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

556s Melanoma/Skin Cancers
8564 General Poster Session (Board #34F), Sun, 8:00 AM-12:00 PM
High-risk uveal melanoma: A prospective study evaluating the role of
magnetic resonance imaging of the liver. Presenting Author: Ernie Marshall,
Clatterbridge Centre for Oncology, Wirral, United Kingdom
Background: Almost 50% of uveal melanomas are fatal. Metastatic death
occurs almost exclusively with tumours showing chromosome 3 loss and 8q
gain. Metastases, which almost always involve the liver, are resectable in
some patients. They are rarely detectable when the patient presents with
the primary ocular tumour. Screening is therefore necessary, but there is no
consensus as to who should be screened, how often, and for how long.
Methods: Uveal melanoma patients with ECOG performance status 0-2
were eligible if their risk of metastatic death at 5 years exceeded 50%.
Survival probability was estimated by multivariate analysis of tumour stage,
histological grade and genetic tumour type. Patients underwent screening
6monthly, clinical examination, non-contrast liver MRI and liver function
tests for at least five years. Results: Between Jan 2000 and November
2010, 279 high-risk patients were referred for screening. Of these, 188
(84 male, 104 female) accepted screening and underwent as least 1 MRI.
The median age was 63 years (IQR 16.5). Median basal tumour diameter
was 16.5mm (IQR 5.25). Chromosome 3 loss was detected in 175
tumours. Median follow up time was 28.8 months (IQR 29.1). Median
relapse-free survival was 33 months (95% CI 28-38) with a 35%
relapse-free survival at 5 years. After a median of 18 months (IQR 20),
screening detected metastases in 90/188 (48%), 83 of whom were
asymptomatic. 12 patients underwent R0 liver resection, which increased
the median survival from 10 (95% CI 8.1 - 11.9) to 24 (95% CI 20.2-
27.8) months. The screening programme stimulated a UK NCRI portfolio of
clinical trials in which 23 of these patients were subsequently treated.
Conclusions: Six-monthly liver MRI detects metastases from uveal melanoma
at an early stage, thereby enhancing opportunities for surgical
metastatectomy, clinical trial participation and prolonging life.
8566 General Poster Session (Board #34H), Sun, 8:00 AM-12:00 PM
Biomarker for benefit from ipilimumab: Correlation of breadth of humoral
tumor-antigen-specific immunity with outcome. Presenting Author: Sarah
Ellis, University Hospital Southampton NHS Foundation Trust, Southampton,
United Kingdom
Background: Checkpoint blockade through CTLA4 with ipilimumab has for
the first time improved survival in patients with advanced melanoma.
Immune-mediated toxicity and increase in humoral and T-cell anti-NY-
ESO-1 immune responses after treatment are both linked with benefit.
However there is currently no broadly relevant, immunological biomarker
for predicting outcome prior to initiation of therapy. Methods: Using a novel
immunological assay developed by Serametrix Corporation we analysed the
presence of antibodies to a proprietary panel of tumour associated antigens
(TAAs) in 34 patients with advanced melanoma, given ipilimumab at
3mg/kg as second or subsequent line of treatment. Results: 34 patients
were consented and analysed, 22 females, 13 males. With a median age of
63 years median overall survival was 24 weeks; 6/34 patients had an
objective response to ipilimumab (17.6%, median survival not reached).
Antibody (AB) responses were tested against the panel of 26 TAAs. This
panel includes BRAF, Cancer/Testis and other described or novel TAAs. We
observed a wide range in the incidence and levels of antibody response. 12
patients had no detectable immunity, 6 an AB response to a single antigen,
5 AB response to 2, and 11 patients to 3 or more TAA. Five patients had
either pre-existing anti-BRAF antibodies or developed these after CTLA4blockade.
Survival was significantly longer in those patients with preexisting
antibodies to 2 or more TAA, compared to those with 0 or 1
specificities (median survival 39.4 vs 16.4 weeks p�0.02). Conclusions:
Patients with advanced melanoma had variable levels of humoral immunity
to a large number of TAA, including to BRAF. The presence of antibody
response to 2 or more TAA correlated with longer survival following
treatment with ipilimumab and appears to provide a biomarker for identifying
those patients that are most likely to respond to checkpoint blockade
with ipilimumab.
