Transcript BRAF

Target therapy in colorectal
cancer
Johnson Lin
Mackay Memorial Hospital
Hemato-oncology
• General concept of target therapy
• Target therapy in colorectal cancer
• Target therapy in pancreatic cancer
Cancer Is a Multifaceted Disease
• Dynamic changes in the human genome
 Gene amplification
 Regulator loss
 Fusion genes
 Activated proteins
• These changes will result in:
 Abnormal growth and proliferation
 Abnormal tumour vasculature
 Abnormal cell to cell signalling
Cancer Development: First Steps
– genetic changes may lead to
uncontrolled cell
proliferation
– a large number of
oncogenes are involved in
signal transduction
• Angiogenesis2
– to grow beyond 1–2mm,
the tumour needs to
initiate
the recruitment of its
own blood vessels
6
• Oncogenesis
(tumourigenesis)
1
What are some of the celluar
changes that lead to cancer?
• Normal cells grow and die
• Malignant cells divide without control and
grow to invade and damage and spead
• Chemical network and molecular signals
under genetic control
What are some of the genetic
changes that lead to cancer
• Genetic alternations production of
abnormal protein cells no longer grow
and divide normally or die as they should
• Proto-oncogenes  oncogenes
development
• Tumor suppressor genes  working
improperly
• Gas pedal vs. Brake pedal
What are targeted therapies?
• Block the growth and spread of cancer
• Interfere with specific molecules involved
carcinogenesis and tumor growth
• Molecular targets vs. molecular targeted
drugs or therapies
• Alone or in combination with other
treatments (eg: chemotherapy)
How do targeted cancer therapies
work?
• Block signal transduction
• Focus on protein involved in signaling
process
• Interfere with cancer cell growth and
division
Types of targeted cancer therapies?
• Small molecule inhibitors focus on tyrosine
kinase, angiogenesis, EGFR pathway etc.
• Apoptosis-inducing drugs
eg: botezomib (block proteosome),
genasense(block BCL-2)
: Monoclonal antibodies, cancer vaccines,
gene therapies
What impact will targeted therpies
have on cancer treatment?
• Individualized based
• More selective, less side effects, improving
quality of life
• Issues on cost-effectiveness
• To be or not to be
So ……………, we need to look at the
tumor cell, as well as its environment
Tumor cell interaction
with :
Potential therapeutic targets
Neovastat
BMS
275291
COL-3
C225
ABX-EGF
Trastuzumab
ZD1839
OSI
774
CI 1033
STI 571
ISIS
2503
Bevacizumab
DC 101
Vitaxin
Cilengitide
FTI
SU5416
SU6668
ZD6474
PKC 412
Bryostatin
UCN-01
ISIS 3521
FTI
Squalamine
BAY 43-9006
ISIS 5132
G3139
CCI-779
CI-1040
FTI
VEGF-targeted Therapy
• Therapy directed at the VEGF receptor
– Sunitinib
– Sorafenib
– Axitinib, Pazopanib
• Therapy directed at the VEGF ligand
– Bevacizumab
Just to recapitulate: ……Tumour Proliferation
Activates Vascular Endothelial Cells
Host
cells
Tumour
Cells
CO2 , Hypoxia 
COX-2 , NO  src,
HER2/neu, ras P53,
VHL Oxidative Stress
FGF
PDGF
VEGF
PDGF
Receptor
FGF
Receptor
VEGF
Receptor
Signal
Transduction
Cascade
Mitotic
Spindle
Proliferation
Invasion
Migration
Degradation
of basement
membrane
Permeability
Capillary tube
formation
and…… tumor Angiogenesis Promotes Tumor
Growth and Metastasis
• The creation of new blood
vessels and lymphatic tissue
by solid tumors allows them
to enlarge and to
metastasize to distal sites
• Inhibition of tumor
angiogenesis, therefore, has
the potential to inhibit
tumor growth and spread
VEGFs Bind to VEGF Receptors on Endothelial
Cells
• VEGF family members bind
to surface receptors on
endothelial cells
• There are three VEGF
receptors: VEGFR-1,
VEGFR-2, and VEGFR-3
• VEGFR-1 and VEGFR-2
stimulate angiogenesis,
VEGFR-3 stimulates
angiogenesis and
lymphangiogenesis
VEGFR-1
VEGFR-2
VEGFR-3
Stabilisation and Maturation of New Tumour Blood Vessels
Dependent on Pericyte Activation by PDGF-
Tumour
Cells
PDGF
Ang-1
VEGF
FGF
Endothelial Cell
Pericyte
Blood
Vessel
Activated of the epidermal growth factor receptor-tyrosine
kinase (EGFR-TK): a pivotal driver of malignancy
RR
RAS RAF
pY
SOS
PI3-K pY
GRB2
pY
MEK
STAT
AKT
MAPK
KK
PTEN
Gene transcription
Cell cycle progression
PP
myc
cyclin D1
Cyclin D1
DNA
Proliferation/
maturation
JunFos
Myc
Chemotherapy/
Metastasis
radiotherapy resistance
Angiogenesis
Survival (antiapoptosis)
Raymond E et al 2000; Woodburn JR 1999; Wells A 1999;
Hanahan D et al 2000; Balaban N et al 1996; Akimoto T et al 1999
Activation of the epidermal growth factor receptor tyrosine
kinase (EGFR-TK): a pivotal driver of malignancy
Activation of the epidermal growth factor receptor tyrosine
kinase (EGFR-TK): a pivotal driver of malignancy
Activation of the epidermal growth factor receptor tyrosine
kinase (EGFR-TK): a pivotal driver of malignancy
ErbB/HER Signaling Network
EGFR signaling biomarkers
I
Anti-EGFR Abs
Cetuximab, Panitumumab,
Matuzumab, h-R3, MDX-447
ATP
Anti-HER1,HER2,HER4 TKIs
I
ATP
PI3K
Gefitinib, Erlotinib, EKB-569, PKI166, GW-572016, CI-1033, AEE788
Grb-2
SOS
Akt
mTOR I
Ras
I
RAS farnesyltransferase
inhibitors
Raf
I
MMS214662, R115777, SCH66336
RAF inhibitors
STAT
3/5
Tumour cell
survival
MEK
MAPK
I
Sorafenib, L-779450
MEK inhibitors
CI-1040, U-0126
Tumour cell
proliferation
mTOR inhibitors
Temsirolimus, RAD001
台灣男女性10大癌症發生分率, 民國95年
(7,167人)肝
17%
22% 乳房 (6,895人)
(5,793人)結腸及直腸
14%
14% 結腸及直腸(4,455人)
(5,756人)肺
14%
9% 肝(2,925人)
(4,879人)口腔
12%
10% 肺(2,992人)
(3,073人)攝護腺
7%
6% 子宮頸(1,828人)
(2,455人)胃
6%
4% 胃(1,339人)
(1,624人)食道
4%
4% 甲狀腺 (1,257人)
(1,406人)膀胱
3%
4% 子宮體 (1,159人)
(1,328人)皮膚
3%
4% 皮膚(1,129人)
(1,116人)鼻咽
3%
3% 卵巢 (1,000人)
(7,420人)其他癌症
17%
男性共42,017人
註:口腔癌含下咽及口咽
20% 其他癌症(6,297人)
女性共31,276人
Chemotherapy has improved CRC survival
but more needs to be done
BSC
5-FU
Irinotecan
Capecitabine
Oxaliplatin
35
30
Months
25
20
15
10
Median OS
5
0
1980
1985
1990
1995
2000
Targeted Therapies
EGFR
ANGIOGENESIS
Overexpression
associated with
poor prognosis in
colorectal cancer
Microvessel density
& VEGF expression
correlate with worse
prognosis in colorectal
cancer.
Strategies;
MAb binding to &
innactivation of receptor
Small molecule inhibition
of active TK site
Strategies;
MAb innactivators of
ligands & receptors
Small molecule TKI
“Targeted” Therapy:
Examples
Growth Factor Inhibitors:
• Anti-EGFR (Epidermal Growth
Factor Receptor)
• Anti-VEGF (Vascular Endothelial
Growth Factor)
EGF Signalling Pathway
EGFR & Cancer
Tumor Type
Colon
RCC
Breast
Ovarian
Glioma
Pancreas
H&N
NSCLC
Bladder
% Expressing
EGFR
25-75%
50-90%
15-90%
35-70%
40-50%
30-50%
80-100%
40-80%
30-50%
EGFR
ligand
Cetuximab
Panitumumab
EMD72000
CETUXIMAB
Chimeric IgG1 Mab for EGFR
Phase II study data
BOND study;
Erlotinib
TK induced
signalling
cascade
1 prior regime
( Ir/5FU )
EGFR +ve
Cetuximab
( n=111 )
OR – 10.8%
mTTP = 1.5month
Cetuximab +
Irinotecan
( n=218 )
OR – 22.9%
mTTP = 4.1month
Further Cetuximab trials
2nd or 3rd line Cetuximab
RR = 9% - 11%; medOS = 6m
Combination with Ox5FU
as 1st line therapy;
RR = 55% - 81%
Combination with Ir5FU
as first line therapy
RR = 43% - 74%
Combination with cytotoxics
and Bevacizumab
Of interest
Cetuximab effective in
patients –ve for EGFR
Degree of skin rash can
act as surrogate marker
for response
Main Epidermal Growth Factor Receptor
Signaling Pathways
Loupakis F. et al., J Clin Oncol. 2009 Jun 1; 27: 2622-29
KRAS, BRAF and
KRAS wt/BRAF wt populations
Population, %
Intention to treat population (n=1198)
KRAS populationa
(n=540)
BRAF populationa
(n=529)
KRAS
wt
(n=348)
KRAS
mt
(n=192)
BRAF
wt
(n=501)
BRAF
mt
(n=28)
KRAS wt/
BRAF wt
(n=313)
KRAS wt/
BRAF mt
(n=28)
KRAS mt/
BRAF wt
(n=188)
KRAS mt/
BRAF mt
(n=0)
All patientsb
64
36
95
5
59
5
36
0
Cetuximab
+ FOLFIRI
49
55
52
39
50
39
55
0
FOLFIRI
51
45
48
61
50
61
45
0
Treatment
arm
aAs
KRAS/BRAF populationa
(n=529)
a proportion of the primary analysis population; bAs a proportion of the relevant subpopulation
BRAF mutations were observed only in patients with KRAS wt disease
Baseline characteristics were slightly more favorable for patients with KRAS and BRAF wt
tumors than for those with tumors mutations
mt, mutant; wt, wild-type
CRYSTAL PFS:
BRAF wt vs. BRAF mt
BRAF wt: 95%
HR: 0.81
p=0.01
BRAF mt: 5%
Internal Use Only
CRYTAL: Primary endpoint (PFS)
ERBITUX + FOLFIRI (n=599)
1.0
FOLFIRI (n=599)
0.9
HR 0.851 [95% CI 0.726–0.998]; p=0.0479
0.8
15% risk reduction for progression
PFS estimate
0.7
0.6
8.9 months
1-year PFS rate:
23% vs 34%
0.5
0.4
8.0 months
48%
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
PFS time (months)
Van Cutsem E, et al. ECCO 2007 (Abstr No. 3001)
Primary endpoint: PFS — KRAS wild-type
1.0
KRAS wild-type (n=348): HR=0.68; p=0.017
0.9
mPFS ERBITUX + FOLFIRI: 9.9 months
mPFS FOLFIRI: 8.7 months
0.8
0.7
PFS
0.6
1-year PFS rate
25% vs 43%
0.5
0.4
0.3
0.2
0.1
0
0
2
4
6
8
10
12
14
16
Time (months)
ERBITUX + FOLFIRI
FOLFIRI
Van Cutsem E, et al. J Clin Oncol 2008;26(Suppl.) [Abstract no. 2]
18
Conclusions
BRAF mutation status
• BRAF mutations were identified in 5% of the population
– KRAS and BRAF mutations were mutually exclusive
• BRAF mutation status
– Prognostic for PFS and OS
– Not predictive of Erbitux efficacy in this retrospective study
• Patients with KRAS wt tumors benefit from Erbitux treatment
independent of BRAF mutation status
• Routine testing of mCRC tumors for BRAF mutation status is unlikely
to be useful for directing treatment in the 1st-line treatment of
metastatic CRC in combination with chemotherapy
Internal Use Only
→In all 27 patients, the PTEN protein was normally expressed in 16 patients, and 10 of them
achieved a PR.
