Combining chemotherapy with an experimental enzyme that lowers pressure within tumors seems to double the amount of time certain patients with metastatic pancreatic cancer have before their disease progresses, suggests an interim analysis of data from an ongoing phase 2 trial. However, the trial must be completed before any definitive conclusions can be drawn, cautioned study principal investigator and pancreatic cancer expert Dr. Sunil Hingorani of Fred Hutchinson Cancer Research Center.
“For me, this ― at an absolute minimum ― says ‘finish this trial,’” said Hingorani, who is presenting the interim results of the Halozyme Therapeutics-sponsored Halo 202 trial this Sunday at the annual meeting of the American Society for Clinical Oncology. The meeting, which begins today in Chicago, runs through June 2.
The trial combines the latest first-line, standard-of-care combination chemotherapy for advanced pancreatic cancer with an enzyme called PEGPH20 that breaks down hyaluronic acid, or HA. HA is a molecule that absorbs water and serves as a natural shock absorber in knee joints. But it’s also produced in high amounts in some tumors and has been linked to a poor prognosis.
In high-HA tumors, the water-loving HA sucks the moisture from surrounding tissues into the tumor, leading to such high pressures that drugs travelling through the bloodstream can’t get in to effectively attack cancer cells.
PEGPH20 is a version of the naturally occurring hyaluronidase enzyme that breaks down HA, which has been modified to be more stable in the body. The idea behind the trial, generated by mouse model research published in 2012 by Hingorani’s team, is that using the enzyme to break down HA and lower the pressure inside the tumors will allow blood to penetrate and deliver cancer-killing drugs to their targets.
Last September, the U.S. Food and Drug Administration granted fast-track status to Halozyme’s PEGPH20 program in pancreatic cancer, a designation that is designed to speed the development and review of drugs that fill an unmet need in treating serious medical conditions.
On Sunday, Hingorani will present results from 135 participants in the trial. So far, these preliminary data show that of the patients with high-HA tumors, those who received the experimental enzyme with their chemo experienced an average of 9.2 months of progression-free survival, more than double the 4.3 months of those with high HA who were treated with chemo but no enzyme. (For the patients with low HA, the enzyme didn’t seem to make a difference; these patients had only around five months of progression-free survival, on average, regardless of whether they had received the enzyme.)
The progression-free survival conferred on the high-HA patients by the experimental treatment is higher than the overall survival (a much more definitive survival measure) seen in a recently completed phase 3 trial of the combination chemotherapy — “which is what makes this so surprising,” Hingorani said.
Halozyme Therapeutics presented these preliminary results to analysts and investors in January. Reuters reported that CEO Helen Torley said PEGPH20 is “a blockbuster in waiting” and cited the wide range of solid tumors known to produce high levels of HA. Halozyme plans to begin a phase 3 trial of PEGPH20 in patients with high-HA pancreatic tumors early next year.
Halo 202’s preliminary results hold out the prospect of doubling the remaining life spans of many patients with metastatic pancreatic cancer, a disease in which survival after diagnosis is measured in months. But Hingorani stressed that these are still small numbers of patients and the results are still preliminary. “I look at this and I say, ‘OK, the hypothesis is still intact,’” said Hingorani, who has no personal financial interest in the study and said he has never owned any of Halozyme’s stock.
But he’s hopeful.
“There are reasons embedded in the data that make me more optimistic that this analysis might be real and these results might be real,” Hingorani said. For example, the preliminary analysis shows that, in the chemo-only group, chemo fends off the tumor for longer when HA is low, which is consistent with the investigators’ hypothesis about the role of HA in disease progression and resistance.
These interim results arrive after last year’s scrutiny of PEGPH20’s effect on patients’ risk of blood clots.
On April 4, 2014, Halozyme announced that it had halted the trial as recommended by its independent data monitoring committee, and the FDA followed up five days later with a formal hold. The committee had observed a higher rate of blood clots in participants receiving PEGPH20, and they needed time to analyze the data and see what steps needed to be taken for patient safety. During the pause, patients on the experimental arm of the trial did not receive PEGPH20.
By early June, the FDA had removed the hold and allowed the trial to resume under a modified experimental protocol recommended by the data monitoring committee. Under the modified protocol, participants have received low-molecular-weight heparin, a blood thinner, to reduce clot risk.
Hingorani said that putting pancreatic cancer patients on blood thinners makes a lot of sense, not only for this trial but also in routine clinical care.
“There are data to support putting pancreas cancer patients on low molecular-weight prophylaxis at the time of diagnosis, because they have the highest thromboembolic [clot] risk at baseline of any cancer,” Hingorani said.
A guideline from the American Society of Clinical Oncology, the principal professional organization in the field, recommends that oncologists consider clot-preventing drugs for all of their hospitalized patients. A 2014 meta-analysis of multiple studies on the risks and benefits of preventive blood thinners in cancer patients recommended that oncologists consider using the drugs in an even broader population of patients.
The interim analysis of Halo 202 that Hingorani is presenting on Sunday pools data from all trial participants so far, including those who did and did not receive the blood-thinning drug and those whose PEGPH20 treatment was stopped temporarily during the hold. Final analyses, which will be completed next year, will reveal whether the blood thinner equalizes the risk of clots between the two arms of the trial.
“It will be important in the end to determine if this was effective in normalizing the clot rate,” Hingorani said. “Because if it was, then we removed the major risk factor, as we understand it, for this enzyme.”
Final analyses will also reveal the effect of the experimental treatment on patients’ overall survival, he said.
Hingorani said he routinely receives calls from people with pancreatic cancer around the world who’ve read about PEGPH20 and are eager to try it. Although he, too, is excited about the potential of PEGPH20 to drastically improve treatment for this disease, he focuses on maintaining his objectivity. He said he tells callers, “‘This is a hypothesis we’re testing. The reason I think it’s worth testing is that I’ve done the science as rigorously as I can, otherwise I wouldn’t even ask you to participate. But I still don’t know the answer.’”
Assuming the interim results of the Halo 202 trial hold out, this experimental treatment may only offer newly diagnosed stage 4 pancreatic cancer patients a few extra months of life. But, according to Miggie Olsson, a nine-year survivor of stage 4 pancreatic cancer, even a few additional months can make a big difference.
“It’s so overwhelming, to all of a sudden be told, ‘You don’t get any more time,’” said Olsson, who now volunteers at Seattle Cancer Care Alliance and in the Pancreatic Cancer Action Network’s Survivor and Caregiver Network. “Any little bit added to that can actually help some people even accept it and get their families used to it. And they can have some extremely meaningful time with family members.”
Although Olsson said she wasn’t familiar with the Halo 202 trial, she said that new treatments are needed for those facing pancreatic cancer.
“Speaking for patients, I think we would all like a chance with something. I know that the patients that are struggling right now would like something to try. Whatever they can get into, they’ll try it. Because it would mean a lot to them to get rid of [their pancreatic cancer], in the best case, or at least delay it for several years.”
To read about other Fred Hutch faculty presentations at this year's annual ASCO meeting, click here.
Susan Keown, a staff writer at Fred Hutchinson Cancer Research Center, has written about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at firstname.lastname@example.org.
Solid tumors, such as those of the pancreas, are the focus of Solid Tumor Translational Research, a network comprised of Fred Hutchinson Cancer Research Center, UW Medicine and Seattle Cancer Care Alliance. STTR is bridging laboratory sciences and patient care to provide the most precise treatment options for patients with solid tumor cancers.