Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition

Richard D. Carvajal, Donald P. Lawrence, Jeffrey S. Weber, Thomas F. Gajewski, Rene Gonzalez, Jose Lutzky, Steven J. O'Day, Omid Hamid, Jedd D. Wolchok, Paul B. Chapman, Ryan J. Sullivan, Jerrold B. Teitcher, Nikhil Ramaiya, Anita Giobbie-Hurder, Cristina R. Antonescu, Michael Heinrich, Boris C. Bastian, Christopher Corless, Jonathan A. Fletcher, F. Stephen Hodi

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Abstract

Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. Experimental Design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon twostage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. Results: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. Conclusions: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

Original languageEnglish (US)
Pages (from-to)2289-2296
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number10
DOIs
StatePublished - May 15 2015

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Melanoma
Confidence Intervals
Neoplasm Metastasis
Brain
Mutation
Survival
Protein-Tyrosine Kinases
Research Design
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Carvajal, R. D., Lawrence, D. P., Weber, J. S., Gajewski, T. F., Gonzalez, R., Lutzky, J., ... Hodi, F. S. (2015). Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clinical Cancer Research, 21(10), 2289-2296. https://doi.org/10.1158/1078-0432.CCR-14-1630

Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. / Carvajal, Richard D.; Lawrence, Donald P.; Weber, Jeffrey S.; Gajewski, Thomas F.; Gonzalez, Rene; Lutzky, Jose; O'Day, Steven J.; Hamid, Omid; Wolchok, Jedd D.; Chapman, Paul B.; Sullivan, Ryan J.; Teitcher, Jerrold B.; Ramaiya, Nikhil; Giobbie-Hurder, Anita; Antonescu, Cristina R.; Heinrich, Michael; Bastian, Boris C.; Corless, Christopher; Fletcher, Jonathan A.; Hodi, F. Stephen.

In: Clinical Cancer Research, Vol. 21, No. 10, 15.05.2015, p. 2289-2296.

Research output: Contribution to journalArticle

Carvajal, RD, Lawrence, DP, Weber, JS, Gajewski, TF, Gonzalez, R, Lutzky, J, O'Day, SJ, Hamid, O, Wolchok, JD, Chapman, PB, Sullivan, RJ, Teitcher, JB, Ramaiya, N, Giobbie-Hurder, A, Antonescu, CR, Heinrich, M, Bastian, BC, Corless, C, Fletcher, JA & Hodi, FS 2015, 'Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition', Clinical Cancer Research, vol. 21, no. 10, pp. 2289-2296. https://doi.org/10.1158/1078-0432.CCR-14-1630
Carvajal, Richard D. ; Lawrence, Donald P. ; Weber, Jeffrey S. ; Gajewski, Thomas F. ; Gonzalez, Rene ; Lutzky, Jose ; O'Day, Steven J. ; Hamid, Omid ; Wolchok, Jedd D. ; Chapman, Paul B. ; Sullivan, Ryan J. ; Teitcher, Jerrold B. ; Ramaiya, Nikhil ; Giobbie-Hurder, Anita ; Antonescu, Cristina R. ; Heinrich, Michael ; Bastian, Boris C. ; Corless, Christopher ; Fletcher, Jonathan A. ; Hodi, F. Stephen. / Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 10. pp. 2289-2296.
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abstract = "Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. Experimental Design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon twostage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. Results: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27{\%}; 95{\%} confidence interval (CI), 8{\%}-56{\%}] and 1 on cohort B (12.5{\%}; 90{\%} CI, 0.6{\%}-47{\%}) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2{\%}; 90{\%} CI, 3{\%}-47{\%}); none were observed in cohort B. The median TTP and OS was 3.3 (90{\%} CI, 2.1-3.9 months) and 9.1 months (90{\%} CI, 4.3-14.2 months), respectively, in all treated patients. Conclusions: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.",
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T1 - Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition

AU - Carvajal, Richard D.

AU - Lawrence, Donald P.

AU - Weber, Jeffrey S.

AU - Gajewski, Thomas F.

AU - Gonzalez, Rene

AU - Lutzky, Jose

AU - O'Day, Steven J.

AU - Hamid, Omid

AU - Wolchok, Jedd D.

AU - Chapman, Paul B.

AU - Sullivan, Ryan J.

AU - Teitcher, Jerrold B.

AU - Ramaiya, Nikhil

AU - Giobbie-Hurder, Anita

AU - Antonescu, Cristina R.

AU - Heinrich, Michael

AU - Bastian, Boris C.

AU - Corless, Christopher

AU - Fletcher, Jonathan A.

AU - Hodi, F. Stephen

PY - 2015/5/15

Y1 - 2015/5/15

N2 - Purpose: Although durable responses can be achieved with tyrosine kinase inhibitors such as imatinib in melanomas harboring KIT mutations, the efficacy of alternative inhibitors after progression to imatinib and the activity of these agents on brain metastases are unknown. Experimental Design: We conducted a phase II study of nilotinib 400 mg twice a day in two cohorts of patients with melanomas harboring KIT mutations or amplification: (A) those refractory or intolerant to a prior KIT inhibitor; and (B) those with brain metastases. The primary endpoint was 4-month disease control rate. Secondary endpoints included response rate, time-to-progression (TTP), and overall survival (OS). A Simon twostage and a single-stage design was planned to assess for the primary endpoint in cohorts A and B, respectively. Results: Twenty patients were enrolled and 19 treated (11 in cohort A; 8 in cohort B). Three patients on cohort A [27%; 95% confidence interval (CI), 8%-56%] and 1 on cohort B (12.5%; 90% CI, 0.6%-47%) achieved the primary endpoint. Two partial responses were observed in cohort A (18.2%; 90% CI, 3%-47%); none were observed in cohort B. The median TTP and OS was 3.3 (90% CI, 2.1-3.9 months) and 9.1 months (90% CI, 4.3-14.2 months), respectively, in all treated patients. Conclusions: Nilotinib may achieve disease control in patients with melanoma harboring KIT alterations and whose disease progressed after imatinib therapy. The efficacy of this agent in KIT-altered melanoma with brain metastasis is limited.

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