(GLOBOCAN 2002, 2004)

1
????????

• ???
• ??????????

2
2002??????????
(GLOBOCAN 2002, 2004)
3
2002??????????
(GLOBOCAN2002, 2004)
4
????????

• ??????????(AGC)?60-80,???????

????????
TNM?? ??? ?????
I 18 56-71 II 15 37 III 27 11-18
IV 39 5
AGC
16-23
66
5
??????????
??????
????
6
??????

• ????????????????,????????????????????,????????
  ????????????????????
• ??????????????(EGFR)???,
• ?????????????????,
• ????????????????????,
• ??????????,
• ?????,
• ????

7
????

• ??????
• MabThera ???( Rituximab,?????)
• Herceptin ???(Trastuzumab,?????)
• Erbitux ???????(Cetuximab,?????)
• Panitumumab ???? ?????
• Avastin ( Bevacizumab,????,)
• ??????
• Glivec ???(STI571, Imatinib,???????)
• Iressa ???(ZD1839, Gefitinib,????)
• Tarceva ???(OSI-774 ,erlotinib,????)
• Nexavar ???(Sorafenib,????)
• Sutent ?? ( Sunitinib,SU11248,????)
• Zactima ????(ZD6474) ?????
• Lapatinib(????)?????

8
??????
?? ?-??
EGFR IRRSA/TARCEVA ?????(C225)
Her-2 Herceptin Lapatinib(???)
VEGF Bevacizumab(Avastin)
??? Sutent(Sunitinib)
9
???????????(EGFR / HER family)
EGFR, epidermal growthfactor receptor
Prigent Lemoine 1992 Earp et al 1995 Harari
Yarden 2000 Mendelsohn Baselga 2000 Olayioye
et al 2000
10
EGFR ????????

• EGFR ???????????

????

???? 7589
??? 95100
?? (??????) 4080
??? 1491
??? 3577
???? 5090
??
???()
?? (NSCLC)
???(SCCHN)
Cunningham et al. N Engl J Med 2004351337345
Grandis et al. Cancer 19967812841292 Salomon
et al. Crit Rev Oncol Hematol 199519183232
Walker Dearing. Breast Cancer Res Treat
199953167176 Folprecht et al. ASCO 2004
(Abstract 283).
11
EGFR??????????????

• ?????????ATP
• Gefitinib and OSI-774?????ATP
• ??????
• ???????

OSI-774 Erlotinib, Tarceva
12
EGFR?????????????
TGFa
???

????
Iressa Tarceva
X
?
X
????
?
??
????
X
X
??
13
IRESSA ( gefitinib ???) First EGFR-TKI

• ???4-(3-?-4-???)-7-???-6-(3-??????)???
• ???C22H24ClFN4O3
• ???446.9

Epidermal Growth Factor Receptor-Tyrosine Kinase
Inhibitor
14
IRRESA???????

• ?????IV?????,75?
• Iressa 250500mg/d
• ?????,???????
• ?????????210?79?,P0.0016

15
IRRESA???????

• ??????1,N75(ASCO2003)
• ???/????????10-12,N56(ASCO 2004)

16
OSI-774(Tarceva)

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

17
Erlotinib(Tarceva)???

• ???/????????16,N17(ASCO 2004)
• ?????????
• N2644,????012(1?CR)(ASCO2005)

18
Cetuximab(???)

• IgG1 (????)
• 150 kDa
• ??????EGFR??????
• ?????EGFR??
• ???? Kd 0.39 nM (M-225 Kd 1 nM),1 log gt ????
• ??????
• ????????,????????,????

19
(No Transcript)
20
EGFR

• ?????(C225)
• ????????????(SWOG)
• ECF?????????????(CALBG)
• FOLFIRI????????
• XP?

