Sunitinib Therapy for Melanoma Patients with KIT Mutations

Published OnlineFirst January 18, 2012; DOI: 10.1158/1078-0432.CCR-11-1987

Clinical Cancer Predictive Biomarkers and Personalized Medicine Research

David R. Minor1, Mohammed Kashani-Sabet1, Maria Garrido2, Steven J. O'Day3, Omid Hamid3, and Boris C. Bastian2

Abstract Purpose: Recent studies have shown activating KIT mutations in melanoma originating from mucosa, acral, or cumulative sun-damaged skin sites. We aimed to assess the predictive role of KIT mutation, amplification, or overexpression for response to treatment with the kinase inhibitor sunitinib. Experimental Design: Tumor tissues from 90 patients with stage III or IV acral, mucosal, or cumulative sun-damaged skin melanoma underwent sequencing of KIT, BRAF, NRAS, and GNAQ genes, FISH analysis for KIT amplification, and immunohistochemistry of KIT protein (CD117). Patients with mutations, amplifications, or overexpression of KIT were treated with sunitinib and responses measured by Response Evaluation Criteria in Solid Tumors (RECIST). Results: Eleven percent of the melanomas tested had mutations in KIT, 23% in BRAF, 14% in NRAS, and none in GNAQ. Of 12 patients treated with sunitinib, 10 were evaluable. Of the 4 evaluable patients with KIT mutations, 1 had a complete remission for 15 months and 2 had partial responses (1- and 7-month duration). In contrast, only 1 of the 6 patients with only KIT amplification or overexpression alone had a partial response. In 1 responder with rectal melanoma who later progressed, the recurring tumor had a previously undetected mutation in NRAS, which was found in addition to the persisting mutation in KIT. Interestingly, among patients with manifest stage IV disease, KIT mutations were associated with a significantly shortened survival time (P < 0.0001). Conclusions: Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma. Clin Cancer Res; 18(5); 1–7. 2012 AACR.

Introduction sun-damaged skin (CSDS; refs. 2, 3). In gastrointestinal KIT Metastatic melanoma is resistant to chemotherapy, and stromal tumors (GIST), mutations are observed in an important avenue of therapeutic melanoma research has about 85% of tumors, and these activating mutations lead centered on the search for genetic changes in the cancer that to an activated KIT receptor that drives tumor growth. promote tumor growth. These genetic changes may provide Small-molecule inhibitors of the KIT receptor have been targets for successful pharmaceutical intervention. Curtin found to be clinically active (4), leading to U.S. Food and and colleagues (1) first described activating mutations in Drug Administration approval of both imatinib and suni- the receptor tyrosine kinase KIT in melanomas originating tinib for the treatment of GISTs. There is considerable KIT from certain primary sites: acral, mucosal, or cumulative overlap in the mutation spectra of mutations found in GISTs and in melanoma, raising the possibility that KIT inhibition may also be a promising strategy for certain Authors' Affiliations: 1California Pacific Center for Melanoma Research melanomas (5, 6). Several case reports of marked responses and Treatment; 2Departments of Dermatology and Pathology and UCSF to imatinib in KIT-mutant patients with melanoma sup- Helen Diller Family Comprehensive Cancer Center, University of California ported this notion (7–9) and a study from China showed San Francisco, San Francisco; and 3The Angeles Clinic and Research Institute, Los Angeles, California responses in 6 of 30 patients (10). The recent multicenter trial described in the study by Carvajal and colleagues Note: Data from this study were reported in part at the ASCO Annual Meeting, Chicago, IL, June 2010: J Clin Oncol 2010;28: 622s (suppl; abstr screened 295 patients for KIT mutations and had 6 respon- 8545). ders in 25 evaluable patients with mutations treated with KIT Clinicaltrials.gov registration number: NCT001631618. imatinib (11). Sunitinib is a potent inhibitor of mutant with additional inhibitory effects on VEGF receptors (12) Corresponding Author: David R. Minor, California Pacific Center for Melanoma Research and Treatment, San Francisco Oncology Associates, that potentially might make it more effective than imatinib 2100 Webster St. #326, San Francisco, CA 94115. Phone: 415-885-8600; against KIT-mutated melanoma. We aimed to study the Fax: 415-885-8680; E-mail: [email protected] mutational status of patients with melanoma with acral, doi: 10.1158/1078-0432.CCR-11-1987 mucosal, or CSDS primaries; correlate mutational status 2012 American Association for Cancer Research. with KIT amplification and protein expression; and explore

