the continuation of biologic agents beyond progression: does it make sense?

The Continuation of Biologic Agents Beyond Progression:

Does It Make Sense?

The Continuation of Biologic Agents Beyond Progression:

Does It Make Sense?

Axel Grothey

Mayo Clinic College of Medicine

Rochester, MN

Axel Grothey

Mayo Clinic College of Medicine

Rochester, MN

Continuation of Chemotherapy Beyond Progression

Continuation of Chemotherapy Beyond Progression

• FOLFOX FOLFIRI Tournigand

• FOLFIRI FOLFOX Tournigand

• LV5FU2 FOLFIRI FOCUS

• LV5FU2 FOLFOX FOCUS

• Irino Irino + Cetuximab BOND, Saltz

• FOLFOX FOLFIRI Tournigand

• FOLFIRI FOLFOX Tournigand

• LV5FU2 FOLFIRI FOCUS

• LV5FU2 FOLFOX FOCUS

• Irino Irino + Cetuximab BOND, Saltz

Murine AbMurine Ab““momab”momab”

ChimericChimericMouseMouse--HumanHuman Ab Ab

““ximab”ximab”

Humanized AbHumanized Ab““zumab”zumab”

FcFc

FabFab

Human AbHuman Ab““mumab”mumab”

Biologic Agents in Colorectal Cancer = Monoclonal Antibodies

Biologic Agents in Colorectal Cancer = Monoclonal Antibodies

(17-1A)(17-1A) CetuximabCetuximab Matuzumab Matuzumab BevacizumabBevacizumab

PanitumumabPanitumumabEGFR

VEGF

Nomenclature of Monoclonal AntibodiesNomenclature of Monoclonal Antibodies

-mab monoclonal antibody

-mo-mab mouse mab

-xi-mab chimeric mab

-zu-mab humanized mab

-mu-mab human mab

-tu-xx-mab tumor-directed xx mab

-li-xx-mab immune-directed xx mab

-ci-xx-mab cardiovascular-directed xx mab

-vi-xx-mab virus-directed xx mab

-mab monoclonal antibody

-mo-mab mouse mab

-xi-mab chimeric mab

-zu-mab humanized mab

-mu-mab human mab

-tu-xx-mab tumor-directed xx mab

-li-xx-mab immune-directed xx mab

-ci-xx-mab cardiovascular-directed xx mab

-vi-xx-mab virus-directed xx mab

Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab

mAbs Target Tumor Cell-Bound EGFRmAbs Target Tumor Cell-Bound EGFR

Extracellular

Intracellular

Ligand

EGF-R

PI3K

Akt

Ras

Raf

MEK

MAPK

Cell Motility

MetastasisAngiogenesisProliferation

Cell survivalDNA

Only a Subgroup of Patients Benefits from anti-EGFR mAbs

Only a Subgroup of Patients Benefits from anti-EGFR mAbs

0.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

MONTHSMONTHS

00 33 66 99 1212 15150.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Weeks from Randomization0 8 16 24 32 40 48 56

Cetuximab Panitumumab

Van Cutsem et al., JCO 2007Jonker et al., AACR 2007

EGFR mAbs - Potential Mechanisms of Resistance (selected)

EGFR mAbs - Potential Mechanisms of Resistance (selected)

• Activation of other RTK which bypass EGFR pathway

• IGF-1R• HER-2

• Constitutive activation of signaling pathways downstream of EGFR

• Inactivation of PTEN• KRAS mutation• Mutated STATs

• EGFR gene amplification

• Overexpression of VEGF

• Activation of other RTK which bypass EGFR pathway

• IGF-1R• HER-2

• Constitutive activation of signaling pathways downstream of EGFR

• Inactivation of PTEN• KRAS mutation• Mutated STATs

• EGFR gene amplification

• Overexpression of VEGF

KRAS Mutation Status Predictive of Response to Cetuximab?

KRAS Mutation Status Predictive of Response to Cetuximab?

Lievre et al. Cancer Res 2006

• 30 patients with CRC on cetuximab

• PR: 11/30 patients (37%)• KRAS mutation in

• 0/11 responders• 13/19 non-responders

(68%)• p=0.0003

• Increased EGFR gene copy number in 10%

• significantly associated with response (p=0.04)

16.3 mo

6.9 mo

Rationale for Combining EGFR- and Angiogenesis- Inhibitors

Rationale for Combining EGFR- and Angiogenesis- Inhibitors

EGFR Inhibitors• Tumor cell growth • Synthesis of angiogenic

proteins

• Response of endothelial cells to angiogenic proteins

Tumor

Angiogenesis Inhibitors

Angiogenic proteinsbFGFVEGFTGF-

Endothelial cells

Herbst et al. J Clin Oncol. 2005;23:2544.

