Starving Tumors of Important Amino Acid May Extend Survival in Pancreatic Cancer

Investigators are evaluating whether eryaspase (Graspa), an L-asparaginase-based therapy that triggers tumor cell death, can extend survival for patients with pancreatic cancer. Patients with advanced pancreatic adenocarcinoma have few effective treatment options outside of a clinical trial or palliative care,¹ and this could solve an unmet medical need.

“Patients [with pancreatic cancer] who progress after first-line therapy only really have 1 option, and that’s nanoliposomal irinotecan (Onivyde),” said Manuel Hidalgo, MD, PhD, a professor of medicine at Harvard Medical School and chief of the Department of Hematology/Oncology at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “However, it is only useful in patients who have not received irinotecan in the first-line setting.”

The randomized, international phase III TRYbeCA-1 trial (NCT03665441) is testing eryaspase added to chemotherapy in this patient population, compared with chemotherapy alone. Investigators seek to determine whether the combination improves overall survival (OS) as the primary endpoint and assess progression-free survival (PFS), objective response rate, dura­tion of response, and disease control rate as the secondary endpoints.²

Eligible patients must have histologically confirmed stage III or IV pancreatic ductal adenocarcinoma, with radiological evidence of disease progression after their most recent prior treatment. Participants must also have an ECOG performance status of 0 or 1 and no active or symptomatic untreated central nervous system (CNS) metastases. Notably, patients with asymptomatic or stable metastases are eligible for the study, provided the CNS metastases are radiologically and clinically stable and the patient does not take steroids for at least 1 month prior to randomization.

Eryaspase will be administered at a dose of 100 IU/kg administered intravenously 1 hour prior to chemotherapy every 2 weeks. The chemotherapy will be chosen based on what the patient had received in the first line. Patients will receive combi­nation gemcitabine and abraxane if they have received prior itinotecan-based therapy, and those who received prior gemcitabine and abraxane will receive irinotecan-based chemotherapy. The inves­tigator can choose either regimen if the patient received neither in the first line.

“The beautiful thing about the trial is that eryaspase can be given with either gemcitabine/ abraxane- or irinotecan-based chemotherapy, which means that it could be more broadly appli­cable to the patient population,” Hidalgo said.

Eryaspase is L-asparaginase encapsulated in red blood cells. L-asparaginase breaks down aspar­agine, an amino acid essential for the survival and proliferation of cancer cells.³ Normal cells can produce the amino acid naturally, but most cancer cells have no or very low levels of L-asparagine synthetase and depend on the serum asparagine present in the microenvironment for survival. Eryaspase depletes the serum asparagine, leading to cell cycle arrest and apoptosis in cancer cells.⁴ Hidalgo also noted that eryaspase helps the chemotherapy reach the tumor cells, making it more effective.

Prior results showed eryaspase’s efficacy in patients with pancreatic cancer. In a phase IIb study of eryaspase in combination with gemcit­abine or FOLFOX (leucovorin, 5-FU, and oxal­iplatin) as second-line therapy (NCT02195180), patients had improved OS and PFS. Patients were randomized to receive either eryaspase with chemotherapy or chemotherapy alone. In the intent-to-treat population (n = 141), the median OS was 26.1 weeks with eryaspase versus 19 weeks with chemotherapy alone (HR, 0.60; 95% CI, 0.40-0.88; P = .009). The median PFS was 8.6 weeks in the eryaspase arm versus 7 weeks in the chemotherapy arm (HR, 0.59; 95% CI, 0.40-0.89; P = .011).³

The safety profile of eryaspase combined with chemotherapy was comparable with the known safety profile for each type of chemotherapy used in the trial. “In general, it was well-tolerated,” Hidalgo said. “Eryaspase did not add toxicities to the chemotherapy; the only event that was higher [with eryaspase combined with chemotherapy] was diarrhea.” The most common adverse events observed in the trial were seen in both arms and included asthenia, nausea, thrombocytopenia, anemia, and vomiting.³

Due to these positive results, eryaspase is being evaluated in other solid tumors including triple-neg­ative breast cancer.⁵ If the trial proves successful, “this could become the preferred or only standard-of-care secondline treatment for all patients [with pancreatic cancer],” Hidalgo said. Eryaspase is being developed by Erytech, which is based in Lyon, France, and Cambridge, Massachusetts.

REFERENCES

1. NCCN Clinical Practice Guidelines in Oncology: Pancre­atic Adenocarcinoma, version 2.2018. National Compre­hensive Cancer Network website. nccn.org/professionals/ physician_gls/pdf/pancreatic_blocks.pdf. Published July 10, 2018. Accessed September 12, 2018.

2. EU clinical trials register. European Medicines Agency website. clinicaltrialsregister.eu/ctr-search/trial/2018- 000572-15/ES. Accessed September 12, 2018.

3. Hammel P, Bachet J-B, Portales F, et al. A phase 2b of eryaspase in combination with gemcitabine or FOLFOX as second-line therapy in patients with metastatic pancre­atic adenocarcinoma (NCT02195180). Presented at: 2017 European Society for Medical Oncology Congress; Septem­ber 8-12, 2017; Madrid, Spain. Abstract 621PD. academic. oup.com/annonc/article/28/suppl_5/mdx369.005/4108704.

4. Hammel P, Bachet J-B, El-Hariry I, et al. A phase IIb of eryaspase in combination with gemcitabine or FOLFOX as second-line therapy in patients with metastatic pan­creatic adenocarcinoma (NCT02195180). J Clin Oncol. 2017(suppl; abstr e15718).

5. Erytech confirms strategic focus or eryaspase on solid tumors and ceases development in acute lymphoblastic leukemia [press release]. Lyon, France, and Cambridge, MA: Erytech; June 24, 2018. investors.erytech.com/phoe­nix.zhtml?c=254271&p=irol-newsArticle&ID=