Demetri George D, von Mehren Margaret, Jones Robin L, Hensley Martee L, Schuetze Scott M, Staddon Arthur, Milhem Mohammed, Elias Anthony, Ganjoo Kristen, Tawbi Hussein, Van Tine Brian A, Spira Alexander, Dean Andrew, Khokhar Nushmia Z, Park Youn Choi, Knoblauch Roland E, Parekh Trilok V, Maki Robert G, Patel Shreyaskumar R
George D. Demetri, Dana-Farber Cancer Institute and Ludwig Center at Harvard, Boston, MA; Margaret von Mehren, Fox Chase Cancer Center; Arthur Staddon, University of Pennsylvania, Philadelphia; Hussein Tawbi, University of Pittsburgh Cancer Institute, Pittsburgh, PA; Robin L. Jones, Seattle Cancer Care Alliance, Seattle, WA; Martee L. Hensley, Memorial Sloan Kettering Cancer Center; Robert G. Maki, Mount Sinai Medical Center, New York, NY; Scott M. Schuetze, University of Michigan, Ann Arbor, MI; Mohammed Milhem, University of Iowa Hospitals and Clinics, Iowa City, IA; Anthony Elias, University of Colorado Cancer Center, Aurora, CO; Kristen Ganjoo, Stanford Hospital and Clinics, Stanford, CA; Brian A. Van Tine, Washington University in St Louis, St Louis, MO; Alexander Spira, Virginia Cancer Specialists, Fairfax, VA; Andrew Dean, St John of God Hospital-Bendat Cancer Centre, Subiaco, Western Australia, Australia; Nushmia Z. Khokhar, Youn Choi Park, Roland E. Knoblauch, and Trilok V. Parekh, Janssen Research & Development, Raritan, NJ; and Shreyaskumar R. Patel, The University of Texas MD Anderson Cancer Center, Houston, TX.
J Clin Oncol. 2016 Mar 10;34(8):786-93. doi: 10.1200/JCO.2015.62.4734. Epub 2015 Sep 14.
This multicenter study, to our knowledge, is the first phase III trial to compare trabectedin versus dacarbazine in patients with advanced liposarcoma or leiomyosarcoma after prior therapy with an anthracycline and at least one additional systemic regimen.
Patients were randomly assigned in a 2:1 ratio to receive trabectedin or dacarbazine intravenously every 3 weeks. The primary end point was overall survival (OS), secondary end points were disease control-progression-free survival (PFS), time to progression, objective response rate, and duration of response-as well as safety and patient-reported symptom scoring.
A total of 518 patients were enrolled and randomly assigned to either trabectedin (n = 345) or dacarbazine (n = 173). In the final analysis of PFS, trabectedin administration resulted in a 45% reduction in the risk of disease progression or death compared with dacarbazine (median PFS for trabectedin v dacarbazine, 4.2 v 1.5 months; hazard ratio, 0.55; P < .001); benefits were observed across all preplanned subgroup analyses. The interim analysis of OS (64% censored) demonstrated a 13% reduction in risk of death in the trabectedin arm compared with dacarbazine (median OS for trabectedin v dacarbazine, 12.4 v 12.9 months; hazard ratio, 0.87; P = .37). The safety profiles were consistent with the well-characterized toxicities of both agents, and the most common grade 3 to 4 adverse effects were myelosuppression and transient elevation of transaminases in the trabectedin arm.
Trabectedin demonstrates superior disease control versus conventional dacarbazine in patients who have advanced liposarcoma and leiomyosarcoma after they experience failure of prior chemotherapy. Because disease control in advanced sarcomas is a clinically relevant end point, this study supports the activity of trabectedin for patients with these malignancies.
据我们所知，这项多中心研究是第一项比较曲贝替定与达卡巴嗪用于蒽环类药物及至少一种其他全身治疗方案治疗失败后的晚期脂肪肉瘤或平滑肌肉瘤患者的Ⅲ期试验。
患者按2:1的比例随机分组，每3周静脉注射曲贝替定或达卡巴嗪。主要终点为总生存期（OS），次要终点为疾病控制——无进展生存期（PFS）、疾病进展时间、客观缓解率、缓解持续时间以及安全性和患者报告的症状评分。
共入组518例患者并随机分配至曲贝替定组（n = 345）或达卡巴嗪组（n = 173）。在PFS的最终分析中，与达卡巴嗪相比，曲贝替定治疗使疾病进展或死亡风险降低45%（曲贝替定与达卡巴嗪的中位PFS分别为4.2个月和1.5个月；风险比，0.55；P < 0.001）；在所有预先计划的亚组分析中均观察到获益。OS的中期分析（64%截尾）显示，与达卡巴嗪相比，曲贝替定组死亡风险降低13%（曲贝替定与达卡巴嗪的中位OS分别为12.4个月和12.9个月；风险比，0.87；P = 0.37）。安全性特征与两种药物已知的毒性一致，曲贝替定组最常见的3至4级不良反应为骨髓抑制和转氨酶短暂升高。
对于先前化疗失败后的晚期脂肪肉瘤和平滑肌肉瘤患者，曲贝替定在疾病控制方面优于传统的达卡巴嗪。由于晚期肉瘤的疾病控制是一个临床相关终点，本研究支持曲贝替定对这些恶性肿瘤患者的有效性。
