Better response was associated with the presence of recurrent mutations or increased mutant-to-wild-type allelic ratios.

Although anti-BRAF treatments have received significant press of late, not all melanomas harbor BRAF mutations. Those that arise on mucosal, acral, and chronically sun-damaged (CSD) sites may harbor KIT alterations (mutations, amplifications, or both) instead. Given a different mechanism, these patients would likely benefit from some drug other than vemurafenib (see JW Dermatol Jun 6 2011).


Investigators conducted a preliminary phase 2, multicenter trial to examine the effectiveness of the KIT inhibitor imatinib (Gleevec) for KIT-mutated tumors. In 295 patients with tumors on acral, mucosal, and sites with apparent CSD who were screened for KIT mutations or amplification, roughly 23% of tumors harbored KIT alterations and 28% had either BRAF or NRAS mutations. Of the 51 patients with KIT alterations, 28 had unresectable advanced disease and were given 400 mg of imatinib orally, twice daily in 6-week cycles until unacceptable toxicity or disease progression occurred.

Two patients had complete responses, 2 had durable partial responses, and 2 had transient partial responses among 25 evaluable patients. The overall durable response rate was 16%; the median time to progression was 12 weeks, and median overall survival was 46.3 weeks. In the post hoc analysis, better response appeared to be linked with recurrent mutations and with a mutant-to-wild-type allelic ratio of more than 1, indicating positive selection for the mutated allele.


Citation(s):

Carvajal RD et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011 Jun 8; 305:2327.