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larotrectinib对成人及儿童TRK融合癌的疗效
Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children


Alexander Drilon ... 肿瘤 妇产科和儿科 • 2018.02.22

篮式试验表明TRK靶向药larotrectinib可有效治疗多种癌症

 

Yu Chen†‡§, Ping Chi†‡§*

† Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; ‡ Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; § Department of Medicine, Weill Cornell Medical College, New York, NY, USA

*通讯作者 

 

传统上,癌症是根据其病理类型和组织起源而进行分类和治疗。测序技术和大规模癌症基因组学研究的进展(如国际癌症基因组联盟[ICGC]和癌症基因组图谱[TCGA])已经发现了许多存在于不同类型肿瘤的、可采取靶向疗法的驱动基因的改变,并基于驱动基因的改变,变更了癌症的亚分类。例如,根据KRASEGFR突变以及ALKROS1易位区分亚类肺腺癌。大多数“驱动”基因改变主要见于某些特定细胞/组织谱系。例如BRAFV600突变在黑色素瘤、甲状腺癌、毛细胞白血病、朗格汉斯细胞组织细胞增多症和结直肠癌的特定肿瘤类型中多发,而在其他组织谱系中则非常少见。不同肿瘤对靶向BRAFV600疗法的应答情况并不一致,有些肿瘤类型(如结直肠癌)表现出组织谱系特异性原发性耐药1-3,这强调了组织谱系特异性的细胞背景。

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摘要


背景

原肌球蛋白受体激酶(TRK)基因家族三员中的一员与不相关基因融合可见于成人及儿童的多种癌症中。larotrectinib是一种高度选择性TRK抑制剂,本研究在成人及儿童TRK融合肿瘤患者中,对该药的安全性和疗效进行了评估。

 

方法

我们设计了三个试验方案:成人1期研究、儿童1~2期研究,以及成人及青少年2期研究;并将顺序、前瞻性发现TRK融合癌(在各研究中心进行的分子表达谱分析中检出)患者纳入研究。综合分析的主要终点是独立审查委员会判定的总缓解率。次要终点包括缓解持续时间、无进展生存期和安全性。

 

结果

研究共纳入55例患者并应用larotrectinib进行治疗,患者年龄介于4月龄至76岁。这些患者共有17种不同类型的TRK融合肿瘤。独立审查委员会判定的总缓解率为75%(95%置信区间[CI],61~85),研究者判定的总缓解率为80%(95% CI,67~90)。研究进行1年时,71%的患者保持持续缓解,55%的患者保持肿瘤无进展。中位缓解持续时间和无进展生存期尚未达到。中位随访9.4个月时,86%(38/44)的有缓解患者继续接受larotrectinib治疗或接受过旨在治愈肿瘤的手术。不良事件以1级为主;研究者判定的larotrectinib相关3级或4级不良事件仅见于5%以下患者。没有患者因为larotrectinib相关不良事件而停止用药。

 

结论

对于TRK融合癌患者,无论年龄大小、肿瘤类型,larotrectinib均表现出明显、持久的抗肿瘤活性(由Loxo Oncology等资助;三项试验在ClinicalTrials.gov注册号分别为NCT02122913、NCT02637687及NCT02576431)。





作者信息

Alexander Drilon, M.D., Theodore W. Laetsch, M.D., Shivaani Kummar, M.D., Steven G. DuBois, M.D., Ulrik N. Lassen, M.D., Ph.D., George D. Demetri, M.D., Michael Nathenson, M.D., Robert C. Doebele, M.D., Ph.D., Anna F. Farago, M.D., Ph.D., Alberto S. Pappo, M.D., Brian Turpin, D.O., Afshin Dowlati, M.D., Marcia S. Brose, M.D., Ph.D., Leo Mascarenhas, M.D., Noah Federman, M.D., Jordan Berlin, M.D., Wafik S. El-Deiry, M.D., Ph.D., Christina Baik, M.D., M.P.H., John Deeken, M.D., Valentina Boni, M.D., Ph.D., Ramamoorthy Nagasubramanian, M.D., Matthew Taylor, M.D., Erin R. Rudzinski, M.D., Funda Meric-Bernstam, M.D., Davendra P.S. Sohal, M.D., M.P.H., Patrick C. Ma, M.D., Luis E. Raez, M.D., Jaclyn F. Hechtman, M.D., Ryma Benayed, Ph.D., Marc Ladanyi, M.D., Brian B. Tuch, Ph.D., Kevin Ebata, Ph.D., Scott Cruickshank, M.A., Nora C. Ku, M.D., Michael C. Cox, Pharm.D., Douglas S. Hawkins, M.D., David S. Hong, M.D., and David M. Hyman, M.D.
From Memorial Sloan Kettering Cancer Center (A. Drilon, J.F.H., R.B., M.L., D.M.H.) and Weill Cornell Medical College (A. Drilon, D.M.H.), New York; University of Texas Southwestern Medical Center–Children’s Health, Dallas (T.W.L.); Stanford Cancer Center, Stanford University, Palo Alto (S.K.), Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California (L.M.), and UCLA David Geffen School of Medicine (N.F.), Los Angeles, and Loxo Oncology, South San Francisco (B.B.T., K.E., S.C., N.C.K., M.C.C.) — all in California; Dana–Farber–Boston Children’s Cancer and Blood Disorders Center (S.G.D.), Dana–Farber Cancer Institute (G.D.D., M.N.), Ludwig Center at Harvard (G.D.D.), and Massachusetts General Hospital (A.F.F.) — all in Boston; the Finsen Center, Rigshospitalet, Copenhagen (U.N.L.); University of Colorado, Aurora (R.C.D.); St. Jude Children’s Research Hospital, Memphis (A.S.P.), and Vanderbilt University, Nashville (J.B.) — both in Tennessee; Cincinnati Children’s Hospital Medical Center, Cincinnati (B.T.); University Hospitals of Cleveland Medical Center (A. Dowlati) and Taussig Cancer Institute, Cleveland Clinic (D.P.S.S.), Cleveland; University of Pennsylvania Perelman School of Medicine, Department of Otorhinolaryngology and Head and Neck Surgery, and the Abramson Cancer Center (M.S.B.), and Fox Chase Cancer Center (W.S.E.-D.), Philadelphia; University of Washington–Seattle Cancer Care Alliance (C.B.), Seattle Children’s Hospital (E.R.R.), and Seattle Children’s Hospital, University of Washington, Fred Hutchinson Cancer Research Center (D.S. Hawkins), Seattle; University of Texas M.D. Anderson Cancer Center, Houston (F.M.-B., D.S. Hong); Inova Schar Cancer Institute, Falls Church, VA (J.D.); START Madrid, Centro Integral Oncológico Clara Campal, Madrid (V.B.); Nemours Children’s Hospital, Orlando (R.N.), and Memorial Cancer Institute–Florida International University, Miami (L.E.R.) — both in Florida; Oregon Health and Science University, Portland (M.T.); and WVU Cancer Institute, West Virginia University, Morgantown (P.C.M.). Address reprint requests to Dr. Hyman at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065, or at hymand@mskcc.org.

 

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