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) Anti-VEGF mAbAnti-EGFR mAb Main target: Tumor cells -
genetically instable - Main target: Endothelial cells - genetically
stable -
Slide 6
Is There a Rationale to Continue Bevacizumab Beyond
Progression?
Slide 7
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
Slide 8
Inadequate for tumor growth Dynamic Effects of Anti-VEGF
Therapy on Tumor Vasculature Normal Tumor vasculatureDays 2-5:
normalized 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.
Slide 9
Placebo Anti-VEGF mAb *P
I4T-MC-JVBBPhase III Trial 2 nd Line FOLFIRI +/- Ramucirumab
Stratification factors: Region KRAS status First-line TTP (6 mos)
1:1 mCRC after failure FP/oxaliplatin + BEV regimen R 525 pts
Ramucirumab IV + FOLFIRI q 2 weeks 525 pts Placebo + FOLFIRI q 2
weeks 35 Primary EP: OS PIs: Tabernero, Grothey
Slide 36
Cytokine increase on BEV therapy Kopetz et al., JCO 2010
Regorafenib Salvage Therapy Registration Trial Primary endpoint
OS:increase OS from 4.5 to 6.0 months; HR = 0.75 Significance
level/power: 0.025 (one-sided)/90% Accrual period (months): 26 (
accrual rate 30 pat./month) Study duration (months): 31.5 Total
number of events: 582 Total number of patients: 690 Primary
endpoint OS:increase OS from 4.5 to 6.0 months; HR = 0.75
Significance level/power: 0.025 (one-sided)/90% Accrual period
(months): 26 ( accrual rate 30 pat./month) Study duration (months):
31.5 Total number of events: 582 Total number of patients: 690
Primary endpoint: OS CRC 3rd/4th line Regorafenib 160 mg od 3wks
on/1 wk off + BSC Placebo + BSC 2:1 randomization Accrual completed
Feb 2011, within 9 mos
Slide 39
Conclusions Continuation of BEV beyond progression (BBP) has
Preclinical rationale and Support from results of observational
cohort studies However Financial and biological implications of
this concept mandate prospective evaluation in randomized phase III
trials before BBP can be considered standard of care A pivotal
European trial has completed accrual results are awaited for late
2011 Continuation of BEV beyond progression (BBP) has Preclinical
rationale and Support from results of observational cohort studies
However Financial and biological implications of this concept
mandate prospective evaluation in randomized phase III trials
before BBP can be considered standard of care A pivotal European
trial has completed accrual results are awaited for late 2011