Another Option in Our KIT of Effective Therapies for Advanced Melanoma

Hodi et al reported the final results of a multicenter phase II trial of imatinib in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene. KIT is a transmembrane receptor tyrosine kinase, normally expressed on melanocytes, that plays a critical role in melanocyte migration, survival, proliferation, and differentiation. Mutations and amplification of KIT have been identified in melanomas arising from mucosal, acral or chronically sun-damaged surfaces, and they characterize a distinct genetic subset of disease. The alterations identified are, in most instances, mutually exclusive of BRAF and NRAS mutations and lead to constitutive activation of downstream signaling pathways including the MAPK, PI3K/AKT, and JAK/STAT pathways. The authors designed their trial to test the efficacy of KIT inhibition with imatinib in a molecularly selected subset of melanoma characterized by KIT alterations, and their results highlight the critical importance of proper patient selection for drug development, as well as the challenges faced in defining selection criteria when the molecular target is characterized by heterogeneous genetic changes. They screened tumor samples from 213 patients with melanomas arising from acral, mucosal, or chronically-sun damaged sites for the presence of KIT mutations or amplification. Fifty cases with KIT alterations were identified, and 25 patients with KIT-mutant or -amplified melanoma were treated with imatinib. Of 24 evaluable patients, seven achieved a partial response (PR) to therapy, with five patients’ responses confirmed on subsequent imaging studies, for an overall confirmed response rate (RR) of 21%. This clinical activity is similar to that observed in two other trials of imatinib in patients with melanoma molecularly selected for the presence of KIT alterations. Our group screened 295 patients for KIT mutations or amplification, identified 51 patients with such alterations, treated 25 evaluable patients, and observed a confirmed RR of 16%, with responses durable for longer than 1 year. Guo et al screened 501 patients for KIT mutations or amplification, treated 43 patients with imatinib, and observed an RR of 23.3%. The significance of the responses observed on these three trials is most evident when placed in the context of three prior negative phase II trials of imatinib in molecularly unselected melanoma patients initiated before the identification of KIT mutations in this disease, in which only one radiographic response was observed in 62 patients treated across the three trials. In the era of targeted agents in molecularly selected patients, such as those patients with BRAF-mutant melanoma in whom an RR of 50% can be achieved, the RR observed with imatinib in KIT-altered melanoma appears modest. However, comparing the spectrum of alterations in BRAF and KIT that were permitted for eligibility in the respective clinical trials provides insight critical to properly assess the efficacy of imatinib in KIT-altered melanoma. Though the phase III trials of vemurafenib and dabrafenib required the presence of a BRAF V600E mutation for eligibility, the trials of imatinib in KIT-altered melanoma permitted inclusion based on the presence of any KIT mutation. Although approximately 70% of KIT mutations identified in melanoma affect the juxtamembrane domain (exon 11, most commonly L576P) and the proximal kinase domain (exon 13, most commonly K642E), others have been identified that likely represent passenger mutations of no biologic significance. Thus, treating patients with such mutations with imatinib would not be expected to result in clinical benefit, and the results reported with imatinib in KIT-mutant melanoma may therefore represent the effects of treatment in a suboptimally selected patient population. Interestingly, all seven responses observed in the study by Hodi et al occurred in the 13 patients enrolled with tumors harboring a KIT mutation, either alone or with concurrent KIT amplification, for an RR in the KIT-mutant population of 54%. Five responses occurred in tumors harboring an exon 11 KIT alteration (including three L576P mutations, one V560D mutation, and one PYD577-582 insertion), one response occurred in a tumor with an exon 13 K642E mutation, and one occurred in a tumor with an exon 17 D820Y mutation. In the trial conducted by our group, all six responses occurred in patients with tumors harboring an exon 11 L576P or an exon 13 K642E KIT mutation, either alone or with concurrent KIT amplification. Similarly, nine of 10 responses observed in the trial by Guo et al occurred in patients with tumor harboring exon 11 or 13 KIT mutations. Of the 53 patients with tumors harboring exon 11 or exon 13 mutations treated across these three phase II trials, 21 responses were observed, for an RR of 40%, a rate that is more in line with the responses observed with BRAF inhibition in BRAF V600E melanoma. Furthermore, significant radiographic responses in KIT mutant melanoma have also been reported with other targeted inhibitors of KIT, including sorafenib, dasatinib, sunitinib, and nilotinib, with all JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 26 SEPTEMBER 1