PEGPH20: A Novel Agent for Pancreatic Adenocarcinoma
Insights From: Andrew Ko, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Andrew Ko, MD: PEGPH20 is a novel drug. It’s actually a recombinant enzyme called hyaluronidase, and it’s pegylated to increase its half-life. Its target is a major component of the extracellular matrix that’s present in pancreatic cancers called hyaluronic acid or hyaluron. And the idea is that the hyaluronic acid that is present in high quantities in many pancreatic tumors increases the interstitial fluid pressure in these tumors. And as a result of that, it causes the blood vessels within the tumor microenvironment to collapse. It decreases the diffusion of drugs from vessels into the surrounding space, so it decreases the ability of drugs to get into tumors. So, by targeting and breaking up this hyaluronic acid, this drug has been shown to improve drug delivery, which hopefully results in improved antitumor efficacy in patients with pancreatic cancer.
PEGPH20, when combined with chemotherapy, may enhance the delivery of chemotherapy, allowing it to penetrate and affect its antitumor activity in tumor sites more effectively. This is by decreasing the interstitial fluid pressure by allowing the blood vessels, that normally are somewhat collapsed, to expand and improve the permeability and the diffusion of concurrently-administered chemotherapy drugs into the site of tumor.
PEGPH20 was studied in a fairly large randomized phase II study. This study focused on patients with metastatic pancreatic cancer who were previously untreated. Patients were randomized to receive either gemcitabine plus nab-paclitaxel—which is a standard of care option for patients with metastatic pancreatic cancer—by itself or in combination with PEGPH20. This was a fairly large study, as noted, of about 260 patients or so, and the results we’ve seen so far look quite promising. And by that, I mean that if you take the entire study population, the addition of PEGPH20 to chemotherapy didn’t lead to an appreciable improvement in progression-free survival or response rate. But when you took the proportion of patients who had elevated levels of hyaluronic acid measured in their tumors, which was approximately 30% to 35% of this study population, then you saw a significant improvement in progression-free survival with the addition of the PEGPH20 to chemotherapy. You saw higher response rates.
Now, these numbers are still fairly small and require further validation, but it offers a promising proof of principle that PEGPH20 may potentially be beneficial when added to chemotherapy, specifically in patients whose tumors express high levels of hyaluronic acid. So, the assay to measure hyaluronic acid in patients’ tumors, basically it’s an immunohistochemical assay, so it’s an antibody that has been further developed and is now being used in the current ongoing phase III study. It requires actual tumor tissues; not just fine needle aspirate, not just some cytology sample, but an actual tissue block where you can measure the content of hyaluronic acid. Right now, the threshold for defining positivity of HA using this tool is 50% or greater staining in the extracellular matrix.
Irrespective of the high versus low levels of HA, the study actually found, in the first stage, that there was a higher-than-expected incidence of thromboembolic events, so blood clots, DVTs, pulmonary emboli. And as a result, the study was temporarily halted, so that the study could be re-designed so all patients would be prophylaxed with low molecular weight heparin. After that point, the incidence of thromboembolic events actually decreased back to baseline or what we would expect in this patient population. The other common side effects that appear to be associated with PEGPH20 include development of edema and muscle cramps or muscle pain myalgias. So, patients are typically pre-medicated with steroids before they get treated. There seems to be perhaps a little higher rate of neutropenia, so low blood counts for patients receiving chemotherapy with PEGPH20.