PTK/ZK Inhibits All Known VEGF Receptors

CONFIRM 2 INTERIM ANALYSIS

Results of an Interim Analysis of a Multinational Randomized, Double-Blind, Phase III Study in Patients With Previously Treated Metastatic Colorectal Cancer (mCRC) Receiving FOLFOX4 and PTK787/ZK 222584

(PTK/ZK) or Placebo

C.-H. Koehne, E. Bajetta, E. Lin, E. Van Cutsem, J.R. Hecht, J.-Y. Douillard, M. Moore, C. Germond, D. Laurent, C. Jacques

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PTK/ZK Inhibits All Known VEGF Receptors

VEGF-A VEGF-B

PlGF

VEGF-CVEGF-D

VEGFR-1/Flt-1 VEGFR-3/Flt-4

Extracellular

Intracellular

Angiogenesis LymphangiogenesisTumor metastasis

Endothelial Cell

PTK/ZK PTK/ZK

VEGF-AVEGF-CVEGF-D

VEGFR-2/KDR

Angiogenesis

PTK/ZK

•PTK/ZK also inhibits PDGFR-and c-KIT

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CONFIRM 2 Study Design

Stratification Factors: PS: 0, 1-2LDH: ≤, >1.5 x ULN

Multinational randomized phase III trial in irinotecan-pretreated mCRC patients

RANDOMIZED

CONFIRM 2 855 patients

FOLFOX 4 +PTK/ZK (n=426)1250 mg po qd

FOLFOX 4 +Placebo (n=429)

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FOLFOX 4 +PTK/ZK 1250 mg po qd

FOLFOX 4 +Placebo

RANDOMIZED

CONFIRM Study Design

Stratification Factors: PS: 0, 1-2LDH: ≤, >1.5 x ULN

CONFIRM 2 855 patients

CONFIRM 1CONFIRM 1 1168 patients1168 patients

1st linemCRC

2nd linemCRC

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CONFIRM 1: Progression Free Survival (ASCO 2005)

FOLFOX4 + PTK/ZKFOLFOX4 + Placebo


0

25

50

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Pro

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%

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Pro

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0 2 4 6 8 10 12

Time Since Randomization, mo

0 2 4 6 8 10

HR = 0.88 (95% CI: 0.74, 1.03)P value = 0.118

HR = 0.60 (95% CI: 0.44, 0.82)P value = 0.001

Overall Patients High LDH Patients


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CONFIRM 2: Main Patient Eligibility Criteria

• Patients with mCRC

• Pretreatment for metastatic disease with irinotecan/fluoropyrimidine-based chemotherapy

• Measurable disease per RECIST

• WHO PS of 0-2

• Adequate hematological and organ function

• No exclusions for prior coagulopathy or bleeding

RECIST = Response Evaluation Criteria in Solid Tumors.

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CONFIRM 2: Study Objectives

• Primary end point: Overall survival

– Statistical hypothesis: One-year overall survival rate from 36% to 45% (HR 0.782, 90% power, 5% level of significance with 692 events)

• Key secondary end points:

– Overall survival in high LDH (> 1.5 x ULN) patients

– Progression free survival*

• Overall population

• High LDH population (> 1.5 x ULN)

– Overall response rate (RECIST)

*Assessed by investigators following RECIST criteria.

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Patient Characteristics

FOLFOX4 Plus

CharacteristicsPTK/ZK(n = 426)

Placebo(n = 429)

Median age, y 62.0 60.0

Number of patients, n (%)

Low LDH (≤ 1.5 x ULN) 302 (71) 303 (71)High LDH (> 1.5 x ULN) 124 (29) 126 (29)

Prior adjuvant chemotherapy, % 31 31Male/female ratio, % 62/38 62/38WHO PS, 0/1-2, % 53/47 53/47Colon/rectum, % 68/30 72/26

Metastasis, %

Liver 73 77Lung 48 44

Number of organs involved, %

1 40 412 34 33≥ 3 26 27

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Patient Disposition

FOLFOX4 Plus

PTK/ZK, %

(n = 426)

Placebo, %

(n = 429)

Patients ongoing* 12 11

Patient discontinuation

Progressive disease 52 70

Adverse event 15 8

Withdrawal of consent 13 5

Other reasons 8 6

*At time of data cut-off, patients are continuing study treatment.

