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
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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.Findings 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).Interpretation 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.
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Chemotherapy regimens FOLFOX and FOLFIRI offer modest improvements in survival outcomes for metastatic colorectal cancer.
“Chemotherapy regimens, such as FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, fluorouracil, and irinotecan), that have long been the cornerstone of mCRC treatment, offer modest improvements in survival outcomes [6,7].”
From KRAS, a New Target for Precision Medicine in Colorectal Cancer? (2024) · cites this paper as [6]
In the TRIBE trial, triplet plus bevacizumab contributed to survival and was effective regardless of RAS mutation status.
“In the TRIBE trial comparing the effectiveness of triplet plus bevacizumab treatment and doublet plus bevacizumab treatment, its contribution to survival was demonstrated, and it was shown to be effective regardless of RAS mutation status [20].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [20]
In the TRIBE trial, survival time of RAS mutant patients was poorer than RAS-BRAF wild patients but better than BRAF mutant patients.
“In this study, the survival time of RAS mutant patients was poorer than that of RAS-BRAF wild patients but was better than that of BRAF mutant patients.”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [20]
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Salem, M. E., Puccini, A., & Tie, J. (2020) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_279867 · Cited by 14 · see citing works
KRAS, a New Target for Precision Medicine in Colorectal Cancer?
Boilève, A., Smolenschi, C., Lambert, A., Boige, V., Delaye, M., Camilleri, G. M., Tarabay, A., Valéry, M., Fuerea, A., Pudlarz, T., et al. (2024) · Cancers · doi:10.3390/cancers16203455 · Cited by 11 · see citing works
Sütcüoğlu, O., Yıldırım, H. Ç., Almuradova, E., Günenç, D., & Yalçın, Ş. (2025) · Medicina · doi:10.3390/medicina61071202 · Cited by 10 · see citing works
- Authors
- Cremolini, C., Loupakis, F., Antoniotti, C., Lupi, C., Sensi, E., Lonardi, S., Mezi, S., Tomasello, G., Ronzoni, M., Zaniboni, A., Tonini, G., Carlomagno, C., Allegrini, G., Chiara, S., D'Amico, M., Granetto, C., Cazzaniga, M., Boni, L., Fontanini, G., & Falcone, A.
- Affiliations
- University of Pisa (IT)
- Istituto Oncologico Veneto (IT)
- Policlinico Umberto I (IT)
- Istituti Ospitalieri di Cremona (IT)
- IRCCS Ospedale San Raffaele (IT)
- Fondazione Poliambulanza Istituto Ospedaliero (IT)
- Università Campus Bio-Medico (IT)
- Federico II University Hospital (IT)
- Ospedale Policlinico San Martino (IT)
- Azienda Sanitaria Ospedaliera S.Croce e Carle Cuneo (IT)
- Azienda Ospedaliera San Gerardo (IT)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- Corresponding author
- Falcone, Alfredo
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 16
- Issue
- 13
- Pages
- 1306-1315
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2129998117
- Cited by
- 1,092
- References
- 26
- Citations by year
- 2026: 55 · 2025: 70 · 2024: 112 · 2023: 105 · 2022: 125 · 2021: 135 · 2020: 132 · 2019: 109 · 2018: 97 · 2017: 90 · 2016: 52 · 2015: 9
- FWCI
- 35.85
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc-nd)
- BOA (University of Milano-Bicocca) (submittedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
- Health Sciences › Medicine › Surgery › Intraperitoneal and Appendiceal Malignancies
- Keywords
- metastatic colorectal cancer, FOLFOXIRI, FOLFIRI, bevacizumab, first-line chemotherapy, overall survival, RAS mutation status, BRAF mutation status, molecular subtypes, oxaliplatin, irinotecan, 5-fluorouracil, leucovorin, progression-free survival, treatment efficacy, prognostic factors
- MeSH terms
- Bevacizumab, Irinotecan, Oxaliplatin, Aged, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Leucovorin, DNA Mutational Analysis, Drug Administration Schedule, Female, Fluorouracil, Humans, Infusions, Intravenous, Italy, Male, Middle Aged, Mutation, Neoplasm Metastasis, Organoplatinum Compounds, Proto-Oncogene Proteins, Time Factors, Colorectal Neoplasms, Proportional Hazards Models, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Disease-Free Survival, ras Proteins, Angiogenesis Inhibitors, Proto-Oncogene Proteins B-raf, Kaplan-Meier Estimate, Intention to Treat Analysis
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