Novel Biologics in the Treatment of Colorectal

Cancer

Howard S. Hochster, MD

Professor of Medicine, NYU School of Medicine

Director, GI Program NYU Cancer Institute

Current Therapies Fluoropyrimidines Oxaliplatin Irinotecan Bevacizumab; anti-angiogenic MoAB Cetuximab; anti-growth factor MoAB

5-Fluorouracil: History

Concept of “All-3-Drugs” - Update 200511 Phase III Trials, 5768 Patients

OS (mos) = 13.2 + ([%3drugs] x 0.1), R^2 = 0.85 Grothey & 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

22

21

20

19

18

17

16

15

14

13

12

Med

ian O

S (

mo

)

Patients with 3 drugs (%)

P =.0001

First-Line Therapy

Multivariate analysis:Effect on OS P

First-line doublet 0.69All 3 drugs 0.005

Source: Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005;23(36):9441-2. Adapted with permission from the American Society of Clinical Oncology.

Functions of Cell Surface Receptors

Proliferation Invasion Migration Survival Angiogenesis

EGFR √ √ √ √ √ √

IGFR √ √ √ √ √ √

c-MET √ √ √ √ √

VEGFR1 √ √ √

uPAR √ √ √ √

Integrins √ √ √ √ √

The best targeted therapies may be those that mediate cell survival

AN INTERESTING

DILEMMA:

Bevacizumab studied with bIFL; how will it be used with oxaliplatin-based Rx?

THE TREE TRIAL (2 cohorts)comparing oxaliplatin schedules

Given that:– 5-FU may be administered as an infusion,

a bolus, or as an oral prodrug formulation– 3 oxaliplatin-fluoropyrimidine regimens

would have: Similar efficacy, if there were equivalent

dose intensities Variant AE profiles, related to the mode of

fluoropyrimidine administration

TREE-1 Rationale

TREE-1 and TREE-2: Treatment Schema

RRAANNDDOOMMIIZZAATTIIOONN

mFOLFOX6 (q14 days)Oxaliplatin-85 mg/m2

LV-350 mg (fixed dose)5-FU-400 mg/m2 IV bolus followed by 2400

mg/m2 IV infusion over 46 hrs on D1

CapeOx (q21days)Oxaliplatin-130 mg/m2 over 2 hours on D1

Capecitabine-1000 mg/m2 twice daily on Days 1-15

bFOL (every 28 days)

Oxaliplatin - 85 mg/m2 IV x 2 hrs days 1,15LV - 20 mg/m2 IV bolus on Days 1,8,15

5-FU - 500 mg/m2 IV bolus on Days 1,8,15

TREE-1 (N=150)(Nov 2002-Oct 30, 2003)

mFOLFOX6 +

Bevacizumab (5 mg/kg q14 days)

CapeOxCapecitabine 850 mg/m2 bid day 1-5

+ Bevacizumab(7.5 mg/kg q21days)

bFOL+

Bevacizumab (5 mg/kg q 2 weeks)

TREE-2 (N=223)(Nov 2003 – April 2004)

RRAANNDDOOMMIIZZAATTIIOONN

TREE-1 TREE-2

mFOLFOX

n=50*

bFOL

n=50*

CapeOx

n=50*

mFOLFOX-B

N=75*

bFOL-B

N=74*

CapeOx-B

N=74*

Median age

(range)

61

(35-79)

62

(31-84)

62.5

(32-84)

64

(31-83)

57.5

(30-85)

62

(32-82)

Gender(%):

Male/Female58/42 62/38 62/38 61/39 49/51 60/40

ECOG PS:

0/1 %62/38 58/42 50/50 59/41 55/45 66/34

Prior adjuvant

therapy (%)44 16 26 23 32 31

* ITT population

TREE-1 vs. TREE-2: Demographics

TREE-1: 5-FU/Capecitabine Dose Reductions

FOLFOXFOLFOX

(149 cycles)(149 cycles)

bFOLbFOL

(82 cycles)(82 cycles)