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Translational Relevance Table 1. Clinical characteristics of patients Recent studies have found KIT mutations in melano- treated with sunitinib mas from acral, mucosal, or cumulative sun-damaged skin sites, but the clinical use of this finding is only now Characteristics Patients (N ¼ 12), n (%) being explored. Our article describes the results of the Age, median (range), y 75 (39–92) molecular analysis in 90 patients with melanoma with KIT Sex the clinical results in 12 patients with aberrations Male 9 (75) treated with sunitinib. We report 3 novel and important KIT Female 3 (25) findings: first, patients with mutations can have Clinical melanoma subtype clinically useful responses to sunitinib therapy; second, Mucosal 7 (58) KIT mutations appear to be an adverse prognostic factor; Acral 2 (17) and third, some patients with melanoma may develop CSDS 3 (25) resistance to a KIT inhibitor as a result of development of KIT NRAS mutation a secondary mutation. Present 6 (50) Absent 6 (50) Stage MIA 3 (25) MIB 3 (25) the clinical activity of sunitinib therapy in patients whose MIC 6 (50) melanomas had mutations, amplifications, or overexpression of KIT.

Patients and Methods used to calculate Kaplan–Meier survival curves and log-rank Patients were eligible for molecular testing if they had tests. stage III or IV metastatic melanoma that had arisen from Although not part of the original study design, we con- primaries originating from the mucosa or acral or CSDS. ducted an exploratory survival analysis of patients who had CSDS was inferred from a primary site on the scalp, face, or molecular testing using the Kaplan–Meier method. This neck and patient age and not necessarily verified by finding analysis was restricted to patients with radiologic or clinical solar elastosis on biopsy specimens, as the primary tumor evidence of unresectable metastatic disease on the date of n ¼ was not always available for review. Acral sites were defined consent for the study ( 79), included 11 of 12 patients as the non–hair-bearing skin of the palms and soles or the treated with sunitinib, and measured survival from date of nail apparatus. Patients were eligible for treatment with consent for molecular testing. The date of onset of meta- sunitinib if molecular analysis showed a KIT mutation in static disease was not collected. exons 9, 11, 13, 17, or 18, any amplification of the KIT gene, FISH was carried out with the Vysis LSI 4q12 Tricolor or immunohistochemistry for CD117 showing strong or probe and a reference probe for the X-centromere (Abbott KIT very strong staining in more than 50% of neoplastic cells. Molecular). was considered amplified if the copy num- Patients were treated with sunitinib (50 mg/d), 4 weeks on ber of the Tricolor probes exceeded the gender-corrected and 2 weeks off, with dose modifications sequentially to copy number of the reference in the majority of neoplastic 37.5 and 25 mg/d for grade III or IV toxicities. Our study cells. Allelic ratios were determined by dividing the peak enrolled patients between September 2007 and July 2010 height of the mutant allele by that of the corresponding and was approved by the Institutional Review Boards for the wild-type allele of an electropherogram trace. Immunohis- protection of human subjects at California Pacific Medical tochemistry for CD117 was carried out using a mouse Center, University of California at San Francisco (San Fran- monoclonal antibody (Dako A4502) at 1:200 dilution, cisco, CA), and the Angeles Clinic and Research Institute. visualized with the Envision system (Dako) with AEC as Clinical characteristics of the 12 patients treated with suni- a chromagen. tinib are listed in Table 1. Our original biostatistical design called for 12 evaluable Tumor responses were measured by computed tomo- patients. However, we feel our sample size of 90 screened graphic scanning every 6 weeks using Response Evaluation patients with 10 patients evaluable for response was ade- Criteria in Solid Tumors (RECIST) 1.0. Duration of quate as we saw several objective responses, and patient response (DR) was defined as the time from the first accrual was difficult due to the small patient population and KIT documentation of objective tumor response (complete or rapid deterioration of patients with mutations making partial responses) that was subsequently confirmed to the some patients with mutations ineligible for treatment. first documentation of objective tumor progression or death due to any cause. Patients were considered nonevaluable for Results response if they received less than 2 weeks of therapy with Laboratory results sunitinib. Fisher’s 2-sided exact test was used to compare We screened the tissues of 90 potentially eligible patients differences between groups, and MedCalc 11.3 software was with metastatic melanoma for mutations or amplifications

