new perspectives in gi malignancies
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Axel Grothey, M.D., Professor of Oncology; Consultant, Medical Oncology, Mayo Clinic New Perspectives in GI Malignancies Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CMETRANSCRIPT
New Perspectives in GI Malignancies
Axel GrotheyProfessor of OncologyMayo 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 200511 Phase III Trials, 5768 Patients
OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85Grothey & Sargent, JCO 2005
0 10 20 30 40 50 60 70 80
Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV
LV5FU2
FOLFOXIRI
CAIRO
2221201918171615141312
Med
ian
OS
(mo)
Patients with 3 drugs (%)
P =.0001
First-Line Therapy
2007
Murine Ab“momab”
ChimericMouse-Human Ab
“ximab”
Humanized Ab“zumab”
Fc
Fab
Human Ab“mumab”
Biologic Agents in Colorectal Cancer = Monoclonal Antibodies
(17-1A) CetuximabBevacizumab
PanitumumabEGFR
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 (n=411)
IFL+ Bevacizumab(n=402) P Value
Median survival (mo) 15.6 20.3 0.00004
PFS (mo) 6.2 10.6 <0.00001
ORR (%)
CR
PR
35
2.2
32.5
45
3.7
41.2
0.0036
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
HR=0.54, P<0.00001Median PFS: 6.2 vs 10.6 mo
0.2
0 10 20 300
0.8
1.0
0.4
0.6
Progression-free survival (mo)
Prop
ortio
n pr
ogre
ssio
n-fr
ee
Treatment GroupIFL + placeboIFL + bevacizumab
Hurwitz et al. N Engl J Med 2004
XELOX + placebo N=350
FOLFOX4 + placebo N=351
XELOX + bevacizumab
N=350
FOLFOX4 + bevacizumab
N=350
XELOX N=317
FOLFOX4 N=317
Initial 2-arm open-label study
(N=634)
Protocol amended to 2x2 placebo-controled design after bevacizumab
phase III data1 became available (N=1401)
RecruitmentJune 2003 – May 2004
RecruitmentFeb 2004 – Feb 2005
XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design
1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy & Saltz, JCO 2008
PFS chemotherapy + bevacizumab superiority: primary endpoint
0 5 10 15 20 25Months
PFS
estim
ate
HR = 0.83 [97.5% CI 0.72–0.95] (ITT)p = 0.0023
9.48.0
1.0
0.8
0.6
0.4
0.2
0
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
XELOX subgroupHR = 0.77 [97.5% CI 0.63–0.94] (ITT)
p = 0.0026
9.37.4
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25
Months
PFS
estim
ate
XELOX+placebo N=350; 270 events XELOX+bevacizumab N=350; 258 events
FOLFOX subgroupHR = 0.89 [97.5% CI 0.73–1.08] (ITT)
p = 0.1871
9.48.6
FOLFOX+placebo N=351; 277 events FOLFOX+bevacizumab N=349; 255 events
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25
Months
Saltz et al., JCO 2008
NO16966 PFS Subgroup Analyses:On-Treatment Population
Saltz et al., ASCO GI 2007
HR = 0.61 [97.5% CI 0.48–0.78]P ≤ .0001
HR = 0.65 [97.5% CI 0.50–0.84]P = .0002
XELOX + placebo FOLFOX4 + placeboXELOX + Bev FOLFOX-4 +
BevVS VS
XELOX Group FOLFOX Group
Surv
ival
1.0
0.8
0.6
0.4
0.2
00 100 200 300 400 500
Study day
1.0
0.8
0.6
0.4
0.2
00 100 200 300 400 500
Surv
ival
Study day
10.6 m8.4 m9.5 m7.0 m
CAIRO2: Study design
Primary endpoint• Progression-free survival
Secondary endpoints• RR• OS time• Toxicity• Translational research
CapOx + BEV
(COB, n=368)
CapOx + BEV + Cetuximab
(COB-C, n=368)
EGFR-detectablemCRC R
Tol et al. NEJM 2009
Oxaliplatin d/c’d after 6 cyclesi.e. after 18 weeks = 4.5 mos
KRAS wild-typen = 314 (61%)
