New Perspectives in GI Malignancies

New Perspectives in GI
Malignancies

Axel Grothey
Professor of Oncology
Mayo Clinic Rochester

Disclosures

• Consulting activities
(honoraria went to the Mayo Foundation)
• Amgen
• Bayer
• Pfizer
• Roche/Genentech
• Sanofi-Aventis
• BMS

I WILL include discussion of investigational or off-label use of a
product in my presentation.

New Perspectives

• CRC
• Duration of anti-VEGF therapy
• Biomarker-driven treatment decisions
• Novel agents
• Gastric/GEJ cancer
• Anti-HER2 therapy
• Pancreas cancer
• FOLFIRINOX

Treatment paradigms for mCRC
• Some patients with stage IV disease can be
cured by an interdisciplinary approach
• In the palliative setting: FOLFOX = XELOX =
FOLFIRI (XELIRI has problems with toxicity)
• Most patients tolerate a chemotherapy
doublet, but not all need it
• The addition of biologics to chemotherapy
has improved outcomes, but not as much as
we hoped
• We are on the verge of individualized
therapy based on molecular predictive
factors

Concept of “All-3-Drugs” - Update 2005
11 Phase III Trials, 5768 Patients

22
First-Line Therapy
21
Median OS (mo)

20 Infusional 5-FU/LV
19 + irinotecan
18 Infusional 5-FU/LV
+ oxaliplatin
17
Bolus 5-FU/LV
16 + irinotecan
15 Irinotecan
+ oxaliplatin
14
Bolus 5-FU/LV
13 P =.0001
12 LV5FU2

0 10 20 30 40 50 60 70 80 FOLFOXIRI
Patients with 3 drugs (%)
CAIRO 2007
OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85
Grothey & Sargent, JCO 2005

Biologic Agents in Colorectal
Cancer = Monoclonal Antibodies

Fab

Fc

Murine Ab Chimeric Humanized Ab Human Ab
“momab” Mouse-Human Ab “zumab” “mumab”
“ximab”
EGFR
(17-1A) Cetuximab Panitumumab
Bevacizumab
VEGF

Nomenclature of Monoclonal Antibodies
-mab monoclonal antibody
-mo-mab mouse mab
-xi-mab chimeric mab
-zu-mab humanized mab
-mu-mab human mab
-tu-xx-mab tumor-directed xx mab
-li-xx-mab immune-directed xx mab
-ci-xx-mab cardiovascular-directed xx mab
-vi-xx-mab virus-directed xx mab

Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab

Phase III Trial IFL +/- Bevacizumab
in MCRC: Efficacy

IFL+ Placebo IFL+ Bevacizumab
(n=411) (n=402) P Value

Median survival (mo) 15.6 20.3 0.00004

PFS (mo) 6.2 10.6 <0.00001

ORR (%) 35 45 0.0036
CR 2.2 3.7
PR 32.5 41.2

Duration of resp. (mo) 7.1 10.4 0.0014

Hurwitz et al. N Engl J Med 2004

Phase III Trial of IFL +/-
Bevacizumab in MCRC: PFS
1.0
Proportion progression-free

HR=0.54, P<0.00001
Median PFS: 6.2 vs 10.6 mo
0.8

0.6

0.4

Treatment Group
0.2 IFL + placebo
IFL + bevacizumab
0
0 10 20 30
Progression-free survival (mo)

Hurwitz et al. N Engl J Med 2004

XELOX vs FOLFOX +/- Bevacizumab
Roche NO16966 study design
Recruitment Recruitment
June 2003 – May 2004 Feb 2004 – Feb 2005

XELOX +
XELOX XELOX + placebo
bevacizumab
N=317 N=350
N=350
FOLFOX4 +
FOLFOX4 FOLFOX4 + placebo
bevacizumab
N=317 N=351
N=350

Initial 2-arm Protocol amended to 2x2 placebo-
controled design after bevacizumab
open-label study phase III data1 became available
(N=634) (N=1401)

1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy & Saltz, JCO 2008

PFS chemotherapy + bevacizumab
superiority: primary endpoint
1.0
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)
0.8 p = 0.0023
PFS estimate

0.6

0.4

0.2

8.0 9.4
0
0 5 10 15 20 25
Months

FOLFOX+placebo/XELOX+placebo N=701; 547 events
FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events
Saltz et al., JCO 2008

PFS chemotherapy + bevacizumab
superiority: XELOX and FOLFOX subgroups
1.0 1.0

0.8 0.8
PFS estimate

0.6 0.6

0.4 0.4

0.2 0.2
7.4 9.3 8.6 9.4
0 0
0 5 10 15 20 25 0 5 10 15 20 25
Months Months
XELOX+placebo N=350; 270 events FOLFOX+placebo N=351; 277 events
XELOX+bevacizumab N=350; 258 events FOLFOX+bevacizumab N=349; 255 events

XELOX subgroup FOLFOX subgroup
HR = 0.77 [97.5% CI 0.63–0.94] (ITT) HR = 0.89 [97.5% CI 0.73–1.08] (ITT)
p = 0.0026 p = 0.1871
Saltz et al., JCO 2008

NO16966 PFS Subgroup Analyses:
On-Treatment Population
1.0
XELOX Group FOLFOX Group
1.0

0.8 0.8
Survival

Survival
0.6 0.6

0.4 0.4

0.2 0.2
7.0 m 9.5 m 8.4 m 10.6 m
0 0
0 100 200 300 400 500 0 100 200 300 400 500
Study day Study day

HR = 0.61 [97.5% CI 0.48–0.78] HR = 0.65 [97.5% CI 0.50–0.84]
P ≤ .0001 P = .0002

FOLFOX4 + FOLFOX-4 +
XELOX + placebo XELOX + Bev
VS placebo VS Bev

Saltz et al., ASCO GI 2007

CAIRO2: Study design

CapOx + BEV
(COB, n=368)
EGFR-detectable
mCRC R

Primary endpoint
CapOx + BEV +
• Progression-free survival Cetuximab
(COB-C, n=368)
Secondary endpoints
• RR
• OS time Oxaliplatin d/c’d after 6 cycles
• Toxicity i.e. after 18 weeks = 4.5 mos
• Translational research
Tol et al. NEJM 2009