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Table 2. Number of tumors with mutations in KIT, BRAF, NRAS,orGNA by primary tumor type

Primary site N KIT, n (%) BRAF, n (%) NRAS, n (%) GNAQ (n) Wild-type (n)

Acral 22 3 (14) 7 (32) 6 (27) 0 6 Mucosal 30 5 (17) 1 (3) 2 (7) 0 22 CSDS 38 2 (5) 13 (34) 5 (13) 0 19 Totals 90 10 (11) 21 (23) 13 (14) 0 47

NOTE: Patient #45 had concurrent KIT and NRAS mutations.

of KIT, as well mutations in BRAF, NRAS, and GNAQ. Forty- found, L576P and V559, are frequent in GISTs (13). 1 KIT two (47%) of the 90 patients with melanoma analyzed mutation was found in exon 13 (E635G) in an acral harbored mutations in KIT, BRAF,orNRAS in their tumors, melanoma. as shown in Table 2. The mutations were found in a Consistent with previous reports (1), mucosal primaries mutually exclusive pattern, with the exception of 1 patient had signiﬁcantly fewer BRAF mutations than the 2 other who had coexistent KIT P577S and NRAS Q61K mutations. groups (P < 0.01). Only 1 mucosal melanoma had a BRAF 9of10KIT mutations affected exon 11, the most frequently mutation (V600K). GNAQ mutations, which are common mutated KIT exon in GISTs as well as melanomas in uveal melanomas (14, 15), were not seen in any patient in (ref. 3; Table 3). 2 patients, both with vulvar primaries, our study. NRAS mutations were more common in acral had exon 11 L576P mutations, the mutation site most than mucosal melanomas, but the difference was of bor- frequently reported in melanoma (5, 6). 2 of the mutations derline signiﬁcance (P ¼ 0.058). Overall our 14% incidence

Table 3. Characteristics and treatment responses of patients with KIT mutations and patients without KIT mutations treated with sunitinib

ID# Primary Mutation and FISHþ CD117þ KIT allelic Treated with % Response and site exon (3þ or 4þ) ratioa sunitinib response durationb

22 Acral KIT 13 E635G N/T No 2:1 No 30 Rectal KIT 11 W557G Yes Yes 1:0 Yes PR (85%) and 7 mo 34 Nasal KIT 11G565V No Yes 1:1 Yes PD 44 Scalp KIT 11 P577S and No Yes 1:1 No NRAS 2 Q61K 56 Rectal KIT 11 V559G Yes Yes 1:1 Yes Not evaluable and 8-d therapy 64 Acral KIT 11L576P No Yes 3:1 No 73 Vulva KIT 11 L576P Yes Yes 1:1 Yes CR (100%) and 15 mo 75 Vulva KIT 11L576P Yes Yes 1:0 Yes PR (40%) and 1 mo 81 Scalp KIT 11 V450D No Yes 1:1 No 82 Acral KIT 11W557R No Yes 1:1 Yes Not evaluable toxicity and G565E 6 Acral BRAF V600E Yes No N/A Yes Stable and 4 mo 24 CSDS BRAF V600E No Yes N/A Yes PD 25 Acral BRAF V600E Yes Yes N/A Yes PD 39 Oral NRAS 2 T11A Yes Yes N/A Yes PD 52 Vulva Wild-type Yes No N/A Yes PD 57 CSDS Wild-type No Yes N/A Yes PR (42%) and 1 month unconﬁrmed