- - -

Targets

BOND-2 Trial - Efficacy (historic comparison with BOND-1)

BOND-2 Trial - Efficacy (historic comparison with BOND-1)

BOND-1 BOND-2 BOND-1 BOND-2

C225C225+BEV

C225+CPTC225+CPT

+BEV

N pts 111 40 218 41

Previous Oxaliplatin (%) 64 90 62 85

RR (%) 11 20 23 37

TTP (mos) 1.5 5.6 4.1 7.9

Med. OS (mos) 6.9 10.2 8.6 18.0

Saltz et al. ASCO 2005; Lenz et al. ASCO GI 2007

PD

NCCTG First-line Randomized Phase II Trial (N0548) - Cetuximab Beyond PD

NCCTG First-line Randomized Phase II Trial (N0548) - Cetuximab Beyond PD

C225 +C225 +BevacizumabBevacizumab

FOLFOX + FOLFOX + BevacizumabBevacizumab

FOLFOX + FOLFOX + C225 C225 + Bevacizumab+ Bevacizumab

Primary endpoint• PFS rate at 6 months

(Goal >50% of patients)• Interim analysis after 45 pts

Secondary endpoints• Response rate• Safety• Angiogenesis markers• Imaging studies

90 patients

R

Characteristics of Anti-EGFR vs Anti-VEGF Therapy

Characteristics of Anti-EGFR vs Anti-VEGF Therapy

• Minimal single agent activity

• In combination with chemo consistent increase in PFS

• Decrease in interstitial pressure, better delivery of chemo

• “Normalization” of vasculature, better oxygenation

• Minimal single agent activity

• In combination with chemo consistent increase in PFS

• Decrease in interstitial pressure, better delivery of chemo

• “Normalization” of vasculature, better oxygenation

• Single agent activity

• In combination with chemo consistent increase in RR

• Increased chemo- and radio-sensitivity

• Resensitization of tumors to chemo (CPT11)

• Single agent activity

• In combination with chemo consistent increase in RR

• Increased chemo- and radio-sensitivity

• Resensitization of tumors to chemo (CPT11)

Anti-VEGF mAbAnti-EGFR mAb

Main target: Tumor cells- genetically instable -

Main target: Endothelial cells- genetically stable -

Is There a Rationale to Continue Bevacizumab Beyond

Progression?

Is There a Rationale to Continue Bevacizumab Beyond

Progression?

Should bevacizumab be “herceptinized”?

Should bevacizumab be “herceptinized”?

Continuation of Bevacizumab Beyond Progression - PRO


• Mechanism of action targets genetically stable (endothelial) cells

• Decreased intratumoral interstitial pressure leads to higher concentrations of chemotherapeutic agents

• Normalization of vasculature and better oxygenation

Cytotoxic effects of all (?) chemotherapeutics, regardless of “line of therapy” enhanced





Inadequate for tumor growth

Dynamic Effects of Anti-VEGF Therapy on Tumor VasculatureDynamic Effects of Anti-VEGF Therapy on Tumor Vasculature

Normal

Tumor vasculature Days 2-5: normalized

Anti-VEGFR Anti-VEGFR

Early effects (days 2-5): Hypoxia / Oxygenation

Tumor vessel pruning

Late effects (day 5):inhibition of blood

vessel growth

Winkler et al. Cancer Cell. 2004;6:553; Jain. Nat Med. 2003;9:685.

Placebo

Anti-VEGF mAb

*P<0.09 vs placebo.†P<0.05 vs placebo.Wildiers et al. Br J Cancer. 2003;88:1979.

Effect of VEGF Inhibition on Vessel Density and Tumoral Chemotherapy Concentration

20

15

10

5

0Tumor H33342concentration

(100 ng/g)

†

Tumor irinotecanconcentration

(µg/g)

*











• In experimental models rapid regrowth of blood vessels after withdrawal of VEGF-inhibitors

• In experimental models rapid regrowth of blood vessels after withdrawal of VEGF-inhibitors

Rapid Regrowth of Tumor Blood Vessels

Rapid Regrowth of Tumor Blood Vessels

Selective inhibition of VEGFR signaling by AG-028262 in RIP-Tag2 mouse tumors

Basement membrane sleeves

Mancuso et al. JCI 2006

Continuation of Bevacizumab Beyond Progression - CON


• Potential alternate pathways to activate angiogenesis apart from VEGF

• Ang-system, FGF, PDGF and others• “Co-option” - recruitment of previously

established vessels• Vascular remodeling, pericyte activation




The Complex Process of Tumor Angiogenesis

The Complex Process of Tumor Angiogenesis

Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade


Huang, J. et al. Mol Cancer Res 2004;2:36-42

Green = SMA(Pericytes)

Control AntiVEGF

PD

GF

PD

GF

R



Huang, J. et al. Mol Cancer Res 2004;2:36-42






• Endothelial cells are not necessarily genetically stable• Concept of cancer stem cells

• BEV is not non-toxic (GIP, ATE, HTN, RPLS…)

• Treatment alternatives exist most of the times

• BEV is expensive




• Endothelial cells are not necessarily genetically stable• Concept of cancer stem cells

• BEV is not non-toxic (GIP, ATE, HTN, RPLS…)

• Treatment alternatives exist most of the times

• BEV is expensive

Clinical experience?Clinical experience?

No prospectively randomized evaluation to date…

No prospectively randomized evaluation to date…

Ceiling Effect of PFS in First-Line CRC?Is BEV a Chemo-Equalizer?

Ceiling Effect of PFS in First-Line CRC?Is BEV a Chemo-Equalizer?

PF

S (

mo

nth

s)

sequential data

5.56.2

7.48.6

7.68.7

5.9

3.7

4.4 1.9

0.83.6 1.2

4.4

0

2

4

6

8

10

12

Kabbinavar 5-FU/LV

HurwitzIFL

Cassidy XELOX

Cassidy FOLFOX

FuchsFOLFIRI

HochsterFOLFOX

HochsterXELOX

PFS + BEVPFS

Efficacy: TREE-1 and TREE-2

FOLFOX bFOL CAPEOX

- BEVN=49

+ BEVN=71

- BEVN=50

+ BEVN=70

- BEV N=48

+ BEV N=72

Conf. RR (%)* 43 53 22 41 35 48

TTF (mo) 6.5 5.8 4.9 5.5 4.4 5.5

TTP (mo) 8.7 9.9 6.9 8.3 5.9 10.3

OS (mo) 19.2 26.0 17.9 20.7 17.2 27.0

Hochster et al., ASCO 2006*per protocol population

If we cannot increase 1st line PFS, why does OS increase?

If we cannot increase 1st line PFS, why does OS increase?

10 months 17 months

1st PFS

OS 27 Months

• More effective use of all active agents?• Continuum of care…

• Use of EGFR-mAbs?

• Use of bevacizumab beyond PD?

Post-1st PD Survival

BEV after 1st Progression in BEV-naïve Patients - E3200

BEV after 1st Progression in BEV-naïve Patients - E3200

FOLFOX + BEV

(N=282)

FOLFOX (N=279)

BEV(N=228)

OS (mos) 12.9 10.8 10.2

PFS (mos) 7.3 4.7 2.7

RR (%) 22.7 8.6 3.3

p=0.0011 p=0.95

p<0.0001 p<0.0001

p<0.0001 p=N/A

B. Giantonio et al., JCO 2007

BBP(n=642)

No BBP(n=531)

No Post-PD Treatment

(n=253)

Evaluablepatients(n=1953)

1st Progression(n=1445)

BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP)

BRiTE:Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo

Grothey et al. ASCO 2007 #4036

Physician decision - no randomization

BRiTE: Patient Outcome Based on Treatment Post 1st PD

BRiTE: Patient Outcome Based on Treatment Post 1st PD

BBP(n=642)

No BBP(n=531)

No Post-PD Treatment

(n=253)

# of deaths (%)

168(66%)

306(58%)

260(41%)

Median OS (mo) 12.6 19.9 31.8

1yr OS rate (%) 52.5 77.3 87.7

OS after 1st PD (mo) 3.6 9.5 19.2


BRiTE: Kaplan-Meier Estimates Based on Treatment Post 1st PD

A B

Survival after 1st PD Overall survival


Limitations of the Analysis

• Patients were not randomized• Actual administration dates for BV and CT

not collected; missing BV and CT stop dates• Potential bias that patients who survived

longer had a greater potential to be treated

with BBP• Possibility of unmeasured factors that may

have biased these results

• First suggestion of survival benefit associated with using BV beyond 1st PD (BBP)

• Improved OS appears to be due to an increase in survival beyond 1st PD in patients treated with BBP

• These findings support the evaluation of BBP in the prospective, randomized phase III Intergroup trial S0600/iBET

BRiTE: Conclusions

SWOG/NCCTG/NCIC 2nd-Line Trial: S0600/iBET (Intergroup BEV Continuation Trial)

(FOLF)IRI/C225(FOLF)IRI/C225

MCRC pretreated with

FOLFOX + BEV or CAPOX + BEV orOPTIMOX + BEV

(FOLF)IRI/C225(FOLF)IRI/C225+ BEV + BEV 10 mg/kg10 mg/kg

N=1,260

Primary endpoint: OS (HR 1.30; 12 15.6 mos)

PI: Phil Gold

(FOLF)IRI/C225(FOLF)IRI/C225+ BEV + BEV 5 mg/kg5 mg/kg

To open 6/15/07

the continuation of biologic agents beyond progression: does it make sense?

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