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

8576 General Poster Session (Board #36B), Sun, 8:00 AM-12:00 PM
Evaluation of chemokine-ligand pathways in pretreatment tumor biopsies
as predictive biomarker of response to adoptive therapy in metastatic
melanoma patients. Presenting Author: Davide Bedognetti, National Institutes
of Health, Bethesda, MD
Background: Adoptive therapy with tumor infiltrating lymphocytes (TILs)
induces objective responses (OR) in approximately 50% of patients with
metastatic melanoma. The recruitment of TILs through CXCR3/CCR5ligand
chemokines is believed critical for immune-mediated rejection.
Here, we investigated the predictive role of a gene-signature based on
CXCR3/CCR5-ligand chemokine transcripts in pre-treatment melanoma
biopsies, its biological role and its relation with CCR5-�32 polymorphism,
which encodes a protein not expressed on cell surface. Methods: Expression
of CXCR3/CXCR3-ligand transcripts (i.e CXCL9, 10, 11) and CCR5/CCR5ligand
transcripts (i.e. CCL3, 4, 5) were assessed in 113 pre-treatment
tumor biopsies from patients enrolled in adoptive therapy trials: 24
patients achieved a complete remission (CR), 34 a partial remission (PR),
and 55 did not respond (NR). Copy number variation and gene expression
profile of these target genes were assessed in 15 biopsy-derived cell lines.
CCR5-�32 was assessed by sequencing germinal DNA. Results: CXCL9, 10
and 11 and CCL5 clustered together and were selected for hierarchical
clustering analysis based on the mean-centered gene expression values. A
signature characterized by the over-expression of these genes was associated
with the likelihood to achieve a clinical response (OR rate: PR�CR:
65% vs 38%, High vs Low, respectively, P�0.015). Neither correlation
between the copy number variation and the gene-expression of the
corresponding genes, nor correlation between the transcripts of the
investigated genes between tumor biopsies and the matched cell lines was
detected. Transcript expression of the target genes did not differ between
CCR5-�32 (n �20) and wild type patients (n�93). Conclusions: Coordinate
over-expression of CXCR3/CCR5 ligands in pre-treatment tumor
samples was associated with responsiveness to treatment. However, the
lack of correlation between in vivo and ex vivo data suggest the inflammatory
status characterized by the up-regulation of these inflammatory
chemokine genes is an in vivo multifactorial phenomenon.
8578 General Poster Session (Board #36D), Sun, 8:00 AM-12:00 PM
Diagnosis of melanoma: Importance of comparative analysis and “ugly
duckling” sign. Presenting Author: Jean Jacques Grob, Dermatology Department,
Timone Hospital, Aix-Marseille University, Marseille, France
Background: “Ugly duckling” (UD) sign is widely admitted as a major sign
for melanoma (MM) detection. UD is based on the concept of intraindividual
comparative analysis, which has never been validated. It is
assumed that, in a given individual, variability of nevi is limited and
represented by a few similarity clusters (SC) grouping all nevi sharing the
same pattern, and that a nevus is suspicious when it does not fit with the
SCs of this individual (UD). Objective: To validate the concept of UD and
SC. Methods: 9 international experts (dermatologists) and 9 novices
(untrained individuals) were blindly tested, using digital images of the nevi
at clinical and dermoscospic scale successively in 80 patients, (2,089 nevi
and 7 MM). Concordance was assessed by kappa statistics for UDs, and
B-cubed metrics for SCs. Results: At clinical scale, experts had a better
concordance for UDs (kappa� 0.53, [0.33 - 0.87]) and SCs (B-cubed �
0.65, [0.55, 0.73]), than novices (0.31, [0.03, 0.51] and 0.56 [0.49,
0.64], respectively). Experts identified a mean number of 1 UD and 2.7
SCs per patient, and agreed on consensual UD and SCs, whatever their
natural propensity to see a high or a low number of UDs and SCs: among the
254 nevi considered as UDs by at least 1 expert, 54 were considered as
such by at least 5, and from them, 20 by all 9 experts. The 20 consensual
UDs included all the MMs (7/7) (sensitivity for MM: 100%). At dermoscopic
scale, concordance tended to be lower for SCs than at clinical scale.
Conclusions: We demonstrated the limited variability of nevi patterns in
each patient, the consistency in the recognition of UD, and its clinical
relevance, supporting evidence that it is useful for experts and to a lesser
degree to general population to spot the skin lesions with the highest
probability of being MM.
