PDGFRA激酶結構域的激活突變占胃間質細胞瘤(GIST)的10%-15%。據報道，最常見的PDGFRA突變是D842V，突變之後會對伊馬替尼和舒尼替尼治療產生的抗性。目前，對於這種突變仍沒有特效療法。Cassier PA等科學家2012年在Clin Cancer Res上發表文章發生D842V突變的GIST患者在接受伊馬替尼一線治療時其中位無進展生存期(PFS)為2.8個月，二線治療的PFS為2.1個月。Crenolanib是一種高選擇性的PDGFRA和FLT3抑製劑，具有抑製PDGFRα D842V突變的活性。先前的劑量調查研究表明，crenolanib治療重度有PDGFRA D842V突變的GIST患者有31%的臨床益處。在總共接受治療的16例患者當中，2例患者達到了PR，3例患者達到了SD。在這些患者當中80%先前接受過伊馬替尼(15例)、舒尼替尼(7例)、達沙替尼(5例)、索拉非尼(2例)、尼洛替尼(2例)和瑞戈非尼(regorafenib2例)的治療，35%的患者經受了至少7個月的研究。基於以上研究成果，crenolanib治療PDGFRA D842V突變的GIST患者開啟了III期臨床試驗。相關研究結果發表在6月2-6日在美國芝加哥舉行的第53屆美國臨床腫瘤學會年會(ASCO)上。

約120名患者2:1隨機分配接受100mg crenolanib治療或者安慰劑治療，

隨機納入組織學或者病理學證實有PDGFRA D842V突變的晚期或轉移性GIST成年患者。經過TKI治療的患者也符合納入條件。所有接受治療的患者均給予最佳的護理。

摘要原文：

摘要編號：# 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.