KRAS mutatedn = 196 (39%)
p value
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
CAIRO2 - KRAS genotyping (n=501)
Tol et al. NEJM 2009
BBP(n=642)
No BBP(n=531)
No Post-PD Treatment
(n=253)
Evaluablepatients(n=1953)
1st Progression(n=1445)
BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)
BRiTE:Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo
Grothey et al. JCO 2008
Physician decision - no randomization
BRiTE: Patient Outcome Based on Treatment Post 1st PD
BBP(n=642)
No BBP(n=531)
No Post-PD Treatment
(n=253)
# of deaths (%)
168(66%)
306(58%)
260(41%)
Median OS (mo) 12.6 19.9 31.8
1yr OS rate (%) 52.5 77.3 87.7
OS after 1st PD (mo) 3.6 9.5 19.2
Grothey et al. JCO 2008
AIO 0504 / Roche ML18147Multinational European Trial
Any-OX+ BEV
Any-IRI+ BEV
Any-IRI+ BEVAny-IRI Any-OX
Any-OX+ BEV
R R
N = 820Primary EP: OS
Accrual completed May 31, 2010
mAbs Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
AktRaf
MEK
MAPK
Cell Motility
MetastasisAngiogenesisProliferation
Cell survivalDNA
PTEN
Ras
mAbs Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
AktRaf
MEK
MAPK
Cell Motility
MetastasisAngiogenesisProliferation
Cell survivalDNA
Ras
PTEN
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 Responseto Cetuximab in Refractory mCRC
Study Treatment N (% wt)ORR, %
mt wtLiévre et al, 2006 C-mab + CT 30 (57) 0 65
Benvenuti et al, 2007 P-mab orC-mab ± CT 48 (67) 6 31
De Roock et al, 2007 C-mab ± CT 113 (59) 0 40Capuzzo et al, 2007 C-mab ± CT 81 (60) 6 26Di Fiore et al, 2007 C-mab + CT 59 (73) 0 28Khambata-Ford et al, 2007 C-mab 80 (62) 0 10Liévre et al, 2008 C-mab ± CT 76 (64) 0 49
Response confined to KRAS wt
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 Mutant KRAS
Meanin Wks
Stratified log rank test: P < .0001
115/124 (93)
Patients With Wild-Type KRAS
1.00.9
Prop
ortio
n W
ith P
FS 0.80.70.60.50.40.30.20.1
00 2 4 6 8 10
Events/N (%)Medianin Wks
Pmab + BSCBSC alone
114/119 (96)12.37.3
19.09.3
HR: 0.45 (95% CI: 0.34-0.59)
12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50 52
Weeks
Prop
ortio
n W
ith P
FS
1.00.90.80.70.60.50.40.30.20.1
00 2 4 6 8 10 12 14 16 18 20 22 24 26 2830 32 3436 38 4042 44 46 48 50
Weeks
Pmab + BSCBSC alone Mean
in Wks
76/84 (90)
Events/N (%)Medianin Wks
95/100 (95)7.47.3
9.910.2
HR: 0.99 (95% CI: 0.73-1.36)
52
Amado et al. JCO 2008
NCIC CTG CO.17: Randomized Phase III Trial in mCRCCetuximab vs BSC (no cross-over)
KRAS mut KRAS wild-type All patients
BSCn=83
Cetuxn=81
BSCn=113
Cetuxn=117
BSCn=285
Cetuxn=287
RR 0% 1.2% 0% 12.8% 0% 6.6%
PFS (mos) 1.8 1.8 1.9 3.8 1.8 1.9
OS (mos) 4.6 4.5 4.8 9.5 4.6 6.1
Karapetis et al. NEJM 2008
<0.0001
<0.0001 <0.0001
0.0046
CRYSTAL Study (1st Line)
FOLFIRI + Cetuximab
FOLFIRI
EGFR-expressingmetastatic CRC PFS
Stratified by:• Regions • ECOG PS
• Primary Endpoint: PFS (independent review)
• Secondary Endpoints: RR, DCR, OS, Safety, QoL
• Sample Size: 1217 patients randomized, ITT: 1198 pts
N = 599
N = 599
Van Cutsem et al. NEJM 2009
R
5-FU/LV/IRI (FOLFIRI) +/- Cetuximab: PFSNon-KRAS adjusted
Months
PFS
estim
ate
1.0
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 2 4 6 8 10 12 14 16 18 20
FOLFIRIFOLFIRI + Cetuximab
Van Cutsem et al. NEJM 2009
HR = 0.851P = 0.0479
8.0 vs 8.9 mos
Subgroupeffect
No benefit