CAIRO2 - KRAS genotyping (n=501)

KRAS wild-type KRAS mutated
p value
n = 314 (61%) n = 196 (39%)
Median PFS (months)
COB 10.6 12.5 0.80
COB-C 10.5 8.1 0.04
p value 0.30 0.003
Median OS (months)
COB 22.4 24.9 0.82
COB-C 21.8 17.2 0.06
p value 0.64 0.03

Tol et al. NEJM 2009

BRiTE Registry - Patients with Bevacizumab
Beyond Progression (BBP)
Evaluable
patients
BRiTE: (n=1953)
Total N=1953
1445 pts with 1st PD
932 deaths (1/21/07 cut-off) 1st Progression
Median follow-up 19.6 mo (n=1445)

Physician decision - no randomization

No Post-PD
No BBP BBP
Treatment
(n=253) (n=531) (n=642)

Grothey et al. JCO 2008

BRiTE: Patient Outcome Based on
Treatment Post 1st PD
No Post-PD
No BBP BBP
Treatment
(n=253) (n=531) (n=642)

# of deaths 168 306 260
(%) (66%) (58%) (41%)
Median OS
12.6 19.9 31.8
(mo)
1yr OS rate
52.5 77.3 87.7
(%)
OS after 1st
3.6 9.5 19.2
PD (mo)
Grothey et al. JCO 2008

AIO 0504 / Roche ML18147
Multinational European Trial

Any-OX Any-IRI
+ BEV + BEV

R R

Any-IRI Any-OX
Any-IRI Any-OX + BEV
+ BEV

N = 820 Accrual completed May 31, 2010
Primary EP: OS

mAbs Target Tumor Cell-Bound EGFR

Ligand

Extracellular
EGF-R

Ras
PI3K
PTEN Raf
Intracellular
Akt
MEK

MAPK

Cell survival
DNA Cell Motility
Proliferation
Angiogenesis Metastasis

RAS (RAt Sarcoma virus)
• Three genes encode highly homologous
proteins:
H-RAS, N-RAS, and K-RAS
• Point mutations in RAS genes occur in 30% of all
cancers
• K-RAS mutations present in 40% of CRC
• Codons 12, 13, and 61 are most commonly
involved
• Mutations result in constitutive activation of
RAS-RAF-MAPK signaling pathway leading to
cell proliferation and enhanced cell survival

KRAS Status and Response
to Cetuximab in Refractory mCRC
Response confined to KRAS wt

ORR, %
Study Treatment N (% wt)
mt wt
Liévre et al, 2006 C-mab + CT 30 (57) 0 65
P-mab or
Benvenuti et al, 2007 C-mab ± CT 48 (67) 6 31

De Roock et al, 2007 C-mab ± CT 113 (59) 0 40
Capuzzo et al, 2007 C-mab ± CT 81 (60) 6 26
Di Fiore et al, 2007 C-mab + CT 59 (73) 0 28
Khambata-Ford et al, 2007 C-mab 80 (62) 0 10
Liévre et al, 2008 C-mab ± CT 76 (64) 0 49

ORR, overall response rate; p-mab, Panitumumab; c-mab, Cetuximab; CT, chemotherapy;
mt, KRAS mt; wt, KRAS wt

KRAS as Biomarker for Panitumumab
Response in Metastatic CRC
• PFS log HR significantly different depending on K-ras status (P < .0001)
• Percentage decrease in target lesion greater in patients with wild-type KRAS
receiving panitumumab

Patients With Wild-Type KRAS Patients With Mutant KRAS

1.0 Pmab + BSC
Median Mean 1.0
BSC alone Events/N (%) Pmab + BSC
0.9 in Wks in Wks Mean
Proportion With PFS

0.9 BSC alone Median

Proportion With PFS
0.8 12.3 19.0 Events/N (%) in Wks in Wks
115/124 (93) 0.8
0.7 114/119 (96) 7.3 9.3 9.9
0.7 76/84 (90) 7.4
0.6 95/100 (95) 7.3 10.2
HR: 0.45 (95% CI: 0.34-0.59) 0.6
0.5 Stratified log rank test: P < .0001 0.5
HR: 0.99 (95% CI: 0.73-1.36)
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52

Weeks Weeks

Amado et al. JCO 2008

NCIC CTG CO.17:
Randomized Phase III Trial in mCRC
Cetuximab vs BSC (no cross-over)
KRAS mut KRAS wild-type All patients
BSC Cetux BSC Cetux BSC Cetux
n=83 n=81 n=113 n=117 n=285 n=287

RR 0% 1.2% 0% 12.8% 0% 6.6%

PFS
1.8 1.8 1.9 3.8 1.8 1.9
(mos)
<0.0001 <0.0001

OS
4.6 4.5 4.8 9.5 4.6 6.1
(mos)
<0.0001 0.0046

Karapetis et al. NEJM 2008

CRYSTAL Study (1st Line)

FOLFIRI + Cetuximab N = 599

EGFR-expressing
metastatic CRC R PFS

Stratified by: FOLFIRI N = 599
• Regions
• ECOG PS

• Primary Endpoint: PFS (independent review)
• Secondary Endpoints: RR, DCR, OS, Safety, QoL
• Sample Size: 1217 patients randomized, ITT: 1198 pts

Van Cutsem et al. NEJM 2009

5-FU/LV/IRI (FOLFIRI) +/- Cetuximab: PFS
Non-KRAS adjusted
1.0
0.9

0.8
Subgroup
0.7
effect HR = 0.851
P = 0.0479
PFS estimate

No benefit
0.6
8.0 vs 8.9 mos
0.5

0.4

0.3

0.2
FOLFIRI + Cetuximab
0.1
FOLFIRI
0.0
0 2 4 6 8 10 12 14 16 18 20
Months

CRYSTAL - KRAS wild-type mCRC
(N=348): PFS
1.0
FOLFIRI + Cetuximab: 9.9 mos
Progression-free survival estimate

0.9 FOLFIRI: 8.7 mos
0.8 HR=0.68, p=0.017
0.7
0.6
1-yr PFS rate
0.5
25% vs 43%
0.4
0.3
0.2
0.1
0.0
0 2 4 6 8 10 12 14 16 18
Months
Cetuximab + FOLFIRI FOLFIRI

CRYSTAL: Efficacy Update
After Additional KRAS Testing
KRAS wild-type FOLFIRI FOLFIRI + P value
cetuximab
n 350 316
RR (%) 39.7 57.3 < 0.0001
mPFS (mos) 8.4 HR 0.7 9.9 0.0012
mOS (mos) 20 HR 0.8 23.5 0.0093

KRAS mutated FOLFIRI FOLFIRI + P value
cetuximab
n 183 214
RR (%) 36.1 31.3 0.34
mPFS (mos) 7.7 7.4 0.26
mOS (mos) 16.7 16.2 0.75

Van Cutsem et al. JCO 2011

COIN (cetuximab): First-line Study

MRC-sponsored study supported Continuous* XELOX
by Merck (109 UK/Irish Hospitals) Arm A
or FOLFOX

First-line mCRC Continuous XELOX
(n= 2445)
R or FOLFOX + Arm B
cetuximab

Intermittent**
Arm C
• Primary endpoints: XELOX or FOLFOX
• OS in patients with K-ras wild-type tumours

• Secondary endpoints include: 65% XELOX; 35% FOLFOX
• OS in K-ras mutant; “all” wild-type
(patient/physician choice)
(K-ras, N-ras, B-raf); “any” mutant, ITT
• PFS
• Response rate
• Quality of life
• Health economic evaluation

*Treatment until disease progression or unacceptable toxicity
**Stop and Go treatment (12 wks then restart at progression)
Maughan, et al. ECCO-ESMO 2009

COIN study: KRAS WT PFS
Survival probability Arm A (XELOX/FOLFOX)
1.00 Arm B (XELOX/FOLFOX + cetuximab)

Arm A Arm B Diff.
0.75 Median PFS, 8.6 8.6 +0.07
months

0.50
HR point estimate = 0.959
95% CI 0.84–1.09
p=0.60
0.25

0
0 6 12 18 24 30 36 42
Time (months)
No. at risk
Arm A 367 245 92 41 18 11 6 1
Arm B 361 249 103 42 22 9 6 0

Maughan, et al. ECCO-ESMO 2009

PFS by KRAS Mutation Status
Final Analysis
WT KRAS MT KRAS
100% 100%
Proportion Event-Free

Proportion Event-Free
90% 90%
80% 80%
70% 70%
60% 60%
50% 50%
40% 40%
30% 30%
20% 20%
10% 10%
0% 0%
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44

Months Months

Median Median
Events (95% CI) Events (95% CI)
n (%) months n (%) months
Panitumumab + 270 / 325 10.0 (9.3 – 11.4) Panitumumab 204 / 221 7.4 (6.9 – 8.1)
FOLFOX4 (83) + FOLFOX4 (92)
FOLFOX4 280 / 331 8.6 (7.5 – 9.5) FOLFOX4 196 / 219 9.2 (8.1 – 9.9)
(85) (89)
HR = 0.80 (95% CI: 0.67 – 0.95) HR = 1.27 (95% CI: 1.04 – 1.55)
Log-rank p-value = 0.01 Log-rank p-value = 0.02

Douillard et al., ASCO 2011

Response Rates Differences Chemo +/-
EGFR mAbs Based on KRAS Status
25
% Response Rate Difference

KRAS wt
20
KRAS mut
15
10
5
0
-5
-10 CRYSTAL PRIME OPUS CAIRO2 COIN NORDIC 181 2nd
line
-15
-20

Clinical Trials

HR of PFS/DFS for EGFR mAbs Phase III
trials in KRAS wt CRC

Salvage
Cetuximab (single agent)
Panitumumab

Second Line
181

CRYSTAL
PRIME First-Line
COIN
Nordic

Adjuvant
N0147

1.2 1 0.8 0.6 0.4 0.2 0
Hazard ratio

Role of PI3K Pathway
• 40% of CRC tumors have
RTKs mutations in PI3K pathway1

PIK3CA
PIP2

P
P P
PIP3

P
P P
P
PIP3
P • PI3K pathway dysregulation
P P IRS2 P p85
PTEN
PDK1 AKT2
P predicts Cetuximab resistance in
PAK4
?
CRC cell lines2
Mutations of PI3K pathway genes in CRC
P
AKT2/ PAK4
Tumours PKK1 AKT2 PAK4 amp IRS2 amp INSRR ERBB4 PTEN PIK3CA

CSX3 T354M wt wt wt wt wt wt wt wt • Of 36 tumors with PI3KCA
CX10 T354M wt wt wt wt wt wt wt wt mutations, 27 also had alteration
MX20

CX7
D527E

wt
wt

S302G
wt

wt
wt

wt
wt

wt
wt

wt
wt

wt
wt

wt
wt

wt
in KRAS1
HX66 wt R371H wt wt wt wt wt wt wt

CO86 wt wt A279T wt wt wt wt 800del/
968del
wt • Patients treated with Cetuximab3
HX63 wt wt E329K wt wt wt wt wt wt

CO78 wt wt wt 15 fold wt wt wt wt wt • 4/31 PI3KCA mutations
CO82

CO84
wt

wt
wt

wt
wt

wt
8 fold

wt
wt

12 fold
wt

wt
wt

wt
wt

wt
wt

wt
(4/16 non-responders)
CO69

HX160
wt

wt
wt

wt
wt

wt
wt

wt
7 fold

6 fold
wt

wt
wt

wt
wt

wt
wt

wt
• 4/31 ↓ PTEN gene copy number
MX5 wt wt wt wt wt T1014M wt wt wt

CO87 wt wt wt wt wt wt I1030M wt wt • 3/30 PTEN mutations
MX9 wt wt wt wt wt wt wt 904-919del wt
(3/15 non-responders)
CX28 wt wt wt wt wt wt wt Y88C wt

HX170 wt wt wt wt wt wt wt L325H/LOH wt

HX199 wt wt wt wt wt wt wt R741/F341V R88Q • PI3KCA mut: early or late event?
HX219 wt wt wt wt wt wt wt A86P/LOH wt