NOTE: Patient 44 had a concurrent NRAS mutation Q61K and patient 75 died of cerebral hemorrhage before response conﬁrmed. Abbreviations: FISHþ, KIT ampliﬁcation; CD117 (3þ or 4þ), immunohistochemistry positive for KIT protein; N/A, not applicable; N/T, not tested; PD, progressive disease. aAllelic ratio indicates the ratio of mutant to wild-type KIT sequence from the electropherogram, a marker previously found to be predictive of response to imatinib in patients with functionally uncharacterized KIT mutations. bPercent (%) response is maximum shrinkage of target lesions.

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Table 4. Positive KIT overexpression, gene ampliﬁcation, and mutation status

N Overexpression (IHC), n (%) Ampliﬁcation (FISH), n (%) KIT mutation, n (%)

Acral 22 9 (41) 6 (27) 3 (14) Mucosal 30 10 (33) 7 (23) 5 (17) CSDS 38 7 (18) 2 (5) 2 (5) Totals 27 (31) 15 (18) 10 (11)

NOTE: Mutation status was determined on all 90 patients; IHC on 86 patients; and FISH on 82 patients. Abbreviation: IHC, immunohistochemistry.

of NRAS mutations was similar to other studies of cutane- 1 patient chose alternative therapy. Fourteen patients with ous melanoma. The NRAS mutations were found at codons KIT amplification or KIT overexpression without mutation 11 (n ¼ 1), 12 (n ¼ 5), and 61 (n ¼ 7). There were 6 NRAS were not treated with sunitinib because of clinical deterio- Q61R mutations. ration before obtaining results of KIT analysis in 2 patients The immunohistochemical assay using the CD117 anti- and physician preference for alternate therapy in 12 pati- body to assess KIT overexpression was positive in 27 of 86 ents. 1 patient, no. 82, developed congestive heart failure, patients tested (31%; Table 4). Although 8 of the 10 KIT possibly due to sunitinb, after 10 days of treatment and was mutated cases expressed high or very high levels of CD117, taken off therapy. The tolerability and toxicity of sunitinib the other 2 mutant cases were negative based on the criteria in the other 11 patients was similar to that reported in renal for positivity. Conversely, KIT protein was overexpressed in cell cancer and GISTs, with 5 of 12 patients requiring dose 25% of cases without other KIT alterations and 70% of the reductions of sunitinib. cases with KIT overexpression did not show mutations of 1 of the 2 partial responders had a rectal melanoma and KIT. The FISH analysis showed copy number increase of KIT the mutational analysis of the initial biopsy of his 3-cm in 15 of 82 patients tested (18%), 4 of which had detectable primary before treatment revealed a W557G KIT mutation KIT mutations. and no detectable mutations in NRAS or BRAF. After a partial response to sunitinib of 7-month duration, he Clinical results developed disease progression at both the primary site and Of the 90 patients screened, 30 were found to be eligible the regional lymph nodes, and mutational analysis on his for sunitinib therapy based on the molecular analyses out- primary tumor resected at that time showed, in addition to lined above, of which 12 patients initiated therapy. Ten the previously detected KIT mutation, a previously unde- of these 12 patients were evaluable for response, with tected NRAS Q61K mutation. Subsequent treatment with 1 complete response (CR), 3 partial responses (PR; 1 con- imatinib was ineffective. firmed), 1 stable disease, and 5 patients with progressive In our exploratory survival analysis, we limited the disease. All 4 responses were seen within 6 weeks of starting patient population to the 79 patients with overt unresect- sunitinib. 4 of the 10 evaluable patients were enrolled able stage IV disease, thus excluding the 11 patients with because of KIT mutation, 4 because of KIT amplification, and 2 because of KIT overexpression based on immunohistochemistry. Among the 4 evaluable patients with KIT mutations, 1 patient who had liver metastases had a complete remission for 15-month duration, 2 patients had partial remissions (1 unconfirmed), and the remaining patient had disease progression (Table 2). Figure 1 shows the complete response of liver metastases in a patient with a vulvar primary and KIT exon 11 L576P mutation. The patient with the unconfirmed response died of a cerebral hemorrhage. Of the 4 patients enrolled because of KIT amplification, 1 had stable disease for 4 months whereas the other 3 progressed without response. Of the remaining 2 patients on trial who were enrolled because of KIT overexpression by immunohistochemistry, 1 had an unconfirmed partial response of 2-month duration and the Figure 1. Patient 73 had a vulvar melanoma with KIT L576P mutation and other had progressive disease. 3 patients with KIT mutation normal positron emission tomography/computed tomographic (PET/CT) scan in 2009. In April 2010, 3 liver metastases more than 1 cm in size were not treated with sunitinib because of death from appeared on PET/CT scan. Subsequent scans showing complete melanoma or the development of multiple brain meta- response of liver metastases with sunitinib therapy until relapse in August stases whereas molecular testing was being conducted and 2011.

