Entry Detail
| General information | |
| Database: | DB00198 |
| Objective: | Amplifications and mutations in the KIT protooncogene in subsets of melanomas provide therapeutic opportunities |
| Authors: | Hodi FS, et al |
| Title: | Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sundamaged skin. |
| Journal: | J Clin Oncol. |
| Year: | 2013 |
| PMID: | 23775962 |
| Trial Design | |
| Clinical Trial Id: | NCT00424515 |
| Agent: | imatinib mesylate |
| Target: | Abl Plateletderived growth factor receptor Mast/stem cell growth factor receptor |
| Cancer Type: | melanoma |
| Cancer Subtype: | advanced melanoma |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | a multicenterphase II trial |
| Key Patients Feature: | history of primary melanoma arising from mucosa, acral sites, or CSD skin (defined by the presence of solar elastosis or increased abnormal elastin in the midupper dermis and determined as standard of care within the pathology department at the institution where the patient was treated before trial enrollment); unresectable stage III or IV melanoma;ECOG performance status 0 to 2; normal endorgan function; and KIT mutation or amplification as determined by qPCR or FISH. Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. |
| Biomarker: | mutation status or melanoma site. |
| Biomark Analysis: | There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. |
| Control Group Info: | single arm |
| Treatment Info: | Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatmentrelated toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. |
| Primary End Point: | response rate (RR) and time to progression (TTP). |
| Secondary End Point: | assessing tolerability and overall survival (OS) and the association between mutation status and response to therapy. |
| Patients Number: | 25 |
| Trial Results | |
| DLT_MTD: | NA |
| Objective Response Rate: | Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a twostage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). |
| Disease Control Rate: | The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). |
| Median Time to Progression: | Median TTP was 3.7 months (95% CI, 2.6 to 5.6 months). |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | All patients reported AEs with three patients experiencing grade 4 events and seven patients describing a total of 17 grade 3 events. The most commonly reported AEs were nausea (n = 17), fatigue (n = 16), anemia (n = 12), hyperglycemia (n = 11), and vomiting (n = 10). |
| Conclusions: | Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib. |