HX242 wt wt wt wt wt wt wt R47S wt

36 cases wt wt wt wt wt wt wt wt MUT
1. Parsons, et al. Nature 2005. 2. Jhawer, et al.
90 cases wt wt wt wt wt wt wt wt wt
Cancer Res 2008; 3. Perrone, et al. Ann Oncol 2009

PIK3CA Point Mutations
CRC

Exon 9

Hotspots

Exon 20
Bader et al., Nat Rev Cancer 2005

PFS and PIK3CA Mutational Status in mCRC
Patients Treated With Panitumumab/Cetuximab

PIK3CA mut
Exon 9: 4 pts
Exon 20: 11 pts

110 pts Cetuximab 13%
> 85% received
at least 1 prior Panitumumab 20%
Rx Cetuximab/Irinotecan 67%

Sartore-Bianchi A et al, Cancer Res 2009

Fig. 1

PIK3CA mut
Exon 9: 17 pts
Exon 20: 4 pts

Cetuximab 16
Cetuximab/Irinotecan 184
Total Patients 200
Prenen H et al, Clin Cancer Res 2009

PTEN Expression and Cetuximab
Efficacy
PTEN + median PFS = 4.7 months
PTEN – median PFS = 3.3 months
1.0
PTEN + PTEN –
(n=33) (n=22) Log-rank test: p=0.005
0.8 HR=0.49; 95% CI: 0.20–0.75

PFS estimate
Responders
(CR+PR+SD) 12 (36%) 1 (5%)
0.6
Non-responders 21 (64%) 21 (95%)
0.4
PTEN+

n=55 0.2 PTEN-
0.0
0 2.5 5.0 7.5 10.0 12.5 15.0
Months
• Fisher’s Exact Test p=0.008
• Concordance primary tumor sample/metastasis: 27/45 (60%)
CR = complete response; PR= partial response Loupakis et al, ASCO 2008
SD = stable disease Loupakis et al, J Clin Oncol 2009

PTEN and KRAS Status: Effect on
Efficacy
PTEN + KRAS wild-type median
= 5.5 months
All other median PFS
PTEN + KRAS = 3.8 months
wild-type All other 1.0
(n=17) (n=28) Log-rank test: p=0.001
0.8
HR=0.42; 95% CI: 0.17–0.65

PFS estimate
Responders
(CR+PR+SD) 8 (47%) 1 (4%)
0.6
Non responders 9 (53%) 27 (96%) PTEN+
0.4
n=45 PTEN-
0.2

0.0
0 2.5 5.0 7.5 10.0 12.5 15.0
• Fisher’s Exact Test p=0.008 Months

Loupakis et al, ASCO 2008

Challenges with PTEN
• Expression in primary tumors does not reflect
expression in metastases
• PTEN is not mutated in mCRC, its expression
can be regulated by methylation, miRNAs,
and/or other regulatory mechanisms
• Difficulty in standardizing IHC in different labs
Supplemental Figure 1: Representative
examples of PTEN positive (A, B) and
negative (C, D) cases. The cases reported
in A and C panels were evaluated at
Ospedale Niguarda Ca’ Granda (Milan,
Italy) whereas those in B and D at the
Institute of Pathology in Locarno
(Switzerland).

Sartore-Bianchi et al, Cancer Res 2009

BRAF Mutations in CRC

• BRAF is primary effector EGF
of KRAS signaling
Tumor Cell
• BRAF mutations:
• Occur most frequently
in exon 15 (V600E)
Ras
• Found in 4%-14% of P P
patients with CRC Raf
• Mutually exclusive P P
with KRAS mutations
MEK
Tumor cell
proliferation Erk
and survival

Yarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol.
2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.

Wild-type BRAF is required for response
to EGFR inhibitors in mCRC
Patients with KRAS wild-type status

100 BRAF wild-type 100 BRAF wild-type
BRAF mutant BRAF mutant
80 p=0.0010 80 p<0.0001
PFS (%)

OS (%)
60 60

40 40

20 20

0 0
0 100 200 300 400 500 600 700 800 900 0 200 400 600 800 1,000 1,200 1,400

Time since start Time since start
of treatment (days) of treatment (days)

Di Nicolantonio et al., J Clin Oncol 2008

CRYSTAL trial update: outcome in
KRAS wild-type/ BRAF mutated mCRC
KRAS wt/BRAF wt KRAS wt/BRAF mt
(n=566) (n=59)
FOLFIRI FOLFIRI + FOLFIRI FOLFIRI +
Cetuximab Cetuximab
(n= 289) (n= 277) (n=33) (n=26)

mOS (mo) 21.6 25.1 10.3 14.1
HR [95% CI] 0.83 [0.687–1.004] 0.91 [0.507–1.624]
p-valuea 0.0549 0.7440

mPFS (mo) 8.8 10.9 5.6 8.0
HR [95% CI] 0.68 [0.533–0.864] 0.93 [0.425–2.056]
p-valuea 0.0016 0.8656

RR (%) 42.6 61.0 15.2 19.2
[95% CI] [36.8–48.5] [55.0–66.8] [5.1–31.9] [6.6–39.4]
p-valueb <0.0001 0.9136

aStratified log-rank test; bCochran-Mantel-Haenszel test
Van Cutsem et al, JCO 2011

CRYSTAL trial update: outcome in
KRAS wild-type/ BRAF mutated mCRC

Van Cutsem et al, JCO 2011

Response to EGFR mAb-based
Therapy in KRAS wt CRC

Satore-Bianchi et al., PLoS 2009

Bevacizumab vs EGFR Antibodies
in Advanced CRC - Simplified
Agent Strength Weakness

Bevacizumab • Delay in tumor • Limited single
progression agent activity
• Gain in time • Weak effect on RR
• Toxicity profile (per RECIST)
EGFR • Single agent activity • Gain in time to
antibodies • Consistent increase progression
in RR moderate
• Activity independent • Toxicity profile
of line of therapy
• Predictive marker

Take-Home Messages: Optimized
Medical Therapy of Advanced CRC
1. Identify the goal of therapy
• RR only matters for
• conversion therapy of liver metastases or
• if patient is symptomatic from his tumor
burden
• For most patients gain of time and
maintaining QOL is more important
• Strength of BEV
2. Treat to progression – and perhaps beyond?
• Be mindful about toxicities, stop oxaliplatin
before neurotoxicity develops
• Some select patients can have CFI

Take-Home Messages: Optimized
Medical Therapy of Advanced CRC
3. Expose patients to all potentially active agents
• These agents are the oncologist’s tools to
keep patients alive
• Use fluoropyrimidine-based combinations as
default backbone, reserve sequential single
agent therapy for select patients
4. Reutilize chemotherapeutic agents (in different
combinations?) in the course of the therapy
• Continuum of care vs distinct lines of therapy
5. We need new drugs!