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Survival Table 5. Characteristics of the 79 stage IV 100 patients analyzed for survival 80 KIT KIT 60 Group Characteristics mutant wild-type KIT mutation 40 No KIT mutation Patients, n 970 20 Age, mean (range), y 74 (46–92) 64 (29–88)a 0 Male 6 (67%) 41 (59%)

Survival probability (%) 0 5 10 15 20 25 30 35 Female 3 (33%) 29 (41%) Time (mo) Primary site Number at risk Mucosal 4 (44%) 17 (24%) Group I : Acral 3 (33%) 23 (33%) 95110000 CSDS 2 (22%) 30 (43%) Group II : NRAS mutant 1 (11%) 7 (10%) 70 61 38 26 11 6 3 0 BRAF mutant 0 (0%) 20 (29%) Subsequent therapy Figure 2. Kaplan–Meier survival analysis of patients with KIT mutation Ipilimumab 0 11 (16%) versus no KIT mutation. P < 0.0001, log-rank test. Median follow-up was Anti-BRAF 0 2 (3%) 20 months. Stage MIA 1 (12%) 8 (25%) MIB 2 (25%) 12 (33%) MIC 5 (62%) 16 (44%) stage III or resected stage IV disease who were expected to have a much better prognosis. Unfortunately, we did not NOTE: Complete staging information was not available for all have the date of onset of metastatic disease as a starting date patients. Both patients who received anti-BRAF therapy also but used the available date of consent for molecular testing received ipilimumab. as the starting date for survival analysis. This analysis aMean age in KIT mutation group was significantly older than included 9 patients with KIT mutations, 20 with BRAF,7 KIT wild-type group (P ¼ 0.042; unpaired Student t test). with RAS, and 43 wild-type. Remarkably, this analysis showed a significantly worse prognosis for patients with KIT KIT mutations compared with patients without muta- 1 complete response for 15 months and 1 unconfirmed P < tions (Fig. 2; 0.0001, log-rank test). Median survival was partial response. This suggests that sunitinib has consider- KIT only 6 months for patients with mutations, compared able more activity in patients with KIT mutations than in BRAF NRAS with 13 months for , 16 months for , and 17 unselected patients with melanoma, where the response months for patients wild type for the mutations tested. This rate was only 8% (17). 2 of our responders had the L576P KIT difference remains significant even if the 1 patient with a mutation, which also appears sensitive to imatinib (11). mutation and stage III disease is included in the analysis. The few patients we treated with KIT amplification or over- KIT NRAS The single patient with mutations in both and expression based on CD117-positive staining but no had a survival of only 1 week. There was no significant KIT mutations were insufficient to give an indication wheth- BRAF difference in survival between patients with muta- er sunitinib may be useful in these patient populations. NRAS tions, mutations, or wild type. In addition, no sig- 1 weakness of our study is the lack of central pathology nificant difference was seen between patients with acral, review, particularly of CSDS cases. Our study confirms mucosal, or CSDS primaries with median survivals of 17, previous findings (5, 18) of a weak correlation of KIT KIT 10, and 13 months, respectively. However, the muta- overexpression by immunohistochemistry with KIT muta- KIT tion group was significantly older than the wild-type tions but also shows that KIT immunohistochemistry is not P ¼ group with median ages of 74 and 64 years, respectively ( sensitive or specific enough to reliably predict mutation t 0.042, unpaired Student test), and this may have influ- status. Our finding of KIT mutations in 5% of patients with enced their poor survival. Because our patients were treated CSDS is lower than the 28% originally reported by Curtin in 2009 and early 2010, few received ipilimumab or therapy and colleagues (1) but not statistically significantly higher BRAF directed against mutations (Table 5). than the recent report from Australia (ref. 19; P ¼ 0.27, Fisher’s exact test). Discussion Comparisons of sunitinib with other KIT inhibitors in the Our results confirm the previous anecdotal report of treatment of melanoma are fraught with hazard due to the clinically significant responses of patients with melanoma small number of patients that have been reported with each with KIT mutations to therapy with sunitinib (16). Unfor- agent. Carvajal and colleagues recently reported a multi- tunately, 2 of our patients received less than 2 weeks of institutional trial of imatinib therapy for patients with therapy due to toxicity or rapid progression, but of the other melanoma with KIT aberrations and observed 6 responses 4 patients with KIT mutations, 3 had responses, including (4 durable) in 25 evaluable patients (11), with 4 responses

