Antiangiogenic Therapy for Colorectal Cancer Thanks to the investigators for providing p g their slides.

Al B. Benson III, MD, FACP Professor of Medicine Feinberg School of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Combination Bevacizumab Plus IFL: Overall Survival

Impact of Targeted Agents: Adding Bevacizumab to Cytotoxics

100 n=411

Previously untreated mCRC (n=923) (n 923)

IFL + Bevacizumab* n=402 402

PD*

PD*

Overall su urvival (%)

IFL + Placebo

Primary Endpoint: Survival

5-FU/LV +

Bevacizumab*

PD*

n=110

15.6

80

20.3

60 IFL + Bevacizumab

40 20

IFL + placebo

0 0

* 5.0 mg/kg q2w †

Patients receiving bevacizumab could continue therapy past disease progression in combination with second line therapy

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

10

No. at Risk IFL + bevacizumab IFL + placebo

402 411

362 363

20 Months 320 292

30

178 139

73 51

20 12

1 0

0 0

Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342.

Period 2: Overall Survival Data thru Mar 1, 2006 (ITT)

BICC-C Trial: Addition of Bevacizumab FOLFIRI Irinotecan: 180 mg/m2 (D1) LV: 400 mg/m2 over 2 h (D1) 5-FU: 400 mg/m2 (bolus) (D1) 5-FU: 2400 mg/m2 (46(46-h infusion) (D1) q2wks + 5 mg/kg bevacizumab q 2wks

mIFL Irinotecan: 125 mg/m2 (D1, 8) 5-FU: 500 mg/m2 (bolus) (D1, 8) LV: 20 mg/m2 (D1, 8) q3wks + 7.5 mg/kg bevacizumab q 3wks

Median OS (Months)

1 Year

FOLFIRI+ BEV

NR

87%

--

--

mIFL + BEV

18.7

61%

2.5 (1.3,5.0)

0.01

Regimen

R A N D O M I Z A T I O N

Celecoxib 400 mg bid

Placebo

CapeIRI mg/m2

Irinotecan: 250 (D1) Capecitabine: 1000 mg/m2 bid (D1(D1-14) q3wks Stratification: Age, PS, Low dose aspirin use

Proportion of Patients Who Survive ed

R A N D 1st1st-line O mCRC M N = 117 I 5/04– 5/04–12/04 12/04 Z A T I O N

40

1

HR (95% CI)

P Value

0.8 0.6 0.4 FOLFIRI + bevacizumab

0.2

mIFL + bevacizumab

0 0

5

10

15

20

25

30

Months

1

E3200: FOLFOX + Bevacizumab in Second-Line mCRC FOLFOX-4

FOLFOXFOLFOX-4 + FOLFOX-4 Bevacizumab bevacizumab FOLFOX-

PD

FOLFOX-4 + bevacizumab g g q2wk q 10 mg/kg

Previously treated mCRC (n=880) (n 880)

E3200: FOLFOX + Bevacizumab in Second-Line mCRC Results

PD

Bevacizumab monotherapy* 10 mg/kg q2wk

Primary Endpoint:

Response Rate (%)

22%*

9%

3%

Survival S i l

Median PFS (mos.)

7.2*

4.8

2.7

Median OS (mos.)

12.9*

10.8

10.2

PD

*Statistically significant compared with FOLFOX or bevacizumab alone.

• Bevacizumab monotherapy arm discontinued at planned interim

Giantonio BJ, et al. Proc Am Soc Clin Oncol. 2005;23:248s. Abs #2.

Giantonio BJ, et al. Proc Am Soc Clin Oncol. 2005;23:248s. Abs #2.

Randomized Phase II: Final TREE 1 and 2 Trial Results

NO16966 study design

Oxaliplatin+ 5-FU (TREE(TREE-1) Confirmed ITT ORR Median TTP (mo)

mFOLFOX n=45 41%

bFOL n=44 20%

CapeOx n=39 27%

87 8.7

69 6.9

59 5.9

(TREE(TREE-1) + Bevacizumab

FOLFOXFOLFOX-B n=71 52%

bFOLbFOL-B n=70 39%

CapeOxCapeOx-B n=72 46%

9.9

8.3

10.3

Confirmed ITT ORR Median TTP (mo)

Recruitment June 2003 – May 2004

Recruitment Feb 2004 – Feb 2005

XELOX N=317

XELOX + placebo N=350

XELOX + bevacizumab N 350 N=350

FOLFOX4 N=317

FOLFOX4 + placebo N=351

FOLFOX4 + bevacizumab N=350

Protocol amended to 2x2 placebocontrolled design after bevacizumab phase III data1 became available (N=1401)

Initial 2-arm open-label study (N=634)

Hochster HS, et al. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. 2006; 24 (suppl. 18S):3510.

