In a phase II study reported in the Journal of Clinical Oncology, Hingorani et al found that the addition of pegvorhyaluronidase alfa (PEGPH20) to nab-paclitaxel (Abraxane)/gemcitabine improved progression-free survival in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. Excessive hyaluronan accumulation in the tumor microenvironment is characteristic of metastatic disease and is associated with impaired perfusion; PEGPH20 has been shown to degrade hyaluronan, potentially increasing drug delivery.
In the trial, a total of 279 patients were randomized to receive PEGPH20 plus nab-paclitaxel/gemcitabine (n = 166) or nab-paclitaxel/gemcitabine alone (n = 113). The trial was put on hold after an early imbalance of thromboembolic events in the PEGPH20 group was observed (stage 1, March 2013 to April 2014). The trial was subsequently resumed (stage 2, August 2014 to February 2016) with a 2:1 randomization, with patients with a history of thromboembolic events or risk factors being excluded and all patients receiving enoxaparin prophylaxis. The primary endpoints were progression-free survival and thromboembolic event rate. Tumor hyaluronan levels were measured retrospectively; among 246 patients with hyaluronan data, 84 (34%) had hyaluronan-high tumors.
Median progression-free survival was 6.0 months in the PEGPH20 group vs 5.3 months in the control group among all patients (hazard ratio [HR] = 0.73, P = .049) and 9.2 months vs 5.2 months among patients with hyaluronan-high tumors (HR = 0.51, P = .048). Objective response rates were 40% vs 33% among all patients (P = .23) and 45% vs 31% among those with hyaluronan-high tumors (P = .24). Median overall survival was 9.6 vs 9.2 months among all patients (HR = 0.90, 95% confidence interval [CI] = 0.68–1.19) and 11.5 vs 8.5 months among those with hyaluronan-high tumors (HR = 0.96, 95% CI = 0.57–1.61).
The most common treatment-related grade 3 or 4 adverse events with a significantly higher incidence in the PEGPH20 group included muscle spasms (13% vs 1%), neutropenia (29% vs 18%), and myalgia (5% vs 0%). During stage 1 of the trial, thromboembolic events occurred in 43% of patients in the PEGPH20 group vs 25% in the control group (P = .03). During stage 2, when patients received enoxaparin prophylaxis, thromboembolic events occurred in 14% vs 10% (P = .77).
The investigators concluded: “This study met its primary endpoints of [progression-free survival] and [thromboembolic] event rate. The largest improvement in [progression-free survival] was observed in patients with [hyaluronan]-high tumors who received [PEGPH20 plus nab-paclitaxel/gemcitabine]. A similar [thromboembolic] event rate was observed between the treatment groups in stage 2 of the trial.”
The study was supported by Halozyme Therapeutics, Inc.
Sunil R. Hingorani, MD, PhD, of the Fred Hutchinson Cancer Research Center, is the corresponding author of the Journal of Clinical Oncology article.
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