Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial

BMC Cancer

Research Article

Yoon-Koo Kang¹  Denis Soulières²  Jean-Yves Blay³  Peter Reichardt⁴  Jochen Schuette⁵  Hans Gelderblom⁶  George D. Demetri⁷  Piotr Rutkowski⁸  Kolette Fly⁹  Xin Huang^1,10  Jean-Francois Martini^1,10  Massimo Corsaro^1,11  Maria Jose Lechuga^1,11  David Goldstein^1,12  Seock-Ah Im^1,13  Sudeep Gupta^1,14  Patrick Schöffski^1,15  Michael C. Heinrich^1,16 

[1] Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea;Centre Hospitalier de l’Université de Montreal, Montreal, QC, Canada;Centre Léon Bérard, Université Claude Bernard, Lyon, France;Department of Interdisciplinary Oncology, HELIOS Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125, Berlin, Germany;Hämatoonkologische Schwerpunktpraxis, Düsseldorf, Germany;Leiden University Medical Center, Leiden, The Netherlands;Ludwig Center at Harvard and Dana-Farber Cancer Institute, Boston, MA, USA;Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland;Pfizer Oncology, Groton, CT, USA;Pfizer Oncology, La Jolla, CA, USA;Pfizer Oncology, Milan, Italy;Prince of Wales Hospital, Sydney, Australia;Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea;Tata Memorial Centre, Mumbai, India;University Hospitals Leuven, Leuven Cancer Institute, and Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium;VA Portland Health Care System and Oregon Health & Science University, Portland, OR, USA;

关键词: Sunitinib;    Imatinib;    GIST;    KIT;    KIT;    Imatinib-resistant GIST;    Overall survival;    Progression-free survival;   

DOI  :  10.1186/s12885-016-2051-5

 received in 2015-07-01, accepted in 2016-01-06,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundSeveral small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-α (PDGFRA) contributes in part to the level of clinical effectiveness of sunitinib in gastrointestinal stromal tumor (GIST) patients. This study aimed to correlate KIT and PDGFRA mutational status with clinical outcome metrics (progression-free survival [PFS], overall survival [OS], objective response rate [ORR]) in a larger international patient population.MethodsThis is a non-interventional, retrospective analysis in patients with imatinib-resistant or intolerant GIST who were treated in a worldwide, open-label treatment-use study (Study 1036; NCT00094029) in which sunitinib was administered at a starting dose of 50 mg/day on a 4-week-on, 2-week-off schedule. Molecular status was obtained in local laboratories with tumor samples obtained either pre-imatinib, post-imatinib/pre-sunitinib, or post-sunitinib treatment, and all available data were used in the analyses regardless of collection time. The primary analysis compared PFS in patients with primary KIT exon 11 versus exon 9 mutations (using a 2-sided log-rank test) and secondary analyses compared OS (using the same test) and ORR (using a 2-sided Pearson χ2 test) in the same molecular subgroups.ResultsOf the 1124 sunitinib-treated patients in the treatment-use study, 230 (20 %) were included in this analysis, and baseline characteristics were similar between the two study populations. Median PFS was 7.1 months. A significantly better PFS was observed in patients with a primary mutation in KIT exon 9 (n = 42) compared to those with a primary mutation in exon 11 (n = 143; hazard ratio = 0.59; 95 % confidence interval, 0.39–0.89; P = 0.011), with median PFS times of 12.3 and 7.0 months, respectively. Similarly, longer OS and higher ORR were observed in patients with a primary KIT mutation in exon 9 versus exon 11. The data available were limited to investigate the effects of additional KIT or PDGFRA mutations on the efficacy of sunitinib treatment.ConclusionsThis large retrospective analysis confirms the prognostic significance of KIT mutation status in patients with GIST. This analysis also confirms the effectiveness of sunitinib as a post-imatinib therapy, regardless of mutational status.Trial registrationNCT01459757.

【 授权许可】

CC BY   
© Reichardt et al. 2016