CRYSTAL - KRAS wild-type mCRC (N=348): PFS
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18Months
Prog
ress
ion-
free
sur
viva
l est
imat
e
Cetuximab + FOLFIRI FOLFIRI
FOLFIRI + Cetuximab: 9.9 mos FOLFIRI: 8.7 mosHR=0.68, p=0.017
1-yr PFS rate25% vs 43%
Van Cutsem et al. NEJM 2009
CRYSTAL: Efficacy UpdateAfter Additional KRAS Testing
Van Cutsem et al. JCO 2011
KRAS wild-type FOLFIRI FOLFIRI + cetuximab
P value
n 350 316
RR (%) 39.7 57.3 < 0.0001
mPFS (mos) 8.4 9.9 0.0012
mOS (mos) 20 23.5 0.0093
KRAS mutated FOLFIRI FOLFIRI + cetuximab
P value
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
HR 0.7HR 0.8
COIN (cetuximab): First-line Study
Continuous* XELOX or FOLFOX Arm A
RFirst-line mCRC(n= 2445) Arm B
Continuous XELOX or FOLFOX +
cetuximab
Arm CIntermittent**XELOX or FOLFOX
*Treatment until disease progression or unacceptable toxicity**Stop and Go treatment (12 wks then restart at progression)
MRC-sponsored study supported by Merck (109 UK/Irish Hospitals)
65% XELOX; 35% FOLFOX(patient/physician choice)
• Primary endpoints: • OS in patients with K-ras wild-type tumours
• Secondary endpoints include:• OS in K-ras mutant; “all” wild-type
(K-ras, N-ras, B-raf); “any” mutant, ITT• PFS• Response rate• Quality of life• Health economic evaluation
Maughan, et al. ECCO-ESMO 2009
1.00
0.75
0.50
0.25
0
Survival probability
Time (months)
COIN study: KRAS WT PFS
No. at riskArm A Arm B
0 6 12 18 24 30 36 42
367361
245249
92103
4142
1822
119
66
10
Arm A (XELOX/FOLFOX)Arm B (XELOX/FOLFOX + cetuximab)
Arm A Arm B Diff.
Median PFS, months
8.6 8.6 +0.07
HR point estimate = 0.95995% CI 0.84–1.09
p=0.60
Maughan, et al. ECCO-ESMO 2009
PFS by KRAS Mutation StatusFinal Analysis
Eventsn (%)
Median (95% CI) months
Panitumumab + FOLFOX4
270 / 325 (83)
10.0 (9.3 – 11.4)
FOLFOX4 280 / 331 (85)
8.6 (7.5 – 9.5)
HR = 0.80 (95% CI: 0.67 – 0.95) Log-rank p-value = 0.01
Eventsn (%)
Median (95% CI) months
Panitumumab + FOLFOX4
204 / 221 (92)
7.4 (6.9 – 8.1)
FOLFOX4 196 / 219 (89)
9.2 (8.1 – 9.9)
HR = 1.27 (95% CI: 1.04 – 1.55)Log-rank p-value = 0.02
WT KRAS MT KRAS
Pro
porti
on E
vent
-Fre
e
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Pro
porti
on E
vent
-Fre
e
Months0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Douillard et al., ASCO 2011
Response Rates Differences Chemo +/-EGFR mAbs Based on KRAS Status
% R
espo
nse
Rat
e D
iffer
ence
Clinical Trials-20
-15
-10
-5
0
5
10
15
20
25
CRYSTAL PRIME OPUS CAIRO2 COIN NORDIC 181 2nd line
KRAS wtKRAS mut
HR of PFS/DFS for EGFR mAbs Phase III trials in KRAS wt CRC
00.20.40.60.811.2
Adjuvant
First-Line
Second Line
Salvage (single agent)
Hazard ratio
N0147
NordicCOIN
PRIMECRYSTAL
181
PanitumumabCetuximab
mAbs Target Tumor Cell-Bound EGFR
Extracellular
Intracellular
Ligand
EGF-R
PI3K
AktRaf
MEK
MAPK
Cell Motility
MetastasisAngiogenesisProliferation
Cell survivalDNA
Ras
PTEN
Role of PI3K Pathway• 40% of CRC tumors have
mutations in PI3K pathway1
• PI3K pathway dysregulation predicts Cetuximab resistance in CRC cell lines2
• Of 36 tumors with PI3KCAmutations, 27 also had alteration in KRAS1
• Patients treated with Cetuximab3
• 4/31 PI3KCA mutations (4/16 non-responders)
• 4/31 ↓ PTEN gene copy number
• 3/30 PTEN mutations (3/15 non-responders)
• PI3KCA mut: early or late event?
