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

Peter Reichardt, George D. Demetri, Hans Gelderblom, Piotr Rutkowski, Seock Ah Im, Sudeep Gupta, Yoon Koo Kang, Patrick Schöffski, Jochen Schuette, Denis Soulières, Jean Yves Blay, David Goldstein, Kolette Fly, Xin Huang, Massimo Corsaro, Maria Jose Lechuga, Jean Francois Martini, Michael Heinrich

    Research output: Contribution to journalArticle

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    Abstract

    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.

    Original languageEnglish (US)
    Article number22
    JournalBMC Cancer
    Volume16
    Issue number1
    DOIs
    StatePublished - Jan 15 2016

    Fingerprint

    Platelet-Derived Growth Factor Receptors
    Gastrointestinal Stromal Tumors
    Exons
    Disease-Free Survival
    Mutation
    Therapeutics
    Survival
    sunitinib
    Population
    Appointments and Schedules
    Genotype
    Confidence Intervals
    Imatinib Mesylate

    Keywords

    • GIST
    • Imatinib
    • Imatinib-resistant GIST
    • KIT
    • KIT mutation
    • Overall survival
    • Progression-free survival
    • Sunitinib

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research
    • Genetics

    Cite this

    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. / Reichardt, Peter; Demetri, George D.; Gelderblom, Hans; Rutkowski, Piotr; Im, Seock Ah; Gupta, Sudeep; Kang, Yoon Koo; Schöffski, Patrick; Schuette, Jochen; Soulières, Denis; Blay, Jean Yves; Goldstein, David; Fly, Kolette; Huang, Xin; Corsaro, Massimo; Lechuga, Maria Jose; Martini, Jean Francois; Heinrich, Michael.

    In: BMC Cancer, Vol. 16, No. 1, 22, 15.01.2016.

    Research output: Contribution to journalArticle

    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, M 2016, '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, vol. 16, no. 1, 22. https://doi.org/10.1186/s12885-016-2051-5
    Reichardt, Peter ; Demetri, George D. ; Gelderblom, Hans ; Rutkowski, Piotr ; Im, Seock Ah ; Gupta, Sudeep ; Kang, Yoon Koo ; Schöffski, Patrick ; Schuette, Jochen ; Soulières, Denis ; Blay, Jean Yves ; Goldstein, David ; Fly, Kolette ; Huang, Xin ; Corsaro, Massimo ; Lechuga, Maria Jose ; Martini, Jean Francois ; Heinrich, Michael. / 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. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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    abstract = "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.",
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    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

    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

    VL - 16

    JO - BMC Cancer

    JF - BMC Cancer

    SN - 1471-2407

    IS - 1

    M1 - 22

    ER -