????Cetuximab (Erbitux)

1
????Cetuximab (Erbitux) ?????????
????????? ???? ??? ??????? ?????
2
????

1. ??? 2. ???? Cetuximab (Erbitux) 3. Cetuximab
????????? 4. ????-??????
3
????????, 2006
?? ???? ??? (/105) ??? ???? 135071 591.
8 100.0 ?? 37998 166.5 28.1 ?????
12596 55.2 9.3 ???? 12283 53.8
9.1 ??? 9690 42.5 7.2 ???? 8011
35.1 5.9 ?? 5396 23.6 4.0 ???????
5049 22.1 3.7 ??? 4712 20.6
3.5 ?? 4406 19.3 3.1 ????? 1816
8.0 1.3
4
??????????, 2006
??? ???? ??? (/105) ??? ???? 37998
166.5 100.0 1.?? 7479 32.8 19.7 2.??
7415 32.5 19.5 3.????? 4284 18.8
11.3 4.???? 1439 12.8 3.8 5.??
2398 10.5 6.3 6.??????? 2202 9.6
5.8 7.???? 957 8.3 2.5 8.????
792 7.0 2.1 9.??? 1304 5.7
3.4 10.??? 1247 5.5 3.3 14.???
798 3.5 2.1
5
????????????, 2006
??? ???? ??? (/105) ??? ????
24428 211.0 100.0 1.?? 5383 46.5
22.0 2.?? 5149 44.5 21.1 3.?????
2485 21.5 10.2 4.??????? 2044 17.7
8.4 5.?? 1571 13.6 6.4 6.??? 1230
10.6 5.0 7.???? 957 8.3 3.9 8.???
749 6.5 3.1 9.??????? 733 6.3
3.0 10.??? 611 5.3 2.5
6
????????????, 2006
??? ???? ??? (/105) ??? ????
13570 120.7 100.0 1.?? 2330 20.7
17.2 2.?? 2032 18.1 15.0 3.?????
1799 16.0 13.3 4.???? 1439 12.8
10.6 5.?? 827 7.4 6.1 6.????
792 7.0 5.8 7.??? 498 4.4
3.7 8.??????? 478 4.3 3.5 9.???
467 4.2 3.4 10.??? 380 3.4 2.8
7
????????(?????)???, 2003
??? ??? ???? (/105) ????
36285 315.11 1.?? 6753 58.64 2.??
5025 43.64 3.????? 4677 40.62 4.???????
4040 35.08 5.?? 2308 20.04 6.????
2237 19.43 7.??? 1318 11.45 8.???
1258 10.92 9.??? 1157 10.05 10.???
960 8.34
2007 March ?????? ??????
8
????????(?????)???, 2003
??? ??? ???? (/105) ????
26257 236.77 1.???? 5325 48.02 2.?????
3561 32.11 3.?? 2651 23.91 4.??
2390 21.55 5.???? 2061 18.59 6.??
1226 11.06 7.???? 975 8.79 8.????????
833 7.51 9.???? 793 7.15 10.???
783 7.06
2007 March ?????? ??????
9
???????????
??? 2003??? 1998??? 1.??
6753 (??9404) 5315 2.?? 5025 (??7415) 4088
3.????? 4677 (??8238) 3572 4.????????
4040 2473 ??? 3111 ???
363 199 ??? 519 357
?? 48 28 9.??? 1157
972 ?? 462 384 ????
116 79 ??????? 122
98 ????? 5897 (??6788) 4006
2007 March ?????? ??????
10
???(NPC)??????(SCCHN)???
??? ????? EB?? ?? ?? ?? ???? ???? ??????
? ?? ?? ????? ? ?? ????? ? ?? ?????? ??(?
?) ??(???) ??????? ???? ??? ??????? ?? ?
11
(No Transcript)
12
???????

???? ??????? ????????? ??????? ?????????
13
?????????

??(????) ??????? ??? ???? ???? ?????????
X? ??????
14
?????

???? (T) T1, T2, T3, T4 ???? (N) N0, N1, N2,
N3 ???? (M) M0, M1
15
Stage Classification for SCCHN
T1 T2 T3 T4a T4b N0 I II III IVA IVB N
1 III III III IVA IVB N2 IVA IVA IVA IVA
IVB N3 IVB IVB IVB IVB IVB M1 IVC
16
??????????????????, ?????????????, ????????, ?????
?????, ???????????, ????????????
17
?????? (?)???? (?)???? (?)???? (?)???? (?????????
??????)
18
???????(?)

??? ??,??????? ??,????????
??????? ????????,???
19
???????(?)

?????? ??,???????????? ??,????????
??????? ????????,???
20
???????(?)