21
A phase II study of cetuximab (Cetuximab) with
cisplatin and capecitabine (Xeloda) as 1st line
treatment in advanced gastric cancer

• Methods
• cisplatin 80mg/m2,
• capecitabine 2000mg/m2, d1-14,
• triweekly
• Cetuximab weekly
• (initially at 400 mg/m2, then subsequent
  doses at 250 mg/m2)

2008 ASCO , Abstract No 15663
22
A phase II study of cetuximab (Cetuximab) with
cisplatin and capecitabine (Xeloda) as 1st line
treatment in advanced gastric cancer

• Results N25
• 1 CR 9 PR 13 SD
  2 PD
• RR 40 DCR 92
• Toxicities included Grade 3/4
• neutropenia(14.2)
  nausea/vomiting(11.1)
• rash/desquamation (10.7) fatigue
  (11.1)
• diarrhea (6.3)
  abdominal pain (6 ) Hand-Foot syndrome(2.8)

2008 ASCO , Abstract No 15663
23
A phase II study of cetuximab (Cetuximab) with
cisplatin and capecitabine (Xeloda) as 1st line
treatment in advanced gastric cancer

• Conclusions
• Treatment with XPC is well-tolerated and met
  the pre-specified criteria for objective response
  and disease Control.

2008 ASCO , Abstract No 15663
24
Cetuximab in combination with cisplatin and
docetaxel as first-line treatment in patients
with locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma
(Italian phase II DOCETUX study).

• Methods
• Cetuximab weekly at 400 mg/m2 iv loading dose,
  and then at 250 mg/m2 iv maintenance dose
• cisplatin 75 mg/m2 iv d1
• docetaxel 75 mg/m2 iv d1
• every 3 weeks, for maximum of 6 cycles

2008 ASCO, Abstract No 4575
25
Cetuximab in combination with cisplatin and
docetaxel as first-line treatment in patients
with locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma
(Italian phase II DOCETUX study).

• Results
• The objective responses (RECIST)
• 1 (2.4) CR 16 (38.1) PR,
• 40.5 CR PR (95 CI 25.7-55.3)
• 16 (38.1) SD 9 (21.4) PD
• The PFS at 3 months is 80 (95 CI
  64.3-95.7)
• Survival data are premature
• (75 of the pts are still alive)

2008 ASCO, Abstract No 4575
26
Cetuximab in combination with cisplatin and
docetaxel as first-line treatment in patients
with locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma
(Italian phase II DOCETUX study).

• Grade 3-4 toxicity (CTC v3.0)
• 45.8 neutropenia (22.9 febrile
  neutropenia)
• 6.25 anemia
  2.1 thrombocytopenia
• 22.9 asthenia
  8.3 vomiting
• 6.3 stomatitis
  4.2 diarrhea
• 4.2 hyperbilirubinemia 20
  hyponatremia
• 16 hypokalemia
  4 hypomagnesemia
• Skin reactions gt 2 w as 31.3
• Three deaths occurred within 60 days from
  start of therapy
• (1 bowel occlusion, 1 gastric bleeding,
  1 PD).

2008 ASCO, Abstract No 4575
27
Cetuximab in combination with cisplatin and
docetaxel as first-line treatment in patients
with locally advanced or metastatic gastric or
gastroesophageal junction (GEJ) adenocarcinoma
(Italian phase II DOCETUX study).

• Conclusions
• The combination of cetuximab and
  cisplatin/docetaxel appears to be active (78.6
  of disease control rate), while the greater
  toxicity appears to be limited to neutropenia.

2008 ASCO, Abstract No 4575
28
Cetuximab (C225) plus irinotecan/cisplatin
(CPT/Cis) for CPT/Cis-refractory esophageal cancer

• PROTOCOL
• CPT 65 mg/m2 D1,8
• Cis 30 mg/m2 D1,8
• q3 weeks
• C225 was added at 400 mg/m2 week 1, then 250
  mg/m2 weekly.

2008 ASCO, Abstract No 45580
29
Cetuximab (C225) plus irinotecan/cisplatin
(CPT/Cis) for CPT/Cis-refractory esophageal cancer

• RESULTS
• 6 of 8 Pts were EGFR positive (2 1/ 2 2/2
  3 by IHC).
• Median TTP on prior CPT/Cis was 4.4 months
  (range, 1.8 to 14.4 months)
• 1 confirmed partial response (PR) was seen in
  a Pt with adenoCA (EGFR 3)
• 2 Pts had stable disease (SD) and 5 had
  progressive disease (PD)
• 1 Pt with SD for 2.9 months had SCC (EGFR 2)
  while the other with SD for 3.7 months had
  adenoCA (EGFR negative).

2008 ASCO, Abstract No 45580
30
Cetuximab (C225) plus irinotecan/cisplatin
(CPT/Cis) for CPT/Cis-refractory esophageal cancer

• Significant grade 3/4 toxicities
• lymphopenia (4 Pts, all grade 3)
• neutropenia (1 Pt, grade 4)
• hypomagnesemia (1 Pt, grade 3)
• Rash was manageable, with 4 Pts with grade 1
  and 3 Pts with grade 2 skin toxicity
• 1 Pt died of non-neutropenic sepsis from PD
  after 3 weeks of therapy (this Pt was off
  treatment for 3-4 weeks prior to death)

2008 ASCO, Abstract No 45580
31
Cetuximab (C225) plus irinotecan/cisplatin
(CPT/Cis) for CPT/Cis-refractory esophageal cancer

• CONCLUSION
• Adding C225 to CPT/Cis for CPT/Cis-refractory
  esophageal cancer is well-tolerated 1 PR has
  been observed to date. Accrual is ongoing to 25
  Pts.

2008 ASCO, Abstract No 45580
32
???????????(EGFR / HER family)
EGFR, epidermal growthfactor receptor
Prigent Lemoine 1992 Earp et al 1995 Harari
Yarden 2000 Mendelsohn Baselga 2000 Olayioye
et al 2000
33
Herceptin(Trastuzumab, ?????, ???)

• Herceptin?????HER-2/neu????????/?????,???????HER-2
  ?????????????1998?9???FDA????,???????????HER-2????
  ???????????

34
??? ????HER2 ??
HER2 ??,???????????????

• ?? HER2 ??
• ?????? (Kd 0.1 nM) ????
• 95 ?, 5 ??
• ?????????
• ???????????????

?IgG-1
35
Her-2
???????????? ???????
36
?????HER-2 ???????????11?????? ?,???1,? ?,?
?,???,???(??????????,?? 100853)

• ????
• ?2006?6??2008?6?????????11??????????,??3?
  ,??8?,??44?76??????57????????????,????9?,???2????
  ??????(UICC)TNM????,???????,Kamofsky??7090?,Her2
  /neu??( ?? )?( )????????6?,??4?,???6?,??2??
  ???1?6?,2?3?,3?2??????7?(????),??4??

37
?????HER-2 ???????????11?????? ?,???1,? ?,?
?,???,???(??????????,?? 100853)

• ????
• ??????? 8 mg/kg,??6mg/kg,?3????
• ?? ????(?)

38
?????HER-2 ???????????11?????? ?,???1 ,? ?,?
?,???,???(??????????,?? 100853)

• ?????Herceptin??????????

???? ?? CR PR SD PD RR()
?? ?? 9 2 0 0 8 1 1 1 0 0 88.9 50.0
39
?????HER-2 ???????????11?????? ?,???1 ,? ?,?
?,???,???(??????????,?? 100853)

11???Herceptin??????????????TTP??
TTP??5.6??,??14??,??TTP 8.6??
40
?????HER-2 ???????????11?????? ?,???1 ,? ?,?
?,???,???(??????????,?? 100853)
11???Herceptin?????????????????? 11??????????44.5?
?,??Herceptin???????????23??,??3??,4????
41
?XX,?,66?,??????,??? HER-2 ( )
???? Herceptin 560mg D1, DDP
144mg D1, Xloda 1800mg Bid D1-15
42
?XX,?,66?,??????,??? HER-2 ( )
???? Herceptin 560mg D1, DDP
144mg D1, Xloda 1800mg Bid D1-15
43
VEGF??????
44
Tumor angiogenesis
5. Intravasation
1. Secretion of angiogenic factors
Tumor
4. Appearance of new tumor vasculature
2. Proteolytic destruction of ECM
3. Endothelial cell proliferation and migration
Sprouting capillary
ECM, extracellular matrix
45
Summary of VEGF function

• VEGF is a key angiogenic regulator directly
  implicated in
• endothelial cell proliferation
• endothelial cell migration
• endothelial cell protease expression
• endothelial cell adhesion
• capillary tube formation
• vessel maturation/pericyte recruitment
• It also acts as
• a survival factor for newly formed vasculature
• Vascular Permeability Factor