1Hurwitz

PFS XELOX non-inferiority: primary objective met based on ITT

PFS chemotherapy + bevacizumab superiority: primary objective met

1.0

1.0 HR = 1.04 [97.5% CI 0.93–1.16]

0.8 0.6 0.4 0.2 8.0

8.5

5

10

0.6 0.4 0.2 8.0

0

0 0

HR = 0.83 [97.5% CI 0.72–0.95] (ITT) P = .0023

0.8

Upper limit ≤ 1.23 (non-inferiority margin)

PFS estiimate

PFS estimate

H, et al. Proc ASCO 2003;22 (Abstract 3646)

15 Months

20

FOLFOX/FOLFOX+placebo/FOLFOX+bevacizumab XELOX/XELOX+placebo/XELOX+bevacizumab

25

30

N=1017; 826 events N=1017; 813 events

0

5

9.4

10

15

20

25

Months FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events

2

Figure 3. Separation after ~6 months in bevacizumab-containing arms between ‘general’ and ‘on treatment’ PFS XELOX / FOLFOX-4 + bevacizumab XELOX / FOLFOX-4 + placebo

PFS estima ate

1.0 0.8

ON TREATMENT: HR HR=0.63 0.63 (97.5% CI 0.52–0.75, p75): Safety and Effectiveness

Elderly (>65): Safety and Effectiveness

GI perforation

ATE

Bleeding

Overall effectiveness

BBP

Wound healing complications

2007

2008

2005

2006

Confirmed FOLFOX as most common 1st line CT in combination with Bevacizumab for mCRC in US. Kozloff et al. 2007 Gastrointestinal Cancers Symposium, Orlando, Jan. 19-21, 2007.

* Novel presentations; does not include encore presentations

22

BRiTE Safety: Overview

Figure 1. Schematic of Disease Progression and Interim Disposition of Patients in BRiTE

All Patients (N=1953)

New or worsened HTN (requiring medication), % ATE, % Bleeding events (grade 3/4), %

19.4 1.8 2.4

GI Perforation, %

1.8

Figure 1. Schematic of Disease Progression; OS=overall survival; TTP=time-to-progression

*Nineteen patients received post-progression treatment with BV only and have been excluded from the BBP analysis. The remaining 508 patients have not yet had PD noted by investigator assessment.

Incidence of Bevacizumab-related safety events in BRiTE is similar to incidence of events reported in pivotal trials Grothey et al. ASCO, Chicago, June 1-5, 2007.

Figure 2. Interim Disposition of Patients in BRiTE (N=1953 with 1445 1st PD and 932 Deaths Reported as of the January 21, 2007 Data Cutoff)

Grothey ASCO 2007 23

4

Figure 3. A) Graphical Representation of BV Use in BBP Patients and B) Frequency Distribution of Time from 1st PD to Start of BV Post 1st PD for Patients in the BBP Subgroup

RESULTS (continued) •

The proportion of patients with ECOG PS 0 was higher in the BBP than in the No BBP subgroup (50.2% versus 39.9%) (Table 3).

•

The BBP and No BBP subgroups were balanced on: – – – –

Figure 3A. Graphical Representation of BV Use in BBP Patients Figure 3B. Frequency Distribution of Time from 1st PD to Start of BV Post 1st PD for Orange lines represent the time course of treatment with BV in Patients in the BBP Subgroup days for each patient who has progressed (n=642) with overlay of time of 1st PD (blue asterisks]

•

The pattern of BV use for patients who used BBP is shown in Figure 3. – 312 of 642 (49%), received BV continuously from 1st-line to beyond 1st PD (Figure 3A). – The majority of patients in the BBP subgroup (n=571, 89%) either used BV continuously into 2nd-line, or restarted BV within the 1st 4 months post-1st PD (Figure 3B). – 132 of the 642 BBP patients (20%) discontinued BV prior to 1st PD and restarted BV within 28 days of 1st PD. – 198 of the 642 BBP patients (31%) discontinued BV either prior to or at 1st PD and restarted BV >28 days after 1st PD.

Grothey ASCO 2007

Figures 4, 5. Kaplan-Meier Estimates of A) Survival Beyond 1st PD and B) OS •

Figure 4 displays the Kaplan-Meier curve for survival beyond 1st PD by subgroups based on treatment beyond 1st PD (1st PD occurred at 0 months).

