Asparagine

Asparagine actively transported into RBC

Asparagine hydrolyzed inside RBC

Asparagine degradation products

Shielded Asparaginase remains in RBC

Prolonged Activity

Reduced Toxicity

Study Design

Acknowledgements: The authors wish to thank the patients and their families, all investigators and site personnel. Additional support was provided by Sabine Kacel. Editorial assistance was provided by Cadence Communications and Research, funded by Erytech Pharma.

Corresponding Author: Pascal Hammel, MD, PhD: pascal.hammel@aphp.fr

[AbstractTPS4666] Trybeca-1:Arandomized,phase3studyoferyaspaseincombinationwithchemotherapyversuschemotherapyaloneassecond-linetreatmentinpatientswithpancreaticadenocarcinoma (NCT03665441).

P. Hammel, MD1; R. Berardi, MD2; GY. Creemers, MD, PhD3; E. Van Cutsem, MD, PhD4; A. Cubillo, MD5; R. Greil, MD6; H. Wasan, MD7; JP. Metges, MD8; M. Noel, MD9; P. Nygren, MD10;P. Österlund, MD11; T. Seufferlein, MD12; T. Macarulla, MD13; A. Gupta, BA14; L. Grummer14; N. Biswas-Baldwin14; R. Kay15; H. Youssoufian, MD15; I. El-Hariry, MD14; M. Hidalgo, MD, PhD16

1Hôpital Beaujon, Clichy, France; 2Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona-Umberto, Italy; 3Catharina Hospital Eindhoven, Netherlands; 4University Hospitals Gasthuisberg / Leuven & KULeuven, Belgium; 5HM Hospitales, Madrid, Spain; 6Paracelsus Medical University Salzburg, Salzburg Cancer research Institute-CCCIT, and Cancer Cluster Salzburg, Austria; 7Hammersmith Hospital, London, UK; 8Institut de Cancérologie et D'hématologie Du CHRU Brest, France; 9MedStar Georgetown University Hospital, Washington, DC, USA; 10Akademiska Sjukhuset I Uppsala, Sweden; 11Tampereen yliopistollinen sairaala, Finland; 12Universitätsklinikum Ulm, Germany;

13Vall D’Hebron University hospital, Vall d´Hebrón Institute of Oncology, Barcelona, Spain; 14Erytech Pharma, Lyon, France; 15Consultant to Erytech Pharma, Boston, USA; 16Weill Cornell Medicine, New York, USA.

Study Participants (N = ~500):• Stage III or IV Pancreatic Cancer• One prior therapy in advanced setting• Performance Status of 0/1

• In a recent randomized phase 2 study in patients with advanced PAC whose disease progressed following first-line treatment (NCT02195180), the addition of eryaspase to chemotherapy demonstrated clinically meaningful improvement in median OS (6.0 vs. 4.4 months, respectively), with a 40% risk reduction in death rate.9

• The safety profile of eryaspase combined with chemotherapy was comparable with the known safety profile for each chemotherapy used, respectively.9

• These results provided a rationale for initiating this ongoing confirmatory phase 3 pivotal trial (Trybeca-1, NCT03665441).

StudyRationale

Trybeca-1 Participating Countries

• The observed mortality rate of pancreatic cancer in the United States has continued to increase over the past three decades and is predicted to become the third most common cause of cancer-related deaths by 2035 if new screening and treatment options are not implemented.1

• Pancreatic adenocarcinoma (PAC) is characterized by extensive reprogramming of cellular metabolism, such as constitutive activation of KRAS signaling and utilization of asparagine and glutamine to circumvent the nutrient-poor, hypoxic microenvironment. Perturbation of these pathways through deprivation of glutamine and asparagine results in loss of cell viability.2

• In vitro studies have demonstrated promising anti-cancer effects for L-asparaginase (ASNase) against human pancreatic tumor cell lines.3-5

• The role of ASNase as a therapeutic option in solid tumors has been faced with challenges related to its narrow therapeutic index. In a small pilot Phase 2 study, ASNase was given to 10 patients with advanced pancreatic cancer. No efficacy could be demonstrated, but toxicity was significant.6

• In addition, in Phase 1 study, pegylated ASNase (Oncaspar®) was evaluated in combination with gemcitabine in 17 patients with various solid tumors. The study was terminated early due to toxicity and a selected dose for Phase 2 would have needed to be below the expected biologically effective range. Though inconclusive, this study left the possibility that a safer form of ASNase could be therapeutic.7

• To address this issue, we encapsulated ASNase within red blood cells (RBCs), thereby prolonging the activity and reducing the toxicity of the free enzyme. This form of encapsulated ASNase is the investigational drug product eryaspase.8

• Eryaspase has been previously shown to be a well-tolerated and an effective chemotherapy partner in patients with acute lymphoblastic leukemia (ALL) and PAC.8,9

1LGemcitabine-basedChemotherapy

1LFluoropyrimidine-basedChemotherapy

2LFOLFIRI/NALIRI+/- eryaspase

2LGemcitabine/Abraxane

+/- eryaspase

1:1

1:1

• TreatuntilDiseaseProgressionorUnacceptableToxicity

• Continuetofollowupforsurvival

Key Eligibility Criteria• Eighteen (18) years of age or older• Histologically confirmed pancreatic adenocarcinoma (PAC)• Stage III or IV disease• Received only one prior line of systemic chemotherapy with or without targeted agents,

immunotherapy, or radiotherapy for treatment of advanced PAC• Radiological evidence of disease progression following most recent prior treatment• ECOG PS of 0 or ECOG PS of 1 and score of ≥80 on Karnofsky Performance Status Scale• Available tumor tissue samples• Adequate organ function

