Circulating tumor DNA is prognostic and potentially predictive of eryaspase efficacy in second-line in patients with advanced pancreatic adenocarcinoma

Jean-Baptiste Bachet (1, 2) , Hélène Blons (1, 3) , Pascal Hammel (4, 5) , Iman El Hariry (6) , Fabienne Portales (7) , Laurent Mineur (8) , Jean-Philippe Metges (9) , Claire Mulot (1) , Camille Bourreau (1) , Jason Cain (6) , Jérôme Cros (10) , Pierre Laurent Puig (3, 1)

1 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
2 CHU Pitié-Salpêtrière [AP-HP]
3 HEGP - Hôpital Européen Georges Pompidou [APHP]
4 GERCOR - Cooperator Multidisciplinary Oncology Group
5 Hôpital Beaujon [AP-HP]
6 ERYTECH Pharma
7 CRLC Val d'Aurelle-Paul Lamarque
8 Institut Sainte Catherine [Avignon]
9 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
10 Service d’Anatomie Pathologique [CHU Beaujon]

Purpose: 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.Experimental Design: 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.Results: 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; P = 0.0025) and PFS (1.6 vs. 3.3 months; P = 0.00043). Early change in ctDNA levels was correlated with ORR (20%, 26%, 0%; P < 0.04), PFS (3.7, 3.4, 1.6 months; P < 0.0001), and OS (11.7, 6.5, 4.3 months; P < 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).Conclusions: 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.

Mots clés: L-asparaginase; circulating tumor DNA; phase 2; prognostic; predictive

Domaines: Cancer

Jean-Baptiste Bachet, Hélène Blons, Pascal Hammel, Iman El Hariry, Fabienne Portales, et al.. Circulating tumor DNA is prognostic and potentially predictive of eryaspase efficacy in second-line in patients with advanced pancreatic adenocarcinoma. Clinical Cancer Research, 2020, 26 (19), pp.5208-5216. ⟨10.1158/1078-0432.CCR-20-0950⟩. ⟨hal-02996269⟩