Richard D. Carvajal, MD
Department of Medicine
Memorial Sloan-Kettering Cancer Center
New York City
This is a remarkable time for melanoma research and treatment. Before this year, approved agents available for the treatment of metastatic melanoma were limited to dacarbazine (DTIC) and interleukin-2 (IL-2), with benefits achieved in only a small minority of patients treated with either drug. In 2011, however, two new agents, ipilimumab (YervoyTM) and vemurafenib (ZelborafTM), were approved, with each showing a demonstrable survival advantage in patients with advanced disease.
Ipilimumab, an antibody targeting cytotoxic T-lymphocyte associated antigen 4 (anti-CTLA-4), may be beneficial in all patients irrespective of tumor genotype.1,2 In contrast, it is clear that vemurafenib, a small molecule inhibitor with specificity for mutant BRAF harboring a substitution of glutamic acid for valine at position 600 (V600E), is only effective in patients whose tumors carry such a mutation.3 The clinical success of vemurafenib was dependent upon the discovery of driver mutations in BRAF in 45 percent of melanomas and limiting the inclusion of patients in clinical trials of this agent to those with BRAF-mutant tumors.
Recurrent alterations of other key melanoma oncogenes leading to constitutive activation of growth-signaling pathways have also been identified. In some cases, the tumor is dependent upon one or more of these mutations for survival. Targeting such alterations in select cases may achieve significant clinical benefits potentially comparable to those observed with BRAF targeting. Such is the hope for KIT.
Identification of KIT as a Melanoma Oncogene
KIT is a transmembrane receptor tyrosine kinase normally expressed on hematopoietic progenitor cells, mast cells, primordial germ cells, the interstitial cells of Cajal (the gastrointestinal stromal tumor [GIST] cells of origin), and melanocytes. Binding of its ligand, stem cell factor, results in activation of downstream signaling pathways including the MAPK, PI3K/AKT, and JAK/ STAT pathways. Intracellular signaling through KIT plays a critical role in melanocyte development. Loss of function alleles leads to defects in melanocyte migration, survival, proliferation, and differentiation. Initially, KIT was considered a possible melanoma tumor suppressor gene. It was observed that melanomas lost KIT expression with progression to more advanced stages, suggesting that loss of KIT might, in part, lead to tumor progression. Constitutive activation of KIT in primary melanocytes led to decreased proliferation, and expression of KIT in melanoma cell lines without native KIT expression led to the induction of cell-cycle arrest and apoptosis, findings that also supported the tumor suppressor hypothesis. It was not until the discovery of activating KIT mutations in several distinct clinical subgroups of melanoma that investigators began to take another look at KIT. Bastian and colleagues identified the existence of several distinct molecular subtypes of melanoma, each with a corresponding clinical subgroup and each characterized by a unique frequency of key genetic alterations.4,5 While KIT mutations or amplification were not observed in melanoma arising from non-chronically sun-damaged skin (non- CSD), these changes were observed in 29 percent of mucosal, 18 percent of acral, and 23 percent of CSD-melanomas. The KIT mutations identified included activating mutations in the juxtamembrane domain similar to those found in GIST, a disease known to be dependent upon KIT activation. Preclinical work demonstrated the constitutive activation of KIT kinase activity in mutant cells not observed in KIT wild-type cells. Exposure of mutant, but not wild-type, cells to clinically available KIT inhibitors led to down-regulation of multiple downstream mediators, resulting in cell cycle arrest, induction of apoptosis, and a reduction of cell proliferation.4,5
From Bench to Bedside
Identification of these oncogenic KIT mutations led to the hypothesis that KIT targeting would be an effective treatment strategy for melanomas driven by such alterations. Indeed, dramatic tumor responses achieved with imatinib mesylate or dasatinib, two small molecule inhibitors of KIT, were observed, including cases of two patients with melanoma arising from the anorectal mucosa, one harboring an exon 13 K624E mutation and one harboring a seven-codon duplication of exon 11. Both were treated with imatinib. A third case of melanoma arising from the vaginal mucosa and harboring an exon 11 L576P mutation significantly responded to dasatinib.6-8 These reports are all the more remarkable given the negative results of three completed phase II studies of imatinib for patients with advanced melanoma.9-11 These studies were initiated before the identification of KIT mutations in melanoma and enrolled primarily patients with the more common melanomas arising from non-CSD skin not associated with KIT aberrations. In this molecularly unselected patient population, imatinib was ineffective, with only one response observed among the 62 evaluable patients enrolled across these three trials. Interestingly, the patient who achieved a durable, near-complete response had an acral melanoma. Although his tumor was characterized by a KIT splice site mutation in exon 15, the significance of the resulting aberrant protein is unknown. While negative, these studies are not inconsistent with the hypothesis that KIT inhibition in the proper genetic context is an effective therapy for advanced melanoma. Rather, they support the hypothesis that KIT inhibition in molecularly unselected patients is ineffective.
