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The Continuation of Biologic Agents Beyond Progression: Does It Make Sense? Axel Grothey Mayo Clinic College of Medicine Rochester, MN
Continuation of Chemotherapy Beyond Progression • FOLFOX FOLFIRI Tournigand • FOLFIRI FOLFOX Tournigand • LV5FU2 FOLFIRI FOCUS • LV5FU2 FOLFOX FOCUS • Irino Irino + Cetuximab BOND, Saltz
EGFR Biologic Agents in Colorectal Cancer = Monoclonal Antibodies Fab Fc Murine Ab “momab” Chimeric Mouse-Human Ab “ximab” Humanized Ab “zumab” Human Ab “mumab” (17-1A) Cetuximab Matuzumab Bevacizumab Panitumumab VEGF
Nomenclature 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-directedxx mab -li-xx-mab immune-directedxx mab -ci-xx-mab cardiovascular-directedxx mab -vi-xx-mab virus-directedxx mab Inf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab
mAbs Target Tumor Cell-Bound EGFR Ligand Extracellular EGF-R Ras PI3K Raf Intracellular Akt MEK MAPK Cell survival Cell Motility DNA Proliferation Angiogenesis Metastasis
1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 8 16 24 32 40 48 56 Weeks from Randomization Only a Subgroup of Patients Benefits from anti-EGFR mAbs 1.0 0.9 0.8 Cetuximab Panitumumab 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 3 6 9 12 15 MONTHS Jonker et al., AACR 2007 Van Cutsem et al., JCO 2007
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 EGFR mAbs - Potential Mechanisms of Resistance (selected)
KRAS Mutation Status Predictive of Response to Cetuximab? • 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 Lievre et al. Cancer Res 2006
- - - Rationale for Combining EGFR- and Angiogenesis- Inhibitors EGFR Inhibitors Angiogenesis Inhibitors • Tumor cell growth • Synthesis of angiogenic proteins • Response of endothelial cells to angiogenic proteins Targets Angiogenic proteins bFGF VEGF TGF- Endothelial cells Tumor Herbst et al. J Clin Oncol. 2005;23:2544.
BOND-2 Trial - Efficacy (historic comparison with BOND-1) Saltz et al. ASCO 2005; Lenz et al. ASCO GI 2007
NCCTG First-line Randomized Phase II Trial (N0548) - Cetuximab Beyond PD FOLFOX + Bevacizumab C225 + Bevacizumab R PD FOLFOX + C225 + Bevacizumab 90 patients • 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
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) Characteristics of Anti-EGFR vs Anti-VEGF Therapy Anti-EGFR mAb Anti-VEGF mAb Main target: Tumor cells - genetically instable - Main target: Endothelial cells - genetically stable -
Is There a Rationale to Continue Bevacizumab Beyond Progression? 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
Dynamic Effects of Anti-VEGF Therapy on Tumor Vasculature Early effects (days 2-5): Hypoxia /Oxygenation Tumor vessel pruning Normal Late effects (day 5): inhibition of bloodvessel growth Anti-VEGFR Anti-VEGFR Tumor vasculature Days 2-5: normalized Inadequate for tumor growth Winkler et al. Cancer Cell. 2004;6:553; Jain. Nat Med. 2003;9:685.
20 Placebo Anti-VEGF mAb 15 10 5 0 Effect of VEGF Inhibition on Vessel Density and Tumoral Chemotherapy Concentration * † Tumor irinotecan concentration (µg/g) Tumor H33342 concentration (100 ng/g) *P<0.09 vs placebo.†P<0.05 vs placebo. Wildiers et al. Br J Cancer. 2003;88:1979.
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 • In experimental models rapid regrowth of blood vessels after withdrawal of VEGF-inhibitors
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
Control AntiVEGF PDGF PDGFR Pericytes Proliferate in Tumors Resuming Growth During Chronic VEGF Blockade Green = SMA (Pericytes) Huang, J. et al. Mol Cancer Res 2004;2:36-42
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 • 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? No prospectively randomized evaluation to date…
Ceiling Effect of PFS in First-Line CRC?Is BEV a Chemo-Equalizer? PFS ( months) sequential data
Efficacy: TREE-1 and TREE-2 *per protocol population Hochster et al., ASCO 2006
If we cannot increase 1st line PFS, why does OS increase? 17 months 10 months Post-1st PD Survival 1st PFS OS 27 Months • More effective use of all active agents? • Continuum of care… • Use of EGFR-mAbs? • Use of bevacizumab beyond PD?
BEV after 1st Progression in BEV-naïve Patients - E3200 p=0.0011 p=0.95 p<0.0001 p<0.0001 p<0.0001 p=N/A B. Giantonio et al., JCO 2007
BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP) Evaluablepatients(n=1953) BRiTE: Total N=1953 1445 pts with 1st PD 932 deaths (1/21/07 cut-off) Median follow-up 19.6 mo 1st Progression (n=1445) Physician decision - no randomization No Post-PD Treatment(n=253) No BBP(n=531) BBP(n=642) Grothey et al. ASCO 2007 #4036
BRiTE: Patient Outcome Based on Treatment Post 1st PD No Post-PD Treatment(n=253) No BBP(n=531) BBP(n=642) 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
BRiTE: Conclusions • 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
SWOG/NCCTG/NCIC 2nd-Line Trial: S0600/iBET (Intergroup BEV Continuation Trial) To open 6/15/07 (FOLF)IRI/C225 MCRC pretreated with FOLFOX + BEV or CAPOX + BEV orOPTIMOX + BEV (FOLF)IRI/C225 + BEV 5 mg/kg (FOLF)IRI/C225 + BEV 10 mg/kg N=1,260 Primary endpoint: OS (HR 1.30; 12 15.6 mos) PI: Phil Gold