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

546s Melanoma/Skin Cancers
8524 Poster Discussion Session (Board #13), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase II single arm study of pazopanib and paclitaxel as first-line
treatment for unresectable stage III and stage IV melanoma: Interim
analysis. Presenting Author: John P. Fruehauf, UCI Comprehensive Cancer
Center, Orange, CA
Background: Metastatic melanoma lacks effective therapy. Pazopanib is a
small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has
antiangiogenic activity in renal cell cancer as well as inhibition of
melanoma tumor xenografts. We designed a phase II single arm, open label
clinical trial evaluating pazopanib in combination with metronomic paclitaxel
as first line therapy for subjects with unresectable stage III and stage
IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax
design, with a planned interim analysis to confirm �3 responders to move
to the second stage. To date, 20 eligible patients have been enrolled with
17 evaluable for response. All subjects were treatment naïve and received
paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and
pazopanib at 800mg as a continuous daily oral dose. The primary endpoint
is 6 month progression free survival. Exploratory endpoints include biomarker
analysis that may be associated with treatment outcomes (serum
VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation
status). An additional exploratory endpoint includes the in vitro activity of
pazopanib and paclitaxel on patient biopsy material co-cultured with
vascular endothelial cells. RECIST criteria were used to define treatment
response. Results: For the 17 evaluable patients treated to date the
following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall
RR (CR�PR) was 40%. Total disease control rate was 80% (PR�SD). The
most common AEs/lab abnormalities were nausea (71%), hypertension
(57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included
hypertension (28%), transaminitis (21%) and neutropenia (14%). One
patient discontinued for grade 4 transaminitis which subsequently resolved
completely. Dose reductions were required for pazopanib in 5 patients and
for paclitaxel in one patient. Conclusions: Planned interim analysis of this
phase II study demonstrated that pazopanib in combination with paclitaxel
was well tolerated and resulted in a 40% response rate, indicating that this
combination is of further interest. Accrual will continue to reach a goal of
60 patients.
8526 Poster Discussion Session (Board #15), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Targeting hyperactivation of the AKT survival pathway to overcome therapy
resistance of melanoma brain metastases. Presenting Author: Friedegund
Elke Meier, University of Tuebingen, Tuebingen, Germany
Background: Brain metastases are a major contributor to mortality in stage
IV melanoma patients. In melanoma, the RAF-MEK-ERK (MAPK) and
PI3K-AKT-mTOR (AKT) signaling pathways play a major role in tumor
progression and therapy resistance. On the basis of significant improvement
in overall survival, the BRAF inhibitor vemurafenib recently gained
FDA approval for the treatment of patients with metastatic BRAFV600E
mutated melanoma. However, ongoing clinical studies suggest short-lived
responses to BRAF inhibitors in melanoma brain metastases. Methods: We
observed in several melanoma patients that chemotherapeutics or BRAF
inhibitors yielded a significant regression of extracerebral metastases while
brain metastases progressed or newly occurred. We therefore aimed at
identifying factors that may contribute to treatment resistance of brain
metastases. Results: Immunohistochemistry of matched brain and extracerebral
melanoma metastases demonstrated an identical pattern of ERK,
p-ERK and AKT staining but a different pattern of p-AKT and PTEN
staining with hyperactivation of AKT and loss of PTEN expression in brain
metastases. Mutation analysis revealed no difference in BRAF, NRAS or
KIT mutation status in matched brain and extracerebral metastases. By
contrast, in monolayer culture expression of ERK, p-ERK, AKT, p-AKT and
PTEN was identical in cell lines derived from brain and extracerebral
metastases. Furthermore, melanoma cells stimulated by astrocyteconditioned
medium showed hyperactivation of AKT compared to melanoma
cells stimulated by fibroblast-conditioned medium. When inhibiting
the MAPK and AKT signaling pathways at different levels in cells freshly
isolated from melanoma brain metastases, growth inhibition and apoptosis
induction was most pronounced with novel PI3K inhibitors such as
BKM120 and BEZ235. Conclusions: These data suggest that 1) hyperactivation
of the AKT survival pathway is brain environment-induced and
relevant for the survival of melanoma cells in the brain parenchyma and
that 2) inhibition of AKT signaling may be a suitable strategy to enhance
and/or prolong the antitumor effect of chemotherapeutics or BRAF inhibitors
in melanoma brain metastases.