1. Parsons, et al. Nature 2005. 2. Jhawer, et al. Cancer Res 2008; 3. Perrone, et al. Ann Oncol 2009
RTKs
P P PP P P PP P PP
P
P
IRS2 p85PIK3CA
PTENPDK1 AKT2
PAK4
PIP3PIP2 PIP3
?
Tumours PKK1 AKT2 PAK4AKT2/ PAK4
amp IRS2 amp INSRR ERBB4 PTEN PIK3CA
CSX3 T354M wt wt wt wt wt wt wt wt
CX10 T354M wt wt wt wt wt wt wt wt
MX20 D527E wt wt wt wt wt wt wt wt
CX7 wt S302G wt wt wt wt wt wt wt
HX66 wt R371H wt wt wt wt wt wt wt
CO86 wt wt A279T wt wt wt wt 800del/968del wt
HX63 wt wt E329K wt wt wt wt wt wt
CO78 wt wt wt 15 fold wt wt wt wt wt
CO82 wt wt wt 8 fold wt wt wt wt wt
CO84 wt wt wt wt 12 fold wt wt wt wt
CO69 wt wt wt wt 7 fold wt wt wt wt
HX160 wt wt wt wt 6 fold wt wt wt wt
MX5 wt wt wt wt wt T1014M wt wt wt
CO87 wt wt wt wt wt wt I1030M wt wt
MX9 wt wt wt wt wt wt wt 904-919del wt
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
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
90 cases wt wt wt wt wt wt wt wt wt
Mutations of PI3K pathway genes in CRC
PIK3CA Point Mutations
Bader et al., Nat Rev Cancer 2005
Hotspots
Exon 9
Exon 20
CRC
Sartore-Bianchi A et al, Cancer Res 2009
PFS and PIK3CA Mutational Status in mCRC Patients Treated With Panitumumab/Cetuximab
Cetuximab 13%Panitumumab 20%Cetuximab/Irinotecan 67%
110 pts> 85% received at least 1 prior
Rx
PIK3CA mutExon 9: 4 pts
Exon 20: 11 pts
Prenen H et al, Clin Cancer Res 2009
Fig. 1
Cetuximab 16Cetuximab/Irinotecan 184Total Patients 200
PIK3CA mutExon 9: 17 ptsExon 20: 4 pts
PTEN Expression and Cetuximab Efficacy
• Fisher’s Exact Test p=0.008
• Concordance primary tumor sample/metastasis: 27/45 (60%)
PTEN +(n=33)
PTEN –(n=22)
Responders (CR+PR+SD) 12 (36%) 1 (5%)Non-responders 21 (64%) 21 (95%)
Loupakis et al, ASCO 2008Loupakis et al, J Clin Oncol 2009
n=55
1.0
0.8
0.6
0.4
0.2
0.00 2.5 5.0 7.5 10.0 12.5 15.0
Months
PFS
estim
ate
Log-rank test: p=0.005HR=0.49; 95% CI: 0.20–0.75
PTEN + median PFS = 4.7 monthsPTEN – median PFS = 3.3 months
CR = complete response; PR= partial response SD = stable disease
PTEN-
PTEN+
PTEN and KRAS Status: Effect on Efficacy
n=45
PTEN + KRAS wild-type median= 5.5 monthsAll other median PFS= 3.8 months
• Fisher’s Exact Test p=0.0080 2.5 5.0 7.5 10.0 12.5 15.0
Months
PTEN + KRAS wild-type
(n=17)All other (n=28)
Responders (CR+PR+SD) 8 (47%) 1 (4%)Non responders 9 (53%) 27 (96%)
Log-rank test: p=0.001HR=0.42; 95% CI: 0.17–0.65
1.0
0.8
0.6
0.4
0.2
0.0
PFS
estim
ate
Loupakis et al, ASCO 2008
PTEN-
PTEN+
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 atOspedale 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 of KRAS signaling
• BRAF mutations: • Occur most frequently
in exon 15 (V600E)• Found in 4%-14% of
patients with CRC• Mutually exclusive
with KRAS mutations
Raf
MEK
Erk
P
P P
P
Tumor cellproliferationand survival
EGF
Tumor Cell
Ras
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
Di Nicolantonio et al., J Clin Oncol 2008
BRAF wild-typeBRAF mutant
p=0.0010
Patients with KRAS wild-type status
100
80
60
40
20
0O
S (%
)0 200 400 600 800 1,000 1,200 1,400
BRAF wild-typeBRAF mutant
p<0.0001
Time since start of treatment (days)
Time since start of treatment (days)
100
80
60
40
20
0
PFS
(%)
0 100 200 300 400 500 600 700 800 900
CRYSTAL trial update: outcome in KRAS wild-type/ BRAF mutated mCRC
KRAS wt/BRAF wt (n=566)
KRAS wt/BRAF mt (n=59)
FOLFIRI
(n= 289)
FOLFIRI +Cetuximab
(n= 277)
