Circulating Tumor DNA is Prognostic and Potentially Predictive of Eryaspase Efficacy in Second-line in Patients with Advanced Pancreatic Adenocarcinoma.

Abstract

Eryaspase is composed of l-asparaginase encapsulated in erythrocytes and has demonstrated significant efficacy in a randomized phase II trial. We assessed the prognostic and predictive value of circulating tumor DNA (ctDNA) in patients, plasma included in this trial. Samples prospectively collected pretreatment were centrally analyzed by next-generation sequencing. Prognostic values of baseline ctDNA and ctDNA early changes between day 0 and 28 were assessed in both arms combined on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS); three groups were defined: negative ctDNA (Neg), ctDNA responders (Resp), and ctDNA nonresponders (NResp). Predictive value of ctDNA for eryaspase efficacy was investigated. ctDNA was positive at baseline in 77 patients of the 113 tested patients (68%). Detectable ctDNA was an independent negative prognostic factor for OS (4.6 vs. 8.8 months; <i>P</i> = 0.0025) and PFS (1.6 vs. 3.3 months; <i>P</i> = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; <i>P</i> < 0.04), PFS (3.7, 3.4, 1.6 months; <i>P</i> < 0.0001), and OS (11.7, 6.5, 4.3 months; <i>P</i> < 0.0001) according to the three defined groups (Neg, Res, NResp, respectively). In patients with ctDNA detectable at baseline, eryaspase was associated with better PFS [HR = 0.53; 95% confidence interval (CI): 0.3-0.94)] and OS (HR = 0.52; 95% CI: 0.29-0.91). We confirm from a prospective randomized trial that: (i) the presence of ctDNA at baseline is a major prognostic factor, (ii) the early change of ctDNA correlates with treatment outcome, and (iii) the ctDNA could be a predictive biomarker of eryaspase efficacy.