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Sunitinib Therapy for Melanoma Patients with KIT Mutations

Article in Clinical Cancer Research · March 2012

DOI: 10.1158/1078-0432.CCR-11-1987 · Source: PubMed

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 Clinical
Cancer
Predictive Biomarkers and Personalized Medicine Research

Sunitinib Therapy for Melanoma Patients with KIT Mutations

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); 1457–63. 2012 AACR.

Introduction sun-damaged skin (CSDS; refs. 2, 3). In gastrointestinal

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

www.aacrjournals.org 1457
 Minor et al.

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 Sex
the clinical results in 12 patients with KIT aberrations Male 9 (75)
treated with sunitinib. We report 3 novel and important Female 3 (25)
findings: first, patients with KIT 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 mutation
a secondary NRAS 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 overexpres-
sion of KIT.

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

1458 Clin Cancer Res; 18(5) March 1, 2012 Clinical Cancer Research
 Sunitinib Therapy for Melanoma with KIT Mutations

Table 2. Number of tumors with mutations in KIT, BRAF, NRAS, or GNA 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-
two (47%) of the 90 patients with melanoma analyzed
harbored mutations in KIT, BRAF, or NRAS in their tumors,
as shown in Table 2. The mutations were found in a
mutually exclusive pattern, with the exception of 1 patient
who had coexistent KIT P577S and NRAS Q61K mutations.
9 of 10 KIT mutations affected exon 11, the most frequently
mutated KIT exon in GISTs as well as melanomas
(ref. 3; Table 3). 2 patients, both with vulvar primaries,
had exon 11 L576P mutations, the mutation site most
frequently reported in melanoma (5, 6). 2 of the mutations
found, L576P and V559, are frequent in GISTs (13). 1 KIT
mutation was found in exon 13 (E635G) in an acral
melanoma.
Consistent with previous reports (1), mucosal primaries
had significantly fewer BRAF mutations than the 2 other
groups (P < 0.01). Only 1 mucosal melanoma had a BRAF
mutation (V600K). GNAQ mutations, which are common
in uveal melanomas (14, 15), were not seen in any patient in
our study. NRAS mutations were more common in acral
than mucosal melanomas, but the difference was of bor-
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.
a
Allelic 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.
b
Percent (%) response is maximum shrinkage of target lesions.

www.aacrjournals.org Clin Cancer Res; 18(5) March 1, 2012 1459

 Minor et al.
Table 4. Positive KIT overexpression, gene amplification, and mutation status
N Overexpression (IHC), n (%)
Acral 22 9 (41)
Mucosal 30 10 (33)
CSDS 38 7 (18)
Totals 27 (31)
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-
ous melanoma. The NRAS mutations were found at codons
11 (n ¼ 1), 12 (n ¼ 5), and 61 (n ¼ 7). There were 6 NRAS
Q61R mutations.
The immunohistochemical assay using the CD117 anti-
body to assess KIT overexpression was positive in 27 of 86
patients tested (31%; Table 4). Although 8 of the 10 KIT
mutated cases expressed high or very high levels of CD117,
the other 2 mutant cases were negative based on the criteria
for positivity. Conversely, KIT protein was overexpressed in
25% of cases without other KIT alterations and 70% of the
cases with KIT overexpression did not show mutations of
KIT. The FISH analysis showed copy number increase of KIT
in 15 of 82 patients tested (18%), 4 of which had detectable
KIT mutations.
Clinical results
Of the 90 patients screened, 30 were found to be eligible
for sunitinib therapy based on the molecular analyses out-
lined above, of which 12 patients initiated therapy. Ten
of these 12 patients were evaluable for response, with
1 complete response (CR), 3 partial responses (PR; 1 con-
firmed), 1 stable disease, and 5 patients with progressive
disease. All 4 responses were seen within 6 weeks of starting
sunitinib. 4 of the 10 evaluable patients were enrolled
because of KIT mutation, 4 because of KIT amplification,
and 2 because of KIT overexpression based on immuno-
histochemistry. Among the 4 evaluable patients with KIT
mutations, 1 patient who had liver metastases had a com-
plete 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 over-
expression by immunohistochemistry, 1 had an uncon-
firmed partial response of 2-month duration and the
other had progressive disease. 3 patients with KIT mutation
were not treated with sunitinib because of death from
melanoma or the development of multiple brain meta-
stases whereas molecular testing was being conducted and
1460 Clin Cancer Res; 18(5) March 1, 2012
Amplification (FISH), n (%) KIT mutation, n (%)
6 (27) 3 (14)
7 (23) 5 (17)
2 (5) 2 (5)
15 (18) 10 (11)
1 patient chose alternative therapy. Fourteen patients with
KIT amplification or KIT overexpression without mutation
were not treated with sunitinib because of clinical deterio-
ration before obtaining results of KIT analysis in 2 patients
and physician preference for alternate therapy in 12 pati-
ents. 1 patient, no. 82, developed congestive heart failure,
possibly due to sunitinb, after 10 days of treatment and was
taken off therapy. The tolerability and toxicity of sunitinib
in the other 11 patients was similar to that reported in renal
cell cancer and GISTs, with 5 of 12 patients requiring dose
reductions of sunitinib.
1 of the 2 partial responders had a rectal melanoma and
the mutational analysis of the initial biopsy of his 3-cm
primary before treatment revealed a W557G KIT mutation
and no detectable mutations in NRAS or BRAF. After a
partial response to sunitinib of 7-month duration, he
developed disease progression at both the primary site and
the regional lymph nodes, and mutational analysis on his
primary tumor resected at that time showed, in addition to
the previously detected KIT mutation, a previously unde-
tected NRAS Q61K mutation. Subsequent treatment with
imatinib was ineffective.
In our exploratory survival analysis, we limited the
patient population to the 79 patients with overt unresect-
able stage IV disease, thus excluding the 11 patients with
Figure 1. Patient 73 had a vulvar melanoma with KIT L576P mutation and
normal positron emission tomography/computed tomographic (PET/CT)
scan in 2009. In April 2010, 3 liver metastases more than 1 cm in size
appeared on PET/CT scan. Subsequent scans showing complete
response of liver metastases with sunitinib therapy until relapse in August
2011.
Clinical Cancer Research
 Sunitinib Therapy for Melanoma with KIT Mutations

Survival Table 5. Characteristics of the 79 stage IV

Survival probability (%)

100 patients analyzed for survival

80
60 Group Characteristics KIT mutant KIT wild-type
KIT mutation
40 No KIT mutation Patients, n 9 70
20 Age, mean (range), y 74 (46–92) 64 (29–88)a
0 Male 6 (67%) 41 (59%)
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%)
9 5 1 1 0 0 0 0 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 a
Mean 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 mutations compared with patients without KIT muta- 1 complete response for 15 months and 1 unconfirmed
tions (Fig. 2; P < 0.0001, log-rank test). Median survival was partial response. This suggests that sunitinib has consider-
only 6 months for patients with KIT mutations, compared able more activity in patients with KIT mutations than in
with 13 months for BRAF, 16 months for NRAS, 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
difference remains significant even if the 1 patient with a KIT 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-
The single patient with mutations in both KIT and NRAS 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-
difference in survival between patients with BRAF muta- er sunitinib may be useful in these patient populations.
tions, NRAS 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
10, and 13 months, respectively. However, the KIT muta- overexpression by immunohistochemistry with KIT muta-
tion group was significantly older than the KIT wild-type tions but also shows that KIT immunohistochemistry is not
group with median ages of 74 and 64 years, respectively (P ¼ sensitive or specific enough to reliably predict mutation
0.042, unpaired Student t 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
directed against BRAF 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

