit of Medical Oncology, Hospital San Gerardo, Monza, Italy.
Marina
M
Cazzaniga
Clinical Trials Coordinating Center, Toscano Cancer Institute, University Hospital Careggi, Florence, Italy.
Luca
L
Boni
Department of Surgical Pathology, Medical, Molecular, and Critical Area, University of Pisa, Pisa, Italy.
Gabriella
G
Fontanini
Department of Oncology, University Hospital of Pisa, Pisa, Italy; Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy. Electronic address: alfredo.falcone@med.unipi.it.
Alfredo
A
Falcone
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D057194:Intention to Treat Analysis; D000077146:Irinotecan; D007558:Italy; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013997:Time Factors; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics
D020533:Angiogenesis Inhibitors; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D000068258:Bevacizumab; D000077146:Irinotecan; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin