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

264s Gastrointestinal (Noncolorectal) Cancer
4103 General Poster Session (Board #48F), Mon, 8:00 AM-12:00 PM
A phase II trial of MEK inhibitor BAY 86-9766 in combination with
sorafenib as first-line systemic treatment for patients with unresectable
hepatocellular carcinoma (HCC). Presenting Author: Ho Yeong Lim, Division
of Hematology-Oncology, Department of Medicine, Samsung Medical
Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
Background: Sorafenib (S) is the only approved systemic treatment for
unresectable HCC. Nevertheless, there remains an unmet medical need for
more effective treatment options for this disease. BAY 86-9766 (B) is an
oral, allosteric inhibitor of MEK, a key component of the MAP kinase
pathway. This study evaluated the efficacy and safety of a combination
therapy with B plus S in patients (pts) with HCC. Methods: This is a single
arm, open-label, phase 2 study. Eligible were pts with unresectable HCC,
Child-Pugh Class A, performance status (PS) 0-1, and no prior systemic
anticancer therapy for HCC. Pts started Cycle 1 (21 days) with B 50 mg bid
orally plus S 600 mg daily (200 mg AM, 400 mg PM) orally. If there was no
hand-foot skin reaction, fatigue, or gastrointestinal toxicity � grade 2, S
was escalated to 400 mg bid from Cycle 2 on. Treatment continued until
progression or withdrawal criteria were met. Tumor assessment was
performed every 6 weeks during treatment. Safety was evaluated every
week for the first 6 weeks and every 3 weeks thereafter. Results: Seventy pts
from Asia started study treatment. Pts were predominantly male (86%);
median age was 56 years; 54% had PS of 0 and 46% PS of 1. The vast
majority had liver cirrhosis (83%) and infection with HBV (76%) or HCV
(17%). Sixty-five were evaluable for efficacy per protocol. Three pts (5%)
had confirmed partial response and 25 pts (38%) had prolonged stable
disease (�10 weeks), with a disease control rate of 43%. Median
time-to-progression was 4.1 months. Survival data are not mature, yet. The
most frequent drug-related adverse events (AEs) were rash (60%), diarrhea
(59%), AST elevation (43%), vomiting (30%), nausea (29%), ALT elevation
(26%), and anorexia (26%). There were 4 Grade 5 related AEs (hepatic
failure, sepsis/hepatic encephalopathy, tumor lysis syndrome, and unknown
cause, respectively). Dose modifications due to AEs were necessary
in almost all pts. The median daily dose was 64.2 mg for B and 443.3 mg
for S, respectively. Conclusions: B in combination with S showed antitumor
activity in pts with HCC. However, frequent dose modifications due to AEs
might have limited the treatment effect of this combination.
4105 General Poster Session (Board #48H), Mon, 8:00 AM-12:00 PM
Randomized phase II study of the x-linked inhibitor of apoptosis (XIAP)
antisense AEG35156 in combination with sorafenib in patients with
advanced hepatocellular carcinoma (HCC). Presenting Author: Ann Sing
Lee, Tuen Mun Hospital, Tuen Mun, Hong Kong
Background: XIAP inhibits caspases which are proteases responsible for
apoptotic cell death. It is highly expressed in HCC. AEG35156 is a second
generation antisense oligonucleotide targeting XIAP mRNA, thus lowers the
apoptotic threshold of cancer cells. It also accumulates in the liver. This
study is designed to assess the added benefit of combining AEG35156 with
sorafenib. Methods: Patients with histologically or clinically diagnosed
(AASLD criteria) HCC who had failed or were unsuitable for resection or
ablative therapies were randomized (2:1) to receive either weekly injection
of AEG35156 300mg in combination with sorefanib 400mg BID or
sorefanib alone. The primary end point was progression-free survival (PFS).
Other endpoints were overall survival (OS), response rates and safety.
Results: 51 patients were recruited. 48 patents were evaluable. There were
31 patients in the combination arm and 17 in the control arm. The median
age was 60. 88% of patients were male. 81% of patients were hepatitis B
carrier. 90% of patients belong to Child-Pugh class A. The median
follow-up was 16.2 months. The PFS for the combination arm was 4.0
months (95% CI: 1.2-4.1) and 2.6 months for control arm. The OS for the
combination arm was 6.5 months (95% CI: 3.9-11.5) and 5.4 months for
the control arm. There were 3 partial responders (Choi’s criteria) in the
combination arm (10%, 95% CI: 3-27%) and none (0%) in the control
arm. Patients who had the study treatment interrupted (PFS 4.0, 95% CI:
2.4-5.4) or had dose modification (PFS 4.45, 95% CI: 1.0-6.5) according
to protocol did significantly better than those who had no dose reduction
(PFS 1.2, 95% CI: 1.2-4.0) and those in the control arm (PFS 2.6, 95% CI:
1.2-5.4). This also applies to OS. Regarding toxicities, there were one
AEG35156 related serious adverse event (SAE) of hypersensitivity and two
sorafenib related gastrointestinal SAE. Conclusions: AEG35156 in combination
with Sorafenib was well tolerated in patients with advanced HCC.
