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  • Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

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Original article
Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study
  1. Khurum Khan1,2,
  2. Mihaela Rata3,
  3. David Cunningham1,
  4. Dow-Mu Koh3,
  5. Nina Tunariu3,
  6. Jens C Hahne2,
  7. George Vlachogiannis2,
  8. Somaieh Hedayat2,
  9. Silvia Marchetti2,
  10. Andrea Lampis2,
  11. Mahnaz Darvish Damavandi2,
  12. Hazel Lote1,2,
  13. Isma Rana1,
  14. Anja Williams1,
  15. Suzanne A Eccles4,
  16. Elisa Fontana1,
  17. David Collins3,
  18. Zakaria Eltahir1,
  19. Sheela Rao1,
  20. David Watkins1,
  21. Naureen Starling1,
  22. Jan Thomas1,
  23. Eleftheria Kalaitzaki1,5,
  24. Nicos Fotiadis3,
  25. Ruwaida Begum1,
  26. Maria Bali3,
  27. Massimo Rugge6,
  28. Eleanor Temple1,
  29. Matteo Fassan6,
  30. Ian Chau1,
  31. Chiara Braconi1,4,
  32. Nicola Valeri1,2
  1. 1 Department of Medicine, The Royal Marsden NHS Trust, London and Sutton, UK
  2. 2 Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, UK
  3. 3 Division of Radiotherapy and Imaging, Cancer Research UK Imaging Centre,The Institute of Cancer Research and Royal Marsden Hospital, London, UK
  4. 4 Division of Cancer Therapeutics, The Institute of Cancer Research, London and Sutton, UK
  5. 5 Department of Statistics, The Royal Marsden NHS Trust, London and Sutton, UK
  6. 6 Department of Medicine (DIMED) and Surgical Pathology, University of Padua, Padua, Italy
  1. Correspondence to Dr Nicola Valeri, Division of Molecular Pathology, The Institute of Cancer Research, London and Sutton, 15 Cotswold Road, Belmont, Sutton Surrey, SM2 5NG, UK; nicola.valeri{at}icr.ac.uk

Abstract

Objective Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.

Design Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.

Results Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).

Conclusions Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

  • regorafenib
  • anti-angiogenic treatment
  • cancer therapeutics
  • DCE-MRI
  • liquid biopsy
  • colorectal cancer

This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

https://doi.org/10.1136/gutjnl-2017-314178

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    Footnotes

    • DC and NV contributed equally.

    • Contributors Trial design: KK, DC, IC, NV. Enrolment in the trial: KK, DC, SR, DW, NS, IC, NV. Data acquisition: KK, MR, D-MK, NT, JCH, GV, SH, SM, AL, MDD, HL, IR, AW, SAE, EF, DC, ZE, JT, RB, MB, MR, ET, MF, CB, NV. Statistical analysis: EZ. Writing and final approval of the manuscript: all the authors.

    • Funding This work was supported by Cancer Research UK(grant number CEA A18052), European Union FP7 (grant number CIG 334261) and theNational Institute for Health Research (NIHR) Biomedical Research Centre (BRC)at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research(grant numbers A62, A100, A101, A159) to NV, by a Bayer Oncology Group ResearchGrant to DC. The authors acknowledge support from the National Institute for HealthResearch Biomedical Research Centre at The Royal Marsden NHS Foundation Trustand The Institute of Cancer Research.

    • Competing interests DC received research funding from: Roche, Amgen, Celgene,Sanofi, Merck Serono, Novartis, AstraZeneca, Bayer, Merrimack and MedImmune. KK has had advisory role with Bayer. IC has had advisory roles with Merck Serono, Roche, Sanofi Oncology, Bristol Myers Squibb, Eli-Lilly, Novartis, Gilead Science. He has received research funding from Merck-Serono, Novartis, Roche and Sanofi Oncology, and honoraria from Roche, Sanofi-Oncology, Eli-Lilly, Taiho. All other authors declare no conflict of interest

    • Patient consent All the patients consented on trial consent forms as per trial protocol.

    • Provenance and peer review Not commissioned; externally peer reviewed.