Oral communication, iL39

Official XXIst International Pigment Cell Conference website - 21-24 Sept 2011, Bordeaux - France | updated: September 04 2011

KIT Aberrations in Melanoma and Therapeutic Implications

The identification of distinct molecular subgroups of melanoma is becoming of increasing therapeutic relevance. The most common melanoma subtype in the US arises from non-chronically sun-damaged (non-CSD) skin and often harbors activating mutations in BRAF. Melanoma arising from mucosal, acral, and CSD sites infrequently have BRAF mutations, but commonly have amplifications or activating mutations of KIT. The importance of KIT in normal melanocyte development is well-established; however, its role as an oncogene and therapeutic target in melanoma has only recently become clear. While KIT is expressed in some melanomas, loss of expression is observed with progression of disease from superficial to invasive to metastatic stages, suggesting that KIT possesses tumor suppressive functions. Furthermore, three phase II studies of metastatic melanoma treated with imatinib mesylate (IM), an orally available ATP-competitive inhibitor of several tyrosine kinases including KIT, did not demonstrate clinical activity. These trials accrued before the discovery of activating mutations of KIT in melanoma and did not select patients based upon the presence of KIT mutations or amplification. KIT is an established therapeutic target in cancers with activating mutations of KIT such as gastrointestinal stromal tumors (GIST), and significant benefit is achieved with various small molecule inhibitors of KIT including IM. Several melanoma cell lines with KIT mutations are highly sensitive to IM. Furthermore, several patients with melanoma harboring KIT alterations, including a K642E mutation as well as a seven-codon duplication of exon 11, have been reported to achieve major durable responses to IM. Given the preclinical and anecdotal clinical activity of IM observed in KIT mutant melanoma, we and others have conducted clinical trials of IM and other inhibitors of KIT to test the hypothesis that inhibition of KIT in a molecularly selected subgroup of patients with melanomas harboring mutations or amplification of KIT will result in objective regression and disease control. In our multicenter phase II study of IM in melanoma harboring somatic alterations of KIT, we screened tumor samples from 295 patients with melanoma for the presence of KIT mutations or amplifications and identified 51 cases with such alterations. KIT mutations or amplifications were identified in 23.8% of acral melanomas, 24.7% of mucosal melanomas, and 18.8% of melanomas arising from skin with histopathologically signs of chronic sun-induced damage. Twenty-eight of the 51 patients whose tumors harbored KIT mutations or amplification were treated with IM: 13 (46%) with mucosal melanoma, 10 (36%) with acral melanoma, and 5 (18%) with melanoma arising from CSD sites (3 arising from the head and neck and 2 arising from the trunk). Twenty-five were evaluable for the primary endpoint of response. Treated patients received IM 400 mg twice daily. We observed 2 complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks amongst the 25 evaluable patients. The overall durable response rate was 16% (95% confidence interval, 2-30%), with a median time to progression of 12 weeks (interquartile range, 6-18 weeks; 95% confidence interval, 11-18 weeks), and a median overall survival of 46.3 weeks (interquartile range, 28 weeks-not achieved; 95% confidence interval, 28 weeks-not achieved). To separate bona fide driver from passenger alterations of KIT, we sought evidence for tumor selection of specific mutations. We observed that IM has greater activity in tumors harboring recurrent KIT mutations found in melanoma or GIST, as well as in tumors with a mutant KIT allele in greater abundance than the wild-type allele. Response rate was superior in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio greater than one (40% versus 0%, p=0.05) indicating positive selection for the mutated allele. When combining those whose tumors have an allelic ratio greater than 1 with those whose tumors harbor recurrent primary mutations found in GIST or melanoma, we observed a superior RR (40% versus 0%, p=0.05), TTP (16 versus 8.3 weeks; 95% CI, 11-35.6 versus 3.6-11.7 weeks; p=0.02) and survival (80.5 versus 28.3 weeks; 95% CI, 28.3-not reached versus 14.4-61.3 weeks; p=0.04) when compared with other cases. We conclude that, in patients with advanced melanoma harboring KIT alterations, treatment with IM results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance.

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