Novel Agent Shows Promise in Advanced Pancreatic Cancer

Becky McCall

October 11, 2013

AMSTERDAM — The combination of PEGPH20 (pegylated recombinant human hyaluronidase), a first-of-kind investigational compound, plus gemcitabine (Gemzar) for the treatment of metastatic pancreatic cancer suggests optimum survival benefit in patients with high levels of hyaluronan, according to phase 1b results.

The key finding was a relation between the level of hyaluronan, which forms a protective matrix around the tumor, and responsiveness to PEGPH20, the researchers report. Effectively, the more hyaluronan, the better the response.

Extracellular Matrix

PEGPH20 has its roots in research on the extracellular matrix conducted by Gregory Frost, PhD, who was based at the University of California, San Francisco at the time.

His work led to an understanding of the way a tumor uses hyaluronan to create a protective matrix around itself. This later drove the development of the PEGPH20 enzyme, which degrades the hyaluronan matrix surrounding the tumor.

Initially, it seems counterintuitive to effectively remove the envelope around a tumor and expect this to control progression, but results suggest it works.

"Nobody else is taking this approach to the cancer," explained Dr. Frost. "When we first started, people thought we were crazy, thought we would make the tumor spread and explode. Now we are somewhere between people thinking this is crazy and thinking this is the obvious solution." These days, Dr. Frost is chief executive officer of Halozyme Therapeutics, the company developing PEGPH20.

Central to the development of the product is the finding that a tumor is only responsive to PEGPH20 if it produces hyaluronan; without this substance, which is found in a range of solid tumors, PEGPH20 does not have a target. "Study of the natural biology of cancer showed that early pancreas cancers with high levels of hyaluronan had a poorer prognosis than those that did not," explained Dr. Frost.

When PEGPH20 is given intravenously, in the mildly acidic conditions of the tumor it becomes far more potent and degrades the hyaluronan. It liberates fluid from the tumor, pressure normalizes, reperfusion occurs, and tumor metabolism changes. Counterintuitively, rather than triggering a flare of the tumor, its activity relinquishes, Dr. Frost said.

Because of this increased perfusion, "it makes sense to introduce a powerful additional drug," said Dr. Frost. "The shift to a normoxic environment with reduced pressure activates pathways that make the tumor more sensitive."

This increased sensitivity means that gemcitabine, proven to be effective in pancreatic cancer, is more effective when used in combination with PEGPH20.

Sunil R. Hingorani, MD, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, who was lead investigator of the phase 1b study, presented the data here at the European Cancer Congress 2013.

The researchers enrolled 28 patients with untreated stage IV pancreatic ductal adenocarcinoma. Patients were treated with 1 of 3 doses of PEGPH20 (1.0, 1.6, or 3.0 μg/kg) twice weekly for 4 weeks, and weekly thereafter, in combination with gemcitabine 1000 mg/m² administered intravenously once a week for weeks 1 to 7, followed by 1 week of rest.

Earlier results from this trial, presented in at the annual meeting of the American Society of Clinical Oncology in June, showed that an overall response rate of 42% (95% confidence interval, 22 - 62%) was achieved in the intent-to-treat population (n = 24) treated with gemcitabine plus PEGPH20 at doses of 1.6 and 3.0 μg/kg.

Notably, a partial response was seen in 64% (7 of 11) of patients with high levels of hyaluronan and available biopsies, and in 33% of patients with low levels of hyaluronan.

Furthermore, 43% (6 of 14) of patients saw a reduction of at least 70% in serum carbohydrate antigen 19-9, a biomarker that often correlates with tumor cell burden.

Now, the more mature data, albeit in small patient numbers, demonstrate that progression-free survival was longer in the 6 patients with high levels of hyaluronan than in the 11 patients with low levels (219 vs 108 days). The same was true for overall survival (529 vs 174 days)

In the 24 patients in the intent-to-treat group, progression-free survival was 154 days and overall survival was 200 days.

The phase 1b dose-escalation trial also established the recommended phase 2 dose of 3 μg/kg.

