The clinical utility of plasma cell-free DNA (cfDNA) in NET-02: Randomised, phase II trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line (2L) therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).

Mairead Geraldine McNamara University of Manchester/The Christie NHS Foundation Trust, Manchester, United Kingdom info_outline Mairead Geraldine McNamara, Simon Pearce, Jayne Swain, Mollie Anne Halford, Rohini Sharma, Olusola Olusesan Faluyi, Jonathan Wadsley, Carys Morgan, Lucy R. Wall, Ian Chau, Nick Reed, Debashis Sarker, Jane Margetts, Alan Anthoney, Jamie B. Oughton, Angela Lamarca, Richard Hubner, Dominic G. Rothwell, Juan W. Valle, Alexandra Clipson

Authors Mairead Geraldine McNamara University of Manchester/The Christie NHS Foundation Trust, Manchester, United Kingdom info_outline Mairead Geraldine McNamara, Simon Pearce, Jayne Swain, Mollie Anne Halford, Rohini Sharma, Olusola Olusesan Faluyi, Jonathan Wadsley, Carys Morgan, Lucy R. Wall, Ian Chau, Nick Reed, Debashis Sarker, Jane Margetts, Alan Anthoney, Jamie B. Oughton, Angela Lamarca, Richard Hubner, Dominic G. Rothwell, Juan W. Valle, Alexandra Clipson Organizations University of Manchester/The Christie NHS Foundation Trust, Manchester, United Kingdom, CRUK Manchester Institute, Manchester, United Kingdom, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom, Imperial College London, London, United Kingdom, Clatterbridge Cancer Centre, Wirral, United Kingdom, University of Sheffield, Sheffield, United Kingdom, Velindre Cancer Centre, Cardiff, United Kingdom, Western General Hospital, Edinburgh, United Kingdom, The Royal Marsden NHS Foundation Trust, London, United Kingdom, University of Glasgow, Glasgow, United Kingdom, King's College London, London, United Kingdom, Newcastle Hospital NHS Foundation Trust, Newcastle, United Kingdom, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom, Fundacion Jimenez Diaz University Hospital, Las Rozas, Alava, Spain, Medical Oncology Department, The Christie NHS Foundation Trust, Manchester, United Kingdom, CRUK Cancer Biomarker Centre, CRUK Manchester Institute, University of Manchester, Manchester, United Kingdom, University of Manchester and the Christie NHS Foundation Trust, Manchester, United Kingdom, Cancer Research UK Manchester Institute Cancer Biomarker Centre, Manchester, United Kingdom Abstract Disclosures Research Funding Servier Background: In NET-02, nal-IRI/5-FU, but not docetaxel, met the primary endpoint of 6-month (mo) progression-free survival (PFS) rate in pts with progressive PD-EP-NEC (1). The prognostic potential of cfDNA in progressive PD-EP-NEC has not been explored in a prospective randomised trial. Methods: NET-02 was a multi-centre, randomised (1:1), phase II trial of IV nal-IRI/5-FU/folinic acid, Q14 days (ARM A), or IV docetaxel, Q21 days (ARM B), as 2L therapy in pts with progressive PD-EP-NEC. Plasma samples were taken at baseline (T0), following 6 weeks of treatment (T1) and at progression (T2). Samples were analysed using a multi-omic next-generation sequencing (NGS) approach (T7-MBD-seq) (measures genome-wide methylation and low pass whole genome copy number alterations (CNA)). The tumour fraction (TF) of cfDNA was determined using ichorCNA and correlated with clinical outcomes using Cox proportional hazards model and Logistic regression. Results: Of 56 pts evaluable for efficacy, there were 54 (96%) T0 samples (48 passed quality control), 31 (55%) at T1 and 20 (36%) at T2. At T0, 36/48 (75%) samples had detectable TF by copy number (using 3% TF cut-off). For the entire cohort, T0 TF was negatively prognostic for overall survival (OS) (Hazard Ratio (HR) 1.17, 95% Confidence interval (CI) 1.00-1.37, P=.044), but not for 6 mo PFS rate (Odds ratio (OR) 1.25, 95% CI 0.91-1.73, P=.17), response rate (RR) (OR 1.11, 95% CI 0.67-1.76, P=.65) or PFS (HR 1.04, 95%CI 0.91-1.20, P=.53). In the entire cohort, median OS split by TF (N=16 each) was 10.2 mo (95% CI 4.1-not available (NA)) for low (TF≤8.6%), 6.9 mo (95% CI 3.4-14.8) for medium (8.6<TF≤24.3%) and 3.7 mo (95% CI 2.8-NA) for high (TF>24.3%). T0 TF was also negatively prognostic for 6 mo PFS rate and OS in ARM A (P=.02, P=.03), but not ARM B (P=.61, P=.48), but was not prognostic for RR or PFS (Table). TF correlated with the presence of liver metastases (Wilcoxon Rank Sum P=.009), but not with ECOG PS (P=.14), sex (P=.10), Ki-67 (P=.39) or age (Spearman rank correlation P=.45). Longitudinal copy number and methylation cfDNA analysis is on-going. Conclusions: These results suggest that it may be possible to stratify prognosis based on amount of baseline TF in patients with progressive PD-EP-NEC, and may also identify patients who would benefit most from the nal-IRI combination. 1. McNamara 2023, EClin Med. Clinical trial information: 03837977. Impact of TF (Continuous Variable) at T0 on: ARM A nal-IRI/5-FU (N=24) ARM B Docetaxel (N=24) 6 mo PFS rate OR 1.87 (95% CI 1.15-3.65, P=.02) OR 0.85 (95% CI 0.39-1.49, P=.61) RR OR 1.27 (95% CI 0.60-2.52, P=.46) OR 0.98 (95% CI 0.43-1.91, P = .95) PFS HR 1.23 (95% CI 0.97-1.57, P=.09) HR 0.93 (95% CI 0.77-1.11, P=.42) OS HR 1.37 (95% CI 1.03-1.81, P=.03) HR 1.07 (95% CI 0.88-1.31, P=.48)