• Sunil R Hingorani, Lei Zheng, Andrea J Bullock, Tara E Seery, William P Harris, Darren S Sigal, Fadi Braiteh, Paul S Ritch, Mark M Zalupski, Nathan Bahary, Paul E Oberstein, Andrea Wang-Gillam, Wilson Wu, Dimitrios Chondros, Ping Jiang, Sihem Khelifa, Jie Pu, Carrie Aldrich, and Andrew E Hendifar.
• Sunil R. Hingorani, Fred Hutchinson Cancer Research Center; William P. Harris, University of Washington, School of Medicine, Seattle, WA; Lei Zheng, Johns Hopkins University School of Medicine, Baltimore, MD; Andrea J. Bullock, Beth Israel Deaconess Medical Center, Boston, MA; Tara E. Seery, Chan Soon-Shiong Institute for Medicine, El Segundo; Darren S. Sigal, Scripps Cancer Center, La Jolla; Wilson Wu, Dimitrios Chondros, and Ping Jiang, Halozyme Therapeutics, San Diego; Andrew E. Hendifar, Cedars-Sinai Medical Center and Samuel Oschin Cancer Center, Los Angeles, CA; Fadi Braiteh, Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Paul S. Ritch, Froedtert Hospital and Medical College of Wisconsin, Milwaukee, WI; Mark M. Zalupski, University of Michigan, Ann Arbor, MI; Nathan Bahary, University of Pittsburgh Medical Center Cancer Pavilion, Pittsburgh, PA; Paul E. Oberstein, Columbia University Medical Center, New York, NY; Andrea Wang-Gillam, Washington University, St Louis, MO; and Sihem Khelifa, Jie Pu, and Carrie Aldrich, Ventana Medical Systems, Tucson, AZ.
• J. Clin. Oncol. 2018 Feb 1; 36 (4): 359-366.

AbstractPurpose 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.

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