Phase II Study of Nilotinib in Melanoma Harboring KIT Alterations Following Progression to Prior KIT Inhibition.

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 two-stage 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.

• Authors: 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 C Heinrich, Boris C Bastian, Christopher L Corless, Jonathan A Fletcher, F Stephen Hodi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 10 Pg. 2289-96 (May 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25695690 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Pyrimidines
• Proto-Oncogene Proteins c-kit
• nilotinib

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (therapeutic use)
• Brain Neoplasms (drug therapy, genetics, secondary)
• Disease Progression
• Drug Resistance, Neoplasm
• Female
• Humans
• Male
• Melanoma (drug therapy, genetics, secondary)
• Middle Aged
• Proto-Oncogene Proteins c-kit (genetics)
• Pyrimidines (therapeutic use)
• Skin Neoplasms (drug therapy, genetics, pathology)
• Treatment Outcome