PEGPH20 extends PFS in metastatic pancreatic ductal adenocarcinoma

CHICAGO — The addition of PEGPH20 to chemotherapy significantly prolonged PFS among patients with untreated metastatic pancreatic ductal adenocarcinoma, according to randomized study results presented at the ASCO Annual Meeting.

Patients with high levels of hyaluronan in their tumors derived the greatest benefit.

Hyaluronan in the tumor microenvironment produces elevated tumor pressure, vascular compression and reduced drug delivery.

The investigational therapy PEGPH20 (Halozyme) targets and degrades hyaluronan — a naturally occurring sugar in the body that accumulates in higher concentrations around many solid tumors — thereby increasing the access and therapeutic access of anticancer agents, according to study background.

Sunil R. Hingorani, MD, PhD, member of the clinical research division at Fred Hutchinson Cancer Research Center, and colleagues conducted a phase 2 study to assess the activity and safety of PEGPH20 in combination with nanoparticle albumin-bound paclitaxel (Abraxane, Celgene) — commonly called nab-paclitaxel — and gemcitabine in patients with untreated metastatic pancreatic ductal adenocarcinoma.

In the study’s first stage, researchers randomly assigned patients to chemotherapy with or without PEGPH20. Patients received nab-paclitaxel and gemcitabine via IV once a week for 3 weeks for all treatment cycles. Those assigned PEGPH20 received twice-weekly IV doses in the first cycle and weekly doses in subsequent cycles.

Researchers observed an imbalance in thromboembolic events in the PEGPH20 group, leading to a clinical hold. Approximately 40% of patients discontinued PEGPH20 treatment. Investigators subsequently excluded patients at high risk for thromboembolic events and initiated enoxaparin prophylaxis to patients in both treatment groups.

In the study’s second stage, Hingorani and colleagues randomly assigned patients 2:1 to chemotherapy with or without PEGPH20. Researchers used the novel Ventana HA RxDx assay — co-developed by Ventana Medical Systems and Halozyme — to assess tumor hyaluronan.

PFS in all evaluable patients and thrombotic event rate in the study’s second stage served as primary endpoints. Secondary endpoints included PFS by hyaluronan level and overall response rate.

The study included 279 patients, of whom 231 were evaluable for efficacy; of the 246 patients with hyaluronan level data, 84 (34%) had hyaluronan-high tumors.

Researchers reported a significant improvement in median PFS with PEGPH20 among all evaluable patients (6 months vs. 5.3 months; HR = 0.73; 95% CI, 0.53-1) and those with hyaluronan-high tumors (9.2 months vs. 5.2 months; HR = 0.51; 95% CI, 0.26-1).

The PEGPH20 combination also appeared associated with a higher ORR (45% vs. 31%) among those with hyaluronan-high tumors.

An exploratory analysis showed PEGPH20 extended median OS among patients with hyaluronan-high tumors (11.5 months vs. 8.5 months; HR = 0.96; 95% CI, 0.57-1.61).

After enoxaparin initiation, thrombotic events occurred at similar rates among patients who received PEGPH20 and those who did not (14% vs. 10%). Patients assigned PEGPH20 appeared more likely to experience all-grade treatment-related peripheral edema (63% vs. 26%), muscle spasms (56% vs. 3%), neutropenia (34% vs. 19%) and myalgia (26% vs. 7%).

“These data support hyaluronan content as a potential predictive biomarker for patient selection for PEGPH20,” Hingorani told HemOnc Today.

The ongoing global, phase 3 HALO 301 study is designed to assess the combination of PEGPH20 with nanoparticle albumin-bound paclitaxel and gemcitabine in patients with treatment-naive stage IV metastatic pancreatic ductal adenocarcinoma whose tumors express high levels of hyaluronan. The trial’s primary endpoints are OS and PFS. – by Mark Leiser

Reference:

Hingorani SR, et al. Abstract 4008. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.

Disclosure: Hingorani reports consultant or advisory roles with Aduro Biotech and Halozyme, as well as research funding to his institution from Halozyme. Please see the abstract for a list of all other researchers’ relevant financial disclosures.