Annual Meeting Proceedings Part 1 - American Society of Clinical ...

8520 Poster Discussion Session (Board #9), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Clinical significance of genomic alterations of the CDK4-pathway and
sensitivity to the CDK4 inhibitor PD 0332991 in melanoma. Presenting
Author: Grant A. McArthur, Department of Medical Oncology, Peter
MacCallum Cancer Centre, Melbourne, Australia
Background: Activation of CDK4 by amplification, increased expression of
Cyclin D1 (CCND1) or reduced expression of the CDK inhibitor p16
(CDKN2A) can contribute to transformation of melanocytes indicating that
CDK4 can act as an oncogene in melanoma.To explore if CDK4 may be a
viable target for the treatment of human melanoma we have analyzed the
frequency and clinico-pathological associations of genomic alterations of
the CDK4 pathway in primary human melanoma and examined the genomic
predictors of sensitivity to the highly selective CDK4/6 inhibitor PD
0332991 (991) in a panel of melanoma cell lines. Methods: A series of 167
primary melanomas with clinical, molecular and pathological annotation,
including median follow up of 6.6 years, were analyzed for copy number
variation (CNV)- gain of CDK4 or CCND1 (average gene copy �2.4) or loss
of CDKN2A (average gene copy �1.4), by fluorescence in situ hybridization.
A panel of 39 cell lines were treated with 991 in vitro and GI50s
calculated. The mean GI50 of the melanoma cell lines was used to define
sensitivity. Gene expression profiling and mutation or CNV in CDKN2A were
used to identify predictors of sensitivity. Results: 75% of primary melanomas
had at least one CNV (75%, 70% and 82% for BRAF, NRAS or
wild-type BRAF/NRAS mutation status respectively). 55% showed loss of
CDKN2A. 28% of melanomas had two or more CNVs. Melanomas with two
or more CNVs involving CCND1 had worse overall survival (HR 5.56,
p�0.02). Low CDKN2A mRNA expression or mutation or loss of CDKN2A
predicted sensitivity to 991 with 30/33 mutant/loss lines being sensitive
compared to only 2/6 wild type lines (p�0.006). Expression of CDK4,
CCND1 or other cyclins or CDK-inhibitors did not predict sensitivity to 991.
Conclusions: Genomic alterations in the CDK4 pathway are frequent in
melanoma and are associated with worse survival, particularly when
melanomas harbor two or more CNVs involving CCND1. Mutation, loss or
low expression of CDKN2A in melanoma cell lines predicted sensitivity to
the CDK4 inhibitor 991. Taken together these data support evaluation of
CDK4 inhibitors in melanoma and suggest that CDKN2A maybe a genomic
predictor of sensitivity to these agents.
8522 Poster Discussion Session (Board #11), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase II trial of dasatinib in patients with unresectable locally advanced
or stage IV mucosal, acral, and solar melanomas: An Eastern Cooperative
Oncology Group study (E2607). Presenting Author: Kevin Kalinsky, Columbia
University Medical Center, New York, NY
Background: Pre-clinical studies report a critical role of c-KIT mutations in
mucosal, acral, and solar melanomas. Clinical trials of KIT-directed therapy
with imatinib and sunitinib demonstrate activity in these subtypes. Unlike
other TKIs, dasatinib inhibitory activity is seen in melanoma cell lines with
the most common KIT mutation at exon 11L576P. E2607 tests the
efficacy of dasatinib in treatment-naïve or previously treated patients (pts)
with these unresectable subtypes. Methods: Pts receive dasatinib 70 mg PO
twice daily for this two-stage phase II trial. The primary objective is
response rate (RR: RECIST). Stage I was open to KIT mutated (KIT�) and
wild-type (KIT-) tumors with these subtypes (n�56). Depending upon the
interim analysis, stage II would pre-select for KIT�. If the overall response
rate were � 5%, the study would be terminated. Secondary objectives
include progression-free survival (PFS), overall survival (OS), safety, and
KIT mutation status. Results: Between May 2009-Dec 2010, 57 pts have
been accrued to stage I. Of 54 (2 no therapy, 1 ineligible), 26 have mucosal
(48%), 13 acral (24%), and 15 solar melanomas (28%). As of Jan 2012,
the median f/u is 15 months (mo, range: 4-24 mo). Best responses (n�52)
are 1 complete (CR: 2%), 3 partial (PR: 6%), 13 stable disease (25%), 29
progression (56%), and 6 unevaluable (11%). 51/52 have progressed
(median PFS: 1.9 mo, 95% CI: 1.5-2.8) and 40/54 died (median OS: 7.4
mo, 5.7-10.8). KIT status has been assessed in 42 pts: 39 KIT- (93%) and
3 KIT� (7%). PR is seen in 1/39 KIT-. All KIT- have died: median PFS (1.8
mo, 95% CI: 1.4-2.9) and OS (6.8 mo, 95% CI: 5.2-10.8). Of the 3 KIT�
(1 acral, 2 mucosal), 2 have died (PFS 1.4-2.5 mo, OS: 1.4-10.5 mo), and
1 refused f/u (OS: 13.3� mo). The pt with a CR is alive at 14.4� mo
(unknown KIT status). Toxicities include 1 grade IV (elevated lipase) and
grade III dyspnea (n�7), nausea (n�6), and vomiting (n�3). Conclusions:
Further evaluation of dasatinib should be pursued in pts selected for KIT�
and subtype, given the lack of promising results in Kit-(�5% RR). The
current trial is revised to enroll only KIT� acral, mucosal, and vulvovaginal
melanomas and available via CTSU.
