Lack of clinical efficacy of imatinib in metastatic melanoma.
This two-centre phase-II trial aimed at investigating the efficacy of imatinib in metastasised melanoma patients in correlation to the tumour expression profile of the imatinib targets c-kit and platelet-derived growth factor receptor (PDGF-R). The primary study end point was objective response according to RECIST, secondary end points were safety, overall and progression-free survival. In all, 18 patients with treatment-refractory advanced melanoma received imatinib 800 mg day(-1). In 16 evaluable patients no objective responses could be observed. The median overall survival was 3.9 months, the median time to progression was 1.9 months. Tumour biopsy specimens were obtained from 12 patients prior to imatinib therapy and analysed for c-kit, PDGF-Ralpha and -Rbeta expression by immunohistochemistry. In four cases, cell lines established from these tumour specimens were tested for the antiproliferative effects of imatinib and for functional mutations of genes encoding the imatinib target molecules. The tumour specimens stained positive for CD117/c-kit in nine out of 12 cases (75%), for PDGF-Ralpha in seven out of 12 cases (58%) and for PDGF-Rbeta in eight out of 12 cases (67%). The melanoma cell lines showed a heterogenous expression of the imatinib target molecules without functional mutations in the corresponding amino-acid sequences. In vitro imatinib treatment of the cell lines showed no antiproliferative effect. In conclusion, this study did not reveal an efficacy of imatinib in advanced metastatic melanoma, regardless of the expression pattern of the imatinib target molecules c-kit and PDGF-R.
Ugurel
S
S
German Cancer Research Center Heidelberg, Department of Dermatology, University Hospital of Mannheim, Theodor-Kutzer-Ufer 1, D-68167 Mannheim, Germany. s.ugurel@dkfz.de
Hildenbrand
R
R
Zimpfer
A
A
La Rosée
P
P
Paschka
P
P
Sucker
A
A
Keikavoussi
P
P
Becker
J C
JC
Rittgen
W
W
Hochhaus
A
A
Schadendorf
D
D
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001483:Base Sequence; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000188:drug therapy; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor