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

8592 General Poster Session (Board #38B), Sun, 8:00 AM-12:00 PM
Molecular profiling and comparative genomic hybridization analysis in
human melanoma cell lines and identification of BRAF amplification in a
PLX4032 acquired resistance cell line. Presenting Author: Erika Maria Von
Euw, University of California, Los Angeles School of Medicine/Translational
Oncology Research Laboratory, Los Angeles, CA
Background: Melanoma is the most aggressive form of skin cancer. Its
management is evolving rapidly due to an improved understanding of the
molecular heterogeneity and the development of effective, personalized
targeted therapies. PLX4032 is a BRAF inhibitor that induces tumor
response in patients with BRAF mutation whose response is limited due to
acquired resistance. We used comprehensive microarray and genomic
analysis to molecularly characterize a panel of melanoma cell lines with the
goal of identifying new molecular subgroups. To better understand the
mechanisms of acquired resistance to PLX4032, we included two cell lines
that were conditioned in vitro to acquire resistance. Methods: Using
microarray, we studied 52 melanoma cell lines for mRNA expression and
performed array CGH using genome microarrays. Data analysis was done
using Rosetta Resolver and Agilent Analytics 4.0 software. Results: Microarray
analysis suggests melanoma is comprised of at least two distinct
molecular groups. One group has a differentiated melanocyte phenotype
and the other has an expression signature characteristic of progenitor-like
cells. The progenitor-like group expresses SOX9, WNT5A and WNT5B and
also has the lowest relative expression of MITF. The most differentiated
group had the highest MITF and SOX5 levels, while the progenitor-like cell
lines have decreased expression. MITF appears to be a strong candidate
marker for this group. Positive correlation exists between MITF expression
levels and gene copy number, as almost all of the MITF samples amplified
by CHG analysis are also overexpressed. A third group shows strong
expression of SOX5, SOX10 and Nestin. One of the most important findings
is M14-R cell line, conditioned to acquire PLX4032 resistance, has a focal,
high level amplification of BRAF (Log2 ratio � 3, 8-fold amplification)
when compared with the parental cell line, which is extremely sensitive to
PLX4032. Conclusions: These results afford new insight into the potential
pathogenesis and classification and provide a greater understanding of
melanoma. BRAF amplification could be a novel mechanism of resistance
to PLX4032.
8594 General Poster Session (Board #38D), Sun, 8:00 AM-12:00 PM
A phase IB study of lenvatinib (E7080) in combination with temozolomide
for treatment of advanced melanoma. Presenting Author: David S. Hong,
University of Texas M. D. Anderson Cancer Center, Houston, TX
Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting
VEGFR1-3, FGFR1-4, RET, KIT and PDGFR�. In phase I studies of
lenvatinib partial responses were observed in melanoma as well as thyroid,
endometrial, and renal cancers. Methods: Patients (pts) with stage 4 or
unresectable stage 3 melanoma were treated in sequential cohorts of
escalating doses of lenvatinib by continuous once daily dosing and
temozolomide (TMZ) days 1-5 every 28 days. Cohort 1: lenvatinib 20mg,
TMZ 100 mg; cohort 2: lenvatinib 24 mg, TMZ 100 mg; cohort 3:
lenvatinib 24 mg, TMZ 150 mg. Adverse events were recorded according to
CTCAE v3.0 and tumor response assessed according to RECIST 1.0.
Results: 32 pts were treated: cohort 1: 6 pts, cohort 2: 4 pts, cohort 3: 22
pts. Demographics: median age: 58; males: 63%. Dose limiting toxicities
occurred in 0/6 pts in cohort 3 leading to cohort expansion to a total of 22
pts to enable more extensive assessment of toxicity and a preliminary
estimate of efficacy. The most common treatment related adverse events in
the cohort 3 were fatigue: 50% (gr3: 9%), hypertension: 50% (gr3: 9%),
proteinuria: 50% (no gr3), vomiting: 46% (no gr3), hypothyroidism: 46%
(no gr3), anorexia: 41% (no gr3), nausea: 41% (no gr3), diarrhea: 36%
(gr3: 5%), thrombocytopenia: 32% (no gr3). No treatment-related gr4
events were reported in these categories. The best overall responses per
RECIST were partial responses: 5/22 (23%) for cohort 3 pts and 6/32
(19%) for all pts treated at all dose levels. Six-month progression free
survival (PFS) rate was 37% and median PFS was 5.4 months. PK/PD
analysis and correlation of response with genetic mutational status (BRAF
mutations in 31% pts; NRAS mutations in 19% pts) will be presented.
Conclusions: Lenvatinib 24 mg once daily in combination with TMZ 150 mg
days1-5 every 28 days was given without apparent worsening of either
lenvatinib or TMZ related toxicities. Modest clinical efficacy for this
combination was observed.
Melanoma/Skin Cancers
563s
8593 General Poster Session (Board #38C), Sun, 8:00 AM-12:00 PM
Gene expression profiling of whole blood in ipilimumab-treated patients for
identification of potential biomarkers of immune-mediate gastrointestinal
adverse events. Presenting Author: Vafa Shahabi, Bristol-Myers Squibb,
Princeton, NJ
Background: Treatment with ipilimumab, a fully human anti-CTLA-4
antibody approved for treatment of metastatic melanoma (MM), is associated
with a number of immune-mediated Adverse Events (imAEs) such as
colitis and skin rash. Predictive biomarkers that can help identify patients
(pts) who might experience these imAEs could enhance the management of
these toxicities. Methods: Gene expression profiling (using Affymetrix gene
chip HT-HG-U133A) was performed on the whole blood samples from 162
MM pts at baseline, 3 and 11 weeks after the start of ipilimumab treatment
in two phase II clinical trials (CA184004 and -007). Overall, 49 pts
experienced Grade 2 or higher GI-imAE (G2�) during the course of
treatment. A repeated measures ANOVA was used to evaluate the differences
in mean expression levels between the two groups and at the three
time points. Uncorrected p-value of 0.05 was used as a cutoff for this
analysis. Results: In baseline samples, 27 probe sets showed differential
mean expression (� 1.5 fold, p � 0.05) between G2� pts and others. Most
of these genes belonged to three functional categories: immune system,
cell cycle or intracellular trafficking. Changes in gene expression over time
were also characterized. In the G2� pts, 58 and 247 genes had a � 1.5
fold (p � 0.05) change in expression from baseline to week 3 and 11
post-treatment, respectively, compared to 17 and 73 in other pts. In
particular, the on-treatment increases of the expression of CD177 and
CEACAM1, two neutrophil activation markers, were closely associated with
G2� GI-imAE, suggesting a possible role of neutrophils in ipilimumab
associated GI-imAEs. In addition, the expression of several Ig genes
increased over time, with higher increases in the G2� pts. These observations
were reproduced in another ipilimumab monotherapy study in MM
(CA184078). Conclusions: Gene expression profiling of peripheral blood
resulted in the identification of a set of potential biomarkers that may be
predictive of severe GI-imAEs before, or early in the course of treatment
with ipilimumab. Further validation of these biomarkers in a larger patient
cohort is warranted.
8595 General Poster Session (Board #38E), Sun, 8:00 AM-12:00 PM
Patterns of care in adjuvant systemic therapy of patients with stage III
melanoma: A U.S. population-based study. Presenting Author: Boyu Hu,
Case Western Reserve University School of Medicine, Cleveland, OH
Background: Use of adjuvant systemic therapy in patients with stage III
melanoma is widely known to be variable based upon multiple factors such
as patient age and comorbidities as well as the preference and even
geographic location of the oncologist and patient. The purpose of this study
was to compare the use of adjuvant therapy among patients treated in
teaching hospitals and community hospitals. Methods: The study population
consisted of patients with stage III melanoma enrolled into the
National Cancer Database (NCDB) between 2000-2008. Patients were
selected based upon surgery as the first course of therapy which resulted in
a total of 27,353 eligible for analysis. The study population was then
categorized into those who were treated at Teaching Hospitals (TH)
including National Cancer Institute-designated cancer centers or Community
Hospitals (CH). Multiple variables including age, median household
income, insurance status, race and overall survival were compared between
patients in the two hospital groups. Results: The overall proportion of stage
III patients who received adjuvant systemic therapy was approximately
30%. There was no difference in the proportion of patients receiving
adjuvant systemic therapy between patients treated in TH as compared to
CH, and there was no obvious trend towards increased use over time. Of
interest was that the cohort of patients designated as being treated at TH
had a higher proportion of patients less than 70 years old as compared to
CH. Median household income was found to be higher in patients treated at
TH. Finally, despite the observation that the proportion of patients who
received adjuvant therapy was not different, there a significantly higher
5-year overall survival in patients treated at TH as compared to CH.
Conclusions: Although the proportion of patients who received adjuvant
systemic therapy was comparable in TH and CH, there was a significant
increase in 5-year overall survival within TH. Additional factors such as age,
lesser comorbidities, more favorable socioeconomic factors or other unmeasured
factors such as type of adjuvant therapy or whether adjuvant therapy
was completed may have contributed to the improved survival in patients
treated at TH.
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