First melanoma trial to target KIT aberrations with imatinib
The incidence of malignant melanoma is increasing by 4% every year — the highest of any cancer type. At the same time, patients with melanomas arising from mucosal surfaces (eg, sinuses, mouth, vagina) or acral surfaces (eg, non-hair-containing palms, soles, and nailbeds) have very limited treatment options and survive less than 12 months once the disease has disseminated. A recent discovery, however, may offer new hope: a significant fraction of these melanomas and of those arising from chronically sun-damaged skin carry KIT aberrations; F. Stephen Hodi, MD (DFCI), is now leading a clinical trial to target this distinct subtype of melanomas with imatinib (Gleevec), a tyrosine kinase inhibitor (TKI).
Objectives and importance of this trial
KIT, a receptor tyrosine kinase, triggers a cascade of downstream substrates leading to cell growth signaling. Mutations in or amplifications of the KIT gene are estimated to occur in approximately 39% of mucosal melanomas, 36% of acral melanomas, and 28% of melanomas associated with sun-damaged skin, typically found on the face, neck, or hands. While numerous studies have shown that imatinib, a multi-targeted TKI with potent anti-KIT activity, induces major responses in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia, Hodi and colleagues were the first to report on a dramatic response to imatinib in mucosal melanoma. “It was the first time we found a tool to impact these patients,” says Hodi, who runs a translational research lab and practices oncology two days per week. “We had this one patient who was battling mucosal melanoma and responded to imatinib. It drove us to continue our efforts to treat these somewhat rare but devastating melanomas.”
In this study, patients with metastatic mucosal, acral, or sun-associated melanoma and a KIT aberration receive 400 mg of oral imatinib daily for up to one year, a dose that can be doubled if the cancer progresses during treatment. Although the primary objective is to measure response rate and progression-free survival, the study is also comparing KIT aberration status — mutated, amplified, or both — to ascertain which condition confers the greatest sensitivity to imatinib, based on genetic analysis of tissue biopsies.
In addition, investigators are using FDG-PET scanning, before treatment and at one month, to evaluate its use in detecting early biologic response to therapy. “Melanoma is typically the most avid tumor,” says Hodi, meaning it uptakes more of the FDG radioactive glucose than do other cancers and thus may more readily reveal the effects of imatinib on tumors. If patients stop responding to imatinib, biopsies allow investigators to study the molecular mechanisms underlying resistance, says Hodi, who expects that some melanomas may recur. Study patients taking imatinib for GIST, he explains, eventually developed resistance through additional mutations acquired in KIT. “We need to understand the reasons for resistance in our subtypes of melanoma,” he says.
“There’s absolutely no standard treatment for these patients,” he adds. “We hope we’ve found one.”
A Phase II Study of Imatinib in Patients With Mucosal or Acral/Lentiginous Melanoma and Melanomas That Arise on Chronically Sun Damaged Skin.
F. Stephen Hodi, MD (DFCI)
For eligibility criteria, contact information, and sites, go to NCT00424515 on ClinicalTrials.gov.