Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy.
BACKGROUND
Systemic treatment of metastatic melanoma is largely ineffective and alternative approaches are needed. Imatinib mesylate is an oral tyrosine kinase inhibitor that targets bcr-Abl, c-kit, platelet-derived growth factor receptor (PDGFR)-alpha, and PDGFR-beta, leading to remarkable clinical responses in several cancers. Signal transduction via c-kit, PDGFR-alpha, and PDGFR-beta has been demonstrated in malignant melanoma.


METHODS
The primary objective of this Phase II study was to determine the response rate, response duration, and the frequency of 6-month progression-free survival in patients who could receive up to 2 prior therapeutic regimens. Initially, patients received imatinib at at dose of 400 mg twice orally each day. Based on Simon's optimal design, the study allowed entry of 21 patients; if there were > or = 2 objective responses, accrual would then continue to a total of 41 patients.


RESULTS
Twenty-six patients were enrolled. Patients experienced 29 episodes of Grade 3 and 2 episodes of Grade 4 toxicity (according to National Cancer Institute common toxicity criteria). No objective clinical responses were noted among the 25 evaluable patients. The median time to progression was 54 days and the median overall survival was 200 days. No patient was free of disease progression at 6 months. Paraffin-embedded tumor specimens from 15 patients were tested for expression of imatinib responsive kinases by immunohistochemistry. Three tumors had moderate and 5 tumors had weak staining for c-kit. Five tumor samples had weak staining for PDGFR-alpha and -beta.


CONCLUSIONS
Imatinib is an inactive single agent in metastatic melanoma in a population of predominantely pretreated patients. The levels of c-kit and/or PDGFR-alpha, -beta expression in the current study were lower than previously reported. Alternative treatment strategies remain a priority for patients with advanced melanoma.
Wyman
Ken
K
Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Atkins
Michael B
MB
Prieto
Victor
V
Eton
Omar
O
McDermott
David F
DF
Hubbard
Francie
F
Byrnes
Christine
C
Sanders
Kathleen
K
Sosman
Jeffrey A
JA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000737:chemistry / Q000188:drug therapy*; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis; D011743:Pyrimidines / Q000009:adverse effects*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta