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

8552 General Poster Session (Board #33B), Sun, 8:00 AM-12:00 PM
Positron emission tomography/computed tomography to improve staging
and restaging in Merkel cell carcinoma. Presenting Author: Elena B.
Hawryluk, Department of Dermatology, Harvard Medical School, Boston,
MA
Background: Merkel cell carcinoma (MCC) is a rare (~1,500 cases per year)
and highly aggressive (33% mortality) cutaneous neuroendocrine carcinoma
that occurs in older white patients on the UV-exposed skin of the
head, neck, and extremities. As a patient’s stage at presentation is a strong
predictor of survival, and there is a high propensity for locoregional
recurrence and distant progression, imaging remains crucial for initial and
subsequent management. There is, however, no consensus on the timing or
method of imaging for MCC. Methods: We retrospectively reviewed 270
2-fluoro-[ 18F]-deoxy-2-D-glucose (FDG) positron emission tomography/
computed tomography (PET/CT) scans performed in 97 patients at the
Dana-Farber/Brigham and Women’s Cancer Center from August 2003 to
December 2010. Results: The mean SUVmax was 6.5 for primary tumors,
6.4 for regional lymph nodes, 7.2 for distant metastases (all sites), 8.0 for
bone/bone marrow metastases, and 9.4 for non-regional metastases in
those patients with no identified primary. PET/CT imaging performed for
initial management tended to upstage patients with more advanced disease
(50% of stage IIIB patients). Metastases to bone/bone marrow (12
patients, 38%) was the 2nd most common site of distant spread after
non-regional lymph nodes (19 patients, 59%), followed by skin (8 patients,
25%), liver (6 patients, 19%), lung/pleura (5 patients, 16%), adrenal (3
patients, 9%), muscle (3 patients, 9%), pancreas (2 patients, 6%), and
peritoneum (1 patient, 3%). In 10 of 12 patients, PET identified bone/bone
marrow metastases that were not seen on CT imaging, which resulted in
either upstaging or initiation of more targeted palliative therapy. Conclusions:
Added value of PET over CT, such as in the detection of bone/bone marrow
metastases, may lead to more accurate staging, and thus prognostication,
as well as earlier detection of relapse and initiation of salvage treatment. Its
use should be considered in the staging and restaging of MCC.
8554 General Poster Session (Board #33D), Sun, 8:00 AM-12:00 PM
Randomized, double-blind, and multicenter phase II trial of rh-endostatin
plus dacarbazine versus dacarbazine alone as first-line therapy for the
patients with advanced melanoma. Presenting Author: Jun Guo, Peking
University Cancer Hospital and Institute, Beijing, China
Background: rh-endostatin (Endostar, water-soluble, rES) is an inhibitor of
angiogenesis, which is effective as single agent or in combination with
chemotherapy for non-small cell lung cancer in phase I/II clinical trials.
This study (NCT00813449) was a randomized, double-blind and placebocontrolled
phase II trial, aimed to observe the efficacy and safety of rES
with dacarbazine (DTIC) as the 1st line therapy for patients (pts) with
advanced melanoma. Methods: Untreated pts with ECOG 0/1 and unresectable
stage IIIC or IV melanoma (confirmed by histopathology) were
enrolled, and randomized (1:1) into Arm A (DTIC 250 mg/m2 d1-5 �
placebo d1-14) or Arm B (DTIC 250 mg/m2 d1-5 � rES 7.5 mg/m2 d1-14). Treatment was continued in 21-day cycle until progression or intolerable
toxicity occurs. Primary endpoints were progression free survival (PFS) and
overall survival (OS). Secondary endpoints included objective response rate
(ORR) and safety, evaluated every 2 cycles. Results: From Dec. 2008, 120
pts were enrolled and 110 pts evaluable. 30.9% of them were in M1a,
39.1% in M1b, and 29.1% in M1c. Mean treatment cycles were 3.2
(range: 1-10) in Arm A and 4.0 (range: 1-12) in Arm B. Until the last
follow-up in Nov. 2011, 27 pts were still alive. The median PFS was 1.5
months (95% CI: 1.35-1.65) in Arm A and 5.0 months in Arm B (95% CI:
2.45-7.55, P�0.004, log-rank test). The median OS was 7.0 months in
Arm A (95% CI: 4.41-9.59) versus 16.0 months in Arm B (95% CI:
10.46-21.54, P�0.003, Breslow test). 1-year survival rate was 22.2%
versus 51.0%, and 2-year survival rate 8.9% vs.10.2%. No statistical
significance was found for both ORR and toxicities. The most common
toxicities were increased transaminase (28.9% in Arm A versus 56.1% in
Arm B) and leucopenia (14.4% versus 13.4%). The incidence of grade 3-4
toxicity (increased transaminase and thrombocytopenia) was only 1.7% in
Arm B. Conclusions: rES plus DTIC may obviously improve mPFS and mOS
versus DTIC alone as the 1st line therapy for advanced melanoma. That
combining therapy was well tolerated and could be recommended as a new,
safe and effective regimen for untreated pts with advanced melanoma.
