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Treatments after second progression in metastatic colorectal cancer: A pooled analysis of the TRIBE and TRIBE2 studies

  • Author Footnotes
    1 These authors equally contributed to this work.
    Daniele Rossini
    Footnotes
    1 These authors equally contributed to this work.
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Author Footnotes
    1 These authors equally contributed to this work.
    Marco M. Germani
    Footnotes
    1 These authors equally contributed to this work.
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Sara Lonardi
    Affiliations
    Medical Oncology Unit 3, Veneto Institute of Oncology IOV - IRCCS, Via Gattamelata, 64, 35128, Padua, Italy
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  • Filippo Pietrantonio
    Affiliations
    Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian, 1, 20133, Milan, Italy
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  • Emanuela Dell'Aquila
    Affiliations
    Department of Medical Oncology, University Campus Biomedico, Via Álvaro Del Portillo, 21, 00128, Rome, Italy

    Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 0144, Rome, Italy
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  • Beatrice Borelli
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Giacomo Allegrini
    Affiliations
    Department of Oncology, Division of Medical Oncology, Azienda Toscana Nord Ovest, Viale Vittorio Alfieri, 36, 57124, Livorno, Italy
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  • Giulia Maddalena
    Affiliations
    Medical Oncology Unit 3, Veneto Institute of Oncology IOV - IRCCS, Via Gattamelata, 64, 35128, Padua, Italy

    Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
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  • Giovanni Randon
    Affiliations
    Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via Giacomo Venezian, 1, 20133, Milan, Italy
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  • Federica Marmorino
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Alberto Zaniboni
    Affiliations
    Medical Oncology Unit, Poliambulanza Foundation, Via Bissolati, 57, 25124, Brescia, Italy
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  • Angela Buonadonna
    Affiliations
    Medical Oncology Unit, Centro di Riferimento Oncologico di Aviano, Istituto di Ricovero e Cura a Carattere Scientifico, Via Franco Gallini, 2, 33081, Aviano, Italy
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  • Alessandra Boccaccino
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Veronica Conca
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Carlotta Antoniotti
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Alessandro Passardi
    Affiliations
    Department of Medical Oncology, IRCCS Istituto Romagnolo per Lo Studio Dei Tumori (IRST) “Dino Amadori”, Via Piero Maroncelli, 40, 47014, Meldola, Italy
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  • Gianluca Masi
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
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  • Chiara Cremolini
    Correspondence
    Corresponding author: Unit of Medical Oncology 2, Azienda Ospedaliera-Universitaria Pisana, University of Pisa, Via Roma, 67, 56126, Pisa, Italy. Fax: +39 050 992069.
    Affiliations
    Department of Translational Research and New Technologies in Medicine, University of Pisa, Via Roma 67, 56127, Pisa, Italy

    Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56127, Pisa, Italy
    Search for articles by this author
  • Author Footnotes
    1 These authors equally contributed to this work.

      Highlights

      • 53% of mCRC patients treated with upfront doublets/triplet + bev receive a 3rd line.
      • RAS/BRAF wild-type patients achieve more likely a 3rd line versus RAS/BRAF mutants.
      • In 3rd line, RAS/BRAF wild-type patients reach longer disease control with anti-EGFRs.
      • Regorafenib and Tas-102 show modest efficacy, and chemotherapy re-challenge is frequent.
      • The pronounced funnel effect in BRAF mutants endorses early blockade of BRAF + EGFR.

      Abstract

      Background

      The availability of new drugs in the chemo-refractory setting opened the way to the concepts of treatment sequencing in mCRC. However, the impact of later line options in the therapeutic route of metastatic colorectal cancer (mCRC) patients and the attrition rate across subsequent lines of therapy are not well established.

      Methods

      We performed a pooled analysis of treatments administered after the 2nd disease progression in 1187 mCRC patients enrolled in the randomized phase III TRIBE and TRIBE2 studies, where upfront FOLFOXIRI/bev was compared with FOLFOX or FOLFIRI/bev. Per each line, we assessed the attrition rate, treatment choices and clinical outcomes.

      Results

      625 (53%), 326 (27%) and 136 (11%) patients received a systemic treatment after the 2nd, 3rd and 4th disease progression, respectively. PFS and objective response rate decreased along each line. RAS/BRAF wild-type patients received more likely a 3rd line (75%) compared with RAS (66%, p = 0.005) and BRAF (66%, p = 0.11) mutants. In 3rd line, 67% of RAS/BRAF wild-type patients received anti-EGFRs, achieving longer PFS with respect to other therapies (6.4 vs 3.9 months, p = 0.02). A trend towards longer 3rd line OS was observed in TRIBE patients (9.9 vs 7.2 months, p = 0.05).

      Conclusions

      A relevant attrition rate across subsequent lines of therapy is evident, and more pronounced in RAS and BRAF mutated patients, thus highlighting the relevance of the choice of the upfront treatment. The efficacy of anti-EGFR agents among RAS/BRAF wild-type patients unexposed to anti-EGFRs is higher than other options. The reintroduction of chemotherapy remains frequent in clinical practice.

      Trial registration

      Clinicaltrials. gov Identifiers NCT00719797, NCT02339116.

      Keywords

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