PEGPH20 Offers New Mechanism for Attacking Pancreas Tumors

Oncology Live®Vol. 18/No. 18
Volume 18
Issue 18

PEGPH20 (pegvorhyaluronidase alfa), a novel formulation of a naturally occuring enzyme, is being investigated as a biomarker-driven treatment for patients with advanced pancreatic cancer.

Sunil R. Hingorani, MD, PhD

PEGPH20 (pegvorhyaluronidase alfa), a novel formulation of a naturally occuring enzyme, is being investigated as a biomarker-driven treatment for patients with advanced pancreatic cancer.

The drug, which is a PEGylated recombinant human hyaluronidase enzyme, is being tested in combination with standard-of-care gemcitabine and nab-paclitaxel (Abraxane) in patients with stage IV treatment-naïve pancreatic cancer whose tumors express high levels of hyaluronan (HA). PEGPH20 degrades HA, a carbohydrate that can build up in the tumor microenvironment and block the delivery of anticancer therapies.

The phase III, randomized, multicenter HALO- 301 trial seeks to recruit approximately 420 patients with advanced, metastatic pancreatic ductal adenocarcinoma, including patients with disease progression that occurs following resection 6 months or longer after their last therapy (NCT02715804). (Figure).

Figure. PEGPH20 in Pancreatic Cancer

“This is a biomarker-stratified trial because we learned from retrospective analyses that the patients who benefit most from this enzymatic strategy to degrade HA are those with the highest levels of HA in their tumors,” said Sunil R. Hingorani, MD, PhD, director of the Center for Accelerated Translation in Pancreas Cancer at the Fred Hutchinson Cancer Research Center in Seattle and a professor at the University of Washington School of Medicine.

All prospective participants will be tested for HA levels in their tumors. HA-high tumors are defined as having HA staining on greater than 50% of the tumor surface in the extracellular matrix; those with low levels of HA (<50%) will be excluded from participating in the trial.

Additionally, participants must have an ECOG performance status of 0 or 1, and no evidence of deep vein thrombosis, pulmonary embolism, or any other known thromboembolic event.

Eligible patients will be randomized 2:1 to either receive treatment with PEGPH20 combined with standard-of-care gemcitabine and nabpaclitaxel, or the chemotherapeutic agents alone with a placebo. Investigators will be looking to progression-free survival (PFS) and overall survival as the primary endpoints, with overall response rate, duration of response, and safety as secondary endpoints.

The Ventana HA CDx Assay, a companion diagnostic developed by Ventana Medical Systems, will be used to conduct HA testing during the trial. The test is a recombinant HA binding probe designed to be used with the Ventana OptiView DAB IHC Detection Kit on formalin-fixed, paraffin-embedded pancreatic tumor samples.1

The assay was tested for its inter-reader precision by 3 pathologists who evaluated 100 tumor samples with varied HA expression levels. The evaluation showed agreement rates greater than 94%, which investigators said demonstrated the assay’s “high robustness and reproducibility.”1

Drug Targets Tumor Swelling

According to Andrew E. Hendifar, MD, medical oncologist and codirector of Pancreas Oncology at Cedars-Sinai Medical Center in Los Angeles, the trial investigators need to obtain a significant amount of tumor tissue for this test. “Fine-needle aspirates are excluded. You need a core biopsy so you can assess the tissue architecture,” said Hendifar, who is a principal investigator for the trial.Hingorani, who helped develop the trial design and was the international principal investigator for a prior randomized phase II study of PEGPH20,2 highlighted the pressing need for new therapies for patients with pancreatic cancer. He noted that the disease is distinguished by its rapid progression and lethality, including the highest 1-year and 5-year mortality rates of any cancer.

Pancreatic cancer is also difficult to detect early, as it rarely presents with symptoms in the early stages, Hingorani said. When symptoms are present, they can be “vague and misleading, like abdominal discomfort that understandably is misdiagnosed as acid reflux disease, or a low back pain that gets understandably misdiagnosed as musculoskeletal pain,” he said.

Additionally, the treatment of patients with advanced disease is a large unmet need. “The cancer has historically been resistant to all forms of chemical therapies and radiotherapies that have been used,” Hingorani said. “Interestingly, there has also been a large disconnect between the ability to kill pancreatic cancer cells in a dish in the laboratory with at least a handful of drugs, and a largely complete inability of those same drugs to treat the tumor inside a patient.”

This is further complicated by pancreatic tumors with high expression of HA, a polysaccharide that binds water tightly to create a hydrogel inside the tumor. And, because HA is highly negatively charged, as it binds water, it also swells the tumor, according to Hingorani. Therefore, it creates pressure inside the tumor, and this pressure is counteracted by a tethered fibrillar collagen network, with these fibers binding to the surface of the cells. The cells then contract back against the tensional load that fluid-bound HA applies, which allows pressure to increase further.