•

Figure 5 displays the Kaplan-Meier curve for OS by subgroups based on treatment beyond 1st PD.

Use of 1st-line CT Proportion of patients exposed to all 3 active CT agents TTP 1st-line exposure to BV

•

Total duration of BV use was longer in the BBP subgroup, as expected.

•

Of the 1445 patients with PD, 542 (37.5%) used an EGFR inhibitor post 1st PD (including BBP and No BBP); 489 of these (90%) used cetuximab.

Grothey ASCO 2007

Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI and fluoropyrimidines for mCRC: First BEAT S. Berry, D. Cunningham, M. Michael, A. Kretzschmar, F. Rivera, M. DiBartolomeo, M. Mazier, E. Van Cutsem, on behalf of the First BEAT investigators Abstract #350

Figure 4. Kaplan-Meier Estimates of Survival Beyond

Figure 5. Kaplan-Meier Estimates of OS by Subgroups

1st PD by Subgroups Based on Post-PD Therapy

Based on Post-Progression Therapy

Grothey ASCO 2007

Serious Bevacizumab-Related Adverse Events

First BEAT: Study Schema First-line metastatic CRC (1,965)

Bevacizumab + standard chemotherapy

PD

• Bevacizumab: 5mg/kg Q2W or 7.5mg/kg Q3W • Endpoints: safety and efficacy • Median follow-up 22.9 months

Berry 2008 ASCO GI abstract #350

Event (%)

Any AE or SAE (n=1,914)

CTC grade 3–5 or SAE* (n=1,914)

Hypertension

29.9

Proteinuria

10.4

5.3 1.1

Bl di Bleeding

31 0 31.0

34 3.4

Wound-healing complications

4.0

1.1

Arterial thromboembolic events

1.5

1.5

GI perforation

1.9

1.8

Berry 2008 ASCO GI abstract #350

5

The Angiogenic Switch

Angiogenesis • Physiologic

Angiogenic 1-2 mm

Switch

Small tumor • Nonvascular • “Dormant”

Larger tumor • Vascular • Metastatic potential

• Pathologic

– Longitudinal bone growth – Tumor growth – Wound healing – Rheumatoid arthritis – Secondary sexual development – Psoriasis • Corpus luteum formation – Retinopathies – Age-related macular degeneration

Targeted Therapy: Bevacizumab

Indications

Angiogenesis: A Balanced Process Activators VEGF and receptors

• In combination with chemotherapy: – Advanced colorectal cancer – Advanced breast cancer – Advanced lung cancer

Inhibitors TSP-1

bFGF and receptors

Angiostatin

TGFβ and receptors

Endostatin

Others

Interferons-α, -β, and -γ

• Monotherapy:

Interleukins-4, 12, 18

• Indications pending: – Early stage colon cancer – Glioblastoma – Renal cell cancer

uPAR Others TSP-1 = thrombospondin-1; uPAR = urokinase plasminogen activator receptor.

The Angiogenic Switch In Hepatic Micrometastasis 180 uM

290 uM

520 uM

2 mm

We can hypothesize that Bev prevented the “angiogenic switch” and kept tumors beneath the threshold of detection by imaging.

Avascular Within the limits of O2 diffusion

Portal Perfusion

Mixed Portal and Arterial Perfusion

Arterial Perfusion Liu, Matsui. Radiology 2007

6

The Mechanism of Action of Bev in the Adjuvant Setting is Likely to be Different Than in the Advanced Stage Setting

There Are No Known Predictive Biomarkers for Anti-VEGF Therapy IFL +/- Bev Trial

Mechanism

Advanced Disease*

Adjuvant

Anti-angiogenic (block new blood vessel growth)

Possible, (no direct evidence)

Probable, based on C08 findings (no direct evidence)

Induction of EC Apoptosis

Possible

Not likely, cooption likely to provide nutrients in small volume disease

Vasoconstriction

Possible

Unlikely, changes in tumor blood flow not relevant when tumor is microscopic

Normalization

Maybe

Probably not relevant for microscopic tumors

Direct Effect on Tumor Cells

Maybe

✔

Maybe *Ellis, Hicklin. Nat Rev Ca 2008

Proposed Biomarker

Outcome

Plasma VEGF

Not Predictive

Primary Tissue VEGF (ISH, IHC)

Not Predictive

Upstream Mediators of VEGF (ras, raf, P53)