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Safety and Tolerability

FOLFOX4 Plus

Adverse EventsPTK/ZK, %(n = 421)

Placebo, %(n = 421)

( > 5% Patients) Grade 3 Grade 4 Grade 3 Grade 4Neutropenia 17 12 16 12Thrombocytopenia 5 < 1 4 < 1

Peripheral neuropathy 5 0 5 0

Diarrhea 16 < 1 8 0Nausea 11 0 5 0

Vomiting 9 < 1 5 0

Abdominal pain 5 1 5 < 1Hypertension 21 1 5 0Dizziness 8 1 < 1 0Venous thrombosis 5 < 1 < 1 0

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Other Clinically Important Adverse Events

FOLFOX4 Plus

Adverse Events, n (%)PTK/ZK

(n = 421) Placebo

(n = 421)

Bleeding, all grades 59 (14%) 48 (11%)

Bleeding, grade 3/4 9 (2.5%) 10 (2.2%)

Arterial thrombosis, grade 3/4 13 (3%) 6 (1.5%)

Bowel perforation 0 0

Encephalopathy 4 (1%) 0

All cause mortality 36 (9%) 26 (6%)(within 28 days of last study drug administration)

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Response Rate

FOLFOX4 Plus

ResponsesPTK/ZK, %(n = 426)

Placebo, %(n = 429)

Overall response Complete response Partial response

19 2 17

18 1 17

Stable disease 43 43

Progressive disease 31 35

Duration of disease stabilization (duration of CR/PR/SD):

7.7 mo 5.8 mo

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Overall Survival*: Overall Population

*Overall survival results based on interim analysis values; final data available end of 2006.

426429

373377

239234

115119

4856

1414

PTK/ZKPlacebo

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12.1 mo PTK/ZK vs 11.8 mo Placebo

HR = 0.94 (95% CI: 0.77, 1.14)P value = 0.51

0

25

50

75

100


Ove

rall

Su

rviv

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%

0 4 8 12 16 20 240

25

50

75

100

0 4 8 12 16 20 24


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Progression Free Survival: Overall Population

426429

194182

4938

PTK/ZKPlacebo

106

22


HR = 0.83 (95% CI: 0.71, 0.98)P value = 0.026

Pro

gre

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%

0

25

50

75

100

0 4 8 12 16 20

Time since randomization, mo

75


00

15

Pro

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%

0

25

50

75

100


0 4 8 12 16

5.6 mo PTK/ZK vs 3.8 mo PlaceboHR = 0.61 (95% CI: 0.46, 0.80)

P value = < 0.001


Progression Free Survival: High LDH Patients

124126

6848

188

PTK/ZKPlacebo

52

20

16

Ove

rall

Su

rviv

al,

%

*Overall survival results based on interim analysis values; final data available end of 2006.

0

25

50

75

100


0 4 8 12 16 20 24


HR = 0.78 (95% CI: 0.58, 1.05)P value = 0.105


Overall Survival*: High LDH Patients

124126

10894

6145

2116

88

PTK/ZKPlacebo

21

00

17

0.80.60.4 1.61.41.2

Low LDH

Overall Population

1.0

High LDH

1.8

Favors PTK/ZK Favors Placebo

0.026 HR P value

0.83 CONFIRM 2

PFS by LDH Stratum:Hazard Ratio in CONFIRM 2

Progression Free Survival by LDH Stratum: HR in CONFIRM 2

*Investigator-based assessment of CONFIRM 1.

0.83 0.026 CONFIRM 1*

and 1

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Bulky/Hypoxic Tumors Boost HIF-1 Which Upregulates VEGF and LDH

VEGF-AVEGFR-1

HIF-1 stabilization

nucleus

HIF-1/ARNT

GLUT-1, -3

LDH-A

NOS

EPO

HRE

Adapted from Harris AL. Nature Rev Cancer. 2002;2:38-47.

Anaerobic glycolysis

Erythropoiesis

Angiogenesis

LDH-5

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PTK/ZK Summary

• CONFIRM 2

– Well-tolerated safety profile with anticipated antiangiogenic drug-related effects

– No OS benefit for overall population based on interim analysis

– PTK/ZK improved PFS for overall population (HR = 0.83, P = 0.026)

– PTK/ZK significantly improved PFS in high LDH patients (HR = 0.61, P < 0.001)

– PTK/ZK improved OS for patients with high LDH (HR = 0.78, P = 0.105)

• Efficacy and safety results in overall population and high LDH patients are highly consistent between CONFIRM 1 and CONFIRM 2

• New studies in mCRC patients with high LDH are planned

• Further development of PTK/ZK is ongoing in mCRC and additional tumor types

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Acknowledgments

The patients and their families

The investigators in over 200 medical centers worldwide

The Novartis Pharmaceutical Corp, US and Schering AG, Germany CONFIRM team

Related PTK/ZK ASCO presentationsMajor et al. #3529 CONFIRM 1/2 meta-analysisAzuma et al. #3530 Association of serum LDH with genes in the angiogenesis pathways in mCRC patients

PTK/ZK Inhibits All Known VEGF Receptors

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