PDGFRA激酶结构域的激活突变占胃间质细胞瘤(GIST)的10%-15%。据报道，最常见的PDGFRA突变是D842V，突变之后会对伊马替尼和舒尼替尼治疗产生的抗性。目前，对于这种突变仍没有特效疗法。Cassier PA等科学家2012年在Clin Cancer Res上发表文章发生D842V突变的GIST患者在接受伊马替尼一线治疗时其中位无进展生存期(PFS)为2.8个月，二线治疗的PFS为2.1个月。Crenolanib是一种高选择性的PDGFRA和FLT3抑制剂，具有抑制PDGFRα D842V突变的活性。先前的剂量调查研究表明，crenolanib治疗重度有PDGFRA D842V突变的GIST患者有31%的临床益处。在总共接受治疗的16例患者当中，2例患者达到了PR，3例患者达到了SD。在这些患者当中80%先前接受过伊马替尼(15例)、舒尼替尼(7例)、达沙替尼(5例)、索拉非尼(2例)、尼洛替尼(2例)和瑞戈非尼(regorafenib2例)的治疗，35%的患者经受了至少7个月的研究。基于以上研究成果，crenolanib治疗PDGFRA D842V突变的GIST患者开启了III期临床试验。相关研究结果发表在6月2-6日在美国芝加哥举行的第53届美国临床肿瘤学会年会(ASCO)上。

约120名患者2:1随机分配接受100mg crenolanib治疗或者安慰剂治疗，

随机纳入组织学或者病理学证实有PDGFRA D842V突变的晚期或转移性GIST成年患者。经过TKI治疗的患者也符合纳入条件。所有接受治疗的患者均给予最佳的护理。

摘要原文：

摘要编号：# TPS11080

Author(s): Jean-Yves Blay, Michael C. Heinrich, Peter Hohenberger, Paolo Giovanni Casali, Piotr Rutkowski, Cesar Serrano-Garcia, Robin Lewis Jones, Kirsten Sundby Hall, John Randall Eckardt, Margaret von Mehren; Centre Léon-Bérard, Lyon, France; Knight Cancer Institute, Oregon Health & Science University, Portland, OR; Division of Surgical Oncology and Thoracic Surgery, Mannheim University Medical Centre, University of Heidelberg, Mannheim, Germany; Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Vall d’Hebron University Hospital, Barcelona, Spain; Sarcoma Unit, The Royal Marsden Hospital and Institute of Cancer Research, London, United Kingdom; Department of Oncology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Arog Pharmaceuticals, Inc., Dallas, TX; Fox Chase Cancer Center, Philadelphia, PA

A randomized, double-blind, placebo-controlled, phase III study of crenolanib in advanced or metastatic GIST patients bearing a D842V mutation in PDGFRA: The CrenoGIST study.

Background: Activating mutations in the kinase domain of PDGFRA account for 10-15% of GIST. The most common PDGFRA mutation reported is D842V, which is known to confer resistance to imatinib and sunitinib. Currently, there is no approved treatment for GIST patients carrying such mutation. Cassier PA et al. showed that patients with D842V mutated GIST had a short median progression free survival (PFS) of 2.8 months with first line imatinib and 2.1 months with second line (2012 Clin Cancer Res). Crenolanib is a highly selective PDGFRA and FLT3 inhibitor with nanomolar activity against PDGFRα D842V mutation. In a previous dose-finding study, crenolanib showed a 31% clinical benefit rate with 2 pts achieving PR and 3 pts maintaining SD (total evaluable: 16 pts) in heavily pretreated GIST patients harboring the PDGFRA D842V mutation. In this study, 35% patients stayed on study for at least 7 months despite 80% patients having progressed after prior imatinib (15 pts), sunitinib (7 pts), dasatinib (5 pts), sorafenib (4 pts), nilotinib (2 pts), and regorafenib (2 pts). Therefore, a phase III trial has been initiated to further confirm the clinical activity of crenolanib in patients with PDGFRA D842Vmutation. Methods: This randomized phase III study will enroll adult subjects with histologically or cytologically confirmed advanced or metastatic GIST with a PDGFRA D842V mutation. Prior treatment with TKI is allowed. Approximately 120 subjects will be randomized in a 2:1 ratio to receive either crenolanib 100 mg or matching placebo orally 3 times daily in combination with best supportive care. Randomization will be stratified by prior tyrosine kinase inhibitor exposure and ECOG performance status. The primary objective is PFS; key secondary objectives include OS. A formal interim analysis is planned after approximately 50 subjects have met the primary outcome. This study is already opened in the US, France, Norway, and Poland, and will soon be opened in Germany, Italy, Spain, UK and Asia.