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in 21 patients with KIT mutations. Guo and colleagues (10) appear in a mostly mutually exclusive pattern, and given observed 9 responses in 41 evaluable patients (22%) in the higher prevalence of BRAF mutations in most mela- their series. Given the modest response rate to imatinib in noma subtypes, a practical algorithm might be to first test this patient population, our observation of 3 responses in melanomas for BRAF mutations, then assess KIT status in 4 evaluable patients suggests that the activity of sunitinib patients with mucosal, acral, and CSDS melanomas that may be at least comparable with imatinib. Interestingly, did not have BRAF mutations. It has been estimated that the median age of patients in both our series and the study 1.3% of patients with melanoma in the United States. by Carvajal and colleagues was more than 70 years. While have mucosal primaries (25); if 17% have KIT mutations, BRAF mutations are more common in young patients there are less than 200 stage IV patients with KIT-mutated with melanoma, our data suggest that KIT mutations may mucosal primaries in the United States per year. Our be more prevalent in older patients. Dasatinib has also study illustrates the difficulties that beset a study of rare been reported to produce responses in a few cases. Although tumors such as KIT-mutated melanoma: although effec- some in vitro studies have favored dasatinib (20), sunitinib tive therapy may be available, it is difficult to identify may have an advantage over other KIT inhibitors given sufficient patients for a systematic study. Scenarios such its antiangiogenic activity through the inhibition of as this 1 may necessitate a new regulatory pathway for VEGFR1, VEGFR2, VEGFR3, and platelet—derived growth drug approval as even a modest sized phase II or III trial factor receptor (PDGFR). Several phase II studies have may be impossible to complete in a reasonable time shown the activity of other angiogenesis inhibitors in the frame. Most notably a multicenter International random- treatment of unselected patients with metastatic mela- ized phase III trial of nilotinib was started in this patient noma (21, 22). Although the data in GISTs suggest that population in 2010 (Clinical Trials.gov NCT01028222), sunitinib is more effective against patients with exon 9 but despite opening the trial at 83 centers, the difficulty than in exon 11 mutations, we observed responses in 2 of of finding eligible patients necessitated converting the 3 evaluable patients with exon 11 mutations. Although trial to a single-arm phase II study (Novartis, personal almost all of the patients in the study of Carvajal and communication). colleagues who responded to imatinib had a KIT allelic Our finding of responses to sunitinib in KIT-mutated ratio greater than 1, we observed 1 complete response and patients with melanoma requires confirmation in a larger 1 case of progressive disease in 2 evaluable patients with cohort. In addition, because of the poor prognosis of an allelic ratio of 1. patients with mucosal melanoma treated with conven- In 1 patient who had a partial response to therapy, the tional therapy, a prospective study of a KIT inhibitor as a clinical progression was associated with the appearance of a surgical adjuvant, given either preoperative or