May 20, 2021 • 5 Min

Researching More Second-Line Options for Pancreatic Cancer

Dr. Allyson Ocean

During the last decade, continued research has shown that combination chemotherapy provides advanced pancreatic cancer patients with a survival benefit.

On October 25, 2021, ERYTECH Pharma announced that the TRYbeCA-1 trial did not meet its primary endpoint of overall survival. Data from the trial are being analyzed further.

The choice of this so-called front-line regimen, which is based on numerous clinical factors, also plays a significant role in ongoing management of patients. Unfortunately, once patients progress on first-line combination treatment, second-line standard therapeutic options are somewhat limited.

But a large phase III study called TRYbeCA-1 hopes to add a novel medication to second-line options. TRYbeCA-1 is a randomized controlled trial evaluating an agent called eryaspase as a candidate in second-line treatment for metastatic pancreatic cancer. The trial has completed patient enrollment. A total of 510 patients participated in the trial, slightly above the target enrollment of 482. The U.S. Food and Drug Administration has already granted eryaspase Fast Track designation as a second-line treatment for patients with metastatic pancreatic cancer. Eryaspase has also received Orphan Drug status in pancreatic cancer treatment in both the United States and Europe.

A Novel Delivery Method

Eryaspase is developed by ERYTECH Pharma, a clinical-stage biopharmaceutical company developing new therapies by encapsulating therapeutic drug substances inside red blood cells. The investigational medication (eryaspase) is made up of two main ingredients. The first is an enzyme called asparaginase, which destroys essential nutrients in the bloodstream that most cancer cells rely on for their growth. As a result, cancer cells starve and die. The second is donor red blood cells that are chosen to match a participant’s blood type.

More than 90 percent of pancreatic cancer tumors contain KRAS mutations, which play an important role in the metabolism of tumor cells and their requirement for amino acids, explains gastrointestinal oncologist Allyson Ocean, M.D., of Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York.

Cancer metabolism is very complex, but put simply, tumors need amino acids to grow and maintain an energy supply, she says, who is also an Associate Professor of Clinical Medicine at the Weill Medical College of Cornell University

Amino acids are workhorses doing everything from building muscles, aiding in chemical reactions, transporting nutrients, and carrying out other important functions. Asparagine is an amino acid that plays a role in the biosynthesis of proteins. Cancer cells need to eat and one of the amino acids that tumors crave is asparagine. A normal cell gets asparagine though its own synthesis. But cancer cells can’t produce enough asparagine and instead rely on circulating asparagine. But L-asparaginase removes circulating asparagine. Without this key nutrient, cancer cells die.

“It turns out that pancreatic cancer cells have a weakened ability to make new asparagine because of lower levels of the enzyme that makes asparagine, and inhibiting this dependence on amino acids with L-asparaginase can make tumor cells more vulnerable,” says Ocean, who has placed patients on this study. She works closely with Manuel Hidalgo Medina, M.D., Ph.D., Chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine/NewYork-Presbyterian Hospital; he is the lead U.S. investigator for the study.

When L-asparaginase was given to patients in earlier studies, it was too toxic and had many side effects, such as allergic reactions, nausea, vomiting, and pancreatitis, Ocean notes. But when L-asparaginase is encapsulated in red blood cells, these toxicities are no longer evident and the enzyme can be delivered in a safer and more therapeutic way, she adds.

Showing Promise

Full results from a phase IIb trial evaluating eryaspase in metastatic pancreatic cancer were published online in the European Journal of Cancer in January 2020.

The phase IIb trial evaluated eryaspase—L-asparaginase encapsulated in red blood cells—as a second-line treatment in combination with chemotherapy in 141 patients with metastatic pancreatic cancer. In this trial, eryaspase was added to gemcitabine or mFOLFOX chemotherapy and compared to the chemotherapy alone in a 2-to-1 randomization.

Eryaspase in combination with chemotherapy significantly prolonged both overall survival and progression-free survival in the entire patient population, with a 40 percent reduction in the risk of death, and a 44 percent reduction in risk of disease progression on average over time. No unexpected safety findings were reported and eryaspase did not add substantially to the toxicity of chemotherapy.

TRYbeCA-1 phase III enrolled cancer patients at more than 120 clinical sites in Europe and the U.S.. In the trial, eligible patients were randomized 1-to-1 to receive eryaspase in combination with standard chemotherapy, specifically, gemcitabine/nab-paclitaxel or an irinotecan-based regimen or chemotherapy alone. The primary endpoint of TRYbeCA1 is overall survival.

Earlier this year, TRYbeCA-1 phase III was granted permission to continue without modification following a planned interim superiority analysis conducted by an Independent Data Monitoring Committee (IDMC). The interim analysis was triggered when two-thirds of the total number of events had occurred and allowed the potential for stopping the trial early if the primary endpoint reached statistical significance, adjusting the statistical threshold for the interim review. As with the three previous IDMC reviews, no safety issues have been identified and Erytech remains blinded to the primary and secondary endpoint efficacy data. The final analysis is expected in the fourth quarter of 2021.

“Housing an enzyme in a red blood cell that is then able to penetrate tumor cells to kill cancer is very novel and intriguing,” Ocean explains. “This treatment already has shown promise in other tumor types such as leukemias, so it’s great to be able to introduce and test this technology in solid tumors like pancreatic cancer.”