susan-keown_
Susan Keown was a staff editor and writer at Fred Hutchinson Cancer Center from 2014-2022 who has written about health and research topics for a variety of research institutions. Find her on Twitter @sejkeown.
Editor's note: This story was first published in June 2017, when the results of this study were presented at the annual meeting of the American Society for Clinical Oncology. It has been updated to reflect the researchers' publication of their results in the Journal of Clinical Oncology.
Researchers like Dr. Sunil Hingorani who have chosen to take on pancreatic cancer face an intimidating foe, one that swiftly claims patient lives as it races through the body like wildfire and mounts tough defenses against cancer-killing therapies.
“No cancer,” said Hingorani, “is more daunting than pancreas cancer.”
An experimental drug Hingorani helped develop to knock down one of the many defenses that make this cancer so fearsome shows continued potential today as his team publishes the results of their Phase 2 trial of the strategy. Hingorani and colleagues reported in the Journal of Clinical Oncology that in certain metastatic pancreatic cancer patients, adding the drug to a standard chemo regimen lengthened the time patients had before their cancer progressed by an average of four months ― a notable increase in this cancer.
The team's results, Hingorani said, reassure him that it was the right move to advance the drug, called PEGPH20, into the worldwide Phase 3 trial that opened last year.
“We still haven’t fully proven anything yet, strictly speaking,” cautioned Hingorani, who is the Phase 2 trial’s leader and a faculty member at Fred Hutchinson Cancer Research Center. “But I think [this strategy] is very rational. Let me put it this way: I think it would be irresponsible not to finish the global Phase 3 trial as the most rigorous test of this hypothesis. I think we’re obligated now to answer the question.”
Opening a window for chemo
In many pancreatic cancers, the tumors have very high internal pressures that 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.
In the industry-sponsored, Phase 2 trial, called Halo 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. 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, making it an excellent shock-absorber in your knees, for example. But in pancreatic tumors, it spells trouble. As the gel fluid builds up, it raises the tumor’s internal pressure, squeezing local blood vessels shut. Patients whose tumors have a lot of HA also tend to have a poor prognosis.
When the results of all 231 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],” 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 84 patients whose tumors had a lot of HA, adding PEGPH20 to chemo resulted in an average of 9.2 months before disease progression; with chemo alone, this timespan was just 5.2 months.
Resolving questions about safety
The researchers reported that the unexpected, elevated risk of blood clots associated with PEGPH20 ― which resulted in a temporary halt of the trial in 2014 ― equalized, and dropped overall, in both groups of patients after the study was restarted, thanks 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 [PEGPH20] enzyme safely,” Hingorani said.
Other side effects that occurred more commonly in patients receiving PEGPH20 than those receiving chemo alone were swelling in the hands and feet, muscle spasms, low white blood cell counts and muscle aches, the investigators reported. But it was just the muscle aches that most participants noticed, said Dr. Andrew Coveler, an investigator on the Phase 2 trial who treated study participants through the Fred Hutch/University of Washington Cancer Consortium. The aches were less of a concern for most patients after their first month on the drug, he added.
Notably, patients who were receiving PEGPH20 before the trial paused did not receive any more of the experimental drug when it resumed, due to the cautionary measures the investigators implemented, but they were still counted as being in the experimental arm of the trial for the sake of the analysis. That is, some of the patients in the PEGPH20 group may have received many fewer doses of the drug than others, but this didn’t erase the apparent benefit of the drug in giving patients more time before disease progression.
The team’s studies in mice show that just a handful of doses of PEGPH20, in combination with chemo, is enough to permanently reduce the amount of pressure-boosting HA inside the mouse tumors. But it’s impossible to say right now whether this occurs in human patients without further research, Hingorani said.
Hingorani consults for Halozyme, the PEGPH20 drugmaker and the sponsor of these trials, and the company began this year to provide funding through Fred Hutch to support Hingorani’s research on the drug. He has no financial interest in the company.
‘One shot on goal’
For anyone not familiar with the rapid deadliness of pancreatic cancer, it may be hard to see the significance of the few additional months before disease progression this drug seems to offer. But time is an especially precious resource for patients with this cancer: Only about 8 percent of all pancreatic cancer patients survive five years after diagnosis, and that dismal statistic sinks even further for the more than half of patients who already have distant metastases by the time they are diagnosed, according to the National Cancer Institute.
“What probably happens is some people don’t get much benefit [from treatment], and some get a lot,” Coveler said. But given the realities of this disease, he said, “adding another four months to that [median] is a pretty substantial improvement.”
For comparison’s sake, the combination chemotherapy used in the Halo 202 trial became a standard of care after a randomized controlled trial published in 2013 showed that it increased patients’ average lifespan to 8.5 months ― a boost of not quite two months over the comparison group.
Because the Phase 2 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 3 trial. And the Phase 3 trial is designed to offer a more stringent test of the benefits of the new drug than its predecessor: Aimed at advancing the drug toward potential FDA approval, the trial’s goal is to determine whether PEGPH20 actually increases participants’ lifespans, not just their time to disease progression. (It’s possible a treatment could achieve the latter without affecting the former.)
Regardless of the eventual impact on their own survival, Coveler said, the patients he has treated on the PEGPH20 trials are motivated to participate to help others in the future.
“Trial participants want to do things that not only improve things for themselves but that also move the science forward,” said Coveler, who is the lead investigator for the Seattle site of the Phase 3 trial. “The number of people who say, ‘It might not help me, but if it will help others…’ — it’s just an impressive reason to enroll in clinical trials.”
Hingorani launched the Phase 3 trial before handing off its leadership to two other colleagues in the field, Dr. Margaret Tempero of the University of California San Francisco and Dr. Eric Van Cutsem at the University of Leuven in Belgium. As he steps back from his leadership role on this project, Hingorani is satisfied by the solid scientific foundation the investigators have laid to justify moving forward with the development of this drug.
In light of the grim timelines associated with a pancreatic cancer diagnosis, he said, patients have no time to waste on anything less.
“Patients get one shot on goal, if that, with this cancer,” he said.
