Synthetic Genome Brings New Life to Bacterium (Gibson DG et Al., Science, 20 May, 2010)
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Transcript of Synthetic Genome Brings New Life to Bacterium (Gibson DG et Al., Science, 20 May, 2010)
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Synthetic Genome Brings NewLife to Bacterium (Gibson DG et Al., Science, 20 May, 2010)
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“Targeted therapy nella terapia del cancro del
colon retto metastatico”. A che punto siamo?
Prof. Roberto MazzantiDirettore, Oncologia Medica 2
AOUC.Firenze
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Targeted therapy has proven efficacy in Targeted therapy has proven efficacy in colorectal cancer:colorectal cancer:
BevacizumabBevacizumab
CetuximabCetuximab
PanitumumabPanitumumab
Targeted therapy has proven efficacy in Targeted therapy has proven efficacy in colorectal cancer:colorectal cancer:
BevacizumabBevacizumab
CetuximabCetuximab
PanitumumabPanitumumab
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Normal tissueNormal tissue Tumor tissueTumor tissue
Jain: Science; 307: 58-62, 2005Jain: Science; 307: 58-62, 2005
Neo-angiogenesi tumoraleNeo-angiogenesi tumorale
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Il controllo dello switch angiogenetico dipende dall’equilibrio Il controllo dello switch angiogenetico dipende dall’equilibrio tra fattori PRO- ed ANTI-ANGIOGENETICItra fattori PRO- ed ANTI-ANGIOGENETICI
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Bevacizumab (Avastin™): rhuMAb VEGFBevacizumab (Avastin™): rhuMAb VEGF
• Recombinant Humanized Recombinant Humanized Monoclonal Antibody to VEGFMonoclonal Antibody to VEGF
• 93% human, 7% murine93% human, 7% murine
• Recognizes all isoforms of VEGF, Recognizes all isoforms of VEGF, Kd = 8 x 10-10 MKd = 8 x 10-10 M
• Terminal half life 17-21 daysTerminal half life 17-21 days
• Somministrato e.v. insieme a chemioterapciSomministrato e.v. insieme a chemioterapci
• Approvato per il trattamento dei pazienti con carcinoma del colon-Approvato per il trattamento dei pazienti con carcinoma del colon-retto avanzatoretto avanzato
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Sopravvivenza libera da progressione: IFL + placebo, 6,2 mesi; IFL + bevacizumab, 10,6 Sopravvivenza libera da progressione: IFL + placebo, 6,2 mesi; IFL + bevacizumab, 10,6 mesi (p<0,001)mesi (p<0,001)Risposta obiettiva: IFL + placebo, 34,8%; IFL + bevacizumab, 44,8% (p=0,004)Risposta obiettiva: IFL + placebo, 34,8%; IFL + bevacizumab, 44,8% (p=0,004)
Bevacizumab + chemioterapia vs. Placebo + chemioterapiaBevacizumab + chemioterapia vs. Placebo + chemioterapia
Hurwitz e coll. New Engl J Med, 2004 Hurwitz e coll. New Engl J Med, 2004
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Effect of Avastin on treatment of metastatic colon cancer
BICC-C study. J Clin Oncol 2008;26:689–690.
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Punt CJ, 2009
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Bevacizumab in 3rd line C.T. in mCRC
Kang BW et al. Med Oncol. 2009;26(1):32-7
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TKTK
Survival(anti-apoptosis)
PI3-K
STAT3
AKTPTEN
MEK
Gene transcriptionMAPK
Proliferation/maturation
Chemotherapy /radiotherapy
resistanceAngiogenesis Metastasis
pYpY
RAS RAFSOS
GRB2pY
G1
SM
G2
Anticorpi monoclonali
Piccole molecole anti-TK
Strategie anti-EGFR
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0
0,2
0,4
0,6
0,8
1
0 2 4 6 8 10 12
MONTHS
PR
OP
OR
TIO
N
Mono ComboN 111 218No. events 92 152Median 1.5 4.1
HR (95% CI): 0.54 (0.42; 0.71)
log rank p-value < 0.0001
0
0,2
0,4
0,6
0,8
1
0 2 4 6 8 10 12 14 16
MONTHS
PR
OP
OR
TIO
N
Mono ComboN 111 218No. events 75 140Median 6.9 8.6
HR (95% CI): 0.91 (0.68; 1.21)
log rank p-value = 0.48
Cetuximab vs. CPT-11+Cetuximab in CPT-11 refractory CRC
Pat
ient
s su
rviv
ing
(%)
Pat
ient
s fr
ee o
f pr
ogre
ssio
n (%
)
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Phase III CRYSTAL study: DesignPhase III CRYSTAL study: Design
Stratification factors: Stratification factors: • RegionRegion• ECOG performance statusECOG performance status