FOLFIRI
(n=33)
FOLFIRI +Cetuximab
(n=26)
mOS (mo) 21.6 25.1 10.3 14.1
HR [95% CI]p-valuea
0.83 [0.687–1.004]0.0549
0.91 [0.507–1.624]0.7440
mPFS (mo) 8.8 10.9 5.6 8.0
HR [95% CI]p-valuea
0.68 [0.533–0.864]0.0016
0.93 [0.425–2.056]0.8656
RR (%)[95% CI]
42.6[36.8–48.5]
61.0[55.0–66.8]
15.2[5.1–31.9]
19.2[6.6–39.4]
p-valueb <0.0001 0.9136
aStratified log-rank test; bCochran-Mantel-Haenszel testVan 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 progression
• Gain in time• Toxicity profile
• Limited single agent activity
• Weak effect on RR(per RECIST)
EGFR antibodies
• Single agent activity• Consistent increase
in RR• Activity independent
of line of therapy• Predictive marker
• Gain in time to progression moderate
• Toxicity profile
Take-Home Messages: Optimized Medical Therapy of Advanced CRC1. 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!
Cell membrane
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGFVEGF-B
VEGF-C, VEGF-D
Func
tions
VEGF Biology
VEGF-A
VEGF-R1(Flt-1)
MigrationInvasionSurvival
VEGF-R3(Flt-4)
Lymphangio-genesis
VEGF-R2(KDR/Flk-1)Proliferation
SurvivalPermeability
PlGFVEGF-B
VEGF-C, VEGF-D
Func
tions
Large molecule VEGF inhibitors
Bevacizumab
Ramucirumab
Aflibercept(VEGF Trap)
EFC10262: VELOURPhase III Trial 2nd Line FOLFIRI +/-
VEGF-TRAP (Aflibercept)
Stratification factors:Prior bevacizumab (Y/N)ECOG PS (0 vs 1 vs 2)
1:1
mCRC afterfailure of an oxaliplatin
based regimenR
600 ptsAflibercept 4 mg/kg
IV+ FOLFIRI q 2 weeks
600 pts Placebo + FOLFIRIq 2 weeks
52
30% of patients had prior BEVPIs: Allegra, Van Cutsem
Overall Survival - ITT Population
Cut-off date = February 7, 2011; Median follow-up = 22.28 monthsVan Cutsem, et al. WCGC 2011
Comparison VELOUR vs E3200
VELOUR E3200
Prior Tx Oxaliplatin-based Irinotecan-based (IFL)
Prior BEV 30% none
Arms FOLFIRI+ PL
FOLFIRI + AFL
HRp-value
FOLFOX + PL
FOLFOX + BEV
HRp-value
mOS(mos)
12.06 13.5 0.8170.0032
10.8 12.9 0.750.0011
mPFS(mos)
4.67 6.9 0.7580.00007
4.7 7.3 0.61<0.000
1RR (%) 11.1 19.8 0.0001 8.6 22.7 <0.000
1Van Cutsem, et al. WCGC 2011; Giantonio, et al. JCO 2007
Progression Free Survival – Stratification Factors
ITT Population
ECOG PS:p=0.196
PriorBEV:
p=0.695
Tabernero et al., ECCO/ESMO 2011
I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab
Stratification factors:• Region• KRAS status• First-line TTP (<>6 mos)
1:1
mCRC afterfailure
FP/oxaliplatin+ BEV regimen
R
525 pts Ramucirumab IV+ FOLFIRI q 2 weeks
525 pts Placebo + FOLFIRIq 2 weeks
56
Primary EP: OSPIs: Tabernero, Grothey
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 nMVEGFR-2 Phosphorylation, 293 Cells 8
TIE2-Receptor Phosphorylation, CHO Cells 31PDGFR-β Phosphorylation, Aortic SM Cells 90
mVEGFR3 Phosphorylation, 293 Cells 150Mutant RET Phosphorylation, Thyroid TT Cells 10Mutant 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 nMVEGF/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) 900HCC HepG2 (10% FCS) 560
Regorafenib Salvage Therapy Registration Trial
• 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• Total number of patients: 690
Primary endpoint:
OS
CRC 3rd/4th line
Regorafenib 160 mg od 3wks on/1 wk off + BSC
Placebo + BSC
2:1 randomization
Accrual completed Feb 2011, within 10 mos
Cape +/- Perifosine Rand Phase II
R
Perifosine 50 mg PO QD
Capecitabine 825 mg/m2 BID d 1 - 14
Placebo PO QD
