PEGPH20 Could Alter Frontline Treatment in Pancreatic Cancer

Robert R. McWilliams, MD

Optimizing frontline therapy for patients with pancreatic cancer is an ongoing focal point in the field, according to Robert R. McWilliams, MD.

“One of the things to recognize is that most patients with pancreatic cancer get one line of therapy, so often it can be challenging,” McWilliams said in an interview during the OncLive^® 2017 State of the Science Summit^TM on GI Malignancies. “Either chemotherapy can be limited with things like elevated liver function with a bilirubin test, and age and performance status are often considerations.”

Currently, the standard of care for the frontline treatment of pancreatic cancer is nab-paclitaxel (Abraxane)/gemcitabine, but there are targeted agents being explored in clinical trials that are showing promise. As mutations become more understood through advances in molecular testing, treatments for this difficult-to-treat disease are within reach.

Pegvorhyaluronidase alfa (PEGPH20) is currently being explored as a treatment for patients with metastatic pancreatic ductal adenocarcinoma (mPDA) in combination with nab-paclitaxel/gemcitabine. This investigational drug targets the accumulation of hyaluronan (HA) within the tumor microenvironment. By targeting the tumor stroma, investigators believe that agents such as PEGPH20 could improve the delivery of chemotherapy. PEGPH20 has already been shown to degrade HA, reforming the tumor microenvironment.

In a disease landscape that has limited treatment options outside of chemotherapy regimens, PEGPH20 has been shown to induce response in patients who are identified as having high HA expression. HA occurs naturally and is increased in the tumor stroma of pancreatic cancer, and accumulation of tumor HA has been associated with accelerated tumor growth and decreased survival.

The HALO-202 study of previously untreated patients with mPDA demonstrated that tumor HA was shown to be a predictor for response to PEGPH20 treatment.

“Now we are understanding that this disease is treatable, and even more than that, we are understanding that there are different subtypes of pancreas cancer,” Andrew Hendifar, MD, lead author of the HALO-202 study, explained to OncLive at a medical meeting earlier in 2017. “I think that stromal targeted therapies are promising, and we are [exploring] with PEGPH20 and BTK inhibition—hopefully this will open up new avenues of treatment for this disease.”

A total of 133 patients with mPDA were enrolled into the validation set and randomized 2:1 to PEGPH20 plus nab-paclitaxel/gemcitabine or nab-paclitaxel/gemcitabine alone. Patients were stratified by <50% or ≥50% of HA staining in the tumor microenvironment in the validation set, and response was evaluated accordingly.

Patients who were identified as HA-high showed an improvement in median overall survival (OS) and progression-free survival (PFS) when treated with PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine alone.

The exploratory OS in patients who were HA-high was 11.5 months with PEGPH20 plus nab-paclitaxel/gemcitabine versus 8.5 months with nab-paclitaxel/gemcitabine (HR, 0.96; 95% CI, 0.57-1.61). PFS in patients who were HA-high was 9.2 months when treated with PEGPH20 plus nab-paclitaxel/gemcitabine, compared with 5.2 months when treated only with nab-paclitaxel/gemcitabine (HR, 0.51; 95% CI, 0.25-1.00).

Adverse events of all grades were observed with PEGPH20 plus nab-paclitaxel/gemcitabine and nab-paclitaxel/gemcitabine, including peripheral edema (53% vs 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26% vs 7%).

There was an increased risk of thromboembolic events that caused a temporary suspension of the phase II trials of PEGPH20, but the addition of lower molecular-weight heparin reduced the incidence and the trials resumed.

HALO-202 was the first clinical study of a molecularly targeted drug in mPDA, which validated a biomarker for patient selection, and the results of the trial provided support to the ongoing phase III HALO study in patients with stage IV untreated pancreatic cancer (NCT02715804). If the results are positive, it would validate stromal expression of HA as a biomarker for targeted therapy.

“Pancreatic cancer is a big challenge,” said McWilliams. “We work with our surgeons on patients who could potentially go to surgery and have a curative intent. The vast majority of patients are not in that category though, and to be able to pick the right regimen for them and meet their needs will help us improve as we go and get patients on clinical trials.”

With the statistically significant results coming out of the HALO-202 trial, and the impending findings of the phase III HALO-301 trial, PEGPH20 has the potential to be added to the standard first-line therapy for patients with mPDA who are HA-high, experts explained.

References

1. Hendifar A, Bullock A, Seery T, et al. Tumor hyaluronan may predict benefit from PEGPH20 when added to nab paclitaxel/gemcitabine in patients with previously untreated metastatic pancreatic ductal adenocarcinoma (mPDA). [ESMO WGI Abstract O-028]. Ann Oncol. 2017;28(suppl_3):iii137-iii149. doi: 10.1093/annonc/mdx262.
2. Hingorani S, Bullock A, Seery T, 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). J Clin Oncol. 2017;35(15):4008. doi: 10.1200/JCO.2017.35.15_suppl.4008.