Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul.
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul.
Ann Oncol. 2018 May 1;29(5):1220-1226. doi: 10.1093/annonc/mdy055.
Paclitaxel is currently only available as an intravenous (i.v.) formulation. DHP107 is a novel oral formulation of lipid ingredients and paclitaxel. DHP107 demonstrated comparable efficacy, safety, and pharmacokinetics to i.v. paclitaxel as a second-line therapy in patients with advanced gastric cancer (AGC). DREAM is a multicenter, open-label, prospective, randomized phase III study of patients with histologically/cytologically confirmed, unresectable/recurrent AGC after first-line therapy failure.
Patients were randomized 1 : 1 to DHP107 (200 mg/m2 orally twice daily days 1, 8, 15 every 4 weeks) or i.v. paclitaxel (175 mg/m2 day 1 every 3 weeks). Patients were stratified by Eastern Cooperative Oncology Group performance status, disease status, and prior treatment; response was assessed (Response Evaluation Criteria in Solid Tumors) every 6 weeks. Primary end point: non-inferiority of progression-free survival (PFS); secondary end points: overall response rate (ORR), overall survival (OS), and safety. For the efficacy analysis, sequential tests for non-inferiority were carried out, first with a non-inferiority margin of 1.48, then with a margin of 1.25.
Baseline characteristics were balanced in the 236 randomized patients (n = 118 per arm). Median PFS (per-protocol) was 3.0 (95% CI 1.7-4.0) months for DHP107 and 2.6 (95% CI 1.8-2.8) months for paclitaxel (hazard ratio [HR] = 0.85; 95% CI 0.64-1.13). A sensitivity analysis on PFS using independent central review showed similar results (HR = 0.93; 95% CI 0.70-1.24). Median OS (full analysis set) was 9.7 (95% CI 7.1 - 11.5) months for DHP107 versus 8.9 (95% CI 7.1-12.2) months for paclitaxel (HR = 1.04; 95% CI 0.76-1.41). ORR was 17.8% for DHP107 (CR 4.2%; PR 13.6%) versus 25.4% for paclitaxel (CR 3.4%; PR 22.0%). Nausea, vomiting, diarrhea, and mucositis were more common with DHP107; peripheral neuropathy was more common with paclitaxel. There were only few Grade≥3 adverse events, most commonly neutropenia (42% versus 53%); febrile neutropenia was reported infrequently (5.9% versus 2.5%). No hypersensitivity reactions occurred with DHP107 (paclitaxel 2.5%).
DHP107 as a second-line treatment of AGC was non-inferior to paclitaxel for PFS; other efficacy and safety parameters were comparable. DHP107 is the first oral paclitaxel with proven efficacy/safety for the treatment of AGC.
CLINICALTRIALS.GOV: NCT01839773.
紫杉醇目前仅作为静脉（i.v.）制剂使用。DHP107 是一种新型的口服紫杉醇脂质体制剂。在二线治疗晚期胃癌（AGC）患者中，DHP107 与 i.v.紫杉醇相比具有相似的疗效、安全性和药代动力学。DREAM 是一项多中心、开放性、前瞻性、随机 III 期研究，纳入了一线治疗失败后组织学/细胞学确认的不可切除/复发性 AGC 患者。
患者按 1:1 随机分为 DHP107（200mg/m2 口服，每日两次，第 1、8、15 天，每 4 周一次）或 i.v.紫杉醇（175mg/m2，第 1 天，每 3 周一次）。患者按东部肿瘤协作组表现状态、疾病状态和既往治疗进行分层；每 6 周评估一次（实体瘤反应评价标准）。主要终点：无进展生存期（PFS）的非劣效性；次要终点：总缓解率（ORR）、总生存期（OS）和安全性。对于疗效分析，首先进行了非劣效性的序贯检验，第一次使用 1.48 的非劣效性边界，然后使用 1.25 的边界。
236 名随机患者的基线特征平衡（每组 118 名）。DHP107 的中位 PFS（方案规定）为 3.0（95%CI 1.7-4.0）个月，紫杉醇为 2.6（95%CI 1.8-2.8）个月（风险比[HR]为 0.85；95%CI 0.64-1.13）。使用独立中央审查的 PFS 敏感性分析显示了类似的结果（HR 为 0.93；95%CI 0.70-1.24）。DHP107 的中位 OS（全分析集）为 9.7（95%CI 7.1-11.5）个月，紫杉醇为 8.9（95%CI 7.1-12.2）个月（HR 为 1.04；95%CI 0.76-1.41）。DHP107 的 ORR 为 17.8%（CR 4.2%；PR 13.6%），紫杉醇为 25.4%（CR 3.4%；PR 22.0%）。DHP107 更常见的不良反应有恶心、呕吐、腹泻和黏膜炎；紫杉醇更常见的不良反应是周围神经病变。只有少数患者出现 3 级以上不良事件，最常见的是中性粒细胞减少症（42%比 53%）；发热性中性粒细胞减少症报告频率较低（5.9%比 2.5%）。DHP107 无过敏反应（紫杉醇 2.5%）。
DHP107 作为 AGC 的二线治疗，与紫杉醇相比在 PFS 方面非劣效；其他疗效和安全性参数相当。DHP107 是第一个经证实对 AGC 治疗有效的口服紫杉醇。
临床试验.gov：NCT01839773。
