Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study.
Loading...
Embargo End Date
Authors
Khan, K
Rata, M
Cunningham, D
Koh, D-M
Tunariu, N
Hahne, JC
Vlachogiannis, G
Hedayat, S
Marchetti, S
Lampis, A
Damavandi, MD
Lote, H
Rana, I
Williams, A
Eccles, SA
Fontana, E
Collins, D
Eltahir, Z
Rao, S
Watkins, D
Starling, N
Thomas, J
Kalaitzaki, E
Fotiadis, N
Begum, R
Bali, M
Rugge, M
Temple, E
Fassan, M
Chau, I
Braconi, C
Valeri, N
Rata, M
Cunningham, D
Koh, D-M
Tunariu, N
Hahne, JC
Vlachogiannis, G
Hedayat, S
Marchetti, S
Lampis, A
Damavandi, MD
Lote, H
Rana, I
Williams, A
Eccles, SA
Fontana, E
Collins, D
Eltahir, Z
Rao, S
Watkins, D
Starling, N
Thomas, J
Kalaitzaki, E
Fotiadis, N
Begum, R
Bali, M
Rugge, M
Temple, E
Fassan, M
Chau, I
Braconi, C
Valeri, N
Document Type
Journal Article
Date
2018-08-01
Date Accepted
2017-05-23
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.
Citation
Gut, 2018, 67 (8), pp. 1484 - 1492
Source Title
Publisher
BMJ PUBLISHING GROUP
ISSN
0017-5749
eISSN
1468-3288
Research Team
Signal Transduction & Molecular Pharmacology
Gastrointestinal Cancers Clinical Trials
Medicine (RMH Smith Cunningham)
Evolutionary Genomics & Modelling
Functional Genomics
Gastrointestinal Cancer Biology and Genomics
Systems and Precision Cancer Medicine
Magnetic Resonance
Gastrointestinal Cancers Clinical Trials
Medicine (RMH Smith Cunningham)
Evolutionary Genomics & Modelling
Functional Genomics
Gastrointestinal Cancer Biology and Genomics
Systems and Precision Cancer Medicine
Magnetic Resonance