CapeOXCapeOX

(88 cycles)(88 cycles)

5-FU or 5-FU or

capecitabine capecitabine

dose reductions: dose reductions:

cycles (%)cycles (%)

1717 1212 5050

DSMB recommended that the capecitabine dose be reduced

(to 850 mg/m2 b.i.d. x 14 days) in the CapeOX arm (30/10/03)

TREE-1 vs. TREE-2Comparative Grade 3/4 toxicities –First 12 weeks of treatment

EventsTREE 1 TREE 2

mFOLFOX

n=49*

bFOL

n=50*

CapeOx

n=48*

mFOLFOX-B

n=71*

bFOL-B

n=70*

CapeOx-B

n=72*

Vomiting 8 6 19 1 11 7Dehydration 4 10 21 6 11 8Diarrhea 22 22 27 10 26 17Neutropenia 35 14 13 35 13 4Febrile neutropenia 0 0 2 3 1 0Hand-foot syndrome 6 2 13 0 0 7Neurotoxicity 4 4 19 3 4 7Hypertension 0 0 0 9 4 10Bleeding 0 4 2 0 4 1Thrombosis (arterial) 0 0 2 0 0 1Proteinuria 0 0 0 0 0 1Any Grade 3 or 4 76 44 73 65 60 58

TREE-2: Grade 3/4Toxicities during the First 12 Weeks of Rx

0

10

20

30

40

Neutropenia FebrileNeutropenia

Vomiting Dehydration Diarrhea Gr. 3Neurotoxicity

Bleeding Thromboembolic

Event

mFOLFOX6 +Bev

bFOL+Bev

CapeOx+Bev

mFOLFOX+Bev

n=71 (%)

bFOL+Bev

n =70(%)

CapeOx+Bev

n=72(%)

GI Perforation 3 (4.2) 2 (2.9) 2(2.8)

Impaired Wound Healing 4 (5.6) 1 (1.4) 4 (5.6)

Treatment-related Deaths 0

3 (4.3)

(2 sepsis,

1 peritonitis)

3 (4.2)

(1 arrhythmia,

1 CVA,

1 SBO)

TREE-2: Absolute Number of Patients with Specific Treatment-related Toxicities

TREE-1 vs. TREE-2Comparative Response Rate

0

10

20

30

40

50

60

70

FOLFOX FOLFOX+B bFOL bFOL+B CapeOx CapeOx+B

Confirmed ORR Best ORR

(p<0.004, from the pooled logistic regression analysis, likelihood ratio test)

FOLFOX bFOL CapeOX

TREE-1 vs. TREE-2Comparative Analysis

FOLFOX CapeOx bFOL

- BEV

N=49

+ BEV

N=71

- BEV

N=48

+ BEV

N=72

- BEV

N=49

+ BEV

N=71

Conf. RR (%) 41 52 27 46 20 35

TTF (mo) 5.7 5.8 4.2 5.5 4.8 5.5

TTP (mo) 8.4 9.9 5.9 10.3 6.9 8.3

Hochster et al., ASCO 2005 and GI ASCO 2006

TREE-2 Conclusions Two sequential cohorts within same protocol, same

investigators CapeOX not tolerated at 1000 mg/m2 bid x 14 days;

good tolerance at 850 mg/m2 bid Addition of Bevacizumab to oxaliplatin plus

fluoropyrimidines is safe with expected toxicities and overall gr 3-4 rates

Addition of Bevacizumab increases RR by approximately 10%– Also improves TTP – TTF is increased less by bevacizumab

• Chemical differences

• PK differences

• Differences in spectrum of activity– VEGFR and other receptors

Differences in toxicity

All TKIs Are Not the Same

Small Molecule Inhibitors• 1st Generation

PTK787 /ZK 22854 SU5416SU6668SU11248

Newer InhibitorsAAL993CEP-7055CP-547,632GW654652AMG 706AZ 2171

• Combined InhibitorsZD6474AEE788BAY 43-9006

PTK787/ ZK 225846 (Vatalanib)

