Abstract
The HA-degrading drug PEGPH20 plus standard therapy extends survival in metastatic pancreatic cancer.
Major finding: The HA-degrading drug PEGPH20 plus standard therapy extends survival in metastatic pancreatic cancer.
Approach: A phase II trial tested nab-paclitaxel plus gemcitabine alone and with PEGPH20 in pancreatic cancer.
Impact: PEGPH20 may enhance the efficacy of standard-of-care chemotherapy in patients with HA-high tumors.
In patients with metastatic pancreatic ductal adenocarcinoma (mPDA), excessive accumulation of the large linear polysaccharide hyaluronan (HA) in the extracellular matrix is associated with poor survival. HA has a high affinity for water, which can create an immobile gel–fluid phase that can induce vascular collapse, elevate interstitial pressure, and impair perfusion in the tumor microenvironment. A pegylated recombinant human hyaluronidase, pegvorhyaluronidase alfa (PEGPH20), degrades intratumor HA and has demonstrated antitumor activity in preclinical and early clinical studies. In a phase II clinical trial, Hingorani and colleagues compared the efficacy of nab-paclitaxel plus gemcitabine (AG), the standard of care for mPDA, to PEGPH20 in combination with AG (PAG) in patients with mPDA. A total of 279 patients with previously untreated mPDA were enrolled and randomly assigned to receive PAG or AG, 246 had HA data available, and 231 were evaluable for efficacy. The primary endpoints were progression-free survival and thromboembolic (TE) event rate, and secondary endpoints included progression-free survival by HA level, and objective response rate. In the entire population, median progression-free survival was 6 months in the PAG arm compared with 5.3 months in the AG arm. However, in the 84 patients with HA-high tumors the median progression-free survival was 9.2 months in the PAG arm and 5.2 months in the AG arm, indicating that PAG may be more effective in this population. In the HA-high group the objective response rate was 45% with PAG and 31% with AG. PAG had a manageable toxicity profile with treatment-related serious adverse events occurring in 44% of patients compared with 31% of patients in the AG arm. The TE event rate was similar in both arms after enoxaparin prophylaxis was initiated to reduce the incidence of TE. Altogether, these findings support further investigation of PEGPH20 combination therapy in patients with HA-high PDA.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.
