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

554s Melanoma/Skin Cancers
8556 General Poster Session (Board #33F), Sun, 8:00 AM-12:00 PM
Everolimus in combination with paclitaxel and carboplatin in patients with
advanced melanoma: A phase II trial of the Sarah Cannon Research
Institute (SCRI). Presenting Author: Ralph J. Hauke, Nebraska Cancer
Specialists, Omaha, NE
Background: The PI3k/AKT pathway is activated in most metastatic melanomas;
mTOR is a critical component of this pathway. Everolimus, an mTOR
inhibitor, has demonstrated single-agent activity in patients with advanced
melanoma. We evaluated the efficacy and toxicity of everolimus in
combination with paclitaxel/carboplatin in patients with advanced melanoma.
Methods: Eligible patients had stage IV or unresectable stage III
melanoma, unselected for braf status, previously untreated with chemotherapy
or targeted agents. Previous immunotherapy was allowed. Additional
eligibility criteria: ECOG PS 0 or 1; measurable disease; no active
brain metastases; adequate bone marrow, kidney, and liver function;
informed consent. All patients received paclitaxel 175mg/m2 , 1-3 hour IV
infusion, and carboplatin AUC 6.0 IV on day 1 of each 21-day cycle.
Everolimus 5mg PO was given daily. Patients were evaluated for response
every 6 weeks; treatment continued until progression or undue toxicity.
Median progression-free survival (PFS) for paclitaxel/carboplatin treatment
is 4 months; we looked for a median PFS of 6 months with this novel
combination. Results: Seventy patients were treated between 2/2010 and
2/2011; median age 63, 90% had stage IV melanoma. 91% of patients
received at least 2 cycles of therapy; median cycles received: 4 (range:
1-25�). Twelve patients (17%) had partial responses; an additional 42
patients (60%) had stable disease at first reevaluation. After a median 13
months of followup, the median PFS for the entire group was 4 months
(95% CI: 2.8 – 5.0 months); 96% had progressed during the first 12
months. Median survival was 10 months (95% CI: 7.3 – 10.9 months).
Toxicity was as previously described with these agents; neutropenia was the
most common grade 3/4 toxicity (27%). Only 3 patients stopped treatment
due to toxicity. Conclusions: The addition of everolimus to paclitaxel/
carboplatin was feasible and well-tolerated; however, efficacy results were
similar to those reported with paclitaxel/carboplatin alone. Further development
of this combination regimen for treatment of metastatic melanoma is
not recommended.
8558 General Poster Session (Board #33H), Sun, 8:00 AM-12:00 PM
Patterns of progression in patients (pts) with V600 BRAF-mutated melanoma
metastatic to the brain treated with dabrafenib (GSK2118436).
Presenting Author: Mary W. F. Azer, The Crown Princess Mary Cancer
Centre Westmead, Sydney, Australia
Background: Dabrafenib has shown efficacy in pts with previously untreated
brain metastases (BM) but most will progress. We report the pattern of
disease progression (PD) in pts with either previously treated (surgery (Sx),
SRS, WBRT) or untreated BM on dabrafenib. Methods: Clinicopathologic
parameters were collected on 23 pts enrolled in the brain cohort of the
BRF112680 phase I and BRF113929 phase II BM study of dabrafenib at
Westmead Hospital between Sept 2009 and June 2011. Pts with RECIST
PD but ongoing clinical benefit were allowed to continue dabrafenib.
Results: 12 pts (52%) had previously untreated BM and 11 (48%) were
previously treated with evidence of progression prior to dabrafenib. Median
OS from study entry (8.4 mo, 95% CI 5.0-11.8), diagnosis of first BM
(11.0 mo, 95% CI 9.1-13.0), and stage IV diagnosis (17.5 mo, 95% CI
12.1-23.0) were not different between the two groups. Similarly, PFS did
not differ between groups. Of the 19 pts who had RECIST PD at datacut, 13
pts had intracranial (IC) PD with no pts progressing in new brain lesions
alone (see table). At IC PD, 3/13 underwent SRS/Sx, 5/13 WBRT and 5/13
had no salvage local therapy to BM. 8 pts continued dabrafenib beyond IC
PD, median 36 days; range 28-273. All measures of baseline disease
burden correlated with worse OS; elevated LDH (HR 1.003, 95% CI
1.0-1.007, P�0.044), increased number (no.) metastatic sites (HR 1.32,
95% CI 0.97-1.81, P�0.08), increased no. of IC lesions (HR 1.04, 95%CI
1.00-1.09, P�0.04), increased no. extracranial (EC) lesions (HR 1.07,
95%CI 1.02-1.12, P�0.01) and increased RECIST sum of diameters
(SoD) (HR 1.012, 95% CI 1.003-1.021, P�0.007). High baseline SoD
was the only factor that predicted worse RECIST response. Conclusions:
Clinical benefit from dabrafenib does not appear to be influenced by prior
local therapies to BM. There was no dominant pattern of progression in pts
with BM on dabrafenib, but PD due to new lesions alone is rare. Pts with IC
PD may benefit from salvage local therapy and continued dabrafenib.
Extent and burden of disease correlates with reduced OS, but not RECIST
response.