Populations:Populations:• Randomized patients (n=1217)Randomized patients (n=1217)• Safety population (n=1202)Safety population (n=1202)• ITT population (n=1198) ITT population (n=1198)
FOLFIRIFOLFIRI
IrinotecanIrinotecan 180 mg/m 180 mg/m22 + 5-FU+ 5-FU//LVLV every 2 weeks every 2 weeks
ERBITUX + FOLFIRIERBITUX + FOLFIRI
ERBITUXERBITUX IV 400 mg/m IV 400 mg/m22 on day 1, on day 1,then 250 mg/mthen 250 mg/m2 2 weeklyweekly
+ irinotecan+ irinotecan 180 mg/m 180 mg/m22 + 5-FU+ 5-FU//LVLV every 2 weeks every 2 weeks
RREGFR-expressing EGFR-expressing
mCRCmCRC
Van Cutsem E, et al. New Engl J Med 2009;360:1408–1417Van Cutsem E, et al. New Engl J Med 2009;360:1408–1417
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Phase II OPUS study: DesignPhase II OPUS study: Design
ERBITUX + FOLFOX4ERBITUX + FOLFOX4aa
400 mg/m400 mg/m22 initial IV infusion (day 1) initial IV infusion (day 1)then 250 mg/mthen 250 mg/m2 2 weeklyweekly+ oxaliplatin 85 mg/+ oxaliplatin 85 mg/mm22 + 5-FU/LV + 5-FU/LV every 2 weeksevery 2 weeks
FOLFOX4FOLFOX4aa
Oxaliplatin 85 mg/Oxaliplatin 85 mg/mm22 + 5-FU/LV + 5-FU/LV every 2 weeksevery 2 weeks
EGFR-detectableEGFR-detectablemCRCmCRC RR
Stratification by:Stratification by:
• ECOG PS 0/1, 2ECOG PS 0/1, 2
Bokemeyer C, et al. Bokemeyer C, et al. J Clin Oncol J Clin Oncol 2009;27:663–6712009;27:663–671
aaTreatment until progression, symptomatic deterioration or unacceptable toxicityTreatment until progression, symptomatic deterioration or unacceptable toxicity
aaTreatment until progression, symptomatic deterioration or unacceptable toxicityTreatment until progression, symptomatic deterioration or unacceptable toxicity
93,5% of the patient evaluated for the KRAS status93,5% of the patient evaluated for the KRAS status
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FOLFOXFOLFOX(n=97)(n=97)
ERBITUX ERBITUX + + FOLFOXFOLFOX
((n=82)n=82)
0
10
20
30
40
50
60
70
Res
pon
se r
ate
(%)
Res
pon
se r
ate
(%)
Erbitux + chemioterapiaErbitux + chemioterapia
Chemioterapia da sola Chemioterapia da sola
57,357,3
34,034,039,739,7
57,357,3
ErbituxErbitux®® improves Response Rate in improves Response Rate in IIstst line KRAS wild-type patients line KRAS wild-type patients
CrystalCrystal11
P<0.0001P<0.0001 p=0.0027p=0.0027
1.1.Van Cutsem E, et al. ECCOESMO 2009 Abs 6077Van Cutsem E, et al. ECCOESMO 2009 Abs 6077
OpusOpus11
FOLFIRIFOLFIRI(n=350)(n=350)
ERBITUX ERBITUX + FOLFIRI+ FOLFIRI
(n=316)(n=316)
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FOLFOXFOLFOX(n=97)(n=97)
ERBITUX ERBITUX + + FOLFOXFOLFOX
((n=82)n=82)
0
5
10
15
20
25
30
mO
S (
mon
ths)
mO
S (
mon
ths)
Erbitux + chemioterapiaErbitux + chemioterapia
Chemioterapia da sola Chemioterapia da sola
23,523,5
18,518,52020
22,822,8
ErbituxErbitux®® improves Overall Survival in improves Overall Survival in IIstst line KRAS wild-type patients line KRAS wild-type patients
CrystalCrystal11
p=0.0094p=0.0094 p=0.3854p=0.3854
1.1.Van Cutsem E, et al. ECCOESMO 2009 Abs 6077Van Cutsem E, et al. ECCOESMO 2009 Abs 6077
OpusOpus11
FOLFIRIFOLFIRI(n=350)(n=350)
ERBITUX ERBITUX + FOLFIRI+ FOLFIRI
(n=316)(n=316)
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Punt, CJ, 2009
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Panitumumab
Vectibix® è indicato come monoterapia per il trattamento di pazienti con carcinoma colorettale metastatico esprimenti il recettore per il fattore di crescita epidermico (EGFR) dopo fallimento di regimi chemioterapici contenenti fluoropirimidine, oxaliplatino e irinotecan, nel caso in cui i tumori presentino il gene KRAS non mutato (wild-type).
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Conclusioni (I)
• Ad eccezione di Vectibix (3° linea) la targeted therapy nel mCRC è efficace solo insieme a C.T. tradizionale.
• Ove disponibili EGRF e Kras (non mutato) è possibile l’uso di cetuximab.
• Bevacizumab è meno tossico ed agisce anche nei Kras mutati
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Conclusioni (II)
• Le triplette (CT+bevac.+cetux) non aggiungono efficacia ma tossicità e costi.
• Idealmente è buona pratica clinica in 1° linea associare CT e bevac. per passare in 2° al cetuximab (se Kras non mutato).
• Panitumumab trova indicazione ad oggi in 3° linea o 2° se Kras mutato.
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