Phase II trial of imatinib mesylate (STI-571) in metastatic melanoma (MM)

Abstract

7528 Background: Imatinib mesylate (Gleevec™), an oral inhibitor of phosphorylation of certain tyrosine kinases (TK), is active in gastrointestinal stromal tumors which are chemotherapy resistant. Perhaps MM may respond to Gleevec, especially if the tumor cells or microenvironment express one of the known TK targets: KIT, PDGF receptors α or β, c-abl, or ARG. Methods: Tumor biopsies from MM patients (pts) were screened by immunohistochemistry (IHC) for TK expression in more than 25% of the cells, as a condition for enrollment in a Phase II trial testing Gleevec @ 400 mg bid. Results: All 31 pts screened met this criterion and 21 of them were treated with Gleevec (median age 58, male [13]; stage IV [19]; PS 0–1 [20]; prior Rx: none [8], Intron-A [8], one chemotherapy [5]). The one patient with strongest expression of KIT in over 75% of tumor cells tolerated treatment for one year and achieved near complete response in in-transit, inguinal/iliac, and lung metastases with marked PET scan improvement as early as 6 weeks. Quantitative dual immunofluorescence in baseline and 2nd week tumor specimens revealed a decrease in phosphoKIT relative to total KIT expression in the responder and also in 4 of 5 non-responders tested to-date. CD31/TUNEL assay showed an increase in both tumor and endothelial cell apoptosis in the responding tumor. Sequencing from this tumor's RNA revealed serine deletion at codon 715 of kit (Exon 15, Kinase II Domain), probably a result of alternate RNA splicing, with a short:long isoform ratio of 5:1. This alternate splicing has been seen in colon cancer but not in normal colon from the same patient and may be a tumor specific event. Sixteen pts (77%) had progressive disease within 6 weeks and 4 pts within 12 weeks, obviating accrual into the 2nd stage. Two pts bled in progressing metastases. Pts experienced nausea/vomiting, rash, fluid retention, fatigue (one each grade III) and only modest myelosuppression - all as reported at lower doses. Conclusions: Strong TK expression in a majority of tumor cells by IHC may predict Gleevec response in MM. More stringent assays to better select the rare patients likely to respond are being investigated, as are other ways to exploit the agent's biologic effects. No significant financial relationships to disclose.