REG demonstrated efficacy in pre-treated mCRC pts. Lack of predictive biomarkers, potential toxicities and cost/effectiveness concerns highlight the unmet need for better patient selection.
RAS mutant mCRC pts with biopsiable metastatic deposits were enrolled in this phase II trial. Tissue biopsies (6-12 cores) were obtained at baseline (BL), after 2 months if stable disease (SD) and at disease progression (PD). Dynamic contrast enhanced (DCE) MRI was acquired pre and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product, KEF [Ktrans*EF/100] were generated. Circulating tumour (ct) DNA was collected monthly until PD and tested for clonal RAS mutations by digital droplet PCR. PDOs derived from responders and non-responders pts were implanted orthotopically in the liver of mice and treated with REG for 5 days. Changes in tumour and fractional blood volume (fBV) were monitored by oxygen-enhanced MRI.
mCRC pts (n = 27) with paired MRI scans were analysed; a single target lesion per pt was chosen (25 liver and 2 pelvic metastases). Median KEF decrease was 58.2%. In the 23 analysable pts (4 received ≤1 cycle of treatment due to toxicities),>70% drop in KEF(8/27) was associated with higher disease control rate (DCR) measured by RECIST 1.1 at 2 months (m) (p = 0.05), progression free survival (PFS) [HR = 0.24 (0.07-0.86), p = 0.03], 6-m PFS (43.8% VS 0%) and overall survival (OS) [HR 0.08 (0.01-0.63), p = 0.02]. In all pts with DCR, PFS was found to be 5.6 vs. 4.2 m [HR 0.30 (95% CI 0.06-1.49), p = 0.140) and OS was 15.2 vs. 5.8 m [HR 0.11 (95% CI 0.01-1.06), p = 0.057]. 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 (0.06 - 0.71), p = 0.01] and OS [HR 0.28 (0.07 - 1.04), p = 0.06]. PDOs xeno-transplants treated with REG compared to controls had significant lower tumour fBV (4.5 VS 10.6, p = 0.03) and lower microvascular density measured by CD31 staining (4.3 VS 8.9, p = 0.02).
Combining DCE-MRI and ctDNA predicts depth and duration of anti-angiogenic response to REG with potential health economic implications.
Clinical trial identification
clinical trials.gov number NCT03010722
Legal entity responsible for the study
The Royal Marsden NHS Foundation Trust
Bayer Oncology Group
K. Khan: Advisory board for Bayer Oncology Group. D. Cunningham: Research funding from: Roche, Amgen, Celgene, Sanofi, Merck Serono, Novartis, AstraZeneca, Bayer, Merrimack and MedImmune. I. Chau: Advisory roles with Merck Serono, Roche, Sanofi Oncology, Bristol-Myers Squibb, Eli-Lilly, Novartis, Gilead Science. Research funding from Merck-Serono, Novartis, Roche and Sanofi Oncology, and honoraria from Roche, Sanofi-Oncology, Eli-Lilly, Taiho. C. Peckitt: Advisory roles with Sanofi. All other authors have declared no conflicts of interest.