ASCO 2017: Adding PEGPH20 to Standard Treatment in Metastatic Pancreatic Cancer May Delay Disease Progression
By adding an experimental drug to a standard chemotherapy regimen, a subset of patients with metastatic pancreatic cancer had a significantly longer period before the cancer progressed as compared with those who received the standard treatment, according to a phase II clinical trial led by an investigator at Fred Hutchinson Cancer Research Center.
The randomized, controlled trial found that when the experimental therapy was given to participants whose tumors had high amounts of the drug's target molecule, they had 4 months more of progression-free survival than participants in the control group who only received standard chemotherapy.
First author Sunil Hingorani, MD, PhD, presented the study results at the 2017 ASCO Annual Meeting (Abstract 4008).
Dr. Hingorani said that the results reassure him that it was the right move to advance the drug, called pegylated recombinant human hyaluronidase (PEGPH20), into the worldwide phase III trial that opened last year.
About PEGPH20 and Hyaluronic Acid
Dr. Hingorani's earlier research led him to the drug because he believed it could address a challenge posed by many pancreatic cancers: the tumors have very high internal pressures that can collapse local blood vessels and prevent cancer-killing drugs from getting in. PEGPH20 reduces those pressures so chemotherapies circulating in the blood can penetrate tumors.
The experimental drug, which was created from the blueprint of a naturally occurring enzyme, breaks down a molecule called hyaluronic acid that is produced in bulk by many pancreatic cancers.
Hyaluronic acid, or HA, is naturally found in the human body; it readily binds water to create a gel fluid. But in pancreatic tumors, as the gel fluid builds up, it raises the tumor's internal pressure, squeezing local blood vessels shut. Patients whose tumors have high amounts of HA also tend to have a poor prognosis.
HALO 202 Background
Dr. Hingorani and his team first conducted studies in mice that showed how PEGPH20, in combination with chemotherapy, permanently reduced the amount of pressure-boosting HA inside the animals’ tumors. It caused the tumors to shrink and increased the mice's survival time.
In the phase II trial (HALO-109-202) patients with late-stage pancreatic cancer were randomly assigned to receive a standard-of-care, first-line combination chemotherapy either with or without PEGPH20. When the results of all 234 evaluable patients on HALO 202 were grouped together, the apparent benefit of PEGPH20 was small—a matter of just a couple extra weeks of progression-free survival.
“If this was all the potential that this strategy represented, I wouldn't pursue this [research further],” Dr. Hingorani said. “That's not enough for me.”
But a stark difference emerged when the results were divided up by how much of the drug's target, HA, patients' tumors contained: in the subset of 80 patients whose tumors had high levels of HA, adding PEGPH20 to chemotherapy resulted in an average of 9.2 months before disease progression; with chemotherapy alone, this timespan was 5.2 months.
Dr. Hingorani also reported that the unexpected, elevated risk of blood clots associated with PEGPH20—which resulted in a temporary halt of the trial in 2014—equalized between the patients receiving PEGPH20 and those in the control group, and dropped overall, after the study was restarted, due to the addition of a blood thinner to all patients' regimens.
“These are the real take-home messages to me, namely, the progression-free survival in target-rich [high-HA] patients and the ability to give the enzyme safely,” Dr. Hingorani said.
Treatment-related adverse events for trial participants included peripheral edema (63% of those receiving PEGPH20 vs 26% for the control group), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%).
Phase III Trial
Because the phase II trial results suggest that the benefit of the experimental drug is restricted to the patients with high levels of HA in their tumors, only patients with such tumors qualify for the new phase III trial. Additionally, the phase III trial is designed to offer a more stringent test of the benefits of the new drug than its predecessor—the trial's goal is to determine whether PEGPH20 actually increases participants' lifespans, not just their time to disease progression. The investigators' exploratory analysis of the phase II trial data suggested that the experimental drug boosted the lifespans of patients with high-HA tumors to an average of nearly a year after diagnosis, which, if shown definitively in the phase III trial, could be a new benchmark for this cancer, Dr. Hingorani said.
Dr. Hingorani launched the phase III trial before handing off its leadership to Margaret Tempero, MD, of the University of California, San Francisco, and Eric Van Cutsem, MD, PhD, at the University of Leuven in Belgium.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