Melanoma/Skin Cancers
545s
8521 Poster Discussion Session (Board #10), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
SWOG S0826: A phase II trial of SCH 727965 (NSC 747135) in patients
with stage IV melanoma. Presenting Author: Christopher D. Lao, University
of Michigan, Ann Arbor, MI
Background: Cyclin-dependent kinases (cdks) function to regulate cell cycle
control and agents that can target cdks in malignant progression remain
viable therapeutic strategies. Selective inhibition of cdk2, in particular,
may be of therapeutic value in a subset of patients with melanoma.
Methods: 60 patients with metastatic melanoma of cutaneous or mucosal
origin were planned to be recruited to a multicenter, single-arm phase II
trial of the cdk inhibitor, SCH 727965 (NSC747135). Patients were
potentially eligible if they had 0-1 previous treatments, PS of 0-1, and
adequate organ function. Ocular melanoma patients and patients with a
history of brain metastases were excluded. SCH 727965 50 mg IV every 3
weeks was given until progression with disease assessment occurring every
2 cycles. Co-primary endpoints were 1-year overall survival (OS) and
6-month progression free survival (PFS). Results: 72 patients were enrolled
from July 1, 2009 to November 1, 2010 at 24 institutions. 68% of
patients had M1c disease and 43% had LDH elevation. 19% had prior
therapy for metastatic disease. 28 patients (39%) experienced Grade 4
adverse events, including 20 cases of neutropenia, one case each of
cardiac ischemia/infarction, cardiac troponin I elevation, dehydration,
abdominal pain, leukopenia, muscle weakness, headache, syncope, and
anterior ischemic optic neuropathy. 65 patients are currently evaluable for
response. The response rate was 0/65 (95% C.I. (0-6%)). Stable disease
was observed in 22%. The estimated median PFS was 1.5 months (95%
CI: 1.4 – 1.5); 6-month PFS was 11% (5-20%). Median OS was 8 months
(95% CI: 5-11 months); 1-year OS was 36% (95% CI: 24-48%). The null
hypothesis of 1-year overall survival�25% was rejected (p�0.04) but
6-month PFS�11% was not (p�0.8). Data Analysis will be updated when
missing data are received. Correlative studies of Rb phosphorylation and
cyclin expression will be pursued. Conclusions: SCH 727965 appears to be
reasonably well tolerated although grade 4 events were relatively common,
particularly near the time of infusion. There were no responses but few
patients had prolonged disease stabilization that may have resulted in
improvement in the 1-year OS rate.
8523 Poster Discussion Session (Board #12), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A Cancer Research UK two-stage multicenter phase II study of imatinib in
the treatment of patients with c-kit positive metastatic uveal melanoma
(ITEM). Presenting Author: Paul D. Nathan, Mount Vernon Cancer Centre,
Middlesex, United Kingdom
Background: The median overall survival (OS) for metastatic uveal melanoma
is less than 6 months with a median progression free survival(PFS) of
3 months. No systemic or regional therapy has shown a survival advantage
over best supportive care. Despite pre-clinical evidence suggesting antitumour
activity for the KIT tyrosine kinase inhibitor imatinib, there are
several negative phase II trials in unselected patients. Our primary aim was
to test the efficacy of imatinib in patients with prospectively-tested c-kit
immunopositive metastatic uveal melanoma. Secondary aims included
assessment of toxicity and patient recruitment. Methods: A phase II UK
multicentre single-arm, two-stage Gehan design recruited 25 evaluable
patients receiving imatinib 400mg OD until progression/unacceptable
toxicity. Primary efficacy outcome was PFS at 3 months. Secondary
outcomes were OS, overall PFS, disease response (RECIST) and toxicity.
Prospective sample collection for putative biomarkers was included.
Results: After 16.6 months 37 patients were screened, with 25 were
registered and included in final efficacy analyses. The sample included PS
0-1 patients with a median age of 63 yrs and a median 9.3 months from
diagnosis of metastatic disease. 82% had high LDH levels (�460IU/L),
65% had no previous treatment for metastatic disease and 8% did not have
liver involvement by metastasis. Preliminary final results indicate the
estimated proportion of patients progression free at 3 months is 0.24 (95%
CI, 0.09 to 0.45). Median PFS and OS were 12.0 weeks (95% CI,11.6 to
14.3) and 29.6 weeks (95% CI, 19.3 to 61.0) respectively. Two patients
had confirmed PR with response duration of 93 and 112 weeks, respectively,
despite the absence of mutations in exons 11, 13, and 17 of the
c-KIT gene. Conclusions: The trial successfully recruited to target in this
rare disease area failing to convincingly show improved PFS in a selected
cohort of c-kit immunopositive patients. Both patients with PR experienced
long periods of disease control. Response was not dependent upon the
presence of activating mutations in KIT. Further translational studies are
ongoing to determine putative biomarkers of response.
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