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

Abstract

ObjectiveRegorafenib 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.DesignPatients 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.ResultsTwenty-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).ConclusionsCombining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

Multimodal Approach to Outcome Prediction in Metastatic Castration-Resistant Prostate Cancer by Integrating Functional Imaging and Plasma DNA Analysis

“…In conclusion, our study integrated the innovative biomarker approaches of functional imaging and genomics, which contributed to better prognostication, as recently seen for patients with metastatic melanoma 37 and colorectal cancer. 38 Combining different predictive and prognostic biomarker strategies could help to overcome the inter-and intrapatient heterogeneity of CRPC, thus improving patient risk stratification and treatment selection. A larger prospective evaluation is warranted.…”

Diagnostic accuracy and safety of coaxial core-needle biopsy (CNB) system in Oncology patients treated in a specialist cancer centre with prospective validation within clinical trial data

“…Common concerns about trials mandating research biopsies include the lack of patient understanding about the purpose of such studies, and the potential risks associated with additional interventional procedures within the research protocols [18][19][20][21]. In the case of our PROSPECT-C trial [1,2], patients included could already access anti-EGFR antibody treatment via the cancer drug fund (CDF) independent of the research biopsy findings, which meant that the research biopsies were of no direct patient benefit. In order to ensure that patients clearly understood the purpose of their participation in PROSPECT-C and other research studies, a prospective patient based survey at the RM was performed.…”

“…PROSPECT-R (clinical trials.gov number [NCT03010722],) [1] were reviewed by the National Research Ethics Committee (NRES) in the UK.…”

Evolving role of regorafenib for the treatment of advanced cancers

“…Recently, early HFSR following sorafenib treatment in HCC has been associated with improved treatment response [106]. Importantly, because these events are observed retrospectively, this approach does not inform the pretreatment selection of patients most likely to benefit from regorafenib, and identification of baseline predictive biomarkers is ongoing [107] (see Markers of regorafenib activity).…”

“…As aforementioned, TTP in RESORCE did not differ between RECIST v1.1 and mRECIST, highlighting the need to develop better tools to capture treatment benefit. However, recent studies suggest that imaging techniques may predict response to regorafenib, and this represents an area of active research [107,[115][116][117]. Some studies have shown that small changes in tumor density and size or early cavitation of lung metastases could predict response to regorafenib [115][116][117].…”