VEGF Biology
PlGF VEGF-C,
VEGF-B VEGF-A VEGF-D

Cell membrane
Functions

VEGF-R1 VEGF-R2 VEGF-R3
(Flt-1) (KDR/Flk-1) (Flt-4)
Migration Proliferation Lymphangio-
Invasion Survival genesis
Survival Permeability

Large molecule VEGF inhibitors
PlGF VEGF-A VEGF-C,
VEGF-B Bevacizumab VEGF-D
Ramucirumab

Aflibercept
(VEGF Trap)
Functions

VEGF-R1 VEGF-R2 VEGF-R3
(Flt-1) (KDR/Flk-1) (Flt-4)
Migration Proliferation Lymphangio-
Invasion Survival genesis
Survival Permeability

52

EFC10262: VELOUR
Phase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Aflibercept 4 mg/kg
600 pts IV
+ FOLFIRI q 2 weeks
mCRC after
failure of an
oxaliplatin R 1:1

based regimen
Placebo + FOLFIRI
Stratification factors: 600 pts
q 2 weeks
Prior bevacizumab (Y/N)
ECOG PS (0 vs 1 vs 2)

PIs: Allegra, Van Cutsem
30% of patients had prior BEV

Overall Survival - ITT Population

Van Cutsem, et al. WCGC 2011
Cut-off date = February 7, 2011; Median follow-up = 22.28 months

Comparison VELOUR vs E3200
VELOUR E3200
Prior Tx Oxaliplatin-based Irinotecan-based (IFL)
Prior
30% none
BEV
Arms FOLFIRI FOLFIRI HR FOLFOX FOLFOX HR
+ PL + AFL p-value + PL + BEV p-value

mOS 12.06 13.5 0.817 10.8 12.9 0.75
(mos) 0.0032 0.0011

mPFS 4.67 6.9 0.758 4.7 7.3 0.61
(mos) 0.00007 <0.000
1
RR (%) 11.1 19.8 0.0001 8.6 22.7 <0.000
1
Van Cutsem, et al. WCGC 2011; Giantonio, et al. JCO 2007

Progression Free Survival – Stratification
Factors
ITT Population

ECOG PS:
p=0.196

Prior
BEV:
p=0.695

Tabernero et al., ECCO/ESMO 2011

56

I4T-MC-JVBBPhase III Trial 2nd Line
FOLFIRI +/- Ramucirumab

525 pts Ramucirumab IV
+ FOLFIRI q 2 weeks

mCRC after
failure
FP/oxaliplatin R 1:1

+ BEV regimen
525 pts Placebo + FOLFIRI
Stratification factors: q 2 weeks
• Region
• KRAS status
• First-line TTP (<>6 mos)

PIs: Tabernero, Grothey
Primary EP: OS

The Complex Process of Tumor
Angiogenesis

Cytokine increase on BEV therapy

Kopetz et al., JCO 2010

Regorafenib – A Multi-Kinase
Inhibitor
Cellular Phosphorylation Assays IC50 nM
VEGFR-2 Phosphorylation, 293 Cells 8
TIE2-Receptor Phosphorylation, CHO Cells 31
PDGFR-β Phosphorylation, Aortic SM Cells 90
mVEGFR3 Phosphorylation, 293 Cells 150
Mutant RET Phosphorylation, Thyroid TT Cells 10
Mutant c-KIT Phosphorylation, GIST 882 Cells 20
FGF-10 FGFR MCF-7 Cells 150-300
MAPK ERK-P HCC, HepG2 Cells 500

Cell Proliferation Assays IC50 nM
VEGF/HuVEC (2% FCS) BrdU 4
bFGF/ HuVEC (2% FCS) BrdU 120
PDGFBB/Aortic SM (0.1% BSA) BrdU 121
Thyroid TT RET C643W (10% FCS) 33
GIST 882 KIT K642E (10% FCS) 45
Breast, MDA MB 231 (10% FCS) 570
Melanoma, A375 (10% FCS) 900
HCC HepG2 (10% FCS) 560

Regorafenib Salvage Therapy
Registration Trial
Regorafenib 160 mg od
3wks on/1 wk off + BSC Primary
CRC 2:1 randomization endpoint:
3rd/4th line
OS
Placebo + BSC

• Primary endpoint OS: increase OS from 4.5 to 6.0 months; HR = 0.75
• Significance level/power: 0.025 (one-sided)/90%
• Accrual period (months): 26 ( accrual rate 30 pat./month)
• Study duration (months): 31.5
• Total number of events: 582 Accrual completed
• Total number of patients: 690 Feb 2011, within 10 mos

Cape +/- Perifosine Rand Phase II
Perifosine 50 mg PO QD
 Patients with 2nd or3rd
line mCRC Capecitabine 825 mg/m2 BID d 1 - 14
 No prior Rx with CAP
in metastatic setting
R Cycle = 21 Days
 Prior Rx with 5-FU or Placebo PO QD
5-FU based regimen
Capecitabine 825 mg/m2 BID d 1 - 14

 Primary Objective:
– To compare time to progression (TTP) of P-CAP vs. CAP as
2nd or 3rd line Rx
 Secondary Objective:
– To compare overall response rate (CR + PR) and overall
survival
– To evaluate the safety of P-CAP vs. CAP

