ABRAXANE

1
ABRAXANE(?????????) ????
2
Nab-Tec ?????????

• ??????????,???????????????????
• ??GP60,???,SPARC????????????,?????????????????????
  ?

3
??????? ?????
??
???

• ????
• ???????
• ???????
• ????
• ????????????????

• ?-?? PK
• ??????2o ??
• ??????
• ?????????
• ????????????

????
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4
????????
??????? ??????????????? ?????????
???? ?????????
???? ???? ?????? ?????????/?????
????? ?????? ?????????? ??????
????? ???????(??????) ???????????
?????? ????????
ten Tije, et al. Clin Pharmacokinet
200342665-685 Gelderblom H, et al. Eur J
Cancer 2001371590-1598 Verweij J, et al. Ann
Oncol 19946495-505 Battafarano DF, et al.
Cancer. 199576110-115 Drori S, et al. Eur J
Biochem. 19952281020-1029.
5
ABRAXANE???????????????(LD50)
??????LD50 ?????? MTD ??????
30.0 mg/kg
175 mg/m2 ????????????? 47.0 mg/kg
300 mg/m2
Desai N, et al. Clin Cancer Res 200612(4),
1317-24
6
?????????????????????

• ???????????????????
• ??EPR???????????
• ??GP60/?????????????
• ???????SPARC????-??-GP60???????????????????,??????
  ?????????????????

7
????
1.? gp60 ? ??????????? 2. ???-???????SPARC
?????????
gp60 receptors
Caveolae and vesicles
Tumor blood vessel endothelial cells
Albumin transcytosis by gp60 and caveolae
Albumin-paclitaxel accumulation with SPARC binding
Tumor interstitium
Paclitaxel-induced tumor cell apoptosis
8
????????????????????

• ????????????????33

MX-1??????????????????
Abraxan(20mg/kg)
Taxol(20mg/kg)
???(nCi/g)
9
???Abraxane?Taxol????????????
MX - 1 ?????? 20 mg/kg Abraxane? Taxol (??? N
5,???1??)
P lt .008 for all tissues
???????(ABX/Taxol)
????
10
MX-1?????????????Abraxane?Taxol(30mg/kg)????
11
?????Abraxane?Taxol????????????(??N 5, IV qd x
5 days)
Lung
Desai N, Yao Z, Soon-Shiong P, et al. Evidence of
enhanced in vivo efficacy at maximum tolerated
dose (MTD) of nanoparticle paclitaxel (ABI-007)
and Taxol in 5 human tumor xenografts of varying
sensitivity to paclitaxel abstract. Proc Am Soc
Clin Oncol. 200221116a. Abstract 462.
12
Abraxane???? CA012

• ????????????????????????
• ????????III?????

13
????
?????????260mg/m2 ????30?? ?3????? ??????
???? (11)n 460
????? 175 mg/m2 ????3?? ?3?????
??????????????? ?H2?????
iv, ????
Gradishar et al. J Clin Oncol. 2005 23 77947803
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????

• ???????????(ABRAXANE)?????????(TAXOL??)?????????
  ?????
• ????
• ????(ORR)
• ???????????????(?????)
• RECIST ??
• ???????
• ????
• ???????(TTP)
• ??????(OS)

TTP,?????? OS,???
Gradishar et al. J Clin Oncol. 2005 23 77947803
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????

• 460 ??????
• ?????????????
• ABRAXANE? 233???
• TAXOL? 227???
• 454 ????????????
• ??????????????
• ABRAXANE? 229???
• TAXOL? 225???