Aminophthalazine Well tolerated oral

inhibitor of VEGFR-1,2,3 Also inhibits c-kit and

PDGFR Promising phase I, II

data Inhibits blood flow on

DCE-MRI CONFIRM 1-2 trials

Phase III Trial of Vatalanib in First-Line MCRC (CONFIRM-1)

Primary end point: PFS, OS

Secondary end points: TTP, TTF, ORR

FOLFOX4 + placebo

n=585PD

n=583PD

•Previously untreated MCRC

•WHO PS 0-2

FOLFOX4 + Vatalanib 1250 mg po qd

RANDOMIZATION

Hecht et al. ASCO, 2005. Abstract 3. Updated from oral presentation.

Dr. Dimitris Voliotis • #24

Phase III Renal Cell Cancer Interim analysis

positive

Filed for market approval in RCC July 2005

Phase III Hepatocellular Carcinoma Started March 2005

Phase II/III Malignant Melanoma Started May 2005

Sorafenib (BAY 43-9006)

Dr. Dimitris Voliotis • #25

* Placebo patients whoprogressed could cross over to sorafenib

• Randomized Discontinuation Design represents an innovative approach for studying novel anticancer drugs

• Bayer and Onyx were the first to apply this design in a major oncology setting

Randomized Discontinuation Study – Treatment Plan

Sorafenib 12-week run-in

Tumor shrinkage ≥25%

Tumor growth/ shrinkage <25%

Tumor growth ≥25%

Off study

Placebo* 12 weeks

Sorafenib 12 weeks

Sorafenib open label

% Progression free at 24 weeks

Ratain MJ, et al. Presented at: ASCO; May 13-17, 2005; Orlando, Fla.

N=202 N= 166 N=32

N=33

N= 79

Dr. Dimitris Voliotis • #26

Data shown for 166 patients (12-week bidimensional measurements were not available for 36 patients).

Tumor Size Changes After 12 Weeks of Treatment as Measured by Radiographic Measurements

≥25% growth

<25% change

≥25% shrinkage

-100

-75

-50

-25

0

25

50

75

100

125

% c

han

ge

fro

m b

asel

ine

in b

idim

ensi

on

al

tum

or

mea

sure

me

nt

Patients with increasein tumor size

Patients with decrease

in tumor size

Source: With permission. Ratain MJ et al. Presentation. ASCO 2005. Abstract 4544

Dr. Dimitris Voliotis • #27

0.00

0.25

0.50

0.75

1.00

Pro

po

rtio

n o

f p

atie

nts

p

rog

ress

ion

-fre

e

0 100 200 300 400 500

Days from randomization

Sorafenib (n=32)

Placebo (n=33)

Censored

12-week run-in period

-84

Median progression-free survival from randomization:Placebo=6 weeksSorafenib=24 weeksp=0.0087

Median Progression-Free Survival for Patients with Renal Cell Cancer Randomized to Placebo or Sorafenib

Source: With permission. Ratain MJ et al. Presentation. ASCO 2005. Abstract 4544

AZD2171 Clinical Data

Extensive and innovative phase I program in a number of tumours:

– 253 patients treated in monotherapy and combination studies

Program has led to a clear view of:

– Pharmacokinetics

– Evidence of inhibition of VEGF signalling in man

– Initial evidence of anti-tumour activity

– Tolerability profile

– Dosing strategy

VEGF Trap (AVE0005)

A novel potent VEGF inhibitor

in Oncology

VEGF Trap (AVE0005)

A novel potent VEGF inhibitor

in Oncology

VEGF TrapPhase I experience

Phase I SQ administration– 25 ug/kg 800 q week 800 ug sq biw– 8/10 stable at 800 ug/kg q wk or biw; one PR in

refractory BAL NSCLC– Toxicity: HTN, proteinuria– T ½ = 25 + 3 days

Phase I IV administration– 0.3 5 ug/kg iv q 2 wks– Usual toxicities– PR: ovarian (ascites), thymoma; 2 MRs

