Phase II trial of imatinib mesylate in patients with metastatic melanoma

Abstract

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Figure 1

Clinical and radiological studies of a partial response to imatinib. All metastatic lesions shrank. (A) Response of in-transit metastases on right thigh. (B) Computed tomographic scan showing response of left external iliac lymph node (arrow). (C) Positron emission tomographic scans showing decrease in fluorodeoxyglucose uptake in all lesions (arrows). (D) Photomicrograph of the strong c-kit expression in the tumour of the responder. (E) Photomicrograph of a case of negative c-kit expression.

Figure 2

Tumour and endothelial cell apoptosis before treatment and during the second week of imatinib treatment. (A) Tumour cell apoptosis in five patients; patient 5 had a partial response. (B) Endothelial cell apoptosis in five patients. (C) Photomicrographs of the TUNEL stains for both melanoma and endothelial cells in the responder. Red in the CD31 column represents the endothelial cells, and green in the TUNEL column represents apoptotic cells. Yellow (indicated by an arrow) in the overlay column represents endothelial cells undergoing apoptosis.

Figure 3

Chromatogram of the sequence for the alternative splicing seen in c-kit mRNA from the responding patient. The c-kit cDNA sequence from the responder displayed a deletion of the first three nucleotides of exon 15, which encoded a serine (codon 715).