Richards et al., ASCO 2010

Median Overall Survival (OS)
ALL EVALUABLE 5-FU REFRACTORY
PATIENTS PATIENTS

Median OS: P-CAP: Median OS: P-CAP:
17.7 mos [95% CI (8.5, 24.6)] 15.1 mos [95% CI (7.3, 22.3)]
Median OS: CAP: Median OS: CAP:
10.9 mos [95% CI (5, 16.9)] 6.6 mos [95% CI (4.7, 11.7)]

p-value = 0.0161 p-value = 0.0112

Hazard ratio: 0.410 Hazard ratio: 0.313
(0.193, 0.868) (0.122, 0.802)

Phase III trial (1:1 Cape/Peri vs Cape) started
Richards et al., ASCO 2010

X-PECT Phase III Trial
Treatment / Schema
Perifosine 50 mg PO QD
 Patients with
refractory mCRC Capecitabine 1000 mg/m2 BID d 1 - 14
 No prior Rx with
CAP in metastatic R Cycle = 21 Days
setting
Placebo PO QD

Capecitabine 1000 mg/m2 BID d 1 - 14

 Randomized 1:1, Double-blind Primary Endpoint:
 N = ~430 patients  Overall Survival
 RECIST v 1.1 Secondary Endpoints:
 CTCAE v 4.0  PFS, ORR, Safety

Gastric cancer: a global disease
• 4th most common malignant disease ~ 930,000
• 2nd most common cause of cancer-related death worldwide ~700,000
• Falling incidence of distal gastric cancer
• Increasing incidence of proximal gastric cancer
• Wide geographical variation

Incidence (males)

>20/100000
≥10 - ≤20/100000
<10/100000
www.cancer.gov
Kamangar F et al. J Clin Oncol 2006;24:2137–50

Esophageal and Gastric Carcinoma
US Incidence in 2009
• 37,600 new cases
• Gastric: 21,130 (56%)
• Esophagus: 16,470 (44%)
• Increase in Esophageal , GEJ, cardia adeno
• Obesity, GERD, Barrett’s, tobacco, EtOH
• Are adenocarcinomas of the distal esophagus, GE
junction, and upper stomach the same?

• Decline in Gastric Cancer, SCC incidence
• 4.5% of U.S. cancer deaths
• Esophageal: 88% fatality rate
• Gastric: 50% fatality rate
• Male > Female Jemal 2009

Metastatic gastroesophageal
cancer
• Longstanding search for a true standard
regimen
• Multiple combinations are feasible in the
first line setting
• No data as to whether combinations are
better than sequential therapy
• Active agents
• Fluoropyrimidines, platinums, taxanes,
irinotecan, (anthracyclines),
trastuzumab in HER2+

Phase III Data of Chemotherapy Regimens
in Advanced Gastric Ca
Regimen RR (%) TTP/PFS OS (mos) Ref
(mos)
CF 35 8.3 Bleiberg,
Cisplatin 100 mg/m2 D1 EJC 1997
5-FU 1000 mg/m2 CIV D1-5

ECF 42 7.0 9.4 Ross,
Epirubicin 50 mg/m2 D1 JCO 2002
Cisplatin 60 mg/m2 D1
5-FU 200 mg/m2/d CIV D1-21

DCF 37 5.6 9.2 Van Cutsem,
Docetaxel 75 mg/m2 D1 JCO 2006
Cisplatin 75 mg/m2 D1
5-FU 750 mg/m2 CIV D1-5
EOX 48 7.0 11.2 Cunningham,
Epirubicin 50 mg/m2 D1 NEJM 2008
Oxaliplatin 130 mg/m2 D1
Capecitabine 625 mg/m2 BID

Targeted Therapies

• Conventional, cytotoxic chemotherapy has
limited benefit
• Targeted agents: attempt to block specific
tumor growth pathways
• Monoclonal antibodies
• Tyrosine kinase inhibitors
• Soluble receptors to growth factors
• Inhibition of pathways involved in
protein synthesis and degradation

Molecular Targets:
Esophagogastric Cancer
• KRAS mutation: < 5-10%
• BRAF mutation: < 5%
• EGFR over expression: 50-80%
• TKI’s inactive
• Cetuximab monotherapy inactive
• EGFR mutation: < 5%
• CMET: < 10%
• HER2 over expression: 10-25%
Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006
Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006

Trastuzumab plus Chemotherapy in
Advanced HER2+ Gastric Cancer: ToGA
Rationale: A subpopulation of gastric cancers overexpress HER2

5-FU or Capecitabine
(investigator discretion)
+ Cisplatin + Trastuzumab
Screen 3807 (n=294)
HER2+ GC
GC patients
for HER2
(n = 810, R
22%) 5-FU or Capecitabine
expression
(n = 584) (investigator discretion)
+ Cisplatin
Stratification by (n=290)
•Gastric vs GEJ
•Advanced vs metastatic
•5-FU vs capecitabine 5-FU 800 mg/m2/d infusional d1-5 q3w X 6
Capecitabine 1000 mg/m2 bid d1-14 q3w X 6
Cisplatin 80 mg/m2 q3w X 6
Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading)
Primary endpoint: OS
Bang et al., Lancet 2010
Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)

Patient demographics and baseline
characteristics
Characteristic F+C F+C + trastuzumab
n=290 n=294
Sex, %
Male / Female 75 / 25 77 / 23
Age, median (range) years 59.0 (21-82) 61.0 (23-83)
Weight, median (range) kg 60.3 (28-105) 61.5 (35-110)
Region, n (%)
Asia 166 (56) 158 (53)
C/S America 26 (9) 27 (9)
Europe 95 (32) 99 (33)
Other 9 (3) 14 (5)
Type of GC (central assessment)
Intestinal 74.2a 76.8b
Diffuse 8.7a 8.9b
Mixed 17.1a 14.3b
Prior gastrectomy 21.4 24.1
Highest recruitment was from Korea, Japan, China and Russia
F, fluoropyrimidine; C, cisplatin an=287; bn=293 Bang et al., Lancet 2010

HER2 Positivity IHC

Bang et al. ASCO 2009

HER2 Positivity Worldwide (ROW)


