The addition of pegvorhyaluronidase alfa (PEGPH20) to standard nab-paclitaxel/gemcitabine improved progression-free survival over standard therapy in patients with metastatic pancreatic ductal adenocarcinoma.
Andrew E. Hendifar, MD, MPH
The addition of pegvorhyaluronidase alfa (PEGPH20) to standard nab-paclitaxel (Abraxane)/gemcitabine improved progression-free survival (PFS) over standard therapy in patients with metastatic pancreatic ductal adenocarcinoma (mPDA), but the response was greatest in patients having higher hyaluronan levels in the tumor microenvironment, according to findings presented during the 2017 ESMO World Congress on Gastrointestinal Cancer (WGI).
Andrew E. Hendifar, MD, MPH, assistant professor of medicine at Cedars Sinai Medical Center and the David Geffen School of Medicine, presented efficacy findings demonstrating PFS was improved in patients with mPDA by adding PEGPH20 to the standard nab-paclitaxel/gemcitabine treatment. In a separate presentation, Andrea J. Bullock, MD, an attending physician at Beth Israel Deaconess Medical Center and instructor of medicine at Harvard Medical School, presented findings from a preplanned analysis of patient core biopsies obtained from the same study, with efficacy results stratified by hyaluronan (HA) expression levels that identified HA levels as putative predictor of response to this treatment.
“The key study primary and secondary endpoints were met,” said Hendifar, “PFS was improved in the overall population and in patients with high hyaluronan levels with PEGPH20.”
The overall response rate (ORR) was 40% with PEGPH20 plus nab-paclitaxel/gemcitabine compared to 33% with nab-paclitaxel/gemcitabine.1
Patients with high levels of HA, defined as ≥50%, in the tumor microenvironment demonstrated an ORR of 45% versus an ORR of 31% in the PEGPH20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine cohorts, respectively. PFS in patients with high hyaluronan was nearly doubled with PEGPH20 plus nab-paclitaxel/gemcitabine over nab-paclitaxel/gemcitabine at 9.2 versus 5.2 months, respectively, with a hazard ratio (HR) of 0.51 (95% CI, 0.26-1.00).1
“Hyaluronan is a naturally occurring polysaccharide that is increased in the tumor stroma of pancreatic cancer and its accumulation is associated with accelerated tumor growth. PEGPH20 is a recombinant human hyaluronidase that degrades hyaluronan and remodels the tumor microenvironment,” Hendifar explained.
“The HALO-109-212 study enrolled an all-comers population, with a plan to measure hyaluronan in tumor tissue retrospectively,” said Hendifar.
Hendifar and colleagues compared PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) to nab-paclitaxel/gemcitabine (AG) in the phase II randomised, multicenter, 2-stage HALO-109-202 study (NCT01839487). HALO-109-202 originally enrolled 146 patients with stage IV mPDA into a training set for the collection and evaluation of diagnostic markers who were randomised 1:1 to either PAG or AG and treated until an increased incidence of thromboembolic events (TEs) was observed in the PAG arm.1 The trial was placed on therapeutic hold. Following a protocol amendment that included TE screening and thromboprophaylaxis, the hold was lifted; 133 patients with mPDA were enrolled into the validation set and randomized 2:1 to PAG or AG. In the validation set, patients were stratified by <50% or ≥50% of HA staining in the tumor microenrvironment and response was evaluated accordingly. The HA-high cohort included 47 of 146 patients in the training set and 37 of 133 patients in the evaluation set.
Patient characteristics were balanced across all cohorts. Overall, the patients’ mean age was 64.5 years and 56% were male; Karnofsky performance status levels were 70 to 90 in 33.7% and ≥90 in 66.3% of patients. The primary location was the head of the pancreas in 39.8% and the body in 66.3% of patients. Liver metastases were reported in 89.6% of patients and lung metastases in 26.5%. Baseline serum calcium 19.9 levels ≥37 U/mL was seen in 83.5% of patients.1
The safety profile was similar between treatment cohorts; treatment-related adverse events (TRAEs) that were observed more frequently with PAG versus AG, respectively, included peripheral edema (53% vs 26%), muscle spasms (56% vs 3%), neutropenia (34% vs 19%), and myalgia (26 vs 7%). Grade ≥3 TEAEs in the respective cohorts included peripheral edema (5% vs 4%), muscle spasms (3% vs 1%), neutropenia (29% vs 18%), and myalgia (5% vs 0%).1
Accumulation of tumor hyaluronan has been associated with decreased survival in pancreatic cancer, according to Bullock, who presented findings from the validation set of HALO-109-212. The intent to treat population included 133 patients, of which 122 were treated and 35 patients were determined as HA-high (≥50% HA levels in tumor microenvironment).2
An affinity histochemistry assay with an algorithm based on the area of HA staining in the extracellular matrix over the entire tumor surface.
“High hyaluronan as a predictive biomarker is supported by the efficacy data which showed positive trends for progression-free survival and overall survival in hyaluronan-high, PEGPH20-treated patients,” said Bullock.
When the response was evaluated in patients stratified by hyaluronan levels, median PFS with PEGPH20 in patients with high hyaluronan was 8.6 versus 4.5 months with standard therapy, (HR 0.63; 95% CI, 0.21-1.93). Median overall survival (OS) with PEGPH20 versus nab-paclitaxel/gemcitabine was 11.7 versus 7.8 months, (HR 0.52; 95% CI, 0.72- 1.73).2
However, PEGPH20 did not improve PFS or OS over paclitaxel/gemcitabine in patients with low HA levels; median PFS was 6.0 versus 7.2 months (HR 1.21; 95% CI, 0.63- 2.21), and median OS was 11.9 versus 10.2 months (HR 0.69; 95% CI, 0.35-1.28).2
“[HALO-109-201] represents the first clinical study of a molecularly targeted drug in pancreatic ductal adenocarcinoma and validates a biomarker for patient selection,” said Bullock. “These data support the ongoing biomarker-driven, phase III HALO-301 multicenter study of PEGPH20 plus paclitaxel/gemcitabine versus placebo plus paclitaxel/gemcitabine in 420 patients with stage IV PDA and high hyaluronan levels,” commented Hendifar.