SUMMARY: The American Cancer Society estimates that in 2017, about 53,670 people will be diagnosed with pancreatic cancer in the United States and about 43,090 patients will die of the disease. Some important risk factors for pancreatic cancer include increasing age, obesity, smoking history, genetic predisposition, exposure to certain dyes and chemicals, heavy alcohol use and pancreatitis. The best chance for long term survival is complete surgical resection, although this may not be feasible in a majority of the patients, as they present with advanced disease at the time of diagnosis. Based on the National Cancer Data Base, the 5 year observed survival rate for patients diagnosed with exocrine cancer of the pancreas is 14% for those with Stage IA disease and 1% for those with Stage IV disease. The FDA approved ABRAXANE® ((Paclitaxel albumin-bound particles) for use in combination with GEMZAR® (Gemcitabine) for the first line treatment of patients with metastatic adenocarcinoma of the pancreas. This approval was based on the demonstration of improved Overall Survival (OS) and Progression Free Survival (PFS), in a multicenter, international, open-label, randomized trial (MPACT study), when compared to single agent GEMZAR®.
PEGPH20 is a PEGylated form of recombinant human Hyaluronidase, for the potential systemic treatment of tumors that accumulate Hyaluronan (HA). PEGPH20 is an enzyme that temporarily degrades Hyaluronan, a dense component of the tumor microenvironment that can accumulate in higher concentrations around certain cancer cells and potentially constrict blood vessels and there by impede treatment access to tumor tissue. It is estimated that 35% to 40% of patients with pancreatic cancer have high expression of Hyaluronan and this biomarker may predict response to PEGPH20.
HALO 202 (Halo 109-202) is a phase 2 multicenter, randomized clinical trial, in which PEGPH20 in combination with ABRAXANE® and GEMZAR® was compared with ABRAXANE® and GEMZAR® alone, in treatment naive patients with metastatic pancreatic carcinoma. In this study, following enrollment of 146 patients in the first stage of the trial, the study was placed on hold to address concerns regarding thromboembolic events, in the group receiving PEGPH20. The protocol was amended to exclude those at high risk for a thromboembolic event and prophylaxis with Low Molecular Weight Heparin was required. One hundred thirty-three patients (N=133) were enrolled into the second stage of the trial for a total of 279 patients. Patients enrolled in stage 2 received Low Molecular Weight Heparin at a starting dose of 40 mg/day or 1 mg/kg/day, to prevent thromboembolic events. PEGPH20 was administered at 3 µg/kg twice weekly for cycle 1 followed by weekly administration in subsequent cycles. ABRAXANE® and GEMZAR® were administered at their standard FDA-approved doses. Tumor biopsy samples for the Hyaluronan analysis were available for 138 patients treated with PEGPH20 and 79 patients treated in the control group across both stages of the study. Overall, 49 patients in the PEGPH20 arm and 35 in the control group had Hyaluronan expression of 50% or more. The primary endpoint of the study was Progression Free Survival (PFS) across the entire treatment group. Following change in the treatment protocol, a second primary endpoint was added to assess thromboembolic event rate. Secondary endpoints included Objective Response Rate, PFS by Hyaluronan level, and Overall Survival. The second stage of this study was also utilized to validate a companion diagnostic for Hyaluronan (HA) levels.
It was noted that across the overall study population, there was a statistically significant increase in Progression Free Survival (PFS) in patients with high levels of Hyaluronan (HA-High) treated with PEGPH20 plus ABRAXANE® and GEMZAR®, compared to HA-High patients receiving ABRAXANE® and GEMZAR® alone. Among the patients in the second stage of this study, there was a 91% improvement in median PFS for HA-High patients in the PEGPH20 group compared to the control group (8.6 months versus 4.5 months) and the additional primary endpoint of a reduction in the rate of thromboembolic events was achieved, in the PEGPH20 group. Across all patients, thromboembolic events were experienced by 14% of those in the PEGPH20 group versus 10% of those in the ABRAXANE® and GEMZAR® group. These events were lower in those receiving Low Molecular Weight Heparin at 1 mg/kg/day dose versus 40 mg/day (6% vs 10%, respectively). The most common adverse events were cytopenias.
The authors concluded that the addition of PEGPH20 to ABRAXANE® and GEMZAR® resulted in significant improvement in Progression Free Survival compared with ABRAXANE®/GEMZAR® alone, in treatment naïve patients with advanced pancreatic cancer. Patients with high levels of expression of the biomarker Hyaluronan, had the best outcomes suggesting that a biopsy-based biomarker for hyaluronan content can potentially identify patients who will have a meaningfully greater response when PEGPH20 is added to standard chemotherapy. A phase III study is underway, evaluating PEGPH20 in combination with ABRAXANE® and GEMZAR® in patients with metastatic pancreatic cancer, with high Hyaluronan levels. Countouriotis A. Study 202 Overall Results and Stage 2 Results [webcast]. Halozyme Investor Call; January 5, 2017. Final analysis of stage 1 data from a randomized phase II study of PEGPH20 plus nab-Paclitaxel/gemcitabine in stage IV previously untreated pancreatic cancer patients (pts), utilizing Ventana companion diagnostic assay. Bullock AJ, Hingorani SR, Wu XW, et al. J Clin Oncol 34, 2016 (suppl; abstr 4104)