HER2 Positivity Histological Type


HER2 Positivity GEJ vs Gastric Ca


ToGA: Primary end point: OS

Event 1.0 Median
Events OS HR 95% CI p value
0.9
0.8 FC + T 167 13.8 0.74 0.60, 0.91 0.0046
0.7 FC 182 11.1
0.6
0.5
0.4
0.3
0.2
0.1 11.1 13.8
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)

No. 294 277 246 209 173 147 113 90 71 56 43 30 21 13 12 6 4 1 0
at 290 266 223 185 143 117 90 64 47 32 24 16 14 7 6 5 0 0 0
risk

T, trastuzumab Bang et al., Lancet 2010

ToGA: Secondary end point: PFS

Event 1.0 Median
Events PFS HR 95% CI p value
0.9
0.8 FC + T 226 6.7 0.71 0.59, 0.85 0.0002
0.7 FC 235 5.5
0.6
0.5
0.4
0.3
0.2
0.1 5.5 6.7
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Time (months)

No. 294 258 201 141 95 60 41 28 21 13 9 8 6 6 6 4 2 0
at risk 290 238 182 99 62 33 17 7 5 3 3 2 2 1 1 0 0 0


ToGA: Efficacy: OS by HER2 status

Subgroup N Median OS Hazard 95% CI
(months) ratio

All 584 11.1 vs 13.8 0.74 0.60, 0.91

Pre-planned analysis
IHC0/FISH+ 61 7.2 vs 10.6 0.92 0.48, 1.76
IHC1+/FISH+ 70 10.2 vs 8.7 1.24 0.70, 2.20
IHC2+/FISH+ 159 10.8 vs 12.3 0.75 0.51, 1.11
IHC3+/FISH+ 256 12.3 vs 17.9 0.58 0.41, 0.81
IHC3+/FISH- 15 17.7 vs 17.5 0.83 0.20, 3.38

Exploratory analysis
IHC0 or 1+/FISH+ 131 8.7 vs 10.0 1.07 0.70, 1.62
IHC2+/FISH+ or IHC3+ 446 11.8 vs 16.0 0.65 0.51, 0.83

0.2 0.4 0.6 1 2 3 4 5
Favors T Risk ratio Favors no T

ToGA: OS in IHC2+/FISH+ or
IHC3+ (exploratory analysis)
Event 1.0 Median
Events OS HR 95% CI
0.9
0.8 FC + T 120 16.0 0.65 0.51, 0.83
0.7 FC 136 11.8
0.6
0.5
0.4
0.3
0.2
0.1 11.8 16.0
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)

No. 228 218 196 170 142 122 100 84 65 51 39 28 20 12 11 5 4 1 0
at 218 198 170 141 112 96 75 53 39 28 20 13 11 4 3 3 0 0 0
risk

Secondary end point:
tumor response rate
Intent to treat
Patients p=0.0017 F+C + trastuzumab
(%) p=0.0145 F+C

47.3%
41.8%

32.1% 34.5%
p=0.0599

5.4%
2.4%

CR PR ORR

ORR= CR + PR
CR, complete response; PR, partial response Bang et al., Lancet 2010

ToGA: Select Grade 3/4 Toxicities*
Fluoropyrimidine +
Fluoropyrimidine +
Cisplatin +
Cisplatin
Trastuzumab
(n = 290)
(n = 294)
Hematologic
Neutropenia 27% 30%
Anemia 12% 10%
Nonhematologic
Diarrhea 9% 4%
Nausea 7% 7%
Asymptomatic LVEF drops
6% 1%
(< 50%)

*2 deaths due to cardiac events in each arm


Pertuzumab and trastuzumab bind to distinct
epitopes on HER2 extracellular domain
Pertuzumab-HER2 complex Trastuzumab-HER2 complex

Pertuzumab Dimerization
domain
Trastuzumab

• Activates antibody-dependent • Activates ADCC
cellular cytotoxicity (ADCC) • Prevents HER2 domain cleavage
• Has a major effect on role of • Inhibits HER2-mediated signalling pathways
HER2 as a co-receptor with HER3
or EGFR
• Inhibits multiple HER-mediated signaling
pathways

Figures adapted from Hubbard SR. Cancer Cell 2005;7:287–288

Trastuzumab plus Pertuzumab in
Gastric Cancer Xenografts
4-1ST (HER2-positive) MKN-28 (HER2-negative)

1,000 1,000
1,000 1,000
Tumor volume (mm3)

Tumor volume (mm3)
a Control

Pertuzumab 40 mg/kg Control

Trastuzumab 20 mg/kg Pertuzumab 40 mg/kg

Pertuzumab 40 mg/kg + Pertuzumab 40 mg/kg +
trastuzumab 20 mg/kg Trastuzumab 20 mg/kg
a, b, c
100 100 100
100

1
1 8
8 15
15 22
22 1
1
8
8
15
15
22
22

Days after treatment started Days after treatment started

Yamashita et al., AACR 2010

Phase III Trials with HER2 Targeted Agents

CapeOx + Placebo N=535
LOGiC Primary EP: OS (was PFS)
CapeOx + Lapatinib Data expected mid 2012

http://clinicaltrials.gov/ct2/show/NCT00680901

RTOG 1010 – Proposed Neoadjuvant
Phase III Trial in Esophagus/GEJ ACA

Primary EP: DFS (15  27 mos, HR 0.56)
N=160 Pts with HER+ PI: H. Safran, Providence, RI

Advanced Esophago-Gastric
Cancer: Summary
• Chemotherapy backbone
• Two drug regimens preferred
(FOLFIRI, FOLFOX, XELOX, Cape-Cis)
• Marginal benefit for 3 drug regimens
(Docetaxel + CF)
• ECF/EOX: is E needed in metastatic disease?
• Molecular Targeted Therapies
• VEGF, EGFR/HER pathways targeted
• Phase II and III development with chemo,
chemoRT
• Molecular markers to select therapy:
• HER2+  Trastuzumab should be used

Median OS in Advanced Gastric/GEJ
Cancer
BSC (1) 12 months
FAMTX (2)
C+S1 (3)
CF (4)
IF (5)
EOF (6)
DCF (4)
ECF (6)
ECX (6)
XP (7)
EOX (6)
Trastuzumab + XP/FP (8) HER2 IHC 2+/FISH+ or IHC 3+
0 5 10 15
Median OS in patients with advanced gastric cancer (months)
1. Murad, AM et al. Cancer 1993; 72:37−41. 2. Vanhoefer U, et al. JCO 2000; 18:2648−2657.
3. Ajani JA, et al. JCO 2009; 27(S15):Abstract 4511. 4. Van Cutsem E, et al. JCO 2006; 24:4991−4997.
5. Dank M, et al. Ann Oncol 2008; 19:1450−1457. 6. Cunningham D, et al. NEJM 2008; 358:36−46.
7. Kang YK, et al. Ann Oncol 2009; 20:666−673. 8. Bang, et al. Lancet 2010.

