2009 07 31 2011 03 30 2011 12 13 2012 05 22 2012 08 15 2012 08 30 2012 11 29 2013 07 08 24 [ ] Herceptin Trastuzumab Injection Zhusheyong Qutuozhu Dankang 1 / 44
[ ] DNA ( CHO) 1.1% 20ml L - L-α,α 20 [ ] 440mg 21mg/ml [ ] HER2 1 HER2 5- HER2 HER2 HER2 IHC3+ IHC2+/FISH+ [ ] 440 mg(20 ml)/ 2 / 44
[ ] HER2 4mg/kg 90 2mg/kg 30 3 8mg/kg 6mg/kg 6mg/kg 90 30 8 mg/kg 3 6 mg/kg 90 17 52 8mg/kg 6mg/kg 90 30 3 / 44
1 52 LVE LVEF 4 1 LVEF LVEF 16 LVEF LVEF 10 4 8 LVEF LVEF 15 LVEF 8 3 2 mg/kg6 mg/kg 4 / 44
2 mg/kg :6 mg/kg 4mg/kg 8mg/kg 90 2 mg/kg 6 mg/kg 21mg/ml, ph 6.0 28 4mg/kg 1 2mg/kg = Kg 4mg/Kg 2mg/Kg 21 mg/ml 8mg/kg 3 6mg/kg = Kg 8mg/Kg 6mg/Kg 21 mg/ml 250ml 0.9% 5% 2 8 24 5 / 44
5% / [ ] [ ] [ ] [ ] [ ] > 5 1/10 1/100 <1/10 1/1,000 <1/100 1/10,000 <1/1,000 <1/10,000 6 / 44
/ 1 * / + ( ) +1 1 +1 7 / 44
8 / 44 * + +
* * ADR 2% ADRs SOC + 1 S3 [ ] - 4% + 9% - 12% 6% - 9% + /27% / 7% - 10% + 2.2% 79% (LVEF) BO16348 12.6 12.4 1 12.6 NSABP B31 NCCTG N9831 AC-TH 23 24 NSABP B31 NCCTG N9831 6% AC (AC LVEF < 50% 15 %) NSABP B31 NCCTG N9831 + BO16348 9 / 44
2 1 2 2 NSABP B31 NCCTG N9831 BO16348 LVEF NSABP B31 NCCTG N9831 AC-TH (n=1606) AC-T (n=1488) BO16348 (n=1678) (n=1708) LVEF <50% 22.8%(366) 9.1%(136) 8.6%(144) 2.7%(46) <50% 18.3%(294) 10% 5.4%(81) 7.0%(118) 2.0%(35) <50% 11.7%(188) 16% 2.2%(33) 3.8%(64) 1.2%(20) LVEF 33.4%(536) 18.3%(272) 10% <20% 22.4%(376) 11.9%(204) LVEF 20% 9.2%(148) 2.4%(36) 3.5%(59) 1.2%(21) 1 NSABP B31 NCCTG N9831 LVEF 10% 50% + -------AC T AC T+H T: H 10 / 44
2 BO16348 LVEF 10% 50% ------- 1 0 3/4 CHF 0.3-0.4% 2.0% 3 AC P + + H 3.2% AC P 0.8% 5 5.5 AC D + AC DH + + DCarbH LVEF 1.0% 2.3% 1.1% CHF 3-4 AC D AC DH DCarbH 5 0.6% 1.9% 0.4% AC D DCarbH AC D DCarbH AC DH LVEF 2.3% AC D DCarbH 1% 1 NYHA III-IV 0.6% 3.6 CHF 0.8% 9.8% CHF 11 / 44
LVEF 60 51 6 3.6 3 4 180 mg/m 2 360 mg/m 2 1.7% BO18255 / FP / H FP LVEF 64 48 ~90 65 50 ~86 1 LVEF BO18255 LVEF 3 LVEF BO18255 LVEF : / / (N = 290) (N = 294) ( ) ( ) * LVEF 10% <50% 1.1% 4.6% <50% 1.1% 5.9% * LVEF 10% 11.8% 16.5% 50% * LVEF LVEF F n=187 H FP n=237 4 BO18255 / (N = 290) ) / (N = 294) ( ( ) 6% 6% 3 NCI CTCAE 3.0 *3% **1% * 9 9 ** 4 5 12 / 44
IRR / IRR/ / [ ] IRR IRR 49% 54% 36% 58% IRR 3 5% 7% 5% 6% IRR 18% 54% 6% 50% IRR 3 0.5% 6% 0.3% 5% WHO 3 1% WHO 4 WHO 3 4 34% 21% 3 4 32% 22% NCI-CTC 23% 17% NCI-CTC BO16348 0.4% 3 4 0.6% 30 vs21 [BO16348 ] NCI-CTC 2~5 12.5 vs 6.6 [ NSABP B31] 0.1 vs0[ncctg N9831] H0649g NCI-CTC 3 < 1% 13 / 44
NCI-CTC 4 5 2 vs 0.7 [NCCTG N9831] 2 5 [NSABP B31] NCI-CTC 3/4 32 vs 2 23 vs 17 SOC 1 5 SOC 异 常 中 3 AE / (N = 290) ) / (N = 294) ( ( ) 30% 27% 10% 12% 3% 5% 3% 5% / / / 3 NCI -CTCAE 3.0 SOC 38 40 12% WHO III IV 60% WHO III IV 7 vs 15 WHO III IV 4 18 14 / 44
