QOL 1
Goldberg, JCO 22:23-30, 2004 N9741: Oxaliplatin in First Line (US) IR 200 mg/m 2 OX 85 mg/m 2 every 3 weeks
Efficacy IFL FOLFOX4 > IFL IROX FOLFOX4 IROX OS TTP RR 15.0 mo 6.9 mo 31 % P=0.0001 P=0.0014 P=0.002 19.5 mo 8.7 mo 45 % P=0.09 P=0.001 P=0.03 17.4 mo 6.5 mo 35 %
Tournigand, JCO 22:229-237, 2004 V308: FOLFIRI and FOLFOX 220 patients PD FOLFIRI FOLFOX6 PD R Irinotecan 180 mg/m 2 + slv5fu2 PD FOLFOX6 FOLFIRI PD Oxaliplatin 100 mg/m 2 + slv5fu2
Efficacy Time to Second Progression Overall Survival FOLFOX6 FOLFIRI FOLFIRI FOLFOX6 FOLFIRI FOLFOX6 FOLFOX6 FOLFIRI median second PFS 14.2 mo 10.9 mo P = 0.64 median OS 21.5 mo 20.6 mo P = 0.99
Concept of All 3 Drugs 11 Phase III Trials, 5768 Patients Median OS (mo) 22 21 20 19 18 17 16 15 14 13 P=0.0001 First Line Therapy Infusional 5 FU/LV + irinotecan Infusional 5 FU/LV + oxaliplatin Bolus 5 FU/LV + irinotecan Irinotecan + oxaliplatin Bolus 5 FU/LV LV5FU2 12 0 10 20 30 40 50 60 70 80 Patients with 3 drugs (%) Grothey, JCO 23:9441-9442, 2005
monoclonal antibody = mab o mab xi mab Rituximab ( ) Cetuximab ( ) zu mab Trastuzumab ( ) Bevacizumab ( ) Alemtuzumab (Campath) u mab Panitumumab (Vectibix)
xi mab zu mab u mab
*: 1957 5 FU/ 1996 ( ) 2001 2002 2004 ( ) 2004 ( ) 2006 ( ) * 2008 7 2007 4
VEGF IGF = insulin like growth factor, PDGF = platelet derived growth factor
bfgf, TGF PD-ECGF
Vol.3
Hurwitz H, et al. N Engl J Med 2004;350:2335 42 IFL : Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 6.2 10.6 (months) IFL + : 6.2 months (95% CI: 5.6 7.7) IFL + : 10.6 months (95% CI: 9.0 11.0) Hazard ratio=0.54 (95% CI: 0.45 0.66) p<0.001 IFL + IFL + 0 10 20 30 PFS (months)
Hurwitz H, et al. N Engl J Med 2004;350:2335 42 IFL : Probability of survival 1.0 0.8 0.6 0.4 0.2 0 (months) IFL + : 15.6 (95% CI: 14.3 17.0) IFL + : 20.3 (95% CI: 18.5 24.2) HR=0.66 (95% CI: 0.54 0.81) p<0.001 15.6 20.3 0 10 20 30 40 Survival (months) IFL + Avastin IFL + placebo
EGFR HER1 erbb1 HER2/neu erbb2 HER3 HER4
EGFR EGFR
ERBITUX (Cetuximab) Mechanism of Action The EGF Receptor: An Important Target for Cancer Therapy ERBITUX Package Insert, March 2006 Baselga J. J Clin Oncol. 2001;18s:41s 44s.
ERBITUX (Cetuximab) Mechanism of Action ERBITUX Inhibits Binding of EGF and Other Ligands ERBITUX Package Insert, March 2006.
CRYSTAL trial CRYSTAL trial First line FOLFIRI+ Cetuximab
KRAS CRYSTAL trial First line FOLFIRI+ Cetuximab : PFS KRAS KRAS (n=348):hr=0.68; p=0.017 PFS Cetuximab+FOLFIRI:9.9 PFS FOLFIRI: 8.7 FOLFIRI+Cetuximab FOLFIRI
KRAS CRYSTAL trial First line FOLFIRI+ Cetuximab : PFS KRAS KRAS (n=192):hr=1.07; p=0.47 PFS Cetuximab+FOLFIRI : 7.6 PFS FOLFIRI : 8.1 FOLFIRI+Cetuximab FOLFIRI
EPIC 2 nd line EGFR R Irinotecan +Cetuximab Irinotecan n=648 n=650 16.4 Cetuximab 400 mg/m 2 then 250 mg/m 2 weekly Irinotecan 300 350 mg/m 2 q 3w 4.2 p<0.0001 100 PFS OS as primary endpoint NEG 50 HR = 0.692 Iri+Cetuximab Irinotecan 95% CI [0.617 0.776] p value < 0.0001 4.0 mo (95%CI=3.2 4.1) 2.6 mo (95%CI=2.1 2.7) 0 0 3 6 9 12 15 18 Sobrero A et al. J Clin Oncol 2008; 26:2311 2319
06 Cunningham, NEJM 351:337-345, 2004 EMR 62202 007 BOND : Cetuximab in Irinotecan refractory
BOND study +CPT-11 (n = 218) 23% (n = 111) 11% 56% 4.1 32% 1.5 Cunningham et al. New Engl J Med 2004; 351:337-345.
Time to Tumor Progression 4.1 vs. 1.5 mo HR=0.54 [95%CI: 0.42 0.71] p<0.001 Overall Survival 8.6 vs. 6.9 mo HR=0.91 [95%CI: 0.68 1.21] p=0.48
NCIC CTG CO.17 3 rd line Cetuximab+BSC n=287 8.0 R Cetuximab 400 mg/m 2 then 250 mg/m 2 weekly p<0.001 EGFR BSC n=285 0 Jonker et al. N Engl J Med 2007; 357:2040 2048