IV VEGF Trap Program:Summary of Ongoing Phase I and Phase II Studies

IV VEGF Trap Program:Summary of Ongoing Phase I and Phase II Studies

Phase I Single-Agent IV Study

Phase Ib Combination-Agent Studies Phase Ib combination with oxaliplatin/5-FU/LV

(FOLFOX4) Phase Ib combination with LV5FU2-CPT11

Phase Ib combination with docetaxel/cisplatin/

fluorouracil Phase Ib combination with docetaxel, then

docetaxel/cisplatin Phase Ib combination with gemcitabine, then GEMOX

Phase II Single-Agent Studies 3rd Line Non-Small-Cell Lung Adenocarcinoma 3rd-Line Advanced Ovarian Cancer Advanced Ovarian Cancer with Symptomatic Malignant

Ascites

PropertiesCetuximab/IMC-C225

IgG1 (chimerized antibody)

Exclusive for EGFR and its heterodimers

Prevents ligand binding to EGFR

Binds to EGFR with high affinity (Kd = 2.0 x 10–10 M) = ONE log higher than the natural ligand

Stimulates receptor internalization

Blocks receptor dimerization, tyrosine kinase phosphorylation, and signal transduction

Cetuximab ± Irinotecan in CRC

Patients with CRC progressed

on or within 3 months of

irinotecan-based chemotherapy

RANDOMIZATION

Irinotecan dose and schedule used during progression

Cetuximab 400 mg/m2 1st infusion, then 250 mg/m2/week

Cetuximab 400 mg/m2 1st infusion,

then 250 mg/m2/week

Irinotecan dose and schedule used during

progression Cetuximab 400 mg/m2

1st infusion, then 250 mg/m2/week

PD

Schema

n=111

n=218

Cunningham D, et al. Proc Am Soc Clin Oncol. 2003;22:252. Abstract 1012 and oral presentation (slide 6).

Combination Antibody Therapy MCRCNCI 5844 (“BOND-2”)

Patients with MCRC who progressed with irinotecan

(N=150)

Bevacizumab + cetuximab + irinotecan

Bevacizumab + cetuximab

At: http://ctep.cancer.gov/forms.

Primary end point:

Response rate

Efficacy Comparison (Historical Controls)

Cetux-Irino

(historical)

Cetux-Irino + Bev

Resp Rate 23% 38%

TTP 4 m 8.5 m

Cetux alone

(historical)

Cetux + Bev

Resp Rate 11% 23%

TTP 1.5 m 6.9 m

“BOND” “BOND-2”

CALGB/SWOG Intergroup Trial 80405

Bevacizumab

Cetuximab

Bevacizumab +Cetuximab

FOLFOXor FOLFIRI

“Dealer’s Choice”

R

N=2289 Primary endpoint: OSHR 1.25 (22 vs 27.5 months)

PACCE Trial*

Bevacizumab

Bevacizumab +Panitumumab

FOLFOXor FOLFIRI

“Dealer’s Choice”

N=1000 Primary endpoint: PFS

R

PACCE: Panitumumab Advanced Colorectal Cancer Evaluation; opened April 2005

Strategies for future developments

“Pile-on” Approach– Combo-chemo+bev– Combo-chemo + bev + cetuximab– Combo-chemo + bev + TKI + cetuximab– Combo-chemo + bev + cetuximab + novel

biologic 1 + novel biologic 2 Semi-STOP and GO

– Biologic interludes Avoid cytotoxics altogether

CONCLUSIONS

Combination Chemotherapy – Effective; “all 3-drugs” OS plateau– Platform for biologics

Angiogenesis Pathway– Validated target for combination with chemotherapy– Multiple approaches– Combinations of VEGF inhibitors?

Growth Factor Pathway– EGFR inhibitors validated– Can we use EGFR-TKIs in colorectal cancer

CONCLUSIONS

Studies underway combining dual-blockade with two antibodies plus chemotherapy

Future goals– Improved survival, decreased toxicity– Identifying the correct target– Confirming adequate inhibition of target