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

548s Melanoma/Skin Cancers
8532 Poster Discussion Session (Board #21), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Randomized phase III trial of intravenous (IV) versus hepatic intra-arterial
(HIA) fotemustine in patients with liver metastases from uveal melanoma:
Final results of the EORTC 18021 study. Presenting Author: Serge Leyvraz,
Centre Pluridisciplinaire d’Oncologie, Lausanne, Switzerland
Background: HIA fotemustine has shown promising results in Phase II
studies that led to the EORTC randomized phase III trial (18021) in
unpretreated patients (pts) with liver metastases from uveal melanoma.
Methods: The treatment consisted in an induction cycle of either HIA
(fotemustine 100 mg/m² over 4 hours, day 1, 8, 15, 22) vs IV control arm
(fotemustine 100 mg/m² over 1 hour, day 1, 8, 15). After a 5-week break,
maintenance cycles were given every 3 weeks. Randomization was stratified
by PS (0 vs 1), LDH (normal vs abnormal) and center. Main endpoint
was overall survival (OS). Required accrual per protocol was set to 262 pts,
with final analysis planned after 220 deaths (hazard ratio (HR) �0.67,
power�85%, 1-sided ��2.5%). Due to poor accrual an interim analysis
was done after 134 deaths, in order to test futility (power�79%). Results:
Between Feb-2005- Feb-2011, 171 pts were randomized (HIA: 86, IV:
85). Characteristics: PS 1: 20%, abnormal LDH: 42%, male: 50%, median
age: 59 y.; balanced between arms. In the HIA arm 20 (23%) pts never
started treatment mainly due to catheter problems and 2 pts in the IV arm.
In those who started the treatment, leucopenia grade 3-4 was 18% and
thrombopenia grade 3-4: 21% in the HIA arm compared to 32% and 42%
in the IV arm. Non-hematological grade 3-4 toxicities were minimal (GI
toxicity, catheter complications). In May 2011, as the OS HR�1.097 was
� critical value 0.87, the IDMC recommended stopping accrual for futility.
The final results from Jan-2012 are presented in the table below.
Treatment comparison adjusted by PS and LDH provided similar results.
Conclusions: Even if HIA fotemustine administration could not start in 23%
of pts, it led to a higher ORR and longer PFS compared to IV administration.
HIA did not translate into an improvement in OS.
All pts
(N�171)
Treatment started
(N�149)
Endpoint HIA (N�86) IV (N�85) HIA (N�66) IV (N�83)
Response
CR�PR�ORR, N (%) 9 (10.5) 2 (2.4) 9 (13.6) 2 (2.4)
PFS
Events, N 84 85 64 83
Median (months) 4.5 3.7 5.4 3.7
HR (95% CI), p value 0.62 (0.45 , 0.84), 0.002 0.53 (0.38 , 0.75), 0.0002
OS
Deaths, N 79 76 59 74
Median (months) 14.6 13.0 14.6 13.7
HR (95% CI), p value 1.09 (0.79 , 1.50), 0.59 1.00 (0.71 , 1.42), 0.98
8534 Poster Discussion Session (Board #23), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Long-term cure after complete resection and adjuvant immunotherapy for
distant melanoma metastases. Presenting Author: Donald L. Morton,
Division of Surgical Oncology, John Wayne Cancer Institute, St. John’s
Health Center, Santa Monica, CA
Background: In phase II trials, postoperative therapy with Canvaxin allogeneic
melanoma cell vaccine plus Bacillus Calmette-Guerin (BCG) improved
the survival of patients with stage IV melanoma. A multicenter, phase III
placebo-controlled study was undertaken to investigate the vaccine’s
efficacy. Methods: After complete resection of melanoma involving up to 5
distant sites, patients were randomized to treatment with BCG plus
Canvaxin (BCG-Canvaxin) or BCG plus placebo (BCG-placebo). The primary
endpoint was overall survival (OS); secondary endpoints were disease-free
survival (DFS) and skin test responsiveness to the study agent. Results:
Between May 1998 and April 2005, 496 patients were randomized. In
April 2005, entry to the study was terminated due to low probability of
demonstrating treatment differences. However, 256 patients from sites
enrolled in a follow-up study were monitored until March 2010. Median OS
and 5-year and 10-year rates of OS were 39.1 months, 43.3% and 33.3%,
respectively, in the BCG-placebo group, versus 34.9 months, 42.5% and
36.4%, respectively, in the BCG-Canvaxin group (hazard ratio, 1.053;
95% confidence interval, 0.81 to 1.36; p�0.6964). Median DFS, 5-year
DFS, and 10-year DFS were 7.6 months, 23.8% and 21.7%, respectively,
for the BCG-placebo group, versus 8.5 months, 30.0%, and 30.0%,
respectively, for the BCG-Canvaxin group (hazard ratio, 0.882; 95%
confidence interval, 0.708 to 1.097; p�0.2595). Positive skin test results
correlated with improved survival. Conclusions: BCG-Canvaxin was not
superior to BCG-placebo, but the highly favorable long-term survival for
combined groups indicates that complete metastasectomy should be
considered as initial therapy for patients with resectable stage IV melanoma
(ClinicalTrials.gov identifier: NCT00052156).