Sites of first RECIST PD
IC only EC only IC and EC Total
Existing lesions only 1 5 2 8
New lesions only 0 0 0 0
Existing and new 4 1 6 11
Total 5 6 8 19
8557 General Poster Session (Board #33G), Sun, 8:00 AM-12:00 PM
The melanoma risk loci as determinants of melanoma prognosis. Presenting
Author: Justin Rendleman, New York University Cancer Institute, New
York, NY
Background: Genetic risk factors of human cancer emerge as promising
markers of clinical outcome. The recent melanoma genome-wide scans
(GWAS) have identified loci associated with the disease risk, nevi or
UV/pigmentation, but the prognostic potential of these variants is yet to be
determined. In this study, we performed the first-to-date systematic
evaluation of the association between established melanoma risk loci and
melanoma progression. Methods: 891 melanoma patients prospectively
accrued and followed up at NYU Medical Center were studied. We
examined the association of 108 melanoma susceptibility single nucleotide
polymorphisms (SNPs), selected or imputed from recent GWASs on
melanoma, nevi or pigmentation, with recurrence-free survival (RFS) and
overall survival (OS). The genotyping was performed using Sequenom
I-plex. Cox PH model was used to test the association between each SNP
and RFS and OS adjusted by age at diagnosis, gender, tumor stage and
histological subtype. ROC curves were used to measure predictive utility of
SNPs in predicting 3-year recurrence. Results: The strong association was
observed for rs7538876 (RCC2) with RFS (HR�2.445, 95% CI 1.57 –
3.8, p�0.0006) and rs9960018 (DLGAP1) with both RFS and OS
(HR�4.7, 95% CI�2.11-10.43, p�0.0061, HR�1.55, 95% CI�1.11-
2.17, p�0.0094, respectively) using adjusted multivariate analysis. In
addition, we identified the classifier with rs7538876 and rs9960018,
stage and histological type at primary tumor diagnosis, achieving a higher
area under the ROC curve (AUC�84%) compared to the baseline
(AUC�78%) in predicting 3-year recurrence. Univariate survival analyses
have identified associations of several SNPs with ulceration and/or tumor
thickness. Conclusions: Our data revealed an association between specific
melanoma susceptibility variants and worse clinicopathological variables at
the time of diagnosis as well as worse disease outcome. The strength of
associations observed for rs7538876 and rs9960018 suggest biological
implication of these loci in melanoma recurrence. The observed predictive
patterns of associated variants with clinical outcome provide for the first
time evidence for the potential utilization of genetic markers in melanoma
prognostication.
8559 General Poster Session (Board #34A), Sun, 8:00 AM-12:00 PM
MAGE-A3 expression in patients screened for the DERMA trial: A phase III
trial testing MAGE-A3 immunotherapeutic in the adjuvant setting for stage
IIIB-C-Tx melanoma. Presenting Author: John F. Thompson, Melanoma
Institute Australia, Sydney, Australia
Background: Administration of MAGE-A3 immunotherapeutic involves the
active immunization of patients (pts) with tumors expressing the MAGE-A3
protein. This new investigational approach has been previously assessed in
two phase II trials, one in pts with metastatic melanoma (NCT00086866)
and another in pts with completely resected non-small cell lung cancer
(NCT00290355). Based on the positive responses observed in both
studies, a randomized phase III placebo controlled trial assessing MAGE-A3
immunotherapeutic as adjuvant treatment in pts with resected, regionally
advanced melanoma (stage IIIB-C-Tx AJCC/UICC 2010) is currently ongoing
(DERMA Phase III trial, NCT00796445). Methods: Formalin-fixed,
paraffin-embedded tumor tissues were prepared from surgically removed
metastatic lymph nodes and tested for MAGE-A3 expression by qRT-PCR.
Other baseline patient and tumor characteristics were collected during
screening to further investigate factors that could potentially influence
MAGE-A3 expression. Results: Between Dec 1, 2008 and Oct 25, 2011,
3917 pts were screened. Of the 3,183 valid samples (excluding the 513
inconclusive tests [66% for poor quality, 27% out-of range, 7% miscellaneous])
and the 221 missing samples, 2,092 (65.7%) were positive for
MAGE-A3 expression. In these stage III melanoma pts, no difference in
MAGE-A3 expression levels were identified with regard to (1) disease stage
- IIIB (62.6%), IIIC (66.5%) and IIITx (66.2%); (2) gender - male (64.2%),
female (68.1%); (3) age group - 18 to 39 years (63.2%), 40 to 49 years
(65.3%), 50 to 59 years (66.8%), 60 to 69 years (68.1%) and 70 years
and over (63.4%) and (4) region: Europe (66.1%), North America (63.0%)
and rest of the world including Argentina, Brazil, Australia, Mexico, Taiwan,
Japan, Korea (67.9%). Conclusions: Expression of the MAGE-A3 gene in
the DERMA trial population (stage IIIB-IIIC-IIITx) was 66%. It was not
correlated with age, gender, disease stage or geographic region. This
expression frequency is consistent with published data in metastatic
melanoma (Van den Eynde, 1997; Vourc’h-Jourdain et al, 2009) and has
potentially important clinical implications.
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