8565 General Poster Session (Board #34G), Sun, 8:00 AM-12:00 PM
MicroRNA alterations associated with BRAF status in melanoma. Presenting
Author: Michelle W. Ma, New York University School of Medicine, New
York, NY
Background: We hypothesize that BRAF mutations result in microRNA
(miRNA) alterations which contribute to orchestrating the mutant BRAF’s
oncogenic effects in melanoma. Our study is the first to examine the
association between the BRAF mutation status in primary melanomas and
the expression of miRNAs that target known tumor suppressors. Methods:
84 prospectively accrued melanoma patients at New York University
Langone Medical Center were studied. DNA and total RNA were extracted
from consecutive sections of formalin-fixed paraffin-embedded primary
tissues. BRAF mutation status was determined by DNA sequencing. RNA
was hybridized to miRCURY miRNA microarrays containing 1314 probes.
Normalized miRNA data were analyzed using the t-test (p�0.05) to
identify differentially expressed miRNAs between BRAFmut vs. BRAFwt
cases. Those with an average fold change (FC) � 2 were selected for
predicted (TargetScan, PicTar) and validated (miRWalk) gene target
analysis, and overlapping genes targeted by � 2 miRNAs were analyzed
using pathway-mapping algorithms (KEGG, BioCarta, PANTHER). Results:
48 (57%) primaries were BRAFwt and 36 (43%) were BRAFmut (26
V600E, 4 V600K, 1 V600R, 1 V600D, 4 other). 30 miRNAs met the
criteria for statistically significant differential expression and FC thresholding:
let-7i, miR-23c, -26a/b, -27b, -34a, -98, -126*, -141, -148a, -181b,
-195, -199a-3p, -199a/b-5p, -200a/b/c, -203, -205, -455-3p, -491-3p,
-606, -641, -646, -1297, -4301; miRPlus-C1070, -C1110, -G1246-3p
(average FC: 2.3-3.5, all increased in BRAFmut vs. BRAFwt). Predicted
and validated target gene analysis revealed 317 genes, of which 110 (35%)
were convergent targets of � 2 miRNAs. Pathway analyses of the predicted,
validated, and convergent target genes pointed to the potential impact of
BRAFmut-associated miRNAs on known tumor suppressors FAS, PTEN,
and TNF and the p53 pathway. Conclusions: Differentially expressed
miRNAs in BRAFmut vs. BRAFwt primaries target genes with known roles
in melanoma biology and/or treatment response. These miRNAs warrant
further study as potential effectors of the BRAFmut oncogenic program.
8567 General Poster Session (Board #35A), Sun, 8:00 AM-12:00 PM
A single-arm, open-label, U.S. expanded access study of vemurafenib in
patients with metastatic melanoma. Presenting Author: Lynn Mara Schuchter,
University of Pennsylvania, Philadelphia, PA
Background: Vemurafenib (vem) has been FDA approved for the treatment
of unresectable or metastatic BRAFV600E mutated melanoma since August
2011 based on results of a randomized phase III study (treatment-naive)
and a single arm phase II study (previously treated). We report results of an
expanded access study that allowed appropriate patients (pts) to receive
vem until the drug was approved. Methods: Eligible pts had metastatic
melanoma with a BRAFV600E mutation as detected by the cobas 4800
BRAF V600
Mutation Test. Enrolled pts received oral vem 960 mg b.i.d.
Adverse events (AEs) were evaluated for vem-related toxicities; tumor
responses were assessed using RECIST 1.1. Results: 29 US sites screened
745 pts and enrolled 374 from December 2010 until October 2011. The
following results are based on a median follow up time and treatment
duration of 2 months. At baseline, mean age of pts was 54 y with 22% of
pts �65 y; 75% had stage M1c disease; 29% had received radiotherapy for
brain metastases. 19% of pts were ECOG PS 2 or 3; 71% of pts had prior
systemic therapy for metastatic melanoma (21% 1 regimen; 50% �2
regimens). 50 pts had prior adjuvant treatment. At data cut-off, 243 pts
had sufficient follow-up time for tumor assessment. In this group, the
unconfirmed overall response rate was 52% (95% CI, 46 to 59). The
median time to response was 1.8 months. Based on 240 pts with available
ECOG PS status at time of analysis, response rate was 53% for pts with
ECOG PS 0 or 1 (n�209), and 45% for pts with ECOG PS 2 or 3 (n�31).
370 pts were evaluable for safety analysis. The most common vem-related
AEs were rash (36%), arthralgia (33%) and fatigue (21%) with the majority
(~90%) of grade 1 or 2. 25 vem-related serious AEs were reported in 5.4%
of pts with a slightly higher rate of pts with ECOG PS 2 or 3 (8.7%)
compared to ECOG PS 0 or 1 (4.7%). 18% of pts missed at least one dose
and 11% of pts required dose reduction of at least one level due to AEs.
Conclusions: This expanded access study, with its limited follow-up time,
confirms the established rapid and high tumor response rate with vem. No
new safety signals were detected. Compared to the overall population, pts
with an ECOG PS 2 or 3 demonstrated a similar benefit.
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