Not Predictive

Other Angiogenic Mediators (TSP-2)

Not Predictive Jubb et al. J Clin Oncol 24:217-227, 2006 Ince et al. J Natl Cancer Inst. 97(13):981-9, 2005 Holden et al. ASCO. Abstract: 3555, 2005

Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody Thamar H. Stollman, Marian G.W. scheer, William P.J. Leenders, Kiek C.N. Verrijp, Annemieke C. Soede, Wim J.G. Oyen, Theo J.M. Ruers, and Otto C. Boerman

Kaplan-Meier estimates for progression-free survival (PFS) of patients with low and high baseline volume transfer constant of contrast agent (Ktrans) and blood plasma volume fraction (Vp) Hahn, O. M. et al. J Clin Oncol; 2008

Figure 3. Biodistribution of In-111 bevacizumab in athymic male mice with s.c. LS174T tumors at 1, 3 and 7 days post injection (5 mice/group).

Figure 4. Scintigraphic images of athymic male mice with s.c. LS174T tumors immediately after injection and at 1, 3 and 7 days post injection of In-111-bevacizumab (25 Ci/mouse, 3g/mouse).

7

Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100 Bryan P. Schneider, Molin Wang, Milan Radovich, George W. Sledge, Sunil Badve, Ann Thor, David A. Flockhart, Bradley Hancock, Nancy Davidson, Julie Gralow, Maura Dickler, Edith A. Perez, Melody Cobleigh, Tamara Shenkier, Susan Edgerton, Kathy D. Miller

Schneider, et al. JCO 2008, 26(28), 4672-4678

Fig 1. Kaplan-Meier curve for overall survival (OS) in experimental arm by genotype; (A) vascular endothelial growth factor (VEGF)-2578 C/A; (B) VEGF-1154 G/A

Candidate Single Nucleotide Polymorphisms Gene and Single Nucleotide Polymorphism

White: Frequency of Rare Allele

African American: Frequency of Rare Allele

-2578 C/A

Promoter

A = 49%

A = 24%

-1498 C/T

Promoter

C = 49%

C = 33%

-1154 G/A

Promoter

A = 33%

A = 10%

-634 G/C

5’ Untranslated region

C = 32%

C = 35%

936 C/T

3’ Untranslated region

T = 15%

T = 13%

889 G/A (V297I)

Exon 7

A = 9%

A = 20%

1416 A/T (Q472H)

Exon 11

T = 25%

T = 10%

VEGFR-2

Schneider, B. P. et al. J Clin Oncol; 26:4672-4678 2008

Fig 2. Kaplan-Meier curve for overall survival (OS) in the experimental arm (by vascular endothelial growth factor genotype) compared with the control and combination arms (not subdivided by genotype)

Schneider, B. P. et al. J Clin Oncol; 26:4672-4678 2008 Copyright © American Society of Clinical Oncology

Location

VEGF

Schneider, B. P. et al. J Clin Oncol; 26:4672-4678 2008 Copyright © American Society of Clinical Oncology

Hypertension and Overall Survival: Axitinib

Rini, BI et al. Proc. ASCO 2008, Abstract 3543

Relationship Between HTN and the Efficacy of Anti-VEGF Rx Reference

N

Scartozzi et al.

39;25;1 1

Malignancy

Treatment

Colorectal cancer

5-FU, irinotecan + bevacizumab

Main Findings 20% grade 2-3 HT; response in patients with grade 2-3 HT: 75% (n = 8) versus 32% (n = 31), P = 0.04

Rixie et al.

40; 32

mRCC

Sunitinib

22.5% grade 3 HT; response in patients with grade 3 HT: OR 5.69 (95% CI 2.51-12), P = 0.03

Rini et al.

52

Cytokineresistant mRCC

Axitinib

Overall survival in patients with DBP ≥90 mmHg: not reached (n = 32) versus 12.9 months (n = 20)

Rini et al.

62

Sorafenibresistant mRCC

Axitinib

Overall survival in patients with DBP ≥90 mmHg: not reached (n = 39) versus 8.4 months (n = 23)

Spano et al.

69

Pancreatic carcinoma

Gemcitabine + Axitinib

6% grade 3 HT, 22% all-grade HT; overall survival in patients with DBP ≥90 mmHG: 13.0 months (95% CI 8.5-16.6) versus 5.6 months (95% CI 4.8-7.2)

Friberg et al.

52

Pancreatic carcinoma

Gemcitabine + bevacizumab

19% grade 3 HT; overall survival in patients with early HT (