8525 Poster Discussion Session (Board #14), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase II trial of RO4929097 Notch gamma-secretase inhibitor in metastatic
melanoma: SWOG S0933. Presenting Author: Kim Allyson Margolin,
University of Washington, Seattle, WA
Background: The Notch pathway regulates expression of genes for cell
cycle, tissue-specific differentiation, and vasculogenesis. Notch target
genes affect melanomagenesis, and Notch levels can influence stemlike
versus differentiated tumor cells. Gamma-secretase, which activates intracellular
Notch, can be inhibited to kill melanoma cells. We designed this
trial to test RO4929097 in pts with melanoma and its effects on T
lymphocytes and tumor gene expression. Methods: To assess 6-month
progression-free survival (PFS) and 1-year overall survival (OS) in advanced,
untreated melanoma patients (pts), a 2-stage accrual design was
used. Correlative studies: markers of Notch pathway activation in archived
or fresh tumor and T cell functional assays pre-treatment (Rx) and at week
3. Rx dose was 20 mg orally on 3 consecutive days, weekly. Results: 33 pts
were Rx’d in stage 1 (median age 61 [range 32-85]; 70% male; 42%
elevated LDH; 30% unknown primary; 24% bone mets; 36% liver; 55%
lung; 55% lymph node, skin or soft tissue). The clinical outcomes did not
meet criteria for stage 2 accrual. One pt had a confirmed PR of 7 months’
(mo) duration. The median PFS was 1.4 mo, [95% confidence interval, c.i.
1.3-2.7], the 6-mo PFS was 11% [95% c.i 3%-33%], and the 1-year OS
was 45% [95% c.i. 23%-90%]. Treatment was well-tolerated with no grade
(gr) 4-5 tox. The most common gr 2 drug tox were fatigue and nausea in 4
patients (12%) each, and only 4 of 7 gr 3 tox were considered drug-related
(1 increased ALT, 1 QTc prolongation, 1 bradycardia, 1 lymphopenia). Preand
week 3 on-Rx peripheral T cell samples assayed for IL-2 (23 pts) and
IFN-� (22 pts) secretion to Staphylococcal enterotoxin A showed no
significant change, in contrast to in vitro gamma-secretase inhibitors which
blocked T cell activation. Pre- and on-Rx tumor biopsies in one pt showed
no decrease in the Notch target Hey1. Conclusions: RO4929097 at this
dose and schedule has limited activity in molecularly-unselected pts with
melanoma. Lack of effect on T cell function and tumor Hey1 expression
suggests that sustained target inhibition might not have been achieved.
Supported in part by PHS Cooperative Agreements, NCI, DHHS CA32102
and CA38926. ClinicalTrials.gov identifier: NCT01120275.
8527 Poster Discussion Session (Board #16), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
CNS metastases as a site of progression on SWOG intergroup study S0008:
A phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine,
DTIC plus IL-2 (BCT) versus high-dose interferon (HDI) in patients
with high-risk melanoma. Presenting Author: Wolfram E. Samlowski,
Comprehensive Cancer Centers of Nevada, Las Vegas, NV
Background: Central nervous system (CNS) metastases (mets) are common
in stage IV melanoma patients (pts). However, the incidence of CNS mets in
pts with high-risk regional melanoma (HRM; stages IIIA-N2a thru IIIC N3)
is not well described. A recent large prospective S0008 trial provided an
opportunity to evaluate the contribution of CNS mets to treatment failure
and survival. Methods: All pts had HRM treated with wide excision and full
regional lymphadenectomy. Pts were then randomized to receive treatment
with either BCT or HDI. All eligible pts were included in the analysis.
Relapse/progression in the CNS (PCNS) was retrospectively identified only
if clearly documented in case report forms. The cumulative incidence of
PCNS in the presence of the competing hazard of death was estimated and
potential risk factors were explored using the methods of Fine and Gray.
Survival from PCNS was measured from date of PCNS to date of death.
Results: 402 patients were evaluated (BCT: 200, HDI: 202), with median
follow (if alive) of 6 years. The site of progression was identified in 162 (78
%) of 208 pts relapsing on study. Clearly documented PCNS occurred in
53/402 pts (13%). PCNS as a component of initial relapse/progression
occurred in 34 patients (8%) and an additional 19 patients (5%) had
delayed PCNS following initial systemic relapse. Most PCNS (85%)
occurred within 3 years of initial surgery. Differences between arms were
not significant (22 on BCT, and 31 on HDI)(p�0.21). Lymph node
macromets demonstrated a strong correlation with development of PCNS
(p�0.01). Neither primary tumor ulceration nor head and neck primary site
were significant risk factors. Survival from diagnosis of brain mets was short
(median 6 mo BCS, 5 mo HDI, p�0.93). Conclusions: Although the S0008
trial was not specifically designed to evaluate PCNS, a retrospective
analysis identified a high CNS failure rate (at least 13%) in HRM pts,
including 8% as the initial site of relapse. Further studies are needed to
evaluate if screening for CNS mets in high-risk pts is useful and whether
early treatment improves survival.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.