• Brain metastasis is allowed, if stable • Life expectancy of >12 weeks

Statistical Plan• Patients are stratified based on performance status, choice of chemotherapy, and time since diagnosis

of advanced disease• The study assumes a recruitment period of approximately 22 months and a mOS in the control group

of 6 months, and the study size will be based on the recruitment of approximately 500 patients

• There will be a superiority interim analysis built in the study design, when approximately two thirds of the events have been accrued. The design has a power to detect differences based on the hazard ratio of 0.725 of approximately 90%

• An IDMC is established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. IDMC last reviewed the trial safety data in April 2020 and suggested the trial continue as planned.

Treatment Administration• Eryaspase (100 U/kg) will be given every two weeks (on Day 1 and 15 of each 4-week cycle),

intravenously (IV) via a standard infusion line over approximately 30 minutes, followed by chemotherapy

• Chemotherapy will be one of the following two treatment regimens, according to the previous therapy received:

• Gemcitabine (1000 mg/m2)/Abraxane® (125 mg/m2): Days 1, 8, and 15 of each 4-week cycle

• Onivyde® (Onivyde 70 mg/m2)/5-FU (2400 mg/m2 over 46 hours)/leucovorin (400 mg/m2): Days 1 and 15 of each 4-week cycle OR

FOLFIRI [irinotecan (180 mg/m2), 5-FU (5-FU 400 mg/m2 bolus followed by 2400 mg/m2

infusion over 46 hours), and leucovorin (400 mg/m2)]: Days 1 and 15 of each 4-week cycle

Primary Objective• Improvement in OS compared to chemotherapy alone

Secondary Objectives• To compare progression-free survival (PFS), objective response rate (ORR), duration of response

(DoR), and the disease control rate (DCR) between treatment arms• To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus

chemotherapy alone• To assess the effect of eryaspase on quality of life (QoL) • To determine the pharmacokinetics and pharmacodynamics of eryaspase

• To assess the immunogenicity of eryaspase in terms of induction of anti-asparaginase antibodies and neutralizing antibodies

• To evaluate the relationship of clinical outcome with relevant biomarkers and genetic changes present in tumor tissues and blood and/or serum samples

Study Progress• This is a global trial that is enrolling patients in several European countries and the United States• Currently over 75% of the planned 500 patients have already been enrolled into the trial• CTA approvals in: US, UK, Spain, Finland, Netherlands, Belgium, France, Italy, Czech Republic,

Sweden, Austria, and Germany

• If you currently treat patients with advanced pancreatic cancer, you may refer for second-line treatment to the Trybeca-1 investigational center at: trybeca1-protocolinquiry@erytech.com

References1. Ma J, Jemal A, Fedewa SA, et al. The American Cancer Society 2035 challenge goal on cancer mortality

reduction. CA Cancer J Clin. 2019;69(5):351-362.2. Kawada K, Toda K, Sakai Y. Targeting metabolic reprogramming in KRAS-driven cancers. Int J Clin Oncol.

2017;22(4):651-659.3. Wu MC, Arimura GK, Yunis AA. Mechanism of sensitivity of cultured pancreatic carcinoma to asparaginase. Int J

Cancer. 1978;22(6):728-733.4. Yunis AA, Arimura GK, Russin DJ. Human pancreatic carcinoma (MIA PaCa-2) in continuous culture: sensitivity to

asparaginase. Int J Cancer. 1977;19(1):128-135.5. Dufour E, Gay F, Aguera K, et al. Pancreatic tumor sensitivity to plasma L-asparagine starvation. Pancreas.

2012;41(6):940-948.6. Lessner HE, Valenstein S, Kaplan R, DeSimone P, Yunis A. Phase II study of L-asparaginase in the treatment of

pancreatic carcinoma. Cancer Treat Rep. 1980;64(12):1359-1361.7. Borad MJ, Babiker HM, Anthony S, et al. A multicenter, open-label, Phase 1 study evaluating the safety and

tolerability of pegaspargase in combination with gemcitabine in advanced metastatic solid tumors and lymphoma. Cancer Invest. 2015;33(5):172-179.

8. El-Hariry I, Aguera K, Hoke F, et al. Pharmacodynamic characterization of eryaspase (L-asparaginase encapsulated in red blood cells) in combination with chemotherapy in a phase 2/3 trial in patients with relapsed acute lymphoblastic leukemia (NCT01518517). Journal of Clinical Oncology. 2018;36(15_suppl):7049-7049.

9. Hammel P, Fabienne P, Mineur L, et al. Erythrocyte-encapsulated asparaginase (eryaspase) combined with chemotherapy in second-line treatment of advanced pancreatic cancer: An open-label, randomized Phase IIb trial. Eur J Cancer. 2019;124:91-101.

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Time (months)

AsparaginaseEryaspaseArm ControlArm

Median Overall Survival 6 months 4.4 months

Hazard Ratio 0.60, p=0.008

Eryaspase Arm

Control Arm

Number at Risk

Eryaspase Arm 95 83 67 45 29 24 15 11 8 8 4 4 4 1 1 1 1 0

Control Arm 46 35 22 15 8 6 3 0

Eryaspase Mechanism of Action

Previous Phase 2 Study Experience in Pancreatic Cancer