TY - JOUR
T1 - 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
AU - Reichardt, Peter
AU - Demetri, George D.
AU - Gelderblom, Hans
AU - Rutkowski, Piotr
AU - Im, Seock Ah
AU - Gupta, Sudeep
AU - Kang, Yoon Koo
AU - Schöffski, Patrick
AU - Schuette, Jochen
AU - Soulières, Denis
AU - Blay, Jean Yves
AU - Goldstein, David
AU - Fly, Kolette
AU - Huang, Xin
AU - Corsaro, Massimo
AU - Lechuga, Maria Jose
AU - Martini, Jean Francois
AU - Heinrich, Michael C.
N1 - Funding Information:
PRe has received honoraria for lectures and advisory boards from Novartis, Pfizer, Bayer, and Ariad. GDD has served as a consultant and clinical investigator for Pfizer, Novartis, Bayer, GlaxoSmithKline, EMD Serono, Threshold Pharmaceuticals, PharmaMar, and Janssen (Johnson & Johnson); he has received a small royalty from the Dana-Farber Cancer Institute on a patent licensed from Dana-Farber and Oregon Health and Science University on imatinib use in GIST; he has also served as a consultant for Ariad, ZioPharm, and Sanofi; he serves on the board of directors and scientific advisory board (SAB) of Blueprint Medicines, with a minor equity interest; he is also on the SAB of Kolltan Pharmaceuticals, with a minor equity interest; these individual potential conflicts of interest have been reviewed and managed by the Dana-Farber Cancer Institute. PRu has received honoraria for lectures and advisory boards from Novartis, Pfizer, and Bayer. S-AI has served on advisory boards, without compensation, for AstraZeneca, Roche, and Novartis, and received a research grant from AstraZeneca. SG has served on advisory boards, without direct compensation, for Pfizer, Novartis, GlaxoSmithKline, and Roche. Y-KK has received consulting fees from Pfizer, Novartis, Bayer, and Blueprint Medicines, and research grants from Novartis and Bayer. JS has received honoraria for lectures from Novartis. DS received honoraria for lectures from Novartis and Pfizer, and his institution received financial support for genetic testing initiatives. J-YB has received research support and honoraria from Pfizer, Novartis, and Bayer. DG has received research funding from Pfizer. MCH has received consulting fees from Pfizer, Novartis, Blueprint Medicines, Ariad, and MolecularMD and research funding from Ariad, Blueprint Medicines, Deciphera, Novartis, and Pfizer, has equity interest in MolecularMD and intellectual property (patents) related to GIST treatment, and has provided expert testimony to Novartis and Pfizer. HG and PS have declared that they have no competing interests. KF, XH, MC, ML, and J-FM are employees of Pfizer Inc.
Funding Information:
We would like to thank all of the participating patients and their families, as well as the investigators, research nurses, study coordinators, and operations staff. This study was sponsored by Pfizer Inc. Support for this work, in part, was also provided to George D. Demetri from the following sources: Ludwig Center at Harvard, The Pan-Mass Challenge via Team Paul’s Posse, the Russo Family Fund for GIST research, and Gastrointestinal Cancer SPORE Grant 1P50CA127003-05 at Dana-Farber Cancer Institute from the US National Cancer Institute. Medical writing support was provided by Andy Gannon and Ryan Woodrow at ACUMED® (New York, NY, USA), an Ashfield company, part of UDG Healthcare plc, with funding from Pfizer Inc.
Publisher Copyright:
© 2016 Reichardt et al.
PY - 2016/1/15
Y1 - 2016/1/15
N2 - Background: Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-aα (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. Methods: This 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. Results: Of 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. Conclusions: This 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.
AB - Background: Several small studies indicated that the genotype of KIT or platelet-derived growth factor receptor-aα (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. Methods: This 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. Results: Of 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. Conclusions: This 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.
KW - GIST
KW - Imatinib
KW - Imatinib-resistant GIST
KW - KIT
KW - KIT mutation
KW - Overall survival
KW - Progression-free survival
KW - Sunitinib
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UR - http://www.scopus.com/inward/citedby.url?scp=84954328203&partnerID=8YFLogxK
U2 - 10.1186/s12885-016-2051-5
DO - 10.1186/s12885-016-2051-5
M3 - Article
C2 - 26772734
AN - SCOPUS:84954328203
VL - 16
JO - BMC Cancer
JF - BMC Cancer
SN - 1471-2407
IS - 1
M1 - 22
ER -