Gradishar et al. J Clin Oncol. 20052377947803
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????
?????? ??? n 229 ??????? ??? n 225
??????????/?????() 77 78
????????? () 50 58
?????? ()
?(????) 42 40
???? 41 43
???? 10 16
gt?????? 7 2
Gradishar et al. J Clin Oncol. 20052377947803
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???? ???????
ABRAXANE 1293 ?? TAXOL 1174 ??
?5-HT3 ??? () 27 (2) 21 (2)
5-HT3 ??? () 211 (16) 159 (14)
????? () 109 (8) 1146 (98)
???????????????() 23 (2) 1113 (95)
?????? () 12 (lt 1) 21 (3)
Gradishar et al. J Clin Oncol. 2005 23 77947803
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????
ABRAXANE n 229 TAXOL n 225
?????/?? 6 5
?????/?? 5.6 5.2
????/m2/?? 255 mg 171 mg
???????? () 98 98
???????/??/m2 1459 mg 909 mg
Abraxane ????????????????????49
Gradishar et al. J Clin Oncol. 2005 23 77947803
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?????????(ORR)?????
???????? ????????
????????? (n 229 ??????? ??? n 225
???? ???? () ???? ???? () 33 19
95 ???? 95 ???? 2739 1424
P ? P ? P lt 0.001 P lt 0.001
Cochran-Mantel-Haenszel test
Gradishar et al. J Clin Oncol. 20052377947803
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????????????(ORR)?????
?????? ?????? ?????? ??????
?????? ??? n 97(42) ??????? ??? n 89(40) ?????? ??? n 132(58) ??????? ??? n 136(60)
???? ???? () ???? ???? () 42 27 27 13
95 ???? 95 ???? 2739 1424 19-34 8-18
P ? P ? P lt 0.001 P lt 0.001 P 0.006 P 0.006
Cochran-Mantel-Haenszel test
Gradishar et al. J Clin Oncol. 20052377947803
21
???????????????,?????
???????? (?III???????)
CALGB 93421 (n 474) CALGB 93421 (n 474) CALGB 93421 (n 474) ??III?????2 (n 454) ??III?????2 (n 454) ??III?????2 (n 454)
3??? TAXOL 175 mg/m2 TAXOL 210 mg/m2 TAXOL 250 mg/m2 ABRAXANE 260 mg/m2 TAXOL 175 mg/m2
????() 23 26 21 33 19 P 0.001
TTP 3.9 m (16.8 w) 4.1 m (17.6 w) 4.9 m P 0.045 5.4 m 3.9 m P 0.006
4???????? () 34 44 53 9 22 P lt0.001
3????? () 7 19 32 10 2 P lt0.001
CALGB 9342????????????????????,???????????????????
??????????????
1. Winer et al. J Clin Oncol. 2004 22 2061 2.
Gradishar et al. J Clin Oncol. 2005 23 77947803
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??????(TTP)????????
1.00
ABRAXANE (n 229)
TAXOL (n 225)
0.75
P 0.006 HR 0.75
?? 23.0 weeks (19.426.1)
0.50
???????
0.25
Note P value from log-rank test
?? 16.9 weeks (15.120.9)
0.00
0 8 16 24 32 40 48 56 64
72 80 88 96 104 112 120
?
HR, ???
Gradishar et al. J Clin Oncol. 2005 23 77947803
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???????(OS) ???????
1.00
ABRAXANE (n 131)
TAXOL (n 136)
P 0.024 HR 0.73
0.75
?? 56.4 ? (45.176.9)
????
0.50
HR 0.71 (95 CI 0.540.94)
P?log-rank ??
0.25
?? 46.7 ? (39.055.3)
0.00
0 8 16 24 32 40 48 56 64
72 80 88 96 104 112 120 128 136 144
?
Gradishar et al. J Clin Oncol. 2005 23 77947803
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65??????????

• 65??????65?????????????

ABRAXANE n 229 TAXOL n 225
??????? () 23 59
?????? () 10 31
?? () 20 38
??? () 0 19
?? () 0 16
????????,???????????65???????????????
Gradishar et al. J Clin Oncol. 2005 23 77947803
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?????
ABRAXANE n 229 ABRAXANE n 229 TAXOL n 225 TAXOL n 225 P value
Grade 3 Grade 4 Grade 3 Grade 4
??????? () 25 9 32 22 lt 0.001
????? () lt 1 0 lt 1 0 0.290
?? () lt 1 lt 1 0 lt 1 0.279
?????????? () lt 1 lt 1 lt 1 0 0.491
???????? () 0 0 0 0
???????Cochran-Mantel-Haenszel ??
Gradishar et al. J Clin Oncol. 2005 23 77947803
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??????

ABRAXANE n 229 ABRAXANE n 229 ABRAXANE n 229 TAXOL n 225 TAXOL n 225 TAXOL n 225
???? Grade Grade Grade Grade Grade Grade
???? 3 4 3 4 P value
??() 0 0 1 0 0.150
?? () 0 0 0 0 lt 0.001
?????? () 10 0 2 0 lt 0.001
?? () 8 lt 1 3 lt 1 0.062
?? () 7 0 2 0 0.567
??() 3 lt 1 1 0 0.022
?? () 0 0 lt 1 0 0.851
????????Cochran-Mantel-Haenszel ??
Gradishar et al. J Clin Oncol. 2005 23 77947803
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?3??????????????????
1.00 0.75 0.50 0.25 0.00


ABRAXANE (n 24)


????????
ABRAXANE?????? 22 days (95 CI 1722 ?)
0 10 20 30 40 50 60 70 80 90 100 110 120 130
?3??????????
????
ABRAXANE ????. Schaumburg, IL Abraxis,
Oncology 2005
28
? ?