46
Inhibition of VEGF signaling

• Inhibiting VEGF signaling
• inhibits growth of new tumor vessels
• decreases vascular density, diameter and
  permeability
• may induce regression of recently developed tumor
  microvessels
• Therapeutic inhibition of tumor angiogenesis
  should be effective in a broad range of solid
  malignancies
• Target tissue is in direct contact with blood,
  facilitating drug delivery

47
Approaches to the inhibition of VEGF signaling
Ligands
VEGF-A
Anti-VEGF antibodies
VEGF-B
VEGF-C
VEGF-D
Blood vascularendothelial cell
Lymphatic vascularendothelial cell
VEGFR-1
VEGFR-2
VEGFR-3
48
Approaches to the inhibition of VEGF signaling
Ligands
VEGFR-TKIs
VEGF-A
VEGF-B
VEGF-C
VEGF-D
Lymphatic vascularendothelial cell
Blood vascularendothelial cell
VEGFR-1
VEGFR-2
VEGFR-3
Angiogenesis
Lymphangiogenesis
VEGFR-TKI, vascular endothelial growth factor
receptor-tyrosine kinase inhibitor
49
????????(VEGF)

• Bevacizumab,????,Avastin

• ????????IgG1??1 93??, 7 ??
• ????VEGF?????VEGF??2
• ?????20? (??1150?)1
• 8x1010M???

1Avastin (bevacizumab). Prescribing Information.
2004 2Presta et al. Cancer Res. 1997574593.
50
Avastin (bevacizumab)

• ???????????,??????????????????,???????????????????
  ?????CPT11?????????????
• Avastin?????????(2004?)???FDA????????????,????????
  ????
• ???????????????????????,???????????

51
VEGFR

• Bevacizumab??VEGFR
• ??????????????(MSKCC)
• ??ECF??(MAGIC-2??)
• AVAGAST AVASTINDDPXELODA
• PLACEBODDPXELODA

52
??????
Bevacizumab(BEV)??CPT-11DDP ????AGC ---
II?????(ASCO 2005)
N24 3m PFS 89 6m PFS 76 16????????
PR (12/16)75 MR 3 ,SD 1
BEV 15mg/kg d1 CPT 65mg/m2 d1,8 DDP 30mg/m2
d1,8 q3w
????(24?) ¾?????????????? 8 ??(4??2???)6?(20)
2????,2?????(????)
M.A. ShAh et alASCO 2005 abstr 4025
53
Phase II trial of docetaxel, cisplatin,
irinotecan, and bevacizumab in metastatic
esophagogastric cancer.

• Methods
• bevacizumab 10mg/kg d1
• docetaxel 30mg/m2 d 1, 8
• cisplatin 25mg/m2 d 1, 8
• irinotecan 50mg/m2 d 1, 8
• 3-week cycle.

2008 ASCO, Abstract No 4552
54
Phase II trial of docetaxel, cisplatin,
irinotecan, and bevacizumab in metastatic
esophagogastric cancer.

• Results
• 30 patients are evaluable for response
• partial 19 (63) stable 9
  (30)
• progression 2 (7).
• Grade III/IV toxicities
• grade III neutropenia 7 pts (22)
• grade III diarrhea 9 pts (28)
• grade III nausea 2 pts (6)
• grade 4 thromboembolic events 3 pts (9)

2008 ASCO, Abstract No 4552
55
Phase II trial of docetaxel, cisplatin,
irinotecan, and bevacizumab in metastatic
esophagogastric cancer.

• Conclusions
• The combination of docetaxel, cisplatin,
  irinotecan and bevacizumab is well-tolerated and
  has a promising response rate in chemo-naive
  patients with esophagogastric cancer. UGT1A1
  testing appears to predict the risk of severe
  diarrhea/neutropenia in this group of patients

2008 ASCO, Abstract No 4552
56
????????

• IREESA/TARCEVA????????
• C-225???????????????
• HERCEPTIN??????HER-2??????????????
• AVASTIN?????????????????
• ???????????????????????

57
???????

• ??????????,?????????????????????????
• ???????????
• ??????????(cytostatic)???
• ?????????????(DLT)???????(MTD)
• ?????????????????????????
• ?????(?????)??????????
• ????????????,?????????????????????
• ???? ???????????????

58
????
???????
?????
59
????!