The dismal prognosis of pancreatic cancer

• Pancreatic cancer has the 5-year OS
worst survival of any solid
tumor
• In 2007, it is estimated that
there will be:
• 37,170 new cases
• 33,370 deaths
• These dismal statistics
reflect the early distant
spread of PC and the
inadequacy of current
therapies

Gemcitabine vs 5-FU Efficacy

Gem 5-FU p
RR 5.4% 0% —
CBR 24% 5% 0.0022
Med survival (months) 5.7 4.4 0.0025
Time to progressive
disease (months) 2.1 0.9 0.0013
12-month survival 18% 2% 0.0025
Burris JCO 1997

Gemcitabine vs 5-FU Survival

Gemcitabine
5-FU

Log-Rank Test
p = 0.0009

Burris JCO 1997

Pancreas Cancer: Prodige 4 -
ACCORD 11 trial design
for both arms:
R
A FOLFIRINOX CT scans:
N obtained
Metastatic D every 2 months
pancreatic O
cancer M 6 months of
chemotherapy
I Gemcitabine recommended
Z
E

Stratification :

• center
• performance status: 0 versus 1
• location of the tumor: head versus other location of the primary
Conroy et al. NEJM 2011

Experimental Arm: FOLFIRINOX

Oxaliplatin 85 mg/m2 over 2 hours,
Leucovorin 400 mg/m2 over 2 hours,
Irinotecan 180 mg/m2 in 90 mn infusion,
5-FU 400 mg/m2 bolus,
5-FU 2400 mg/m2 on 46-h infusion.

1 cycle = 14 days
Bolus 5-FU 400 mg/m2

2h

Oxaliplatin Leucovorin Continuous 5-FU
85 mg/m2 400 mg/m2 2.400 mg/m2
Irinotecan
2h 180 mg/m2 46 h q2wks
1 h 30

Patients characteristics
Folfirinox Gemcitabine
Characteristics p
N=171 N=171

Median age (yrs) 61 61
NS
[range] [25-76] [34-75]

Sex Male 106 (62%) 105 (61.4%)
Female 65 (38%) 66 (38.6%) NS

Baseline PS 0 64 (37.4%) 66 (38.6%)
1 106 (62.0%) 105 (61.4%) NS
2 1 (0.6%) 0 (0.0%)

Location of primary Head 62 (36.3%) 60 (35.1%)
Other 109 (63.7%) 111 (64.9%) NS


Safety: hematological AEs

Folfirinox Gemcitabine p
AE, % per patient N=167 N=169

All Grade 3/4 All Grade 3/4 Grade 3/4

Neutropenia 79.9 45.7 54.8 18.7 0.0001

Febrile Neutropenia 7.2 5.4 2.4 0.6 0.009

Anemia 90.4 7.8 94.6 5.4 NS

Thrombocytopenia 75.2 9.1 54.8 2.4 0.008

42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm
One toxic death occurred in each arm

Objective Response Rate
p
N=171 N=171

Complete response 0.6% 0%

Partial response 31% 9.4% 0.0001
CR/PR 95% CI [24.7-39.1] [5.9-15.4]
Stable disease 38.6% 41.5%
Disease control
70.2% 50.9% 0.0003
CR+PR+SD
Progression 15.2% 34.5%

Not assessed 14.6% 14.6%

Median duration
5.9 mo. 4 mo. ns
of response

Progression-Free Survival
Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo
1.00 HR=0.47 : 95%CI [0.37-0.59]

0.75
Probability

0.50 p<0.0001

0.25

0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
Number at risk
Gemcitabine 171 88 26 8 5 2 0 0 0 0 0 0 0
Folfirinox 171 121 85 42 17 7 4 1 1 0 0 0 0

Gemcitabine Folfirinox

Overall Survival
Median follow up: 26.6 months [95% CI: 20.5 – 44.9]
p HR
N=171 N=171

Median survival 11.1 mo. 6.8 mo. <0.0001 0.57
[CI 95%] [ 9 - 13.1] [ 5.5 - 7.6]

1-yr. survival 48.4% 20.6%

18-mo. survival 18.6% 6%

Conroy et al. ASCO 2010

Overall Survival
1.00 HR=0.57 : 95%CI [0.45-0.73]

0.75
Probability

0.50 Stratified Log-rank test, p<0.0001

0.25

0.00
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
Number at risk
Gemcitabine 171 134 89 48 28 14 7 6 3 3 2 2 2
Folfirinox 171 146 116 81 62 34 20 13 9 5 3 2 2

Gemcitabine Folfirinox
Conroy et al. ASCO 2010

Where are we in pancreas cancer?
• FOLFIRINOX is new standard of care for good-PS
patients
• Trials in development to use FOLFIRINOX as
adjuvant and neoadjuvant therapy
• Can novel agents be added to FOLFIRINOX?
• Gemcitabine (+/- erlotinib) still FDA regulatory
standard
• Novel agents in phase II/III trials with GEM
• Abraxane, Hedgehog inhibitors, IGFR mAbs
• Biomarker-driven treatment decisions explored
• hENT, ERCC-1, SPARC, KRAS…

Conclusions – Key Issues

• CRC
• Individualized therapy
• Duration of anti-VEGF therapy
• Novel agents
• Gastric/GEJ cancer
• HER2 targeted agents
• Anti-angiogenesis
• Pancreas cancer
• New standard of care
• Difficult drug development for regulatory
purposes

New Perspectives in GI Malignancies

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