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. doi: 10.1200/JCO.2017.74.9564. Epub 2017 Dec 12.
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.
转移性胰腺导管腺癌的特征是肿瘤微环境中透明质酸（HA）过度积累，从而升高细胞间质压力并损害灌注。临床前研究表明，聚乙二醇化重组人尿酸酶（PEGPH20）可降解 HA，从而增加药物递送。
本研究入组了未经治疗的转移性胰腺导管腺癌患者，随机分组接受 PEGPH20 联合 nab-紫杉醇/吉西他滨（PAG）或 nab-紫杉醇/吉西他滨（AG）治疗。采用新型亲和组织化学检测法对肿瘤 HA 水平进行回顾性检测。主要终点为无进展生存期（PFS；总体）和血栓栓塞（TE）事件发生率。次要终点包括总生存期、HA 水平的 PFS 和客观缓解率。PAG 组早期 TE 事件的不平衡导致临床暂停；此后，排除发生 TE 事件的患者，并开始使用依诺肝素预防。
共 279 例患者随机分组，246 例患者有 HA 数据，231 例患者疗效可评估，84 例（34%）患者存在 HA 高肿瘤（即，任何强度的肿瘤表面 HA 染色≥50%的细胞外基质）。总体而言，PAG 治疗显著改善了 PFS（风险比[HR]，0.73；95%CI，0.53 至 1.00；P =.049）和 HA 高肿瘤患者的 PFS（HR，0.51；95%CI，0.26 至 1.00；P =.048）。在 HA 高肿瘤患者中（PAG 组与 AG 组），客观缓解率分别为 45%和 31%，中位总生存期分别为 11.5 个月和 8.5 个月（HR，0.96；95%CI，0.57 至 1.61）。两组间具有显著差异的最常见治疗相关 3/4 级不良事件（PAG 组与 AG 组）包括肌肉痉挛（13%比 1%）、中性粒细胞减少（29%比 18%）和肌痛（5%比 0%）。依诺肝素预防开始后，TE 事件发生率相似（PAG 组 14%，AG 组 10%）。
本研究达到了 PFS 和 TE 事件发生率的主要终点。在 HA 高肿瘤患者中，PFS 改善最显著，这些患者接受了 PAG 治疗。在研究的 2 期，治疗组的 TE 事件发生率相似。
