Transcript Hepatobiliary Malignancy Program

Treatment of Biliary Cancers
Abby B. Siegel, MD, MS
Columbia University
Co-Chair, SWOG Hepatobiliary Committee
NCI Task Force, Hepatobiliary Cancers
Biliary Anatomy
Adapted from De Groen et al, NEJM 1999 Oct 28;341(18):1368-78
Gemcitabine With or Without Cisplatin in Advanced or
Metastatic Biliary Cancer
(UK ABC-02 trial)
Treatment arm
Gem
Gem + Cis
Number of patients
n=206
n=204
Deaths n(%)
141
(68.5)
122 (59.8)
8.3
11.7
Median survival (mo)
Log rank p value
Hazard ratio (95% CI)
0.002
0.70 (0.54, 0.89)
Gemcitabine/Cisplatin in
Perspective
• A standard for advanced disease
• Study results influenced by:
• GB vs IHCC vs EHCC
• Included ampullary cancers
• Patient selection:
– AST/ALT/Alk phos<3XULN
– T Bili < 1.5 ULN
– Accrual in select centers with experience
– 27% locally advanced disease
• Caution about using Gem/cis as the only backbone in
first line therapy
• What about other effective therapies: Gem/cape?
Single Agent Targeted Therapy
Target
Agents in testing
Study type
# of patients
Results
VEGF/Ras-RafMAPK
Sorafenib
(SWOG 0514)
Phase II single agent
NCT01093222
N=31
Median PFS 3 mo
Median OS 9 mo
Sorafenib
Phase II single agent
NCT00238212
N=46
Median PFS 2.3 mo
Median OS 4.4 mo
Trastuzumab
Phase II single agent
Erlotinib
Phase II single agent
NCT00033462
N=42
Median TTP 2.6 mo
Median OS 7.5 mo
Lapatinib
Phase II single agent
N=17
Median PFS 1.8 mo
Median OS 5.2 mo
mTOR
Sirolimus
Phase II single arms
for HCC and ICC
N=9
3/9 SD
Median survival 7 mo
MEK
MEK-162
Phase I
N=26
1CR
AZD6244
Phase II single agent
N=28
1 CR
Median TTP 5.4 mo
MK-2206
Phase II single agent
(Second line)
On-going
EGFR/Her-2 neu
AKT
Closed d/t slow accrual
1CR
Bengala C et al, British Journal of Cancer 2010,102: 68 – 72; Rizell et al, Int J Clin Oncol 2007 13:66-70
Philip, P. A. et al. J Clin Oncol 2006, 24:3069-3074, Ramantaan et al, Cancer Chemother Pharmacol 2009 64:777–783
Combination Targeted Agents
Targets
Agents
Study type
Number of
patients
Results
VEGF/EGFR
Bevacizumab
and Erlotinib
Phase II
(Ph II
consortium)
34 pts (interim
report)
RR 17%
Median TTP 8
months
Bevacizumab
and Erlotinib
Phase II
(Wisconsin)
NCT00356889
53
RR 12%
Median TTP 4.4
OS 9.9 months
Bevacizumab
and Erlotinib
Phase II
(Denmark)
NCT00350753
Sorafenib and
Erlotinib
Phase II
(SWOG0941)
NCT01093222
VEGF/EGFR
Ras/Raf
On-going
32
RR 6% (unconf)
PFS 2 months
OS 6 months
Cytotoxic Chemotherapy with Targeted Agents
Combination
Targeted
agent(s)
Study type
Number
Results
Gemcitabine,
oxaliplatin
Cetuximab
Rand Phase II
150
RR 29%
Median PFS 6 mo
Median OS 12.4 mo
Gemcitabine,
oxaliplatin
Erlotinib
Phase III
268
RR 30%
Median PFS 5.8 mo
Median OS 9.5 mo
Gemcitabine,
oxaliplatin
Bevacizumab
Phase II
35
RR 40%
PFS 8.8 mo
OS 11.6 mo
Gemcitabine,
oxaliplatin,
capecitabine
Panitumumab
Phase II
NCT00779454
On-going
Gemcitabine,
oxaliplatin
Sorafenib
Phase II
NCT00955721
On-going
Gemcitabine,
cisplatin
Sorafenib
Phase II
(MSK)
NCT00919061
On-going
Gemcitabine,
capecitabine
Bevacizumab
Phase II
NCT01007552
On-going
Gemcitabine
Vandetanib
(VEGFR/EGFR)
Randomized
Phase II
NCT00753675
On-going
Adjuvant Therapy for Biliary
Cancers
• No clear prospective randomized data
• Best evidence so far is a meta-analysis
• 6712 patients, non significant