Melanoma/Skin Cancers
8577 General Poster Session (Board #36C), Sun, 8:00 AM-12:00 PM
Rapid rational drug targeting of Merkel cell polyomavirus (MCV)-positive
Merkel cell carcinoma (MCC) using the survivin inhibitor YM155. Presenting
Author: Reety Arora, Cancer Virology Program, University of Pittsburgh
Cancer Institute, Pittsburgh, PA
Background: MCC is an aggressive, chemoresistant skin cancer causing
more deaths each year than chronic myelogenous leukemia. We discovered
a new virus, Merkel cell polyomavirus (MCV), clonally integrated into ~80%
of primary and metastatic MCC in 2008. To find therapeutic targets for this
cancer, we examined cellular genes perturbed by MCV infection. Methods:
Digital transcriptome subtraction was used to discover MCV and also to
reveal survivin gene (BIRC5) upregulation in virus-positive tumors. MCV T
antigen knockdown studies in seven MCC lines and large T (LT) transduction
into BJ fibroblasts were used to confirm this. Drug screening was
performed in vitro using Cell-Titer Glo assays in a two stage analysis. In vivo
screening used an MKL-1 (MCV�) MCC NOD-SCIDg mouse xenograft
model with a single three-week treatment round. Results: MCV large T
oncoprotein induces survivin transcription through retinoblastoma protein
sequestration by the LT LXCXE motif. MCV T antigen knockdown results in
nonapoptotic MCC cell death and loss of survivin expression. YM155, a
phase II survivin transcription inhibitor, causes MCV� MCC cell necroptosis
associated with autophagy at 1-12 nM EC50. Of 1359 other drugs from
LOPAC and NCI Oncology Set II libraries, only bortezomib had in vitro
potency comparable to YM155. In MKL-1 xenograft studies, mice were
treated with saline, bortezomib or YM155 for three weeks using standard
dosings. Bortezomib did not significantly improve mouse survival (33%)
over saline (24%) during treatment. In contrast, all YM155-treated mice
survived (100%, p�0.001) the 3 week treatment period. Tumors resumed
growth once YM155 treatment was stopped suggesting that YM155 is
cytostatic in vivo rather than cytotoxic. Conclusions: Survivin expression is
induced by MCV LT and is critical to MCV� MCC survival. A survivin
inhibitor, YM155 was nontoxic to mice and cytostatic for MCV� MCC
xenografts. Using genomic technologies, in less than four years, the
primary viral cause for most MCC was discovered, new diagnostic tests
developed and a promising rational drug candidate identified. A cooperative
group trial (E1611) for YM155 and bortezomib in MCC patients is
currently planned.
8579 General Poster Session (Board #36E), Sun, 8:00 AM-12:00 PM
Efficacy and safety of the hedgehog pathway inhibitor vismodegib in
patients with advanced basal cell carcinoma (BCC): ERIVANCE BCC study
update. Presenting Author: Aleksandar Sekulic, Mayo Clinic, Scottsdale,
AZ
Background: The ERIVANCE BCC study is the pivotal trial of vismodegib
(GDC-0449), a first-in-class small-molecule inhibitor of Hedgehog signaling,
for treatment of locally advanced (laBCC) and metastatic BCC (mBCC),
for whom there are no other effective therapy options. The study met the
primary endpoint of overall response rate by independent review (Sekulic,
Melanoma Res 2011). Here we report a 6-mo update of investigatorassessed
(I-A) efficacy and safety endpoints as of May 26, 2011. Methods:
This multicenter, international, nonrandomized 2-cohort study enrolled
patients (pts) with laBCC (deemed inoperable or for whom surgery would be
significantly disfiguring), and mBCC pts with RECIST-measurable disease.
Pts received 150 mg oral vismodegib daily. Results: 104 pts (71 laBCC/33
mBCC) enrolled at 31 sites in the US, Europe, and Australia. I-A efficacy
endpoints are shown in the table. One-year survival rate was 77.3% (95%
CI 62.48–92.09%) for mBCC and 93.1% (95% CI 86.49–99.63%) for
laBCC. Adverse events (AEs) in �30% of pts were muscle spasms,
alopecia, dysgeusia, weight decrease, fatigue, nausea, and amenorrhea
(33.3%; 2/6 pts). Serious AEs were reported in 32 pts (31%). No
additional fatal AEs were reported since the prior data cut (n�7, 7%; none
considered related to vismodegib). Conclusions: This 6-mo update of I-A
efficacy and safety endpoints from the ERIVANCE BCC study supports the
significant clinical benefit of vismodegib in both laBCC and mBCC reported
at the primary analysis. Median DOR and PFS increased numerically with
follow-up. The AE profile was consistent with the prior data cut. These
results further support the efficacy of vismodegib for treatment of advanced
BCC.
Parameter
Overall response rate
(ORR), n (%) (95% CI)
Median duration of response
(DOR), mo (95% CI)
Median progression-free survival
(PFS), mo (95% CI)
26 Nov 2010 data cut 26 May 2011 data cut
mBCC
(n�33)
15 (45.5)
(28.1–62.2)
(n�15)
12.9
(5.55–12.91)
9.2
(7.39–NE)
laBCC
(n�63)
38 (60.3)
(47.2–71.7)
(n�38)
7.6
(7.43–NE)
11.3
(9.46–16.82)
mBCC
(n�33)
16 (48.5)
(30.8–66.2)
(n�16)
12.9
(5.55–NE)
9.3
(7.39–16.59)
559s
laBCC
(n�63)
38 (60.3)
(47.2–71.7)
(n�38)
NE
(7.62–NE)
12.9
(10.22–NE)
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