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Axel Grothey
Professor of Oncology
Mayo Clinic Rochester
The Gastrointestinal Malignancy
Pipeline – What does the future
hold for GI Cancers?
Targeting Angiogenesis
DISCLOSURES
• Grant/Research Support
• Bayer
• Eisai
• Eli Lilly
• Imclone
• Genentech
VEGF-A
VEGF-R1(Flt-1)
Migration
Invasion
Survival
VEGF-R3(Flt-4)
Lymphangio-
genesis
VEGF-R2(KDR/Flk-1)
Proliferation
Survival
Permeability
PlGF
VEGF-B
VEGF-C,
VEGF-DF
un
cti
on
s
Large molecule VEGF inhibitors
Bevacizumab
Ramucirumab
Aflibercept
(VEGF Trap)
Ramucirumab (IMC-1121B):a fully human VEGFR2 antagonist
• Isolated from phage display library of human Fab fragments from non-immunized donors1,2
• Fully human anti-VEGFR-2 IgG1 monoclonal antibody1
• High affinity (KD = 50 pM) 1
• Blocks VEGF binding to VEGFR-2 (IC50 0.8-1.0 nM) 1,3
• Biochemical and anti-tumor effects
• Inhibits ligand-dependent VEGFR-2 activation and
signaling4
• Inhibits growth & migration of human endothelial cells1
• Direct anti-tumor effect in NOD-SCID mice inoculated with
VEGFR-2+ HL605
1. Lu D et al. The Journal of Biological Chemistry. 2003;278(44):43496-43507.
2. Lu D et al. International Journal of Cancer. 2002;97:393-399.
3. Hsu J, et al. I 2009; 23(5):289-304.
4. Witte L et al. Cancer and Metastasis Reviews. 1998; 17:155-161.
5.Zhu Z et al. Leukemia. 2003; 17: 604-611.
REGARD Study Design
Ramucirumab 8 mg/kg
q2wk
+
BSC (n = 238)
R
A
N
D
O
M
I
Z
E
Placebo q2wk
+
BSC (n = 117)
S
C
R
E
E
N
Treatment until disease progression or intolerabletoxicity
Tumor assessment, survival, and safety follow-up
N = 355
• Multicenter, randomized, double-blind, placebo-controlled, phase 3 trial
• Gastric or GEJ adenocarcinoma
• Stratification factors: geographic region, weight loss (≥10% vs. <10%
over 3 months), location of primary tumor (gastric vs. GEJ)
• Global: 6 continents, 30 countries, 120 study centers
2:1
Abbreviations: BSC=best supportive care; GEJ= gastroesophageal junction
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.
REGARD Trial: Results
27
HR (95% CI) = 0.776 (0.603-0.998)
Log-rank P value (stratified) =.047
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 26 28
0
20
40
60
80
100
OS
, %
238
117
Number at risk
Ramucirumab
Placebo
154
66
92
34
49
20
17
7
7
43
2
0
0
0
1
Ramucirumab (n = 238)
Placebo (n = 117)
Censored
Time Since Randomization, Months
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.
20
HR (95% CI) = 0.483 (0.376-0.620)
Log-rank P value (stratified) <.0001
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
0
40
60
80
100
PF
S, %
238
117
Number at risk
Ramucirumab
Placebo213
92
5
20
0
113
27
65
11
61
7
45
4
30
2
18
2
18
2
11
2
4
1
2
1
1
0
1
0
1
0
1
0
Time Since Randomization, Months
Ramucirumab (n = 238)
Placebo (n = 117)
Censored
OS PFS
Ramucirumab (N=236) Placebo (N=115)
TEAEs*Any Grade
(%)
Grade ≥3
(%)
Any Grade
(%)
Grade ≥3
(%)
Fatigue† 35.6 6.4 40.0 9.6
Abdominal pain† 28.8 5.9 27.8 2.6
Decreased appetite 24.2 3.4 22.6 3.5
Vomiting 19.9 2.5 25.2 4.3
Hypertension† ‡ 16.1 7.6 7.8 2.6
Constipation 15.3 0.4 22.6 2.6
Anemia† 14.8 6.4 14.8 7.8
Dysphagia 10.6 2.1 10.4 4.3
Ascites 9.7 4.2 9.6 4.3
Dyspnea 9.3 1.7 13.0 6.1
Back pain 7.6 1.3 9.6 2.6
Hyponatraemia 5.5 3.4 1.7 0.9
Treatment-emergent Adverse Events
Fuchs CS, et al. Lancet. 2014;383(9911):31-39.
Why did VEGF inhibition work in REGARD and not in AVAGAST?