improvement in OS for any adjuvant
therapy (HR 0.74, p=0.06)
Adjuvant Therapy for Biliary Cancer:
Horgan A M et al. JCO 2012;30:1934-1940
Adjuvant Therapy for Biliary
Cancers
• No large randomized trials yet, and no clear
guidelines
• Metaanalysis suggests possible benefit of
chemotherapy for all, particularly for node (+)
and margin positive disease
• Radiation is often added in margin (+)
disease
I usually give 6 months gem or gem/cis for
margin (-), consider XRT + chemo for margin
(+) disease; consider re-resection also
Horgan et al. JCO 2012;30:1934-1940
Adjuvant Therapy: SWOG 0809
• Eligibility
– Gallbladder cancer or EHCC
– At least one of the following:
• T2-T4
• N1
• Positive margins
Gemcitabine 1000 mg/m2 IV
over 30 min D1 and D8
+ Capecitabine 750 mg/m2
PO BID x 14 days
Concurrent EBRT with
Capecitabine 665 mg/m2 BID
x 7 days
For 6 weeks
X
4 cycles
4500 cGy (5 days a week, 180
cGy daily) with 900 cGy boost
Adjuvant Therapy in Biliary
Cancers: Current Landscape
• BILCAP (UK): Phase 3: capecitabine versus
observation in GB, IHCC, EHCC (n=360)
• French phase 3 study: gemcitabine and oxaliplatin
versus observation in GB, IHCC, EHCC (n=190)
• ACTICCA-01: Phase 3: adjuvant gemcitabine and
cisplatin versus BSC or capecitabine (depends on
BILCAP)
Potential New Targets in
Cholangiocarcinoma
• MEK
• IDH1/2
• FGFR
MEK Inhibition in Cancer
Therapy
RAS-RAF-MEK pathway
Receptor Tyrosine Kinase
implicated in many
tumors
H-Ras
•
K-Ras
N-Ras
B-Raf mutations:
Mutated and activated
in multiple cancers
0-22% Bile duct tumors
A-Raf
•
B-Raf
C-Raf
K-Ras mutations
3-54% Bile duct tumors
MEK1&2
ERK1&2
Activation of Transcription/Proliferation
MEK Inhibitors in Biliary Cancer
Treatment
Target
No. of
Patients
RR (%)
PFS
(months)
OS
(months)
Toxicity Profile ( grade 3 and 4)
AZD6244
(first and
second line)
MEK
1/2
28
12
1 CR
5.4
9.8
Fatigue (8%), diarrhea ( 16%), rash,
cellulitis
MEK162
(ARRY438162)
MEK
1/2
No ocular toxicities reported
26 eval
8
2.6
N/A
1 CR
(first and
second line)
Bekaii-Saab et al. JCO 2011 29:2357-63, Finn et al, GI ASCO 2012
Anasarca, hypokalemia,
hyponatremia, upper/lower
gastrointestinal hemorrhage and
mucositis (1 pt each)
Retinopathy was the most
frequently reported event (6 pts)
Mek Inhibition Second Line: Trametinib
(SWOG 1310)
5-FU or capecitabinea
(N = 40)
Patients with refractory
advanced biliary cancer
who have failed one
prior line of treatment
Randomize
Single Agent
Trametinib
(2mg QD) (N=40)
IDH Pathway
Yen et al, Oncologist 2012 17:5-8
Yen et al, Oncologist 2012 17:5-8
IDH Mutations Seen in
Cholangiocarcinomas
Borger et al, Oncologist, 2010 17:72-79
Borger et al, Oncologist, 2010 17:72-79
IDH Inhibitors
• Isocitrate dehydrogenase mutations lead to
production of 2-hydroxyglutamate
• 2HG as potential non-invasive biomarker of
response
– Plasma
– MRS
• Inhibitors being actively developed
FGFR2 Fusions Define a Unique Molecular Subtype of Cholangiocarcinoma
Wu Y et al. Cancer Discovery 2013;3:636-647, Arai et al, Hepatology 2013, EPUB ahead of print
Optimizing the Evaluation of Targeted
Agents in Cholangiocarcinoma
• Choosing the “relevant” target(s) or
combination of targets
• Having appropriate preclinical models
• Stratifying by site if target differs based on
location
• Enriching clinical trial population for target