8533 Poster Discussion Session (Board #22), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Neoadjuvant ipilimumab in locally/regionally advanced melanoma: Clinical
outcome and immune monitoring. Presenting Author: Ahmad A. Tarhini,
University of Pittsburgh Cancer Institute, Pittsburgh, PA
Background: Neoadjuvant ipilimumab (ipi) for stage IIIB-C melanoma may
improve the clinical outcomes and provide access to pre/post ipi blood and
tumor to gain insight into host effector and suppressor immune response
mechanisms. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks
x 4doses total) bracketing definitive surgery. Tissue samples were obtained
at baseline and at definitive surgery (week � 6) and serum/PBMC collected
at baseline, 6 weeks, then at 3, 6, 9, 12 months and/or progression. Flow
cytometry was used to monitor the host effector and suppressor immune
response in blood and evaluable tumor. Results: Thirty pts (21 male, 9
female), age 40-87 were enrolled (25 cutaneous primary, 1 unknown, 4
mucosal). Six had AJCC stage IIIB (N2b, N2c) and 24 IIIC (N3) melanoma.
Ninety-three cycles have been delivered (median 4). Worst toxicities
included grade 3 diarrhea/colitis (5 patients; 17%), hepatic enzyme
elevations (2; 7%), rash (2; 7%), lipase (1; 3%), all manageable. Median
follow up is 14 months: among 29 evaluable pts 15 (52%) continue
disease free. Median PFS is 15.5 months, 95% CI � (8.1,-). The
probability of 6 and 12 month PFS is 82.4% (95% CI�0.63, 0.92) and
53% (95% CI�0.31, 0.70) respectively. Peripherally, a significant increase
in frequency of circulating T-regs (CD4�CD25hi� Foxp3�;p�0.02
CD4�CD25hi�CD39�; p�0.001) from baseline to 6 weeks was observed.
Greater increases in T-regs were associated with improved PFS
(p�0.045; HR�0.54). Significant decreases in circulating MDSCs, were
observed in monocytic HLA-DR� /low/CD14� MDSC subtype (p�0.0001).
Spontaneous in vivo cross presentation was observed resulting in Th1 CD4
and CD8 antigen specific T-cell immunity (gp-100, MART-1, NY-ESO-1
peptides) with increase in frequency after ipi. Activated TIL in tumor
increased after ipi (CD3�/CD4�/CD69�;p�0.06 and CD3�/CD8�/
CD69�) with significant induction/potentiation of T-cell memory (CD8�/
CD45RO�/TNF-��;p�0.03). Conclusions: Neoadjuvant ipi exhibits
promising clinical activity and significantly modulates the host effector and
suppressor immune response. Full analysis of this completed trial and its
correlates will be presented. Support: BMS, P30CA047904 and
P50CA121973.
8535 Poster Discussion Session (Board #24), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Sensitivity rate of ultrasound (US)-guided fine-needle aspiration cytology
(FNAC) using the Berlin morphology criteria for lymph node metastases to
reduce the need for surgical sentinel node (SN) staging in melanoma.
Presenting Author: Christiane A. Voit, Charité, University Medicine Berlin,
Berlin, Germany
Background: US-guided-FNAC prior to surgical SN staging is emerging as a
possible cost-effective addition to the staging of melanoma patients (pts).
Formerly, sensitivity (sens) rates of lymph node US in melanoma were
disappointing (20–40%). The introduction of the Berlin Morphology
Criteria has significantly improved sens rates for US-FNAC (J Clin Oncol
2010;28(5):847-52). The aim of the current study was to report on 1000
patients the sens, specificity (spec), positive (PPV) and negative (NPV)
predictive value rates of US-FNAC from our prospective database with
prolonged follow-up. Methods: Since 2001, �1000 stage I/IIconsecutive
melanoma pts have undergone US-FNAC prior to SN. All patients underwent
lymphoscintigraphy. Peripheral Perfusion (PP), Loss of Central
Echoes (LCE), Balloon Shaped (BS) were the Berlin Morphology Criteria
which were registered. FNAC was performed in case of presence of any of
these factors. SN tumor burden was measured according to the Rotterdam
Criteria. All patients underwent SN or LND in case of positive FNAC.
Results: Mean/median Breslow thickness was 2.56 / 1.57 mm (0.2 – 44
mm).Mean/median follow-up was 39 / 32 months (0 – 115). Ulceration was
present in 24 %. SN positivity rates were 20 % (202 / 1000). Sens was 51
%. Spec, PPV and NPV were 99%, 91% and 89%. Sensitivity was highest
for T4 tumors (77%). PP, LCE, BS had sens of 69%, 24%, 25%. SN tumor
burden � 1 mm in largest diameter according to the Rotterdam Criteria was
identified by US-FNAC in 86%. Threshold for positive FNAC was 0.4 mm in
maximum diameter. Conclusions: The new criterion of Periferal Perfusion is
of key importance to achieve the high sensitivity of US-FNAC according to
the Berlin Morphology Criteria (J Clin Oncol 2010; 28:847-852) to identify
lymph node metastases. Especially for T4 patients and in patients with
advanced SN tumor burden it can reduce significantly the need for surgical
SN staging. The EORTC Melanoma Group will launch the prospective
validation study, USE FNAC, in 2012.
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