Capecitabine 825 mg/m2 BID d 1 - 14
Cycle = 21 Days
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
Patients with 2nd or 3rd
line mCRC No prior Rx with CAP
in metastatic setting Prior Rx with 5-FU or
5-FU based regimen
Richards et al., ASCO 2010
Median Overall Survival (OS)5-FU REFRACTORY
PATIENTS
Median OS: P-CAP:15.1 mos [95% CI (7.3, 22.3)]
Median OS: CAP:6.6 mos [95% CI (4.7, 11.7)]
p-value = 0.0112
Hazard ratio: 0.313(0.122, 0.802)
ALL EVALUABLE PATIENTS
Median OS: P-CAP:17.7 mos [95% CI (8.5, 24.6)]
Median OS: CAP:10.9 mos [95% CI (5, 16.9)]
p-value = 0.0161
Hazard ratio: 0.410(0.193, 0.868)
Richards et al., ASCO 2010
Phase III trial (1:1 Cape/Peri vs Cape) started
X-PECT Phase III TrialTreatment / Schema
Cycle = 21 Days
Patients with refractory mCRC
No prior Rx with CAP in metastatic setting
Randomized 1:1, Double-blind N = ~430 patients RECIST v 1.1 CTCAE v 4.0
Primary Endpoint: Overall Survival
Secondary Endpoints: PFS, ORR, Safety
R
Perifosine 50 mg PO QD
Capecitabine 1000 mg/m2 BID d 1 - 14
Placebo PO QD
Capecitabine 1000 mg/m2 BID d 1 - 14
• 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
Gastric cancer: a global disease
www.cancer.govKamangar F et al. J Clin Oncol 2006;24:2137–50
>20/100000
<10/100000 ≥10 - ≤20/100000
Incidence (males)
Esophageal and Gastric CarcinomaUS 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 > FemaleJemal 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 (mos)
OS (mos) Ref
CFCisplatin 100 mg/m2 D15-FU 1000 mg/m2 CIV D1-5
35 8.3 Bleiberg, EJC 1997
ECFEpirubicin 50 mg/m2 D1Cisplatin 60 mg/m2 D15-FU 200 mg/m2/d CIV D1-21
42 7.0 9.4 Ross, JCO 2002
DCFDocetaxel 75 mg/m2 D1Cisplatin 75 mg/m2 D15-FU 750 mg/m2 CIV D1-5
37 5.6 9.2 Van Cutsem, JCO 2006
EOXEpirubicin 50 mg/m2 D1Oxaliplatin 130 mg/m2 D1Capecitabine 625 mg/m2 BID
48 7.0 11.2 Cunningham, NEJM 2008
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
Bang et al., Lancet 2010Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)
Rationale: A subpopulation of gastric cancers overexpress HER2
Stratification by•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 6Cisplatin 80 mg/m2 q3w X 6
Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading)
5-FU or Capecitabine (investigator discretion)
+ Cisplatin + Trastuzumab (n=294)
5-FU or Capecitabine (investigator discretion)
+ Cisplatin(n=290)
(n = 584)
HER2+ GC(n = 810,
22%)R
Screen 3807 GC patients
for HER2 expression
Primary endpoint: OS
Patient demographics and baseline characteristics
Characteristic F+Cn=290
F+C + trastuzumabn=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 (%)AsiaC/S AmericaEuropeOther
166 (56)26 (9)95 (32)
9 (3)
158 (53)27 (9)
99 (33)14 (5)
Type of GC (central assessment)IntestinalDiffuseMixed
74.2a
8.7a
17.1a
76.8b
8.9b
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)
Bang et al. ASCO 2009
HER2 Positivity Histological Type
Bang et al., Lancet 2010
HER2 Positivity GEJ vs Gastric Ca
Bang et al. ASCO 2009
Events
167182
ToGA: Primary end point: OS
Time (months)
294290
277266
246223
209185
173143
147117
11390
9064
7147
5632
4324
3016
2114
137
126
65
40
10
00
No. at
risk
11.1 13.8
0.00.10.20.30.40.50.60.70.80.91.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + TFC
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
MedianOS
13.811.1
T, trastuzumab Bang et al., Lancet 2010
Events
226235
