Sunitinib Therapy for Melanoma Patients with KIT Mutations

DR Minor, M Kashani-Sabet, M Garrido, SJ O'Day… - Clinical cancer …, 2012 - AACR
DR Minor, M Kashani-Sabet, M Garrido, SJ O'Day, O Hamid, BC Bastian
Clinical cancer research, 2012AACR
Purpose: Recent studies have shown activating KIT mutations in melanoma originating from
mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive
role of KIT mutation, amplification, or overexpression for response to treatment with the
kinase inhibitor sunitinib. Experimental Design: Tumor tissues from 90 patients with stage III
or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of
KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and …
Abstract
Purpose: Recent studies have shown activating KIT mutations in melanoma originating from mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive role of KIT mutation, amplification, or overexpression for response to treatment with the kinase inhibitor sunitinib.
Experimental Design: Tumor tissues from 90 patients with stage III or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and immunohistochemistry of KIT protein (CD117). Patients with mutations, amplifications, or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in Solid Tumors (RECIST).
Results: Eleven percent of the melanomas tested had mutations in KIT, 23% in BRAF, 14% in NRAS, and none in GNAQ. Of 12 patients treated with sunitinib, 10 were evaluable. Of the 4 evaluable patients with KIT mutations, 1 had a complete remission for 15 months and 2 had partial responses (1- and 7-month duration). In contrast, only 1 of the 6 patients with only KIT amplification or overexpression alone had a partial response. In 1 responder with rectal melanoma who later progressed, the recurring tumor had a previously undetected mutation in NRAS, which was found in addition to the persisting mutation in KIT. Interestingly, among patients with manifest stage IV disease, KIT mutations were associated with a significantly shortened survival time (P < 0.0001).
Conclusions: Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma. Clin Cancer Res; 18(5); 1457–63. ©2012 AACR.
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