• ???????????
• ?????????,???????,TTP????
• ?????????,????????????????????
• ???????????49,4??????????????????????
• ??????????3?????????
• ?????????????????,?????????????????

Gradishar et al. J Clin Oncol. 2005 23 77947803
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??????????????????????????????????????????

• ABI CA024 ??
• William Gradishar

30
????

1. 300??????????????????4?
2. A,C?D??? MTD
3. ????????????????????????

• ??
• ?????????????? (A, B, C?? D)
• ????3?????????? (B, C ?? A)
• ????????????????????(B ??C)

Gradishar et al. JCO 2009
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???????????????(ORR,RECIST??)
C ?? DP lt 0.001
B ?? DP 0.002
A ?? DNS
74

63
46
39
Docetaxel100 mg/m2 q3w(D n 74)
300 mg/m2q3w(A n 76)
100 mg/m2qw 3/4(B n 76)
150 mg/m2qw 3/4(C n 74)
A ?? B P 0.024A ?? C P 0.002B ?? C NS
?????????
NS, ??????
Gradishar et al. JCO 2009
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???????????DCR (ORR SDgt16?)
C ?? DP 0.005
B ?? DP 0.009
A ?? DNS
91
83
72
69

Docetaxel100 mg/m2 q3w(D n 74)
300 mg/m2q3w(A n 76)
100 mg/m2qw 3/4(B n 76)
150 mg/m2qw 3/4(C n 74)
A ?? B NSA ?? C P 0.014B ?? C NS
?????????
NS, ??????
Gradishar et al. JCO 2009
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??????PFS
????????? 300 mg/m2 q3w (A) ?????????
??100mg/m2(B) ????????? ??150 mg/m2 (C) ???? 100
mg/m2 q3w (D)
1.00
?? ?? PFS (?) ????????P ?
????????? 300 mg/m2 q3w(A) 10.9 NS
????????? 100 mg/m2 3/4 ? (B) 7.5 NS
????????? 150 mg/m2 3/4 ?(?)(n 74) 14.6 P 0.012 HR 0.568
???? (D) 100 mg/m2 q3w 7.8
0.75
???????
0.50
0.25
0.00
PFS, ?????
0 3 6 9 12 15 18
21 24
A ?? B P 0.076, HR 0.702 B ?? C P 0.001
HR 1.972
?
Gradishar et al. JCO 2009
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??????
????????? ????????? ????????? ????????? ????
300 mg/m2 ??(n 76) 100 mg/m2 ??(n 76) 150 mg/m2 ??(n 74) 100 mg/m2 q3w(n 74)
??????, n () 3? 4? ??????, n () 3? 4? 13 (17)0 6 (8)0 10 (14)0 9 (12)0
??????? ???? NCI CTCAE ?? 3? 4? 29 (39)4 (5) 29 (39)4 (5) 15 (20)4 (5) 26 (35)7 (9) 14 (19)54 (75)
????? SD, x 109/L 1.21 1.00 1.21 1.00 1.51 0.96 1.11 0.63 0.38 0.34
NCI CTC AE??????????????? SD??
Gradishar et al. JCO 2009
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???????????????3?????????
????????

• ????????????????
• ??????????????????????????
• ??????
• ?????????300 mg/m2, 100 mg/m2, 150 mg/m2???22,
  22, 19?
• ??????? 37 ?

1.00
?????????300 mg/m2 q3w (A) ?????????100 mg/m2 ??
(B) ?????????150 mg/m2 weekly (C) docetaxel 100
mg/m2 q3w (D)
0.75
0.50
0.25
0.00
0 10 20 30 40 50 60
70 80 90 100
?
Gradishar et al. JCO 2009
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???? ??

• ???????,?????????????????????
• ?????????????????????????????????????????????
• ????????,????????????? 150 mg/m2
  ?????,??????ORR?PFS
• ????OS???,??????????????

Gradishar et al. JCO 2009
37
2010NCCN??????
38
2010NCCN??????
39
Abstract LBA7511,2010 ASCO
??????????????????????????????????????????????????