ToGA: Secondary end point: PFS
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Event
294290
258238
201182
14199
9562
6033
4117
287
215
133
93
82
62
61
61
40
20
00
5.5 6.7
No. at risk
0.00.10.20.30.40.50.60.70.80.91.0
Time (months)
FC + TFC
HR
0.71
95% CI
0.59, 0.85
p value
0.0002
MedianPFS
6.75.5
Bang et al., Lancet 2010
ToGA: Efficacy: OS by HER2 status
Subgroup Median OS (months)
All 11.1 13.8vs
Pre-planned analysisIHC0/FISH+
IHC1+/FISH+IHC2+/FISH+IHC3+/FISH+IHC3+/FISH-
7.210.210.812.317.7
10.68.7
12.317.917.5
Exploratory analysisIHC0 or 1+/FISH+
IHC2+/FISH+ or IHC3+8.711.8
10.016.0
vsvs
0.2 0.4 0.6 1 2 3 4 5
vsvsvsvsvs
0.921.240.750.580.83
0.48, 1.760.70, 2.200.51, 1.110.41, 0.810.20, 3.38
Hazardratio
95% CI
0.74 0.60, 0.91
1.070.65
0.70, 1.620.51, 0.83
Risk ratioFavors T Favors no T
584
6170
15925615
131446
N
Bang et al., Lancet 2010
113
ToGA: OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0363432302826242220181614121086420
Time (months)
11.8 16.0
FC + TFC
Events
120136
HR
0.65
95% CI
0.51, 0.83
MedianOS
16.011.8
Event
0.1
0.3
0.5
0.7
0.9
218 198
40
53
124
2011
228 218
196 170
170 141
142 112
12296
10075
8453
6539
5128
10
00
No. at
risk
3920
2813
Bang et al., Lancet 2010
Secondary end point: tumor response rate
2.4%5.4%
32.1%
41.8%
34.5%
47.3%
Intent to treat
ORR= CR + PRCR, complete response; PR, partial response
p=0.0599
p=0.0145F+C + trastuzumab
F+Cp=0.0017Patients
(%)
CR PR ORR
Bang et al., Lancet 2010
ToGA: Select Grade 3/4 Toxicities*Fluoropyrimidine +
Cisplatin + Trastuzumab
(n = 294)
Fluoropyrimidine + Cisplatin(n = 290)
HematologicNeutropenia 27% 30%
Anemia 12% 10%Nonhematologic
Diarrhea 9% 4%Nausea 7% 7%
Asymptomatic LVEF drops (< 50%) 6% 1%
*2 deaths due to cardiac events in each arm
Bang et al., Lancet 2010
• Activates ADCC• Prevents HER2 domain cleavage• Inhibits HER2-mediated signalling pathways
• Activates antibody-dependent cellular cytotoxicity (ADCC)
• Has a major effect on role of HER2 as a co-receptor with HER3 or EGFR
• Inhibits multiple HER-mediated signaling pathways
Pertuzumab and trastuzumab bind to distinct epitopes on HER2 extracellular domain
Figures adapted from Hubbard SR. Cancer Cell 2005;7:287–288
Trastuzumab-HER2 complexPertuzumab-HER2 complex
Trastuzumab
Dimerization domain
Pertuzumab
Trastuzumab plus Pertuzumab in Gastric Cancer Xenografts
4-1ST (HER2-positive) MKN-28 (HER2-negative)
100
1,000
1 8 15 22
Control
Pertuzumab 40 mg/kg
Trastuzumab 20 mg/kg
Pertuzumab 40 mg/kg +
trastuzumab 20 mg/kg
Days after treatment started
8 15 221
a
a, b, c
1,000
100
Tum
or v
olum
e (m
m3 )
100
1,000
1 8 15 22
Control
Pertuzumab 40 mg/kg
Pertuzumab 40 mg/kg +
Trastuzumab 20 mg/kg
8 15 221
1,000
100
Days after treatment started
Tum
or v
olum
e (m
m3 )
Yamashita et al., AACR 2010
Phase III Trials with HER2 Targeted Agents
http://clinicaltrials.gov/ct2/show/NCT00680901
LOGiCCapeOx + Lapatinib
N=535Primary EP: OS (was PFS)Data expected mid 2012
CapeOx + Placebo
RTOG 1010 – Proposed Neoadjuvant Phase III Trial in Esophagus/GEJ ACA
PI: H. Safran, Providence, RIPrimary EP: DFS (15 27 mos, HR 0.56)
N=160 Pts with HER+
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
0 5 10 15Trastuzumab + XP/FP (8)
EOX (6)XP (7)
ECX (6)ECF (6)DCF (4)EOF (6)
IF (5)CF (4)
FAMTX (2)BSC (1)
C+S1 (3)
HER2 IHC 2+/FISH+ or IHC 3+
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.
