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Translational Therapeutics

Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?

British Journal of Cancer volume 127, pages 957–967 (2022)Cite this article

Subjects

Abstract

Background

Recent data suggest that BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients with right-sided tumours and ECOG-PS = 0 may achieve benefit from the triplet regimen differently than those with left-sided tumours and ECOG-PS > 0.

Methods

The predictive impact of primary sidedness and ECOG-PS was evaluated in a large real-life dataset of 296 BRAFV600E-mutated mCRC patients treated with upfront triplet or doublet ± bevacizumab. Biological differences between right- and left-sided BRAFV600E-mutated CRCs were further investigated in an independent cohort of 1162 samples.

Results

A significant interaction effect between primary sidedness and treatment intensity was reported in terms of both PFS (p = 0.010) and OS (p = 0.003), with a beneficial effect of the triplet in the right-sided group and a possible detrimental effect in the left-sided. No interaction effect was observed between ECOG-PS and chemo-backbone. In the MSS/pMMR population, a consistent trend for a side-related subgroup effect was observed when FOLFOXIRI ± bevacizumab was compared to oxaliplatin-based doublets±bevacizumab (p = 0.097 and 0.16 for PFS and OS, respectively). Among MSS/pMMR tumours, the BM1 subtype was more prevalent in the right-sided group (p = 0.0019, q = 0.0139). No significant differences were observed according to sidedness in the MSI-H/dMMR population.

Conclusions

Real-life data support the use of FOLFOXIRI ± bevacizumab only in BRAFV600E-mutated mCRC patients with right-sided tumours.

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Fig. 1: Forest plot according to sidedness and ECOG-PS of PFS and OS.
Fig. 2: Kaplan–Meier curves of PFS and OS according to sidedness and treatment in the BRAF-BeCool population.
Fig. 3
Fig. 4: Frequency of most common alterations in MSS/pMMR cohort of the CGP population.

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Data availability

Datasets supporting the results of this work are available to editors, referees and readers promptly upon request.

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Acknowledgements

We are grateful to the “BRAF BeCool” investigators from the participating Italian centres.

Funding

The present work was partially funded by Regione Veneto—grant RP-2014-00000395 and by Italian Health Ministry Grant 2019 GR-2019-12368903.

Author information

Author notes

  1. These authors contributed equally: Roberto Moretto, Andrew Elliott.

  2. These authors jointly supervised this work: Michael Korn, Chiara Cremolini.

Authors and Affiliations

  1. Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy

    Roberto Moretto, Daniele Rossini, Veronica Conca, Carlotta Antoniotti, Martina Carullo, Gianluca Masi & Chiara Cremolini

  2. Clinical & Translational Research, Medical Affairs, Caris Life Sciences, Phoenix, AZ, USA

    Andrew Elliott, Pavel Brodskiy & Michael Korn

  3. Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, Pisa, Italy

    Daniele Rossini, Veronica Conca, Carlotta Antoniotti, Martina Carullo, Gianluca Masi & Chiara Cremolini

  4. Oncology Unit 1, Veneto Institute of Oncology—IRCCS, Padua, Italy

    Rossana Intini & Cosimo Rasola

  5. Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Filippo Pietrantonio & Francesca Corti

  6. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Andrea Sartore-Bianchi & Gianluca Mauri

  7. Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy

    Cosimo Rasola

  8. Medical Oncology, University and University Hospital of Cagliari, Cagliari, Italy

    Mario Scartozzi

  9. Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy

    Massimiliano Salati

  10. PhD Program Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy

    Massimiliano Salati

  11. Department of Oncology, ASUFC University Hospital of Udine, Udine, Italy

    Nicoletta Pella

  12. Comprensive Cancer Center, UOC di Oncologia Medica, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Rome, Italy

    Maria Alessandra Calegari

  13. Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy

    Matteo Fassan

  14. Veneto Institute of Oncology—IRCCS, Padua, Italy

    Matteo Fassan

  15. Division of Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Heinz-Josef Lenz

  16. Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA

    Anthony Shields

  17. Oncology Unit 3, Veneto Institute of Oncology—IRCCS, Padua, Italy

    Sara Lonardi

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Contributions

Study concepts: RM, DR, CC, AE, WMK. Study design: RM, DR, CC, AE, WMK. Data acquisition: RM, DR, SL, PB, RI, VC, FP, AS-B, CA, CR, MS, MS, NP, MAC, MC, FC, GM. Quality control of the data and algorithms: RM, DR, PB. Data analysis and interpretation: RM, DR, CC, AE, PB. Statistical analysis: DR, AE, PB. Paper preparation: RM, DR, CC, AE. Paper editing: all authors. Paper review: all authors.

Corresponding author

Correspondence to Sara Lonardi.

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Competing interests

AE: Employee of Caris Life Sciences. PB: Employee of Caris Life Sciences. FP: honoraria for speaker activities and participation in advisory boards from Sanofi, Amgen, Bayer, Merck-Serono, Lilly, Astrazeneca, Servier, Organon, MSD; and research grants from BMS and Astrazeneca. AS-B: Honoraria: Amgen, Bayer, MSD, Servier. Consulting or advisory role—Amgen, Bayer, Novartis, Sanofi, Servier. MS: Advisory board, speakers’ bureau MERCK, MSD, Sanofi, Amgen, BMS, EISAI, Servier. GM: Honraria—Amgen, F. HoffmaneLa Roche, Bayer, Merk Serono, Sirtex. SL: Speakers’ Bureau—Amgen, Merck, Roche, Lilly, Bristol-Myers Squibb, Pierre-Fabre, GSK and Servier. Consulting or advisory role—Amgen, MSD, Merck Serono, Lilly, Astra Zeneca, Incyte, Daiichi-Sankyo, Bristol-Myers Squibb, Servier, Research funding to Institution—Bayer, Merck, Amgen, Roche, Lilly, Astra Zeneca Bristol-Myers Squibb. WMK: Consultant—Merck. Employee of Caris Life Sciences. CC: honoraria—Amgen, Bayer, Merck, Roche and Servier. Consulting or advisory role—Amgen, Bayer, MSD, Roche. Speakers’ Bureau—Servier. Research funding—Bayer, Merck, Servier. Travel, accommodations and expenses—Roche and Servier. The remaining authors declare no competing interests.

Ethics approval and consent to participate

BRAF BeCool study was conducted in accordance with the Declaration of Helsinki. Approval for BRAF BeCool protocol was obtained from local ethics committees of participating sites.

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Moretto, R., Elliott, A., Rossini, D. et al. Benefit from upfront FOLFOXIRI and bevacizumab in BRAFV600E-mutated metastatic colorectal cancer patients: does primary tumour location matter?. Br J Cancer 127, 957–967 (2022). https://doi.org/10.1038/s41416-022-01852-0

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  • DOI: https://doi.org/10.1038/s41416-022-01852-0

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