www.aacrjournals.org Clin Cancer Res; 18(5) March 1, 2012 1461

 Minor et al.
in 21 patients with KIT mutations. Guo and colleagues (10)
observed 9 responses in 41 evaluable patients (22%) in
their series. Given the modest response rate to imatinib in
this patient population, our observation of 3 responses in
4 evaluable patients suggests that the activity of sunitinib
may be at least comparable with imatinib. Interestingly,
the median age of patients in both our series and the study
by Carvajal and colleagues was more than 70 years. While
BRAF mutations are more common in young patients
with melanoma, our data suggest that KIT mutations may
be more prevalent in older patients. Dasatinib has also
been reported to produce responses in a few cases. Although
some in vitro studies have favored dasatinib (20), sunitinib
may have an advantage over other KIT inhibitors given
its antiangiogenic activity through the inhibition of
VEGFR1, VEGFR2, VEGFR3, and platelet—derived growth
factor receptor (PDGFR). Several phase II studies have
shown the activity of other angiogenesis inhibitors in the
treatment of unselected patients with metastatic mela-
noma (21, 22). Although the data in GISTs suggest that
sunitinib is more effective against patients with exon 9
than in exon 11 mutations, we observed responses in 2 of
3 evaluable patients with exon 11 mutations. Although
almost all of the patients in the study of Carvajal and
colleagues who responded to imatinib had a KIT allelic
ratio greater than 1, we observed 1 complete response and
1 case of progressive disease in 2 evaluable patients with
an allelic ratio of 1.
In 1 patient who had a partial response to therapy, the
clinical progression was associated with the appearance of a
previously undetected mutation in the NRAS gene. This
result may be due to genetic heterogeneity in the initial
primary tumor, technical factors, or the development of a
secondary mutation as a consequence of therapy with
sunitinib. As this mutation is expected to lead to activation
of the mitogen-activated protein kinase (MAPK) pathway
and phosphoinositide 3-kinase (PI3K) pathway down-
stream of KIT, it is expected to bypass any inhibition of
these pathways mediated by pharmacologic inhibition at
the level of the upstream receptor KIT. A recent analysis of
patients who developed resistance to the BRAF inhibitor
vemurafenib (PLX4032) also found NRAS mutation as 1
mechanism of resistance to a BRAF inhibitor (23). While
resistance to targeted therapy in chronic myelogenous leu-
kemia is usually related to new mutations in the targeted
BCR-ABL gene, resistance to targeted therapy in melanoma
appears in some cases to be related to tumor cell acquisition
of new mutations in other genes that contribute to tumor
growth.
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
recently been made in a Chinese population of patients
with melanoma (24). Because patients with KIT muta-
tions have a short survival, it will be important to deter-
mine their mutation status earlier during the course of the
disease, to avoid any delays once the disease becomes
widely metastatic. Because KIT and BRAF mutations
1462 Clin Cancer Res; 18(5) March 1, 2012
appear in a mostly mutually exclusive pattern, and given
the higher prevalence of BRAF mutations in most mela-
noma subtypes, a practical algorithm might be to first test
melanomas for BRAF mutations, then assess KIT status in
patients with mucosal, acral, and CSDS melanomas that
did not have BRAF mutations. It has been estimated that
1.3% of patients with melanoma in the United States.
have mucosal primaries (25); if 17% have KIT mutations,
there are less than 200 stage IV patients with KIT-mutated
mucosal primaries in the United States per year. Our
study illustrates the difficulties that beset a study of rare
tumors such as KIT-mutated melanoma: although effec-
tive therapy may be available, it is difficult to identify
sufficient patients for a systematic study. Scenarios such
as this 1 may necessitate a new regulatory pathway for
drug approval as even a modest sized phase II or III trial
may be impossible to complete in a reasonable time
frame. Most notably a multicenter International random-
ized phase III trial of nilotinib was started in this patient
population in 2010 (Clinical Trials.gov NCT01028222),
but despite opening the trial at 83 centers, the difficulty
of finding eligible patients necessitated converting the
trial to a single-arm phase II study (Novartis, personal
communication).
Our finding of responses to sunitinib in KIT-mutated
patients with melanoma requires confirmation in a larger
cohort. In addition, because of the poor prognosis of
patients with mucosal melanoma treated with conven-
tional therapy, a prospective study of a KIT inhibitor as a
surgical adjuvant, given either preoperative or postopera-
tive, appears appropriate for patients with mucosal mela-
noma with KIT mutations. Use of KIT inhibitors, such as
sunitinib, in patients with melanoma and KIT mutations
represents a successful example of personalized oncology
with the use of tumor mutational status to direct therapy.
Disclosure of Potential Conflicts of Interest
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
for Novartis and receives honoraria from Novartis. No potential conflicts of
interest were disclosed by other authors.
Authors' Contributions
D.R. Minor contributed to the literature search and figures.
D.R. Minor and B.C. Bastian contributed to the study design.
D.R. Minor, B.C. Bastian, M. Kashani-Sabet, and M. Garido contributed to
the data analysis and interpretation and writing
All authors contributed to the data collection and approved the final
manuscript.
Acknowledgments
The authors thank Zeena Salman, Brenda Eng, and Dr. Steven Bunker.
Grant Support
This study was supported by Pfizer, Inc., New York.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received August 25, 2011; revised December 31, 2011; accepted January 9,
2012; published OnlineFirst January 18, 2012.
Clinical Cancer Research

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