12 months
The dismal prognosis of pancreatic cancer
• Pancreatic cancer has the 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
5-year OS
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% 0.0025Burris JCO 1997
Gemcitabine vs 5-FU Efficacy
Gemcitabine vs 5-FU Survival
Log-Rank Testp = 0.0009
Burris JCO 1997
Gemcitabine5-FU
Pancreas Cancer: Prodige 4 -ACCORD 11 trial design
Stratification :
• center• performance status: 0 versus 1• location of the tumor: head versus other location of the primary
Metastaticpancreatic
cancer
RANDOMIZE
FOLFIRINOX
Gemcitabine6 months of
chemotherapy recommended
CT scans: obtained
every 2 months
for both arms:
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
1 h 30
2 h
2 h 46 h
Oxaliplatin85 mg/m2
Irinotecan180 mg/m2
Leucovorin400 mg/m2
Continuous 5-FU 2.400 mg/m2
Bolus 5-FU 400 mg/m2
q2wks
Conroy et al. NEJM 2011
Patients characteristics
Characteristics FolfirinoxN=171
GemcitabineN=171
p
Median age (yrs)[range]
61[25-76]
61[34-75]
NS
Sex MaleFemale
106 (62%)65 (38%)
105 (61.4%)66 (38.6%) NS
Baseline PS 012
64 (37.4%)106 (62.0%)
1 (0.6%)
66 (38.6%)105 (61.4%)
0 (0.0%)NS
Location of primary HeadOther
62 (36.3%)109 (63.7%)
60 (35.1%)111 (64.9%) NS
Conroy et al. NEJM 2011
Safety: hematological AEs
AE, % per patient
FolfirinoxN=167
GemcitabineN=169
p
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 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
5.4
42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G armOne toxic death occurred in each arm
Conroy et al. NEJM 2011
Objective Response RateFolfirinox
N=171Gemcitabine
N=171p
Complete response 0.6% 0%
Partial response 31% 9.4% 0.0001CR/PR 95% CI [24.7-39.1] [5.9-15.4]
Stable disease 38.6% 41.5%
Disease controlCR+PR+SD
70.2% 50.9% 0.0003
Progression 15.2% 34.5%
Not assessed 14.6% 14.6%
Median durationof response 5.9 mo. 4 mo. ns
Conroy et al. NEJM 2011
Progression-Free Survival
0.00
0.25
0.50
0.75
1.00P
roba
bilit
y
171 121 85 42 17 7 4 1 1 0 0 0 0Folfirinox171 88 26 8 5 2 0 0 0 0 0 0 0Gemcitabine
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33 36Months
Gemcitabine Folfirinox
p<0.0001
HR=0.47 : 95%CI [0.37-0.59] Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo
Conroy et al. NEJM 2011
Overall Survival
FolfirinoxN=171
GemcitabineN=171
p HR
Median survival[CI 95%]
11.1 mo.[ 9 - 13.1]
6.8 mo.[ 5.5 - 7.6]
<0.0001 0.57
1-yr. survival 48.4% 20.6%
18-mo. survival 18.6% 6%
Median follow up: 26.6 months [95% CI: 20.5 – 44.9]
Conroy et al. ASCO 2010
Overall Survival
0.00
0.25
0.50
0.75
1.00P
roba
bilit
y
171146116 81 62 34 20 13 9 5 3 2 2Folfirinox171134 89 48 28 14 7 6 3 3 2 2 2Gemcitabine
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33 36Months
Gemcitabine Folfirinox
Stratified Log-rank test, p<0.0001
HR=0.57 : 95%CI [0.45-0.73]
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