PEGPH20 (P) degrades HA in the tumor microenvironment to increase access and therapeutic index of anticancer agents. In Stage 1 of this study, Halozyme Therapeutics, Inc. and Ventana Medical Systems, Inc., co-developed a novel HA assay, scoring algorithm, and cut-point, and showed improved progression-free survival (PFS) and objective response rate (ORR) in HA-High patients (pts) with PAG vs AG. Due to an imbalance in thromboembolic (TE) events in the PAG arm, the protocol was amended to add enoxaparin and exclude pts at high risk for TE events in Stage 2, which prospectively validated the algorithm and cut-point for the VENTANA HA RxDx assay.
In Stage 2, pts with mPDA were randomized 2:1 to PAG (P 3 µg/kg IV 2x/wk x 3 wk [C1], then 1x/wk x 3 wk [C2+] + AG) vs AG every 28 days. Endpoints were: primary—PFS and TE events; secondary—PFS by HA level, ORR; OS by HA level was exploratory. Tumor HA was evaluated using the VENTANA HA RxDx assay and algorithm; HA-High was defined by HA staining in the extracellular matrix ≥50% of the entire tumor surface at any intensity.
133 pts were enrolled; 125 pts were treated. As of December 16, 2016, an improvement in median PFS (91%) and median OS (50%) was observed in HA-High pts treated with PAG vs AG (Table), supporting tumor HA as a predictive marker for PEGPH20 efficacy. Among AG-treated pts, those with HA-High tumors showed poorer median PFS and median OS outcomes, suggesting that targeting tumor HA with PEGPH20 may improve the standard of care in mPDA.Table: 743P
|PAG||AG||HR (95% CI)|
|HA-High||n = 24||n = 11|
|PFS, months||8.6||4.5||0.63 (0.21-1.93)|
|OS, months||11.7||7.8||0.52 (0.22-1.23)|
|HA-Low||n = 53||n = 23|
|PFS, months||6.0||7.2||1.21 (0.63-2.30)|
|OS, months||11.9||10.2||0.69 (0.38-1.23)|
This is the first randomized Phase 2 study evaluating and supporting tumor HA as a potential predictive biomarker informing patient selection for PEGPH20 treatment, based on improvement in both PFS and OS in HA-High pts. The results provide support for the ongoing phase 3 HALO 109-301 study with co-primary endpoints of PFS and OS. NCT01839487.
Clinical trial identification
Legal entity responsible for the study
Halozyme Therapeutics, Inc.
Halozyme Therapeutics, Inc.
A. Hendifar: Consulting or advisory role: Genentech, Novartis, Ipsen, Perthera. Travel, accommodations, expenses: Halozyme. A. Bullock: Consulting or advisory board participation support: Halozyme, Celgene, EMD Serono. T. Seery: Consulting or advisory role: Bayer. Speakers\' Bureau: Ipsen, Bayer. L. Zheng: Consultancy or advisory role: Merrimack. Patents, royalties, other intellectual property: GVAX. Licensed to Aduro Biotech. Stock and other ownership: Z&L Medical Intl. Research funding: Bristol-Myers Squibb, Amgen, Iteos Therap, Gradalis, Merck, Halozyme. D. Sigal: Stock or other ownership: Novartis, BMS, Ignyta, Halozyme. Honoraria: Novartis, Serond, Halozyme. Speakers\' Bureau: Novartis, Celgene, Bayer. Research funding: Halozyme. F.S. Braiteh: Author has disclosures to report for: Honoraria, Consulting or Advisory Role,Speaker\'s Bureau,Travels, Accommodation, Expenses. M. Zalupski: Research funding: Halozyme, OncoMed, Newlink Genetics. N. Bahary: Consulting or advisory role: Bayer/Onyx, EMD Serono. Research funding: New Links Genetics. W. Harris: Consulting or advisory role: Neotherma Oncology, Bayer. Research funding: Halozyme, BMS, Exelixis, Argule, Polaris, Medimmune, BTG. J. Pu: Employment: Roche; Research funding: Roche. Patents, royalties, other intellectual property: Roche (for author and institution). F. Lian: Stock or other ownership: Merck (Immediate Family Member). J. Zhu: Employment: Roche. Stock or other ownership: Roche. Honoraria: Roche. Travel, accommodations, expenses: Roche. W. Wu: Employment: Halozyme. Stock or other ownership: Halozyme. D. Chondros: Employee of Halozyme Therapeutics. P. Jiang: Employment: Halozyme. Stock or other ownership: Halozyme Therapeutics Inc. Patents, royalties, other intellectual property: Halozyme Therapeutics Inc. S.R. Hingorani: Consulting or advisory role: Halozyme, Aduro Biotech. Research funding to institution: Halozyme. All other authors have declared no conflicts of interest.