Melanoma/Skin Cancers
553s
8553 General Poster Session (Board #33C), Sun, 8:00 AM-12:00 PM
Effect of the BH3 mimetic ABT-737 on human melanoma cells to
apoptosis induced by selective BRAF inhibitors. Presenting Author: Peter
Hersey, Melanoma Institute Austrailia, Sydney, Australia
Background: Although the introduction of selective BRAF inhibitors has
been a major advance in treatment of metastatic melanoma, approximately
50% of patients have limited responses including stabilisation of disease or
no response at all. The present study aims to identify a novel means of
overcoming resistance of melanoma to killing by BRAF inhibitors. Methods:
We examined the influence of the BH3 mimetic ABT-737 on induction of
apoptosis by the selective BRAF inhibitor PLX4720 on a panel of
melanoma cells with BRAF V600E mutations with or without mutations of
CDK4 and BRAF wildtype cells with or without NRAS mutations. Included
in the studies were cell lines established from 4 patients before and during
treatment with selective BRAF inhibitors. Results: Cell lines with no or low
sensitivity to PLX 4720 underwent synergistic increases and increased
rates of apoptosis when combined with ABT-737. This degree of synergism
was not seen in cell lines without BRAF V600E mutations. Apoptosis was
mediated through the mitochondrial pathway and was due in part to
upregulation of Bim as shown by inhibition of apoptosis following siRNA
knockdown of Bim. Similar effects were seen in cell lines established from
patients prior to treatment but not in lines from patients clinically resistant
to the selective BRAF inhibitors. Conclusions: These results suggest that
combination of selective BRAF inhibitors with ABT-737 or the oral form
ABT-263 may increase the degree and rate of responses in previously
untreated patients with V600E melanoma but not in those with acquired
resistance to these agents.
8555 General Poster Session (Board #33E), Sun, 8:00 AM-12:00 PM
BRAF mutation as a pejorative marker in metastatic melanoma. Presenting
Author: Sophie Brissy, Hopital Timone, Aix-Marseille University, Marseille,
France
Background: BRAF mutation in melanoma has been shown to be associated
with a trend in favour of a spontaneous worse outcome after metastases in a
series of 197 patients in Australia. Objective: To correlate BRAF status in
metastatic melanoma with clinicopathologic features and outcome. Methods:
In our department in France 182 patients with metastatic melanoma have
been tested for BRAF mutation between September 2009 and September
2011. Survival was assessed by log-rank test. Multivariate analysis was
performed with Cox model. Results: From 182 patients, 88 (48.3%) were
B-RAF mutant; 77 (87.5%) V600E, 4 (4.5%) V600K, and 7 (8%) other
mutation subtypes. BRAF-mutant patients were younger than BRAF wildtype
patients at diagnosis of primary melanoma (median age 52.3 vs 60.7
years, respectively, p�0.003), and at diagnosis of distant metastasis
(median age 53.6 vs 64.1 years respectively, p�0.002). 34 patients were
treated by B-RAF inhibitors. There was no significant difference in other
demographic features of patients with metastatic melanoma by mutation
status. Features of the primary melanoma significantly associated with a
BRAF mutation (p�0.05) were histopathologic subtype (SSM), high
mitotic rate (�1/mm2), lower Breslow thickness (median Breslow: 2.2 vs
3.5 mm for BRAF mutant and BRAF-wild-type patients respectively,
p�0.016), truncal location and location on occasionally exposed at sun
site.The interval from diagnosis of first ever melanoma to first distant
metastasis was not significantly different in BRAF-mutant and wild-type
patients. The median overall survival (OS) from diagnosis of primary
melanoma was 6.5 years for BRAF wild-type patients. Median OS was not
reached in BRAF-mutant patients treated (34 of 88) with a BRAF inhibitor,
but also in those not treated (p�0.24, and p�0.06 for treated BRAFmutant
vs BRAF wild-type). The overall survival from diagnosis of first
distant metastasis was not significantly different (p�0.75). These results
remained unchanged in a multivariate analysis. Conclusions: Our results
confirm the characteristics of BRAF-mutant metastatic patients, and the
efficacy of B-RAF inhibitors, but not that the presence of mutant-BRAF is
per se a pejorative predictive marker.
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