Diagnostic Tool to Identify Hyaluronan-Associated Tumors

Halozyme has also been developing a diagnostic tool to aid in the identification of the approximate 20% of tumors that have hyaluronan. "We believe this tool will help identify patients who can benefit most from PEGPH20 treatment. Data observed to date indicate that tumor-cell-associated hyaluronan may be a good predictor of PEGPH20 combination treatment effect," Dr. Hingorani pointed out.

He added that the hyaluronan-diagnostic approach might enable the testing of PEGPH20 in other hyaluronan-rich tumor types. In the future, Halozyme plans to look at other cancers — such as breast, bronchogenic non-small cell lung cancer, prostate, gastric, and colorectal — in which there is around a 20% prevalence of appropriate targets for the PEGPH20 enzyme.

Patient enrichment trials are planned for next year. Dr. Frost pointed out that the important factor is not where the tumor originates, but whether the target is there. "If the tumor doesn't make the target, then PEGPH20 doesn't do anything."

In addition, a phase 2 trial of stage IV metastatic pancreatic cancer is underway using the combination of gemcitabine, nab-paclitaxel, and PEGPH20. That research is based on the recently completed study of gemcitabine and nab-paclitaxel (the phase 3 MPACT study), which the US Food and Drug Administration recently approved as the new standard of care in metastatic stage IV pancreatic cancer.

Cora Sternberg, MD, chief of the Department of Medical Oncology and chair of the division of medical oncology at the San Camillo and Forlanini Hospitals in Rome, was asked by Medscape Medical News to comment on the study. She said she considers PEGPH20 to be "intriguing," and emphasized that there is a dire need for such novel approaches to therapy in advanced pancreatic cancer.

"This initial study of the combination of PEGPH20 and gemcitabine, a chemotherapy that is often used in the treatment of pancreatic cancer, was well tolerated and shows promising efficacy, especially in patients with high intratumoral hyaluronan content."

She acknowledged that more studies are needed to validate whether the therapy can be personalized by measuring intratumoral hyaluronan.

Margaret Tempero, MD, director of the pancreas center and professor of medicine at the University of California San Francisco,
 welcomes the findings. "It's an exciting approach.... I hope this will dramatically improve the therapeutic efficacy of any drugs we use for this disease, but we need to go one step at a time," she told Medscape Medical News in an interview.

Dr. Tempero said that the concept of depleting the hyaluronan is "intriguing.... The fact that we might be able to deplete the stroma has many positive implications in terms of achieving therapeutic control, and is fascinating. We need to remember the clinical data are early, but it's certainly encouraging."

Eileen M. O'Reilly, MD, from the GI Medical Oncology Service at the Memorial Sloan-Kettering Cancer Center in New York City, also approached for comment, said that "targeting the stroma in pancreas adenocarcinoma is a very topical treatment approach, but success to date has been mixed."

Results from this study "provide an early signal that hyaluronan degradation by PEGPH20 may be a relevant strategy. Preclinical modeling in a robust genetically engineered model system has demonstrated that combining gemcitabine with PEGPH20 provides superior benefit to treatment with gemcitabine alone. The phase Ib clinical data also fairly strongly suggest that there is activity for chemotherapy combined with PEGPH20 in metastatic pancreas cancer, with hyaluronan presence serving as a potential biomarker for benefit," she said.

Randomized trials are underway and/or planned to evaluate the addition of PEGPH20 to combination cytotoxic therapy, to better understand the activity and to further evaluate the biomarker selection opportunity, Dr. O'Reilly noted. "These are exciting early data."

This study was funded by Halozyme Therapeutics. Dr. Frost is CEO of Halozyme Therapeutics. Dr. Hingorani, Dr. Sternberg, and Dr. O'Reilly have disclosed no relevant financial relationships. Dr. Tempero reports being a consultant to Halozyme Therapeutics in the past, and may run a trial in the future.

European Cancer Congress 2013 (ECCO-ESMO-ESTRO): Abstract 2598. Presented September 30, 2013.

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