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Clinical Trial
. 2025 Jun 3:222:115470.
doi: 10.1016/j.ejca.2025.115470. Epub 2025 Apr 26.

The relative dose intensity of first-line FOLFOXIRI and FOLFOX/FOLFIRI both in combination with bevacizumab affects prognosis of metastatic colorectal cancer patients: A pooled analysis of TRIBE and TRIBE2 studies

R Moretto  1 , D Rossini  2 , Mariam Grazia Polito  3 , Carlotta Antoniotti  4 , Rossana Intini  5 , Veronica Conca  4 , Paola Andena  6 , Martina Carullo  4 , Lisa Salvatore  7 , Marco Maria Germani  8 , Francesca Bergamo  5 , Alessandro Passardi  9 , Paolo Ciracì  4 , Emiliano Tamburini  10 , Chiara Boccaccio  4 , Alberto Zaniboni  11 , Gianluca Masi  4 , Filippo Pietrantonio  6 , Sara Lonardi  5 , C Cremolini  12
Affiliations
Clinical Trial

The relative dose intensity of first-line FOLFOXIRI and FOLFOX/FOLFIRI both in combination with bevacizumab affects prognosis of metastatic colorectal cancer patients: A pooled analysis of TRIBE and TRIBE2 studies

R Moretto et al. Eur J Cancer. .

Abstract

Background: The relative dose intensity (RDI) of cytotoxic agents affects cancer patients' clinical outcome, especially in the curative setting. Poor data are available in metastatic colorectal cancer (mCRC) and with specific regard to the use of the triplet FOLFOXIRI.

Methods: We performed a pooled analysis of the phase III TRIBE and TRIBE2 studies comparing FOLFOXIRI/bev to doublets (FOLFOX or FOLFIRI)/bev in order to assess the prognostic impact of the RDI (<80 % versus ≥80 %) during the first 8 cycles of induction treatment of both the triplet and the doublet regimens.

Results: Overall, 282/581 (49 %) and 404/580 (70 %) of patients treated with FOLFOXIRI/bev and doublets/bev, respectively, received RDI≥ 80 %. Patients receiving RDI≥ 80 % had more favorable clinical condition and tumor-related prognostic features. RDI≥ 80 % was associated with higher ORR (62 % vs 53 %, OR: 1.44, 95 %CI:1.13 - 1.82; p = 0.0026), and longer PFS (11.5 versus 10.0 months; HR: 0.80, 95 %CI: 0.71 - 0.91; p < 0.001) and OS (27.9 versus 22.2 months; HR: 0.75, 95 %CI: 0.65 - 0.85; p < 0.001). These results were confirmed in multivariable models (p < 0.001). Similar ORR (58 % vs 56 %, OR: 1.09, 95 %CI: 0.81-1.48; p = 0.57), PFS (10.8 versus 10.0 months; HR:0.96, 95 %CI: 0.83-1.12; p = 0.63) and OS (22.9 versus 24.9 months; HR:1.07, 95 %CI: 0.90-1.26; p = 0.46) were observed between patients treated with FOLFOXIRI/bev receiving RDI< 80 % and those treated with doublets/bev receiving RDI≥ 80 %. These results were confirmed after stratification for unbalanced baseline characteristics between these subgroups (stratified pORR=0.55; pPFS=0.70; stratified pOS=0.33). As expected, patients in the RDI< 80 % group experienced a higher incidence of severe chemo-related adverse events (72 % vs 34 %, p < 0.001).

Conclusions: Maintaining an adequate RDI in the first-line therapy of mCRC improves patients' clinical outcomes. Since there is no benefit from chemotherapy intensification in the case of low RDI, the secondary prophylaxis of chemotherapy-related severe adverse events might be preferrable rather than individual agents' dose reductions.

Keywords: FOLFOXIRI/bevacizumab; Metastatic colorectal cancer; Relative dose intensity.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.M.: Speaker Bureau from Amgen; Advisory/Consultancy from Takeda D.R.: Speaker Bureau from Amgen, Pierre Fabre A.Z.: Speaker Bureau from Amgen, Merck Serono, Servier, BMS, Takeda. L.S.: Consulting or advisory role for Pierre-Fabre, AstraZeneca, Bayer, SERVIER, Merck, Amgen, GSK, Incyte, Leopharma, MSD, Takeda. Research funding by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under My First Grant (MFAG) No. MFAG27367 F.P.: Research funding (to Institution) from Lilly, BMS, Incyte, AstraZeneca, Amgen, Agenus, Rottapharm. Speaker Bureau from BeiGene, Daiichi-Sankyo, Seagen, Astellas, Ipsen, AstraZeneca, Servier, Bayer, Takeda, Johnson & Johnson, BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre. Advisory/Consultancy from BMS, MSD, Amgen, Pierre-Fabre, Johnson & Johnson, Servier, Bayer, Takeda, Astellas, GSK, Daiichi-Sankyo, Pfizer, BeiGene, Jazz Pharmaceuticals, Incyte, Rottapharm, Merck-Serono, Italfarmaco, Gilead, AstraZeneca, Agenus. S.L.: Consulting or Advisory Role: Amgen, Merck Serono, Lilly, Servier, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, MSD, Astellas Pharma, Bayer, GlaxoSmithKline, Takeda, Rottapharm Biotech. Speakers’ Bureau: Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, MSD Oncology, Incyte. Research Funding: Amgen, Merck Serono, Bayer (Inst), Roche (Inst), Lilly (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst) G.M.: Consulting or Advisory Role: AstraZeneca, Eisai, MSD Oncology, Roche, Roche, Terumo. Research Funding: Terumo (Inst). C.C.: Advisory board or consultant role with Astra Zeneca, Bicara Therapeutics, BMS, GSK, Lilly, Merck, Mirati, MSD, Nordic Pharma, Roche, Pfizer, Pierre Fabre, Revolution Medicine, Rottapharm, Takeda, Tempus; invited speaker with compensation for Amgen, Bayer, Merck Serono, MSD, Pierre Fabre Servier, Takeda; Research grants by Amgen, Merck, Pierre Fabre, Roche, Seagen (Pfizer), Servier, Tempus. All remaining authors have declared no conflicts of interest.

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