Addition of Pegylated Recombinant Human Hyaluronidase to FOLFIRINOX in Metastatic Pancreatic Adenocarcinoma


Key Points

  • Accrual was stopped early due to futility.
  • The addition of PEGPH20 to mFOLFIRINOX was associated with worse overall survival.

In the phase I/II SWOG S1313 trial, which was reported in the Journal of Clinical Oncology by Ramanathan et al, researchers found that the addition of pegylated recombinant human hyaluronidase (PEGPH20) to modified (m) FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) worsened outcomes in previously untreated, metastatic pancreatic adenocarcinoma. PEGPH20 degrades hyaluronan (HA; a major component of tumor extracellular matrix) and has been found to prolong survival when combined with chemotherapy in preclinical models.

Study Details

The open-label phase II study accrued 111 eligible patients from May 2015 to March 2017 at 30 SWOG member institutions. Fifty-five patients were randomly assigned to PEGPH20 plus mFOLFIRINOX and 56 were assigned to the control group. Tumor HA status was not required for eligibility. PEGPH20 dosages of 3 mg/kg every 2 weeks were used in the phase II study, since they were more tolerable than twice-weekly dosages used in the phase I study.

The primary endpoint was overall survival.

Treatment Outcomes

The study protocol was amended to include enoxaparin prophylaxis in the PEGPH20 combination group due to an excess of thromboembolic events. The planned interim futility analysis when 35 deaths had occurred resulted in an overall survival hazard ratio (HR) of 2.07 favoring the control group, with the study thus being closed to accrual.

Median overall survival was 7.7 months in the PEGPH20 combination group vs 14.4 months in the mFOLFIRINOX group (HR = 2.07, P < .01).

Treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination group vs the control group (odds ratio = 2.7, 95% confidence interval [CI] = 1.1–7.1). Grade 4 treatment-related adverse events occurred in 7 patients in the combination group vs 4 patients in in the control group, and treatment-related grade 3 adverse events occurred in 33 patients in the combination group vs 26 patients in the control group.

The investigators concluded, “Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly [gastrointestinal] and [thromboembolic] events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median [overall survival] in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good [performance status].”

Philip A. Philip, MD, of the Barbara Ann Karmanos Cancer Institute, Wayne State University, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by grants from the National Institutes of Health/National Cancer Institute, and in part by Halozyme (drug supply only). The study authors' full disclosures can be found at

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