Three additional phase II clinical trials of imatinib in advanced melanoma patients were subsequently initiated to assess the efficacy of KIT inhibition in melanomas harboring KIT aberrations, with a KIT alteration required for eligibility. Of the 25 evaluable patients treated in a study led by Memorial Sloan-Kettering Cancer Center (MSKCC), two achieved complete responses lasting 94 weeks (ongoing) and 95 weeks, two achieved durable partial responses lasting 53 weeks and 89 (ongoing) weeks, and two achieved transient responses lasting 12 and 18 weeks.12
The overall durable response rate was 16 percent; however, significant clinical benefit in terms of disease control was also observed in patients with stable disease. Similar findings were observed in the other studies. Guo, et al reported a 23.3 percent response rate in 43 evaluable patients, with a median progression free survival of nine months for those achieving a response or disease stability, and a median overall survival of 15 months.13 At the 2009 International Melanoma Congress held in Boston, MA, Hodi, et al provided an interim report on a study led by the Dana-Farber Cancer Institute, revealing a 25 percent RECIST (Response Evaluation Criteria In Solid Tumors) response rate in the 20 evaluable patients treated. All five responses were observed in patients whose tumors harbored KIT mutations. Of the 10 patients whose tumors harbored KIT amplification without a mutation, no responses were observed; however, two such patients achieved stable disease lasting six to seven months. Mutations in KIT, unlike those in BRAF, are widely distributed over the coding region (See Figure 1), raising the possibility that not all mutations are equally relevant functionally. Many KIT mutations identified in melanoma have not previously been reported and are present only in individual cases, suggesting that some mutations represent passenger mutations rather than true driver alterations. Interestingly, all six responses in the MSKCC study occurred in tumors with L576P or K642E mutations, the most common mutations found in melanoma.12 Similarly, in the study by Guo, et al,13 nine of the 10 patients who achieved a response to therapy had melanoma harboring a mutation in exons 11 or 13 of KIT, while only one of three patients whose tumors harbored amplified KIT alone achieved a response. These observations suggest that by utilizing more selective molecular criteria, we may be better able to identify those patients who will benefit from imatinib. Only those tumors truly dependent upon a constitutively active KIT signaling pathway will likely be susceptible to KIT inhibition, and the development of biomarkers permitting the reliable identification of these KIT-driven tumors is critical.
While significant benefit is achieved with imatinib in a subset of patients whose tumors harbor KIT aberrations, evaluation of other inhibitors is warranted. The spectrum of activity of each inhibitor for specific KIT mutations or affected domains is unique, thus the sensitivity of a melanoma to a particular inhibitor may differ depending on its KIT mutation. Trials of sunitinib, sorafenib, nilotinib, dasatinib and masatinib in patients with advanced melanoma are ongoing (See Table 1.) A randomized phase III trial of nilotinib versus DTIC in KIT mutant melanoma was initiated in 2010; however, due to challenges with accrual of patients with this uncommon genetic subset of melanoma, the study (the Tasigna Efficacy in Advanced Melanoma, or TEAM, Trial) was recently modified to a single-arm phase II trial of nilotinib alone. Unfortunately, the implications of this modification upon potential drug approval by the US Food and Drug Administration, should the study be positive, is currently unclear.
Further work is necessary to elucidate mechanisms of primary and secondary resistance to KIT inhibition in order to optimize KIT-targeted therapy for this patient population. Evaluation of the sequential use of different KIT inhibitors (a strategy of proven benefit in GIST) in KIT-driven melanoma resistant to one agent is under way. Finally, studies combining KIT inhibitors with chemotherapy, immunotherapy, and other “targeted” agents in an effort to improve outcomes are in development or ongoing. With our increasing knowledge of the biological heterogeneity of melanoma, we are making significant strides in developing effective therapies for this disease; however, this success is dependent upon tumor genotyping. Prospective screening for specific alterations, such as KIT mutations or amplification, will permit us to select specific targeted therapies for genetically appropriate patients, and allow continued improvement in clinical outcomes for those with advanced disease.
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; EJMoa1003466, doi:10.1056/NEJMoa1003466.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011; doi:10.1056/NEJMoa1104621.
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; doi:10.1056/NEJMoa1103782.
- Curtin JA, Busam K, Pinkel D, and Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006; 24:4340-4346, doi:JCO.2006.06.2984 [pii] 10.1200/JCO.2006.06.2984.
- Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005; 353:2135-2147, doi:353/20/2135 [pii]10.1056/NEJMoa050092.\
- Hodi FS, Friedlander P, Corless C, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 2008; 26:2046-2051,doi:26/12/2046 [pii] 10.1200/JCO.2007.14.0707.
- Lutzky J, Bauer J, and Bastian BC. Dose-dependent,complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation.Pigment Cell Melanoma Res 2008; 21:492-493, doi:PCR475 [pii] 10.1111/j.1755-148X.2008.00475.x.
- Woodman SE, Trent JC, Stemke-Hale K, et al. Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Mol Cancer Ther 2009; 8:2079-2085, doi:1535-7163.MCT-09-0459 [pii] 10.1158/1535-7163.MCT-09-0459.
- Wyman K, Atkins MB, Prieto V, et al. Multicenter phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer 2006; 106: 2005-2011, doi:10.1002/cncr.21834.
- Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer 2005; 92:1398-1405,oi:6602529[pii] 10.1038/sj.bjc.6602529.\
- Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer 2008; 99:734-740,doi:6604482[pii] 10.1038/sj.bjc.6604482.
- Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011; 305:2327-2334, doi:305/22/2327 [pii] 10.1001/jama.2011.746.
- Guo J, Si L, Kong Y, et al. Phase II, open-label,single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29:2904-2909, doi:JCO.2010.33.9275 [pii] 10.1200/JCO.2010.33.9275.