The investigational agent pegvorhyaluronidase alfa in combination with gemcitabine and nab-paclitaxel did not show an improvement in overall survival compared with gemcitabine and nab-paclitaxel alone in patients with metastatic pancreatic cancer, missing the primary endpoint of the phase III HALO-109-301 trial.
Helen Torley, MB, ChB, MRCP
The investigational agent pegvorhyaluronidase alfa (PEGPH20) in combination with gemcitabine and nab-paclitaxel (Abraxane) did not show an improvement in overall survival (OS) compared with gemcitabine and nab-paclitaxel alone in patients with metastatic pancreatic cancer, missing the primary endpoint of the phase III HALO-109-301 trial (NCT02715804).1
Results showed that the addition of PEGPH20 led to a median OS of 11.2 months compared with 11.5 months in those who received gemcitabine/nab-paclitaxel alone (HR, 1.00; P = .9692). There was a higher response rate in the PEGPHO20 arm; however, this did not translate into an improvement in progression-free survival (PFS), OS, or duration of response (DOR).
Due to these findings, Halozyme, the manufacturer of PEGPH20, stated in a press release that it intends to halt development activities for PEGPH20 as well as implement an organizational restructuring. The company added that it will solely focus its operations on its ENHANZE® drug delivery technology which facilitates subcutaneous delivery of therapeutics.
"Patients in both treatment arms of the HALO-301 trial surpassed the published median overall survival rates from the pivotal registration study of Abraxane plus gemcitabine as first-line therapy for metastatic pancreas cancer, published in 2013. Based on the lack of benefit over standard-of-care in this study, which performed well versus published data, we will be discontinuing PEGPH20 clinical development,” Helen Torley, MB, ChB, MRCP, president and CEO of Halozyme, stated in the press release.
PEGPH20 is a PEGylated recombinant human hyaluronidase enzyme that briefly degrades hyaluronan (HA), a dense component of the tumor microenvironment that can accumulate in higher concentrations around select cancer cells. This potentially constricts blood vessels and impedes the access of other therapies, the company explained in the press release.
In the double-blind, placebo-controlled, multicenter, randomized HALO-109-301 trial, investigators compared the combination of PEGPH20 with gemcitabine/nab-paclitaxel with gemcitabine/nab-paclitaxel alone in approximately 500 patients with HA-high stage IV previously untreated pancreatic ductal adenocarcinoma. Patients were randomized in a 2:1 fashion to receive the PEGPH20 regimen or standard chemotherapy.
PEGPH20 was given intravenously (IV) at 3.0 μg/kg twice weekly for weeks 1 to 3 of cycle 1, then once weekly for weeks 1 to 3 of cycle 2 and beyond, in combination with 125 mg/m2 of IV nab-paclitaxel and 1000 mg/m2 of IV gemcitabine, given once weekly for weeks 1 to 3 of all treatment cycles. Treatment was administered until patients experienced disease progression, unacceptable toxicity, death, or withdrawal of consent.
To be eligible for enrollment, patients must have been ≥18 years, had stage IV pancreatic ductal adenocarcinoma and had to be determined to have HA-high disease, ≥1 measurable tumor metastasis, an ECOG performance status of 0 or 1, a life expectancy of ≥3 months, and if already received neoadjuvant or adjuvant therapy, disease recurrence or progression must have occurred longer than 6 months after finishing the last dose of therapy. Patients with clinical evidence of deep vein thrombosis or pulmonary embolism; had prior radiotherapy, surgery, chemotherapy, or investigational therapy for metastatic disease; had known central nervous system involvement or brain metastases; or had significant pre-existing carotid artery disease were excluded from the trial.
In November 2018, Halozyme announced that prior to data analysis and following agreement from the FDA that it would change the primary endpoint of HALO-301 study from being PFS and OS to a single primary endpoint of OS.2 As a result, the previously planned interim analysis would not be conducted.
Secondary endpoints included PFS, objective response rate (ORR), DOR, and treatment-emergent adverse events.
Early clinical trials demonstrated that PEGPH20 shows a benefit in patients with metastatic HA-high pancreatic cancer. In the phase II HALO-109-202 study, the ORR in patients with HA-high tumors was 45% with PEGPH20 plus nab-paclitaxel/gemcitabine compared with 31% with nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma.3
Moreover, the median PFS was 9.2 months with the PEGPH20 regimen in patients with HA-high tumors compared with 5.2 months in those who received chemotherapy alone (HR, 0.51; 95% CI, 0.26-1.00; P = .048). The median OS in patients with HA-tumors was 11.5 and 8.5 months, respectively (HR, 0.96; 95% CI, 0.57-1.61).
Overall, the median PFS was 6.0 months and 5.3 months, respectively (HR, 0.73; 95% CI, 0.53-1.00; P = .049), and the ORR was 40% versus 33%, respectively. The median OS was similar between arms at 9.6 and 9.2 months with the addition of PEGP20 and gemcitabine/nab-paclitaxel, respectively (HR, 0.90; 95% CI, 0.68-1.19).
Regarding safety, the most common grade 3/4 treatment-related adverse events included muscle spasms (13% with PEGPH20 vs 1% with gemcitabine/paclitaxel), neutropenia (29% vs 18%, respectively), and myalgia (5% vs 0%).
Previously, the FDA granted PEGPH20 orphan drug designation for the treatment of patients with pancreatic cancer, as well as fast track designation for the agent in combination with gemcitabine and nab-paclitaxel for this patient population. The European Commission also designated PEGPH20 an orphan medicinal product for the treatment of patients with pancreas cancer.
“This well-designed and well-executed study did not have the outcome that we or the study participants wanted or expected,” Torley concluded in the press release. “I would like to extend a heartfelt thank you to all those who supported and who made this study possible, including the patients who were enrolled, their families, our investigators, their staff, our investors and all of the dedicated Halozyme employees.”