Imatinib for melanomas harboring mutationally activated or amplified kit arising on mucosal, acral, and chronically sun-damaged skin

F. Stephen Hodi, Christopher Corless, Anita Giobbie-Hurder, Jonathan A. Fletcher, Meijun Zhu, Adrian Marino-Enriquez, Philip Friedlander, Rene Gonzalez, Jeffrey S. Weber, Thomas F. Gajewski, Steven J. O'Day, Kevin B. Kim, Donald Lawrence, Keith T. Flaherty, Jason J. Luke, Frances A. Collichio, Marc S. Ernstoff, Michael Heinrich, Carol Beadling, Katherine A. ZukotynskiJeffrey T. Yap, Annick D. Van Den Abbeele, George D. Demetri, David E. Fisher

Research output: Contribution to journalArticle

255 Citations (Scopus)

Abstract

Purpose Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. Patients and Methods We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. Results Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. Conclusion Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

Original languageEnglish (US)
Pages (from-to)3182-3190
Number of pages9
JournalJournal of Clinical Oncology
Volume31
Issue number26
DOIs
StatePublished - Sep 10 2013

Fingerprint

Solar System
Melanoma
Extremities
Skin
Mutation
Imatinib Mesylate
Proto-Oncogenes
Therapeutics
Oncogenes
Mass Spectrometry
Neoplasms
Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Imatinib for melanomas harboring mutationally activated or amplified kit arising on mucosal, acral, and chronically sun-damaged skin. / Hodi, F. Stephen; Corless, Christopher; Giobbie-Hurder, Anita; Fletcher, Jonathan A.; Zhu, Meijun; Marino-Enriquez, Adrian; Friedlander, Philip; Gonzalez, Rene; Weber, Jeffrey S.; Gajewski, Thomas F.; O'Day, Steven J.; Kim, Kevin B.; Lawrence, Donald; Flaherty, Keith T.; Luke, Jason J.; Collichio, Frances A.; Ernstoff, Marc S.; Heinrich, Michael; Beadling, Carol; Zukotynski, Katherine A.; Yap, Jeffrey T.; Van Den Abbeele, Annick D.; Demetri, George D.; Fisher, David E.

In: Journal of Clinical Oncology, Vol. 31, No. 26, 10.09.2013, p. 3182-3190.

Research output: Contribution to journalArticle

Hodi, FS, Corless, C, Giobbie-Hurder, A, Fletcher, JA, Zhu, M, Marino-Enriquez, A, Friedlander, P, Gonzalez, R, Weber, JS, Gajewski, TF, O'Day, SJ, Kim, KB, Lawrence, D, Flaherty, KT, Luke, JJ, Collichio, FA, Ernstoff, MS, Heinrich, M, Beadling, C, Zukotynski, KA, Yap, JT, Van Den Abbeele, AD, Demetri, GD & Fisher, DE 2013, 'Imatinib for melanomas harboring mutationally activated or amplified kit arising on mucosal, acral, and chronically sun-damaged skin', Journal of Clinical Oncology, vol. 31, no. 26, pp. 3182-3190. https://doi.org/10.1200/JCO.2012.47.7836
Hodi, F. Stephen ; Corless, Christopher ; Giobbie-Hurder, Anita ; Fletcher, Jonathan A. ; Zhu, Meijun ; Marino-Enriquez, Adrian ; Friedlander, Philip ; Gonzalez, Rene ; Weber, Jeffrey S. ; Gajewski, Thomas F. ; O'Day, Steven J. ; Kim, Kevin B. ; Lawrence, Donald ; Flaherty, Keith T. ; Luke, Jason J. ; Collichio, Frances A. ; Ernstoff, Marc S. ; Heinrich, Michael ; Beadling, Carol ; Zukotynski, Katherine A. ; Yap, Jeffrey T. ; Van Den Abbeele, Annick D. ; Demetri, George D. ; Fisher, David E. / Imatinib for melanomas harboring mutationally activated or amplified kit arising on mucosal, acral, and chronically sun-damaged skin. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 26. pp. 3182-3190.
@article{c4eb1945405b452c9e3d000f946896f6,
title = "Imatinib for melanomas harboring mutationally activated or amplified kit arising on mucosal, acral, and chronically sun-damaged skin",
abstract = "Purpose Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. Patients and Methods We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. Results Twenty-five patients were enrolled (24 evaluable). Eight patients (33{\%}) had tumors with KIT mutations, 11 (46{\%}) with KIT amplifications, and five (21{\%}) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29{\%} (21{\%} excluding nonconfirmed responses) with a two-stage 95{\%} CI of 13{\%} to 51{\%}. BORR was significantly greater than the hypothesized null of 5{\%} and statistically significantly different by mutation status (7 of 13 or 54{\%} KIT mutated v 0{\%} KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50{\%} but varied significantly by KIT mutation status (77{\%} mutated v 18{\%} amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. Conclusion Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.",
author = "Hodi, {F. Stephen} and Christopher Corless and Anita Giobbie-Hurder and Fletcher, {Jonathan A.} and Meijun Zhu and Adrian Marino-Enriquez and Philip Friedlander and Rene Gonzalez and Weber, {Jeffrey S.} and Gajewski, {Thomas F.} and O'Day, {Steven J.} and Kim, {Kevin B.} and Donald Lawrence and Flaherty, {Keith T.} and Luke, {Jason J.} and Collichio, {Frances A.} and Ernstoff, {Marc S.} and Michael Heinrich and Carol Beadling and Zukotynski, {Katherine A.} and Yap, {Jeffrey T.} and {Van Den Abbeele}, {Annick D.} and Demetri, {George D.} and Fisher, {David E.}",
year = "2013",
month = "9",
day = "10",
doi = "10.1200/JCO.2012.47.7836",
language = "English (US)",
volume = "31",
pages = "3182--3190",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "26",

}

TY - JOUR

T1 - Imatinib for melanomas harboring mutationally activated or amplified kit arising on mucosal, acral, and chronically sun-damaged skin

AU - Hodi, F. Stephen

AU - Corless, Christopher

AU - Giobbie-Hurder, Anita

AU - Fletcher, Jonathan A.

AU - Zhu, Meijun

AU - Marino-Enriquez, Adrian

AU - Friedlander, Philip

AU - Gonzalez, Rene

AU - Weber, Jeffrey S.

AU - Gajewski, Thomas F.

AU - O'Day, Steven J.

AU - Kim, Kevin B.

AU - Lawrence, Donald

AU - Flaherty, Keith T.

AU - Luke, Jason J.

AU - Collichio, Frances A.

AU - Ernstoff, Marc S.

AU - Heinrich, Michael

AU - Beadling, Carol

AU - Zukotynski, Katherine A.

AU - Yap, Jeffrey T.

AU - Van Den Abbeele, Annick D.

AU - Demetri, George D.

AU - Fisher, David E.

PY - 2013/9/10

Y1 - 2013/9/10

N2 - Purpose Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. Patients and Methods We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. Results Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. Conclusion Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

AB - Purpose Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. Patients and Methods We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. Results Twenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. Conclusion Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.

UR - http://www.scopus.com/inward/record.url?scp=84881512367&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84881512367&partnerID=8YFLogxK

U2 - 10.1200/JCO.2012.47.7836

DO - 10.1200/JCO.2012.47.7836

M3 - Article

C2 - 23775962

AN - SCOPUS:84881512367

VL - 31

SP - 3182

EP - 3190

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 26

ER -