REGARD AVAGAST
Agent Ramucirumab Bevacizumab
Setting 2nd line 1st line
Study drug Single agent Added to chemo
Comparator PL/BSC Chemo
% Asian pop 15 49
% GEJ 25 14
Comparison REGARD / AVAGAST
REGARD (2nd line) AVAGAST (1st line)
% Pop HR OS HR PFS % Pop HR OS HR PFS
Asia 15 49 0.97 0.92
Europe 32 0.85 0.71
Americas 19 0.63 0.65
Total 0.78 0.48 0.87 0.80
Treat until
disease
progression
or
intolerable
toxicity
• Important inclusion criteria:
- Metastatic or loc. adv. unresectable gastric or GEJ* adenocarcinoma
- Progression after 1st line platinum/fluoropyrimidine based chemotherapy
•Stratification factors:
- Geographic region,
- Measurable vs non-measurable disease,
- Time to progression on 1st line therapy (< 6 mos vs. ≥ 6 mos)
Ramucirumab 8 mg/kg day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
of a 28-day cycle
N = 330
Placebo day 1&15
+ Paclitaxel 80 mg/m2 day 1,8 &15
N = 335
S
C
R
E
E
N
R
A
N
D
O
M
I
Z
E
Survival and
safety
follow-up
VEGFr: RAINBOW: Study Design
1:1
Wilke GI Symposium 2014 LBA 7
RAINBOW: Ramucirumab + Paclitaxelfor Metastatic Gastric Cancer
• 665 pts with POD on fluorinated pyrimidine + platinum
• Weekly paclitaxel 80 mg/m2 + /- Ram 8 mg/kg
• PFS improved 2.9 months 4.4 months (HR 0.635, P<.0001)
• OS improved 7.4 months 9.6 months (HR 0.807, P = .0169)
• RR improved from 16% to 28% (p = 0.0010 (P<.0001)
• Inceased toxicity neutropenia and hypertension
Wilke GI Symposium 2014 LBA 7
VEGF Adjuvant Trials Gastric Cancer
• MAGIC 2 Trial: EOX + / - Bevacizumab
• Amended for HER2 + patients
• Randomized to + / - Lapatinib (HER1-2 TKI)
Apatinib in Gastric Cancer
• Small-molecule multitargeted TKI with high activity against VEGFR
• 144 patients in China, Phase II trials of placebo vs850 mg/d or 425 mg BID in refractory GC
• OS 2.5 months 4.0 months, 4.5 months
• RR 10%
• Phase III Trial Planned
Li J, et al. J Clin Oncol. 2013;31(26):3219-3225.
Apatinib in Gastric Cancer
Li J, et al. J Clin Oncol. 2013;31(26):3219-3225.
PFS
OS
I4T-MC-JVBB Phase III Trial 2nd Line CRC FOLFIRI +/- Ramucirumab (RAISE)
Stratification factors:• Region• KRAS status• First-line TTP (<>6 mos)
1:1
mCRC afterfailure
FP/oxaliplatin+ BEV regimen
R
525 ptsRamucirumab IV
+ FOLFIRI q 2 weeks
525 ptsPlacebo + FOLFIRI
q 2 weeks
17
Primary EP: OS
Accrual completedPIs: Tabernero
1st line CRC Ph2 : mFOLFOX6 + RAM
Median 11.5 months
(95% CI: 8.61 – 13.11)
Garcia-Carbonero R et al., ASCO GI 2012.
Response (n=48)
CR 1 2%
PR 27 56%
SD 17 35%
PD 1 2%
NE 2 4%
RR 28 58%
(95% CI: 43-72%)
DCR 45 94%
95% CI: 83-99%
Progression Free SurvivalKaplan-Meier Plot (mITT Population)
Best Overall % Change from
Baseline Target Lesion Measurement (mITT Population)
A Broad Array of Kinases are Involved in Cancer Cell Growth, Proliferation, and Survival
Sorafenib Axitinib Cediranib Brivanib
Percent Control
10-35% 5-10%
1-5%
0.1-1%
0.1%
0%
Regorafenib
DMSO, dimethyl sulfoxide.
Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. Sorafenib [Prescribing Information]. Wayne, NJ: Bayer HealthCare; 2012.
Regorafenib Shows a Kinase Selectivity Profile That is Distinct and Different From Other Multikinase Inhibitors
• Kinome-wide selectivity profiles were determined by Ambit Biosciences (San Diego CA, USA)
• 402 kinases were analyzed using a single dose of 1 μM
• Binding activities are displayed as the percentage of the kinase that remained bound to a reference bait compound in the presence of the test compounds compared to the DMSO control
Observations on MKIs in CRC
• All studies combining MKIs with chemotherapy in first and second-line CRC have been negative• Sunitinib
• Axitinib
• Cediranib
• Vatalanib
• Brivanib
• Sorafenib
• Perifosine
• Only regorafenib worked
• Unique property of this agent or a matter of trial design?
