Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial

Abstract

This Phase IIb (NCT02195180) open-label study evaluated erythrocyteencapsulated asparaginase (eryaspase) in combination with chemotherapy in second-line advanced pancreatic adenocarcinoma. Methods: Eligible patients were randomized 2:1 to either eryaspase in combination with gemcitabine or mFOLFOX6 (eryaspase arm), or to gemcitabine or mFOLFOX6 alone (control arm). Co-primary endpoints were overall survival (OS) and progression-free survival (PFS) in patients with low asparagine synthetase (ASNS) expression. Secondary endpoints included OS and PFS in the entire population. Results: 141 patients were randomized (eryaspase arm, n Z 95; control arm, n Z 46). Median OS and PFS in patients with low ASNS expression were 6.2 months (95% CI, 5.1e8.8) in the eryaspase arm versus 4.9 months (3.1e7.1) in the control arm (HR, 0.63; 95% CI, 0.39e1.01; P Z 0.056) and 2.0 months (95% CI, 1.8e3.4) in the eryaspase arm versus 1.8 months (1.4 e3.8) in the control arm (HR, 0.67; 95% CI, 0.40e1.12; P Z 0.127), respectively. In the entire population, median OS and PFS for the eryaspase arm versus control were 6.0 months versus 4.4 months (HR, 0.60; P Z 0.008) and 2.0 months versus 1.6 months (HR, 0.56; 95% CI, 0.37 e0.84; P Z 0.005), respectively. The combination of eryaspase and chemotherapy was well tolerated. The most frequent Grade 3/4 adverse events in the eryaspase arm (n Z 93) were gamma-glutamyltransferase increase (16 [17.2%]), neutropenia (12 [12.9%]), and physical health deterioration (12 [12.9%]). Conclusion: Eryaspase in combination with chemotherapy is associated with improvements in OS and PFS, irrespective of ASNS expression in second-line advanced pancreatic adenocarcinoma. A Phase III trial is underway.

Reprogramming of Amino Acid Metabolism in Pancreatic Cancer: Recent Advances and Therapeutic Strategies

“…In a phase I clinical trial (NCT01523808), asparaginase encapsulated in erythrocytes (ERY-ASP) was well-tolerated by patients with metastatic PDAC ( 144 ). Recently, a completed phase IIb clinical trial (NCT02195180) exploring efficacy and safety of ERY-ASP in combination with chemotherapeutic drugs gemcitabine or FOLFOX displayed clinical benefit associated with improvements in overall survival (OS) and progression-free survival (PFS) irrespective of ASNS expression when used in the second-line treatment of advanced pancreatic cancer ( 145 ) ( Table 2 ).…”

Ongoing Developments and Clinical Progress in Drug-Loaded Red Blood Cell Technologies

“…Asparaginase-loaded RBCs were also evaluated in a phase I study in patients with pancreatic adenocarcinoma [32] with a reasonable safety profile. Results of a phase IIb study with erythrocyte-containing asparaginase (now named eryaspase) in combination with chemotherapy in secondline treatment of advanced pancreatic cancer were recently published [33]. The study, funded by Erytech Pharma, was conducted using the ERYCAPS ® technology.…”

Translatome-based classification reveals a dual metabolic dependency of a new tumor subtype of pancreatic cancer

“…For example, asparagine restriction induced using a recombinant asparaginase treatment led to reduced PDA tumor growth, although this treatment also induced a translational reprogramming and survival of tumor cells, in part through activation of the GNC2-ATF4 axis (Pathria et al 2019). Combining asparaginase to GCN2 inhibitor showed synergistic antiproliferative effect by reducing ATF4 and favoring apoptosis (Nakamura et al 2018).. Interestingly, a recent Phase IIb clinical trial using Gemcitabine or mFOLFOX6 in combination with erythrocyte-encapsulated asparaginase has shown very encouraging results by improving overall and progression free survival of PDA patients in second-line treatment (Hammel et al 2020). Altogether, these data highlight the potential of identifying PDA amino-acid dependency as metabolic weakness, whose targeting may open therapeutic windows for precision medicine.…”