• Socinski,MA Bondarenko,I Karaseva,NA
  Makhson,AMVynnychenko,IO Okamoto,I Hon,J
  Hirsh,V Bhar,P Iglesias,J

40
nab-P/C?P/C?????????

• ????????
• 100mg/m2 ,?1?8?15?
• ??AUC 6,?1?
• ????
• N525

???? PS 0-1 ?b/ ?? NSCLC N1,050
11

• ??????
• 200mg/m2 ,?1?
• ??AUC 6,?1?
• ???????????
• N525

• ????
• ??(?b? ??)
• ??(lt70?gt70)
• ??
• ???(????\?????)
• ??

????
41
????

• ????
• ?????????RECIST????????
• ????????(CRPR)
• ????
• ?????????
• ?????CRPR????(SD)16?
• ???(NCI CTCAE V3)

42
??????

• ??????
• ???/???????b/ ??NSCLC????
• ECOG??????0?1
• ??RECIST????,????????
• ???????????????
• ???????????????(????????1??????)
• ??????
• ????????(???????????????)
• ?????????2?

43
??????
??? 45(29???)
??? 4(6???)
??? 24(16???)
?? 12(25???)
?? 14(21???)
????2007?12?14?-2009?8?1? ????
2007?12?14?-2009?7?14? ????18?? ????1052? ?????
1052? ????1038?
???? 1(5???)
44
??????(1)
Nab-P/C (n521) P/C (n531) ???? (n1052)
??,??(??)?? 60(28,81) 60(24,84) 60(24,84)
lt70?,n() 448(86) 449(85) 897(85)
70?,n() 73(14) 82(15) 155(15)
??,n() 129(25) 134(25) 263(25)
ECOG,n()
0 133(26) 113(21) 246(23)
1 385(74) 416(78) 801(76)
???????,n()
?? 254(49) 264(50) 518(49)
????? 228(44) 221(42) 449(43)
???? 9(2) 13(2) 22(2)
?? 29(6) 33(6) 62(6)
??????,n()
?? 99(19) 107(20) 206(20)
?? 421(81) 424(80) 845(80)
??1???????
45
??????(2)
Nab-P/C (n521) P/C (n531) ???? (n1052)
???????,n() 12(2) 8(2) 20(2)
????,n() 513 521 1034
???? 138(27) 144(28) 282(27)
??? 165(32) 146(28) 311(30)
???? 210(41) 231(44) 441(43)
46
????ORR--???????
RR 1.31 (1.082-1.593) P 0.005
Nab-P/C
P/C
33
????
25
???????
47
????ORR--???????
RR 1.31 (1.082-1.593) P 0.005
RR 1.26 (1.060-1.496) P 0.008
Nab-P/C(n521)
P/C(n531)
37
33
30
????
25
???????
?????
48
????ORR--?????
??
Plt0.001
P 0.060
Nab-P/C
P/C
41
37
????
29
24
???????
?????
n228
n221
49
????ORR--?????
??
???
P 0.060
P0.808
P 0.069
Plt0.001
Nab-P/C
P/C
41
37
37
????
30
29
26
25
24
???????
?????
???????
?????
n310
n292
n228
n221
50
?????????
Nab-P/C (N514) P/C (N524)
???????(mg/m2/wk) ??(??, ??) 83(26.7,102.9) 66(32.9,88.9)
???? ??(??,??) 6(1,17) 6(1,22)
????????
51
???
nab-P/C (n 514) nab-P/C (n 514) P/C (n 524) P/C (n 524)
????, 3? 4? 3? 4? 3/4? P?
????
??????? 33 12 33 23 0.009
????? 13 4 6 2 lt 0.001
?? 22 5 6 lt 1 lt 0.001
?????????? lt 1 lt 1 1 lt 1 NS
?????
?? 4 lt 1 6 lt 1 NS
?????? 3 0 10 0 lt 0.001
?? 2 0 lt 1 0 NS
?? 1 0 lt 1 lt 1 NS
?? lt 1 0 2 0 0.011
nab-PC??P/C??
?????nab-P/C???????? P/C??3???????(???1?2?3?)
52
??

• ???????????,?????????????????????????
  (33vs.25,Plt0.001)
• ??????????????????????????????????41?24
  (Plt0.001)
• ??????????????????????,?????????????????????
• ?????????,???????????????????????
• 2010????????????

53
2010NCCN???????????NSCLC???
54

• ? ?!