Dose reduced AEG35156 in combination with sorafenib have shown more
activity than sorafenib alone and warrants further investigation.
4104 General Poster Session (Board #48G), Mon, 8:00 AM-12:00 PM
A prospective cohort study using a Japanese nationwide survey to evaluate
the therapeutic effects of surgery and percutaneous ablation for hepatocellular
carcinoma. Presenting Author: Kiyoshi Hasegawa, Hepato-Biliary-
Pancreatic Surgery Division, Department of Surgery, Graduate School of
Medicine, University of Tokyo, Tokyo, Japan
Background: Which is the best treatment for less advanced hepatocellular
carcinoma (HCC) with good liver function remains one of the most
important and unsolved problems. To solve this problem, we conducted this
study and evaluated the therapeutic impacts of surgical resection (SUR),
percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA)
on long-term outcomes in patients with HCC. Methods: A large-scale
database constructed by a Japanese nationwide survey was used for this
study. Between 2000 and 2005, 28,510 patients with HCC were treated
by SUR, PEI, or RFA, among whom we identify 12,968 patients with no
more than 3 tumors (�3cm) and liver damage of class A or B. The patients
were divided into SUR group (n�5,361), RFA group (n�5,548), and PEI
group (n�2,059). Rates of overall and recurrence-free survival were
compared among them. Results: Median follow-up was 2.16 years. Overall
survival rates at 3 and 5 years were respectively 85.3%/71.1% in the SUR
group, 81.0%/61.1% in the RFA, and 78.9%/56.3% in the PEI. Recurrence-free
survival rates at 3 and 5 years were 56.7%/36.2%, 42.8%/
28.3%, and 35.7%/23.1%, respectively. On multivariate analysis, the
hazard ratio for death was significantly lower in the SUR group than in the
RFA (SUR vs. RFA:0.84, 95% confidence interval, 0.74-0.95; p�0.006)
and the PEI (SUR vs. PEI:0.75, 0.64-0.86; p�0.0001). The hazard ratios
for recurrence were also lower in the SUR group than in the RFA (SUR vs.
RFA:0.74, 0.68-0.79; p�0.0001) and the PEI (SUR vs. PEI:0.59,
0.54-0.65; p�0.0001). Conclusions: Surgical resection would provide
longer overall and recurrence-free survival than either RFA or PEI in
patients with HCC.
4106 General Poster Session (Board #49A), Mon, 8:00 AM-12:00 PM
Blood signatures for early liver cancer detection in patients with chronic
hepatitis B. Presenting Author: Choong-Chin Liew, GeneNews Ltd, Richmond
Hill, ON, Canada
Background: Some 20-30% of patients with chronic hepatitis B (CHB)
eventually develop hepatocellular carcinoma (HCC), a disease with poor
prognosis and high mortality unless detected early. Ultrasound and/or
alpha-fetoprotein (AFP) are widely used for HCC surveillance. However
these technologies are operator-dependent, have low sensitivity and are
considered inadequate for screening. This study describes a blood-based
gene-expression signature prognostic for HCC in CHB patients. Methods:
PaxGene was used to extract RNA from whole blood samples taken from
more than 1,000 Malaysian patients (matched HCC, CHB, healthy controls).
Complementary DNA was generated from isolated RNA via reverse
transcription and analyzed using Affymetrix U133Plus 2.0 with MAS 5.0
normalization. To minimize bias we developed a novel algorithm based on
SentinelPair regression analysis to identify biomarker panels. A Monte
Carlo search identified pair combinations that could differentiate between
cancer and controls. Twelve genes were selected for qRT-PCR Cohort 1
verification (n�139). Six genes were then short-listed for qRT-PCR Cohort
2 verification using independent samples (n�150). Results: Multivariate
quantitative microarray analysis of 147 samples (HCC�47; CHB�50;
controls�50) identified 12 probe sets differentially expressed between
HCC patients and controls and CHB (ROC AUC�0.90). These genes were
evaluated using qRT-PCR on the same cohort (ROC AUC�0.86). Six genes
were subsequently short listed for qRT-PCR Cohort 2 verification. The AUC
of the 6-gene-combination of Cohort 2 (HCC�50; CHB�50; controls�50)
was 0.80. Importantly, of the thirteen HCC with low AFP (�15ng/ml), 9
were predicted as “positive.” Conclusions: Blood RNA biomarkers identified
in this study may form the basis of a test that can be used in patients with
CHB for detection of early HCC, potentially improving prognosis for this
cancer. This blood-based test would represent a significant clinical
alternative to ultrasound and/or AFP.
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