Adding Enzyme to Chemo Combo Improves Outcomes in Pancreatic CA

Adding pegvorhyaluronidase alfa (PEGPH20) to nanoparticle albumin-bound paclitaxel (Abraxane) plus gemcitabine (Gemzar) boosted progression-free survival (PFS) in patients with untreated metastatic pancreatic ductal adenocarcinoma (mPDA), researchers said.

In the phase II HALO-202 trial, PFS was significantly improved with the combined regimen (6 months versus 5.3 months; HR 0.73, 95% CI 0.53 to 1.00, P=0.049), according to Sunil Hingorani, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

However, the largest PFS increase was seen in patients with excessive hyaluronan (HA) in their tumors who were treated with the triple combination (PAG) compared to those treated with the dual combo (AG), (9.2 months versus 5.2 months; HR 0.51, 95% CI 0.26 to 1.00, P=0.048), the researchers reported online in the Journal of Clinical Oncology.

The objective response rate was also higher in patients with HA-high tumors treated with PAG versus AG (45% versus 31%), as was the median overall survival (11.7 versus 9.7 months).

“This highlights the importance of patient selection for targeted therapies,” they wrote. “Although further investigation in a larger cohort is warranted, these results clearly support the therapeutic potential of PAG treatment in patients with HA-high mPDA.”

Currently, AG is the first-line standard of care for patients with mPDA. When HA accumulates in the tumor, however, it elevates interstitial pressure and impairs perfusion. Preclinical studies have demonstrated that the pegylated recombinant human hyaluronidase PEGPH20 degrades HA, improving drug delivery.

“Pancreas cancers have been notoriously resistant to virtually all forms of chemical and radiotherapies with a particularly notable disconnect between the ability to kill these cells in a dish versus in a patient,” Hingorani told MedPage Today.

“This randomized phase II trial provides further rationale supporting a compelling explanation for at least part of this resistance, namely very high interstitial concentrations of hyaluronan,” he continued. “These data also support the use of tumor HA as a potential predictive biomarker for patient selection in the ongoing, global phase III study of PAG versus AG in patients with HA-high PDA.”

The HALO-202 trial was conducted in two stages. In stage 1 (March 2013 to April 2014), 146 patients were randomized 1:1 to receive PAG or AG — but researchers observed an imbalance in thromboembolic events early in the study. The trial was subsequently put on hold and 29 patients receiving PAG continued treatment with AG alone. Seven of these patients went back on PEGPH20 therapy when stage 2 of the trial started (August 2014 to February 2016) with an amended protocol.

In stage 2, patients with thromboembolic events were excluded, enoxaparin (Lovenox) prophylaxis was initiated in both arms, and an additional 133 patients were randomized 2:1 to PAG or AG. A primary safety endpoint for thrombolic events was added to determine the efficacy of enoxaparin prophylaxis, and any patient who experienced such an event had to discontinue PEGPH20.

Of the total 279 patients enrolled, 84 (34%) had HA-high tumors.

Each 4-week cycle consisted of 3 weeks on and 1 week off treatment. During cycle 1, PEGPH20 (3 mg/kg) was administered intravenously twice weekly and this was reduced to once weekly during subsequent cycles. AG was administered at standard doses: nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2.

The combination had a manageable toxicity profile and anti-coagulant prophylaxis with enoxaparin reduced thromboembolic event rates in both treatment arms (14% PAG versus 10% AG), they reported.

There were also significant differences in the rates of treatment-related grade 3/4 adverse events between the PAG and AG treatment arms. The most common AEs included muscle spasms (13% PAG versus 1% AG), neutropenia (29% versus 18%), and myalgia (5% versus 0%).

In the phase III trial currently underway, Hingorani predicted that outcomes will “only be as good as the companion drugs that are given along with the enzyme [PEGPH20].” Although standard chemotherapies are unlikely to achieve a cure in the metastatic setting, the approach could potentially produce the kind of meaningful and durable responses seen with treatment for other non-curable cancers, he said.

“If we can at least have the opportunity to increase longevity, we can give patients and their families some time to adjust to the reality of their diagnosis,” Hingorani said.

Limitations of the study include the relatively small number of patients with HA-high tumors available for evaluation of enoxaparin prophylaxis. There were 49 patients with HA-high tumors in the PAG arm and 35 in the AG arm. Discontinuation rates during the temporary clinical hold also precluded robust statistical analyses of overall survival and objective response rate by HA level, the study authors said.