??? ??,??????? ??????????????? ?????????? ????
????,???
21
????
???? ??????? ??????(??)??
22
(No Transcript)
23
?????? ?????(??)??
T3, T4 ?? (??? T4) ??????,????????? ???????? ?????
? ??????????
24
???????????
????
25
??????????
(?)???????????(Varian RapidArc)
(???????) (?)?????????????(Tomotherapy)
(?????) (?)????????(CyberKnife) (?) ??????
(Proton)
26
kV X-ray imager
kV X-ray tube
MV X-ray imager
27
Targeting System
X-ray sources
Manipulator
Synchrony camera
Linear accelerator
Robotic Delivery System
Image detectors
Note The promotion and use of the
CyberKnife System is only for approved
indications in the country of use. Each
distributor is responsible for marketing the
CyberKnife System and appropriate options based
upon the regulatory approvals in their territory
28
(No Transcript)
29
(No Transcript)
30
Dependence on Number of Beams
mm
mm
mm
1 Beam
11 Beams
5 Beams
17 Beams
25 Beams
51 Beams
mm
mm
mm
31
????
????? ????????? ????????
32
????????? ????????
? ? ? ??? ?? ( ??)
33
Outpatient weekly MEMOCLUB
?
?
MTX 30 mg/m2 Epirubicin 30 mg/m2 MMC 4.0
mg/m2 Oncovin 1.0 mg/m2 Cisplatin 25
mg/m2 Leucovorin 120 mg/m2 5-FU 1000
mg/m2 Bleomycin 10 mg/m2
On week 1,3,5,7
On week 2,4,6,8
34
????
???? ????
EGFR????????
35
(No Transcript)
36
Human Epidermal Growth Factor Receptors Family
37
(No Transcript)
38
EGFR ????(Erbitux)
39
??????????,??????, ??? ????,?????
??????TK???????,???
????????????????
40
EGFR activation
Anti-EGFR mechanism (Cetuximab)
41
Cetuximab (ERBITUX) properties and mechanism of
action

• IgG1 monoclonal antibody induces apoptosis and
  ADCC
• Exclusive for EGFR
• High affinity Kd 0.39 nM
• Preclinical data synergisticactivity in
  combination with chemotherapyand radiotherapy

ADCC antibody-dependent cellular cytotoxicity
42
Mechniasm of ligand-induced EGFR dimerization
Li et al (2005) Cancer cell 7301-311
43
????EGFR?????
???
??
?????
44
??????

• EGFR ?????,????,??,??,?????????????
• ????????????EGFR
• EGFR???????,???????,??????
• EGFR?????????????
• EGFR ???????????

45
???????????????? ?? vs. ???? (1999-4?2002-3)

• Stratified by
• KPS
• Nodal involvement
• Tumor stage
• RT fractionationa

?? (n213)
???? ??? ??? (n424)
R
?? ?? (n211) ???? (400 mg/m2) x 1 (250
mg/m2) x 7 ??7-8?

• ?????? ???????
• ?????? ????, ???, ???

Bonner J, et al. N Engl J Med 2006354567578
46
Phase III study ?????
100
80
60
Locoregional control ()
ERBITUX RT (n211)
40
20
14.9
24.4
RT (n213)
0
0
10
20
30
40
50
60
70
Months
Hazard ratio 0.68 (95 CI 0.520.89) Log-rank
p0.005
Bonner J, et al. N Engl J Med 2006354567578
47
Phase III study ????
100
80
60
ERBITUX RT (n211)
Overall survival ()
40
RT (n213)
20
29.3
49.0
0
0
10
20
30
40
50
60
70
Months
Hazard ratio 0.74 (95 CI 0.570.97) Log-rank
p0.03
Bonner J, et al. N Engl J Med 2006354567578
48
??(?????)?????
aFishers exact test bListed for its
relationship to ERBITUX
Bonner J, et al. N Engl J Med 2006354567578
49
??/?????
50
gt50
40
???????? ??????
30
Percentage of cases
20
10
10
0

• ????
• ??
• ???
• ???
• ????

• Cisplatin-based ????
• ????? 30
• ???(??) 69 ??

50
EXTREME??/????????????????

• Patients stratified according to
• KPS (lt80 vs 80)
• Prior chemotherapy (yes vs no)

Group A (????) Cetuximab 400 mg/m2 initial dose
then 250 mg/m2 weekly EITHER carboplatin (AUC
5, d1) OR cisplatin (100 mg/m2 IV, d1) 5-FU
(1000 mg/m2/d IV, d14) 21-day cycles(6 cycles
maximum)
R A N D O M I Z E
Cetuximab
Progressive disease or unacceptable toxicity
Group B (??) EITHER carboplatin (AUC 5, d1) OR
cisplatin (100 mg/m2 IV, d1) 5-FU (1000
mg/m2/d IV, d14) 21-day cycles(6 cycles maximum)
No treatment
Vermorken JB, et al. ECCO 2007 (Abstract No.
5501 updated information presented)
51
EXTREME ?????
aStratified CochranMantelHaenszel test
Vermorken JB, et al. ECCO 2007 (Abstract No.
O5501 updated information presented)
52
????????????EXTREME Study
Vermorken, ASCO 2007
53
EXTREME ???????? ??????
1.0










0.9

















Cetuximab CTX
0.8





CTX only
0.7


HR (95CI) 0.538 (0.431, 0.672)

0.6

Strat. log-rank test lt0.0001



5.6 months
Progression free ()
0.5
3.3 months



0.4







0.3



0.2



0.1


0.0
0
3
6
9
12
15
PFS time (months)
Patients at risk
222
138
72
29
12
7
220
103
29
8
3
1
Vermorken JB, et al. ECCO 2007 (Abstract No.
5501 updated information presented)
54
HN ??????
??????????????

• 2.??????????????(98/7/1)
• (1)???????????,??????platinum-based ?????platinum
  ???????????????????????????????????,????
• I. ??? 70 ?,?Ccr lt50ml/min ???????
• II. ECOG ? 2?
• (2)????????8 ???????
• (3)????????????

55
Current Treatment Revolution SCCHN?????????
NeoCT Erbitux Altered fractionated RT
Erbitux Concurrent CT Erbitux Adj Erbitux
56
Summary of Erbitux in SCCHN
Economic consideration Effective in new
patients Useful in post-op adjuvant
setting Effective in 1st line rec/met Effective
in refractory cases Useful in NPC Easy to use,
less toxicity Combined with appropriate S, RT
57
? ? ? ?!