→In contrast, no benefit was documented in 11 patients with loss of PTEN activity (P<0.001).
Frattini M, et al., Br J Cancer. 2007; 97: 1139–1145
VEGF and Angiogenesis
The Angiogenic Switch and
Antiangiogenic Therapy
Somatic
mutation
Small
avascular
tumor
Tumor secretion of
angiogenic factors
stimulates
angiogenesis
Rapid tumor growth,
invasion and metastasis
Carmeliet and Jain. Nature. 2000;407:249.
Angiogenic inhibitors
may reverse this
vascularization
Anti-angiogenic agents
Bevacizumab
Humanized anti VEGF monoclonal
antibody
Inhibits angiogenesis
VEGF-R
Registration trial; Phase III
1st line advanced colorectal cancer
Bevacizumab
PTK/ZK
IFL/placebo
(n=412)
RR
mTTP
mOS
35%
6.2
15.6
IFL/bevacizumab
(n=403)
45%
10.6
20.3
Toxicity – hypertension / perforation
使用癌思停(Avastin)有哪些
需要特別注意的事項?
胃腸穿孔：轉移性大腸或直腸癌患者在使用癌思停
(Avastin)及化學療法時，會有發生胃腸穿孔的危
險，發生的機率約1.5%。
高血壓：以癌思停(Avastin)治療之患者的高血壓
發生率較高。建議在治療期間，每二個星期定期監
測患者的血壓。如果高血壓無法以藥物治療控制，
應永久停用癌思停(Avastin)的治療。
傷口癒合 ：重大手術後至少28天或手術傷口完全
癒合後，再開始進行癌思停(Avastin)的治療。
47
使用癌思停(Avastin)有哪些
需要特別注意的事項?
動脈血栓栓塞 ：有動脈血栓栓塞病史或年齡超過
65歲的患者，在癌思停(Avastin)治療期間發生動
脈血栓栓塞的危險性會增加。
出血 ：在癌思停(Avastin)治療期間出現3級或4級
出血的患者應永久停用癌思停(Avastin)。
48
N. Wolmark et al., #LB A4
Addition of Bevacizumab to
Oxaliplatin-Based Chemotherapy
Does Not Prolong DFS in Stage II/III
Colon Cancer
N. Wolmark, G. Yothers, M. J. O'Connell, S.
Sharif, J. N. Atkins, T. E. Seay, L.
Feherenbacher, S. O'Reilly, C. J. Allegra
Study conducted from
September 2004 - October 2006
Global Strategic Marketing
A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus
bevacizumab in stage II or III carcinoma of the colon:
Results of NSABP Protocol C-08.
• Primary endpoint: DFS
• Median follow-up: 35.6 months
• Median duration of bevacizumab therapy: 11.5 months
Stratified by
number of
postitive nodes
Paients with
stage II/III
colon cancer
(N=2710)
mFLOFOX (n=1356)
Bevacizumab
+
mFLOFOX
(n=1354)
6 months
2009 ASCO information update
Bevacizumab
(n=1354)
6 months
A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus
bevacizumab in stage II or III carcinoma of the colon:
Results of NSABP Protocol C-08.
No significant improvement in 3-year DFS rate with addition of bevacizumab
to mFOLFOX6 chemotherapy in patients with stage II/III colon cancer
N
3 year-DFS
mFF6
1338
75.5
mFF6+B
1334
77.4
P
0.15
Tumor stage did not significant affect DFS at 3 years
HR
P value
Stage II
0.82
NS
Stage III
0.90
NS
2009 ASCO information update
Development of Systemic Chemotherapy in CRC
1980
1985
1990
1995
2000
2005
5-FU
UFT
Irinotecan
Capecitabine
Oxaliplatin
Target Therapy
Therapeutic Concepts
Palliative chemother .
Adjuvant chemotherapy
Neoadjuvant chemotherapy
Questions and Answers
• Combination is trendy
• Interaction will vary with different agents and
distinctive biology of tumor
• In vitro data can not predict In vivo results
• Stored patient materials can provide certain
answers with retrospective analysis as new
knowledge and trial results emerge