Reference Detail

Ref Type

Journal Article

PMID

(26772734)

Authors

Reichardt P, Demetri GD, Gelderblom H, Rutkowski P, Im SA, Gupta S, Kang YK, Schöffski P, Schuette J, Soulières D, Blay JY, Goldstein D, Fly K, Huang X, Corsaro M, Lechuga MJ, Martini JF, Heinrich MC

Title

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
BMC cancer	16		2016 Jan 15	22	BMC Cancer

URL

Abstract Text

Several 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.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 χ(2) test) in the same molecular subgroups.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.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.NCT01459757.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT exon9	gastrointestinal stromal tumor	sensitive	Sunitinib	Clinical Study - Cohort	Actionable	In a retrospective analysis, GIST patients with KIT exon 9 mutations showed improved progression-free survival (PFS), overall survival, and objective response rate (ORR) compared to patients with exon 11 mutations, with a median PFS of 12.3 months vs. 7.0 months, and an ORR of 19% (8/42) vs. 6% (9/143) following treatment with Sutent (sunitinib) (PMID: 26772734).	26772734
KIT exon11	gastrointestinal stromal tumor	sensitive	Sunitinib	Clinical Study - Cohort	Actionable	In a retrospective analysis, Sutent (sunitinib) treatment demonstrated efficacy in gastrointestinal stromal tumor (GIST) patients harboring KIT mutations previously treated with Gleevec (imatinib), and resulted in an objective response rate (ORR) of 6% (9/143) and median progression-free survival (mPFS) of 7.0 months in patients with KIT exon 11 mutations, and ORR of 19% (8/42) and mPFS of 12.3 months in patients with KIT exon 9 mutations (PMID: 26772734; NCT01459757).	26772734