Regorafenib (BAY 73-4506), an Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways
Wilhelm SM, et al. Int J Cancer. 2011;129(1):245-255.
Mross K, et al. Clin Cancer Res. 2012;18(9):2658-2667.
Strumberg D, et al. Expert Opin Invest Drugs. 2012;21(6):879-889.
KIT
PDGFR
RET
PDGFR-β
FGFR
VEGFR1-3
TIE2
Inhibition of neoangiogenesis
Inhibition of tumor microenvironment
signaling
Inhibition of proliferation
RegorafenibF
Cl
F
F F
OO
O
N
HN
H
N
H
N
Biochemical
Activity
Regorafenib IC50
mean ± SD nmol/l (n)
VEGFR1 13± 0.4 (2)
Murine VEGFR2 4.2± 1.6 (10)
Murine VEGFR3 46± 10 (4)
TIE2 311± 46 (4)
PDGFR-β 22 ± 3 (2)
FGFR1 202± 18 (6)
KIT 7± 2 (4)
RET 1.5± 0.7 (2)
RAF-1 2.5 ± 0.6 (4)
B-RAF 28 ± 10 (6)
B-RAFV600E 19 ± 6 (6)
Confidential • Advisory Board • 30 Sept 2012
CORRECT study design
• Multicenter, randomized, double-blind, placebo-controlled, phase III• 2:1 randomization
• Strat. factors: prior anti-VEGF therapy, time from diagnosis of mCRC, geographical region
• Global trial: 16 countries, 114 active centers
• 1,052 patients screened, 760 patients randomized within 10 months
• Secondary endpoints: PFS, ORR, DCR
• Tertiary endpoints: duration of response / stable disease, QOL, pharmacokinetics, biomarkers
mCRC after
standard
therapy
RANDOM I ZAT I ON
Regorafenib + BSC 160 mg orally once daily
3 weeks on, 1 week off
Placebo + BSC 3 weeks on, 1 week off
2 : 1
Primary
Endpoint:
OS90% power to
detect 33.3%
increase
(HR=0.75), with
1-sided overall
a=0.025
Grothey et al., Lancet 2012
Overall survival (primary endpoint)
Primary endpoint met prespecified stopping criteria at interim analysis
(1-sided p<0.009279 at approximately 74% of events required for final analysis)
1.00
0.50
0.25
0
0.75
200100500 150 300250 400350 450
Days from randomization
Su
rviv
al
dis
trib
uti
on
fu
ncti
on
Placebo N=255
Regorafenib N=505
Median 6.4 mos 5.0 mos95% CI 5.9–7.3 4.4–5.8
Hazard ratio: 0.77 (95% CI: 0.64–0.94)
1-sided p-value: 0.0052
Regorafenib Placebo
Grothey et al. Lancet 2012
Questions for Regorafenib in CRC
• In addition to the salvage therapy setting, where could Regorafenib be developed
• As single agent
• Maintenance therapy?
• Adjuvant therapy?
• In combination with chemo
• Is it really different than other MKI?
• Will we ever find a predictive biomarker or a biomarker signature?
Key Phase II/III Trials of Regorafenib as Single Agent in GI Malignancies
Tumor Phase Setting Status
CRC III Adjuvant after liver resection Open
CRC II 1st line in frail pts Open
CRC II 1st line maintenance Planned
CRC II Rego before EGFR Planned
HCC III 2nd line after Sorafenib Open
Pancreas II Salvage therapy Open
Esophago-gastric II Salvage therapy Planned
Esophageal Ca II Adjuvant high-risk Planned
Ang2 System
Cascone T , and Heymach J V JCO 2012;30:441-444
Ang/Tie2 Inhibitors in Clinical Trials
Agent Class Target(s)
AMG 386 Peptibody Ang1, Ang2
CVX-060 CovX-Body Ang2
CVX-241 CovX-Body Ang2, VEGF-A
MEDI-3617 mAb Ang2
REGN910 mAb Ang2
AMG 780 mAb Ang2
RO5520985 Cross-Mab Ang2, VEGF-A
CEP-1198 MKI Tie2, VEGFR
ARRY-614 MKI P38, Tie2, Abl, VEGFR2
MGCD265 MKI Tie2, cMet, VEGFR1-3, Ron
Regorafenib MKI Tie2, VEGFR1-3, PDGFR etc
Summary
• Angiogenesis inhibitors are very much alive in GI malignancies!
• Search for biomarker so far elusive
• While focus of drug development tries to shift to molecularly targeted approaches, angiogenesis inhibitors have shown efficacy in various GI malignancies in unselected patients