No abstract

Circulating tumour DNA (ctDNA) has the potential to be a specific biomarker for the monitoring of tumours in patients with colorectal cancer (CRC). Here, our aim was to develop a personalised surveillance strategy to monitor the clinical course of CRC after surgery. We developed patient-specific ctDNA assays based on multiplexed detection of somatic mutations identified from patient primary tumours, and applied them to detect ctDNA in 44 CRC patients, analysing a total of 260 plasma samples. We found that ctDNA detection correlated with clinical events – it is detectable in pre-operative but not post-operative plasma, and also in patients with recurrent CRC. We also detected ctDNA in 11 out of 15 cases at or before clinical or radiological recurrence of CRC, indicating the potential of our assay for early detection of metastasis. We further present data from a patient with multiple primary cancers to demonstrate the specificity of our assays to distinguish between CRC recurrence and a second primary cancer. Our approach can complement current methods for surveillance of CRC by adding an individualised biological component, allowing us not only to point to the presence of residual or recurrent disease, but also attribute it to the original cancer.

4590 Background: Nivolumab (N) and Y90-radioembolization (RE) are both therapeutic options in advanced hepatocellular carcinoma (aHCC). Increasing evidence suggests that radiotherapy synergizes with immune checkpoint inhibitors to augment anti-tumour effects. Methods: Eligible Child-Pugh A aHCC patients (pts) were treated with Y90-RE followed by N 240mg, 21 days after Y90-RE and every 2 weeks thereafter. Pre- and on-treatment tumor biopsies together with circulating biomarkers were obtained. Primary end-point was overall response rate (ORR) (per RECIST v 1.1). Overall response was defined as the composite overall response observed for the lesions within Y90-RE field and outside Y90-RE field. Key secondary end points included disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety. 36 evaluable pts were needed to assess whether the addition of N improved the ORR of Y90-RE from 21% to 41% as determined by Simon two-stage optimal design with 80% power and one sided significance level of 0.05. Results: Forty pts were enrolled of which 36 were evaluable. At baseline: 63.9% were HepB in aetiology; 63.9% BCLC stage C; 47.2% had AFP > 400ng/mL; number of liver lesions – median 5 (range 1- 20); size of largest liver lesion – median 80mm (range 14-177mm); 27.8% had prior TACE; and 13.9% had prior systemic therapy. ORR was 31% (95% CI 16.4 - 48.1%). Eight out of 11 responders had not progressed at study cut-off. DCR was 58.3%. 81% of target lesions within Y90-RE field regressed. With a median follow up of 16.4 months, median PFS and OS were 4.6 months (95% CI 2.3m - 8.4m) and 15.1 months (95% CI 7.8m - NE) respectively. Six- and 12-month PFS rates were 44.2% (95% CI 27.3% - 59.9%) and 26.1% (95% CI 11.2% - 43.8%) respectively. Overall, N+ Y90-RE was well tolerated and safe; only 11% had grade 3/4 treatment related adverse events (AEs). Responders demonstrated significant alterations of LIF, MIG and Eotaxin3 levels in the pre-treatment cytokine analyses. Conclusions: Combination N+Y90-RE resulted in an encouraging ORR of 31% (95% CI 16.4 - 48.1%) in aHCC. 81% of target lesions within Y90-RE field regressed suggesting synergy in combining Y90-RE with nivolumab. This combination is safe and tolerable with low G3/4 treatment related AEs of 11%. Further biomarker analyses will be presented at the meeting. Clinical trial information: NCT03033446 .

2584 Background: The Wnt signalling pathway is involved in cellular proliferation, differentiation, migration and implicated in stem cell function in several cancers. ETC-159 is a selective small molecule inhibitor of porcupine, an enzyme required for palmitoylation and secretion of all Wnt ligands. In preclinical studies, ETC-159 induced tumour regression in patient-derived xenograft models. Methods: Open-label, multi-centre study to determine safety, maximum tolerated dose, pharmacokinetics, pharmacodynamics (PD) of ETC-159 given orally, once every other day in a 28d cycle. PD was evaluated by AXIN2 mRNA levels in whole blood and hair follicles and bone turnover by radiological and serum markers. Dose escalation was by ordinal continual reassessment method with a dose-limiting toxicity (DLT) period of 28d. Results: As of 18 Jan 2017, 16 patients (pts) were treated in 6 cohorts at 1 mg (2pts), 2 mg (2pts), 4 mg (3pts), 8 mg (4pts); 16 mg (3pts), and 30 mg (2pts). 80% were male, median age (range) was 55yr (19-68). One DLT was seen at 16 mg due to hyperbilirubinaemia. Adverse events (≥ 20%) were vomiting (32%); anorexia and fatigue (31%); dysgeusia and constipation (25%). ETC-159 Cmax increased with dose with a mean t1/2 of 14 hr. Plasma levels of ETC-159 that inhibited colony formation in vitro were attained from 4 mg onwards. Reduction of whole blood and hair follicle AXIN2 mRNA levels and doubling of serum β-CTX levels was first observed at 4 mg and at C1D15 in some patients. PD modulation increased with dose, consistent with on-target modulation of Wnt signalling. Two pts had β-CTX rise > 1000 pg/mL (reference limit) and a ≥ 5% reduction in bone density by C3D1. Both took vitamin D and calcium supplements and were given i.v. bisphosphonates. No responses were seen but 2 pts (2 mg: colorectal and 4 mg: peritoneal carcinoma) had stable disease for 6 and 8 cycles respectively. Dose-escalation is ongoing at 30 mg. Conclusions: ETC-159 inhibits Wnt signalling at doses that are well tolerated. β-CTX levels increased early on, and in two pts were associated with reduced bone mineral density. Early and regular monitoring of bone turnover is indicated. This study was sponsored by D3 which is funded by NMRC, NRF and BMRC Singapore. Clinical trial information: NCT02521844.