postopera- previously undetected mutation in the NRAS gene. This tive, appears appropriate for patients with mucosal mela- result may be due to genetic heterogeneity in the initial noma with KIT mutations. Use of KIT inhibitors, such as primary tumor, technical factors, or the development of a sunitinib, in patients with melanoma and KIT mutations secondary mutation as a consequence of therapy with represents a successful example of personalized oncology sunitinib. As this mutation is expected to lead to activation with the use of tumor mutational status to direct therapy. of the mitogen-activated protein kinase (MAPK) pathway and phosphoinositide 3-kinase (PI3K) pathway down- Disclosure of Potential Conflicts of Interest stream of KIT, it is expected to bypass any inhibition of The manuscript represents an original clinical trial. D.R. Minor and B.C. Bastian receive research support from Pfizer and B.C. Bastian is a consultant these pathways mediated by pharmacologic inhibition at for Novartis and receives honoraria from Novartis. No potential conflicts of the level of the upstream receptor KIT. A recent analysis of interest were disclosed by other authors. patients who developed resistance to the BRAF inhibitor vemurafenib (PLX4032) also found NRAS mutation as 1 Authors' Contributions mechanism of resistance to a BRAF inhibitor (23). While D.R. Minor contributed to the literature search and figures. D.R. Minor and B.C. Bastian contributed to the study design. resistance to targeted therapy in chronic myelogenous leu- D.R. Minor, B.C. Bastian, M. Kashani-Sabet, and M. Garido contributed to kemia is usually related to new mutations in the targeted the data analysis and interpretation and writing BCR-ABL gene, resistance to targeted therapy in melanoma All authors contributed to the data collection and approved the final manuscript. appears in some cases to be related to tumor cell acquisition of new mutations in other genes that contribute to tumor Acknowledgments growth. The authors thank Zeena Salman, Brenda Eng, and Dr. Steven Bunker. Our exploratory survival analysis suggests that the presence of a KIT mutation is an adverse prognostic factor for patients with melanoma; a similar observation has Grant Support This study was supported by Pfizer, Inc., New York. recently been made in a Chinese population of patients The costs of publication of this article were defrayed in part by the with melanoma (24). Because patients with KIT muta- payment of page charges. This article must therefore be hereby marked tions have a short survival, it will be important to deter- advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. mine their mutation status earlier during the course of the disease, to avoid any delays once the disease becomes Received August 25, 2011; revised December 31, 2011; accepted January 9, widely metastatic. Because KIT and BRAF mutations 2012; published OnlineFirst January 18, 2012.

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www.aacrjournals.org Clin Cancer Res; 18(5) March 1, 2012 OF7

Sunitinib Therapy for Melanoma Patients with KIT Mutations

David R. Minor, Mohammed Kashani-Sabet, Maria Garrido, et al.

Clin Cancer Res Published OnlineFirst January 18, 2012.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-11-1987

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