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
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
• 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)
*
Continuation of Bevacizumab Beyond Progression - PRO
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
• 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
• 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
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
• 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
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
Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade
Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade
Huang, J. et al. Mol Cancer Res 2004;2:36-42
Continuation of Bevacizumab Beyond Progression - CON
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
• 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
• 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
• 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
Grothey et al. ASCO 2007 #4036
BRiTE: Kaplan-Meier Estimates Based on Treatment Post 1st PD
A B
Survival after 1st PD Overall survival
Grothey et al. ASCO 2007 #4036
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
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