There is swelling contained within a cage of fibrillar collagen that’s contracting back against it, and the result is that the pressure can rise up very high, upward of 100 mmHg, such that the vessels inside the tumor largely collapse under this pressure, and it becomes very difficult for hydrostatic pressure within the body to counteract that and deliver any systemically introduced agents,” Hingorani explained. The hypothesis is that 1 of the primary mechanisms of resistance in pancreatic cancer is that many drugs introduced into the bloodstream do not reach therapeutic concentrations inside the tumor due to this swelling pressure.

PEGPH20 is a PEGylated form of recombinant hyaluronidase, an enzyme that degrades HA. Although there are natural forms of hyaluronidase, the drug is a cloned version that creates a clinical-grade reagent, according to Hingorani. That molecule is then PEGylated to increase its half-life in circulation by upward of 10 to 20 hours.

Notably, PEGPH20 is also one of few treatments that have been developed to target the tumor stroma. According to Hendifar, pancreatic cancer is characterized by the role of the stroma, which has been under investigation as a potential target for treating advanced tumors. “Because of the hyaluronan, the [pancreas] tumor is tough and firm, like a golf ball and, given this kind of enzyme, you soften the tumor, which allows treatment to work better,” Hendifar said.

Early Clinical Findings

Hingorani said that applying “small amounts of this enzyme [PEGPH20] can lead to a self-reinforcing process.” He said the enzyme degrades the HA polymer, releasing the bound water from the tumor. “The intratumor pressures start to fall, which allows more enzyme that’s in the circulation—because it has this extended half-life&mdash;to enter into the tumor and further the degradation process,” Hingorani said.The rationale for the HALO-301 trial was established in the phase II HALO-202 study, which randomized 279 and treated 260 patients to PEGPH20 combined with gemcitabine and nabpaclitaxel versus the chemotherapy agents alone.

The median PFS difference in the 2 regimens was modest, but statistically significant in favor of the PEGPH20 treatment arm (6.0 vs 5.3 months, respectively; HR, 0.73; P = .045). In patients with HA-high tumors (n = 84), the median PFS benefit was significantly higher in the PEGPH20 arm at 9.2 months compared with 5.2 months with chemotherapy alone (HR, 0.51; 95% CI, 0.26-1.00; P = .048).2

“The HALO-202 study was for all-comers, and there was benefit there, but in the HA-high tumors, the benefit was greater,” Hendifar said. One of the main adverse events (AEs) associated with PEGPH20 is the increased risk of thromboembolic and clotting events. In the HALO-202 study, the thromboembolic event rate was 43% in the PEGPH20 arm compared with 25% in the chemotherapy arm.2

“That required an amendment to the protocol, instituting the use of prophylactic low-molecular weight heparin, which then reduced the thromboembolic event rate in both arms,” Hingorani said. “Pancreatic cancer [creates] a highly coagulable state, so patients with pancreatic cancer are already at an increased risk for thromboembolic events.” Other significant AEs of any grade in the PEGPH20 arm included peripheral edema (63%), muscle spasms (56%), neutropenia (34%), and myalgia (26%). Febrile neutropenia was rare, and did not differ between the 2 arms.2

Although PEGPH20 has shown efficacy in this patient population, the HALO-301 trial will determine whether it is a feasible treatment option in combination with gemcitabine and nab-paclitaxel in the first-line metastatic setting. “If this phase III study establishes the efficacy in this subgroup of patients with certain tumor characteristics with having high hyaluronan expression, then the drug will be further developed in similar tumors that have similar expression, like cholangiocarcinoma, lung cancer, and other tumors,” Hendifar said.

Hingorani noted that the drug partners paired with PEGPH20 are important to the efficacy of the strategy. “The flipside of [PEGPH20’s mechanism of action] is that ultimately the responses and the benefit we’re going to see are only as good as the companion drugs that are given along with the enzyme,” he said. “If we’re still using standard chemotherapies, it’s unlikely that we’re going to see cures in the metastatic setting but at least, hopefully, we will get some meaningful and durable responses such that we can approach this cancer like we think about other cancers—where you at least have the opportunity to increase longevity&mdash;and you can give some time to the patients and their families to adjust to the reality of their diagnosis.”


  1. Khelifa S, Pu J, Aldrich C, et al. Development of a companion diagnostic assay for tissue hyaluronan detection and treatment with PEGPH20 in metastatic pancreatic ductal adenocarcinoma patients [ASCO abstract e15749]. J Clin Oncol. 2016;34(suppl).
  2. Hingorani SR, Bullock AJ, Seery TE, et al. Randomized phase II study of PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) vs AG in patients (Pts) with untreated, metastatic pancreatic ductal adenocarcinoma (mPDA) [ASCO abstract 4008]. J Clin Oncol. 2017;35(suppl).

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