Phase IB/II Randomized Study of FOLFIRINOX Plus Pegylated Recombinant Human Hyaluronidase Versus FOLFIRINOX Alone in Patients With Metastatic Pancreatic Adenocarcinoma: SWOG S1313

Abstract

PURPOSE Pegylated recombinant human hyaluronidase (PEGPH20) degrades hyaluronan (HA) and, in combination with chemotherapy, prolongs survival in preclinical models. The activity of PEGPH20 with modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) was evaluated in patients with metastatic pancreatic cancer (mPC). MATERIALS AND METHODS Patients had untreated mPC, a performance status of 0 to 1, and adequate organ function. Tumor HA status was not required for eligibility. After a phase Ib dose-finding study of mFOLFIRINOX plus PEGPH20, the phase II open-label study randomly assigned patients (1:1) to the combination arm or to mFOLFIRINOX alone (n = 138). The primary end point was overall survival (OS). RESULTS PEGPH20 dosages of 3 µg/kg every 2 weeks were more tolerable than twice-weekly dosages used in the phase I study, so 3 µg/kg every 2 weeks was the phase II dosage. An amendment instituted enoxaparin prophylaxis in the PEGPH20 combination arm as a result of increased thromboembolic (TE) events. The planned interim futility analysis when 35 deaths (of 103 analyzable patients) occurred resulted in an OS hazard ratio (HR) of 2.07 that favored the control arm, and the study was closed to accrual. The treatment-related grade 3 to 4 toxicity was significantly increased in the PEGPH20 combination arm relative to control (odds ratio, 2.7; 95% CI, 1.1 to 7.1). The median OS in the mFOLFIRINOX arm was 14.4 months (95% CI, 10.1 to 15.7 months) versus 7.7 months (95% CI, 4.6 to 9.3 months) in the PEGPH20 combination arm. CONCLUSION Addition of PEGPH20 to mFOLFIRINOX seems to be detrimental in patients unselected for tumor HA status. This combination caused increased toxicity (mostly GI and TE events) and resulted in decreased treatment duration compared with mFOLFIRINOX alone. The median OS in the mFOLFIRINOX control arm (14.4 months) is, to our knowledge, the longest yet reported and can be considered for patients with good PS.

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer

“…PDAC patients with a high expression of HA were more susceptible to therapy targeting HA . Addition of HA blockade to FOLFIRINOX did not show any benefit in patients unselected for tumor HA status . Interestingly, in our study, the more pronounced association with survival of baseline HA according to types of treatments in patients undergoing palliative chemotherapy was observed in participants treated with gemcitabine and nab‐paclitaxel combination (Supporting Information Fig.…”

Ipilimumab and Gemcitabine for Advanced Pancreatic Cancer: A Phase Ib Study

“…This could be a novel strategy to target the stroma and immune system simultaneously. The best-studied attempt to target the stroma directly with pegylated recombinant human hyaluronidase had disappointing results [38], but the stroma likely still represents an important resistance mechanism that must be overcome with novel approaches.…”

Pancreatic Cancer Stem Cells May Define Tumor Stromacharacteristics and Recurrence Patterns in Pancreatic Ductal Adenocarcinoma

“…Interestingly, contrary to the hypothesis that highly desmoplastic tumor stroma may lead to adverse outcomes, patients with loose stroma had a worse clinical course suggesting that dense stroma may provide a physical barrier function to restrain the primary tumor and reduce local invasion. These ndings collectively hypothesize that strategies targeting dense PDAC stroma may not improve outcome and speculatively may incur a negative outcome [18,37]. The relationship between tumor stroma and cancer stem cell markers.…”

“…[17,18] These disappointing ndings have resulted in signi cant loss of interest in SHH inhibitors and most recently, other stroma modifying agents including PEGPH20, a pegylated version of hyaluronidase, was investigated in metastatic PDAC patients. The combination of this agent with FOLFIRINOX and gemcitabine nab-paclitaxel chemotherapies did not result in any survival bene t and led to detrimental outcomes in patients who received PEGPH20 with concurrent FOLFIRINOX, [19][20][21].…”