HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

Purpose Metastatic pancreatic ductal adenocarcinoma is characterized by excessive hyaluronan (HA) accumulation in the tumor microenvironment, elevating interstitial pressure and impairing perfusion. Preclinical studies demonstrated pegvorhyaluronidase alfa (PEGPH20) degrades HA, thereby increasing drug delivery. Patients and Methods Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were randomly assigned to treatment with PEGPH20 plus nab-paclitaxel/gemcitabine (PAG) or nab-paclitaxel/gemcitabine (AG). Tumor HA levels were measured retrospectively using a novel affinity histochemistry assay. Primary end points were progression-free survival (PFS; overall) and thromboembolic (TE) event rate. Secondary end points included overall survival, PFS by HA level, and objective response rate. An early imbalance in TE events in the PAG arm led to a clinical hold; thereafter, patients with TE events were excluded and enoxaparin prophylaxis was initiated. Results A total of 279 patients were randomly assigned; 246 had HA data; 231 were evaluable for efficacy; 84 (34%) had HA-high tumors (ie, extracellular matrix HA staining ≥ 50% of tumor surface at any intensity). PFS was significantly improved with PAG treatment overall (hazard ratio [HR], 0.73; 95% CI, 0.53 to 1.00; P = .049) and for patients with HA-high tumors (HR, 0.51; 95% CI, 0.26 to 1.00; P = .048). In patients with HA-high tumors (PAG v AG), the objective response rate was 45% versus 31%, and median overall survival was 11.5 versus 8.5 months (HR, 0.96; 95% CI, 0.57 to 1.61). The most common treatment-related grade 3/4 adverse events with significant differences between arms (PAG v AG) included muscle spasms (13% v 1%), neutropenia (29% v 18%), and myalgia (5% v 0%). TE events were comparable after enoxaparin initiation (14% PAG v 10% AG). Conclusion This study met its primary end points of PFS and TE event rate. The largest improvement in PFS was observed in patients with HA-high tumors who received PAG. A similar TE event rate was observed between the treatment groups in stage 2 of the trial.

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…HA is a large, linear, glycosaminoglycan that plays an important structural role in the ECM, and accumulates in conditions involving rapid and invasive cell division, including cancer. Clinical studies of PEGPH20 are also promising with phase II data already demonstrating significant efficacy of this agent when combined with chemotherapy, effect particularly prominent in patients with HAhigh tumours [248], highlighting the potential utility of intratumoural HA as a predictive biomarker of response [248][249][250]. Pegylated recombinant human hyaluronidase (PEGPH20) and 4-methylumbelliferone are two key examples of compounds that inhibit and/or break down HA.…”

“…HA regulates interstitial gel fluid pressure within tumours, often impacting on drug delivery. Favourable results are particularly observed when PEGPH20 is combined with Gemcitabine and Abraxane [248,251,252], whereas FOLFIRINOX in contrast may be better utilised in other settings [253]. Of note, PEGPH20 has already shown significant promise in PDAC.…”

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

“…A first step towards personalised antistroma therapies might represent enzymatic depletion of HA by PEGPH20. Encouraging results from a phase I/II study (NCT01839487) combining PEGPH20 and gemcitabine showed that patients with high levels of HA had improved response rates 48. These results led to the initiation of a large phase III study that is currently enrolling patients (NCT02715804) combining gemcitabine with nab-paclitaxel and PEGPH20 or placebo.…”

Pancreatic cancer: treatment approaches and trends

“…A pegylated recombinant human hyaluronidase (PEGPH20) is an agent that degrades the hyaluronic acid and normalizes interstitial . Hingorani et al [96] showed the results from a phase II comparison study between PEGPH20 [plus nab-paclitaxel/gemcitabine (AG)] (PAG) vs. AG in patients with untreated metastatic pancreatic ductal adenocarcinoma (NCT01839487). Because of an imbalance in thromboembolic events in PAG patients 40% patients were excluded from the study.…”