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