BO18255 NCI-CTC AE 3.0 3 FP H 3 2 NCI-CTC AE 3.0 3 SOC FP H 1 <1 46 vs 30 [H0648g] NCI-CTC 2-5 22 vs [ NSABP B31] 3-5 14 / 3.3 vs 1.4 [NCCTG N9831] NCI -CTC 2 5 14 vs 5 [NSABP B31]NCI-CTC 3 5 2 3.4 vs 1 [NCCTG N9831] NCI -CTC 2 5 12 vs 4 [ NSABP B31] NCI -CTC 2 52.5 vs 0.1 [NCCTG N9831] / 0.7 0.3 3 1 1 15 / 44
[ ] / 3.0 vs 1.3 [ NSABP B31] 2.1 vs 0 [H0648g] NCI-CTC 2 5 6.2 vs 4.8 [ NSABP B31]NCI-CTC 3 5 1.6 vs 0 [NCCTG N9831] NCI-CTC 1 4 7 vs 1 [BO16348] 27 BO18255 109 37% 80 (28%) NCI-CTCAE 3.0 FP FP+H 4% 9% 3 903 1 ELISA ADA ADA ADA 16 / 44
17 / 44 6
18 / 44 7 [ ]
[ ] CHF [NYHA]II-IV CHF 28-38 27 27 ECG / MUGA CHF 3 6 24 LVEF 10 50% 3 LVEF 6-8 19 / 44
ACE ARB β MBC EBC EBC 3 6 24 5 LVEF CHF NYHA II IV EBC 18 4 > 50 LVEF LVEF < 55% LVEF BMI 20 / 44
EBC 180 mg/m 2 360 mg/m 2 65 MUGA LVEF LVEF 3 LVEF 6 LVEF 4 LVEF [ ] NSABP B31 16% 136/844 LVEF BO16348 2.6% 44/1678 BO16348 32 CHF NSABP B31 NCCTG N98311 21 / 44
LVEF 50% NSABP B31 NCCTG N9831 BO16348 8 * 2% (32/1677) 0.4% (7/1600) 2% (30/1678) 0.3% (5/1708) * 1 9 * I-IV III-IV H0648g 28% 7% 19% 3% (AC) H0648g 11% 1% 4% 1% H0649g ** 7% N/A 5% N/A * LVEF ** 1 IRR IRR ] IRR β - 22 / 44
/ 440 mg 3 1 ] IRR 23 / 44
NCI CTC 3 4 ] HER2 HER2 HER2 HER2 HER2 HercepTest TM CONFIRM TM anti-her-2/neu (4B5) Primary Antibody HER-2/NEU IHCHER2 FISH pharmdx TM INFORM HER2 DNA Probe HER2 DNA Rabbit anti-dnp Antibody DNPINFORM Chromosome 17 Probe 17 DDISH HER2 Probe DDISH HER2 (FISH ) IHC FISH FISH HER2 H0648g IHC FISH 13 NCCTG BO16348 N9831 IHC FISH 10 HER2 HER2 HER2 BO18255 HER2 BO18255 24 / 44
16 HER2 HER2 HER2 HER2 HER2 IHC HER2 CISH HER2 3+ IHC FISH CISH IHC 0 < 10% 1+ > 10% / HER2 2+ > 10% 3+ > 10% HER2 17 2 17 HER2 4 FISH 50 HER2 % 5 CISH FISH CISH HER2 HER2 2+ 3+ HER2 HER2 HER2 HER2 HER2 IHC 25 / 44
HER2 SISH FISH SISH HER2 HER2 BO18255 IHC3+ FISH HER2 HER2 IHC 3+ IHC 2+ FISH D008548SISH FISH HER2 >95% IHC ISHHER2 IHC - - HER2 0 <10% 1+ 10% / / 2+ 10 % 3+ 10% HER2 17 2 SISH FISH [ ] 26 / 44
6 1 25 HER2 HER2 20 50 120 150 IgG 12.5 2 mg/kg 3 27 / 44
[ ] 18 [ ] [H0648g H0649g] [NSABP B31 NCCTG N9831] 386 65 253 133 4 65 [ ] 1.5 BO15935 M77004 HER2- + JP16003 HER2- DDI JP19959 BO18255 28 / 44
PK + + [ ] >10 mg/kg [ ] 2 3752 [ NSABP B31 NCCTG N9831] HER2 3386 BO16348 NSABP B31 NCCTG N9831 HER2 IHC 3FISH HER2 NCCTG NSABP N9831 B31 >100mmHg >200mmHg 1 1 AC + 2 4 21 60 mg/m 2 600 mg/m 2 NSABP B31 80 mg/m 2 3 175 mg/m 2 12 NCCTG N9831 4mg/kg 2mg/kg 52 / ] ER / PR 29 / 44
DFS 3752 NSABP B31 NCCTG N9831 49 22 80 6 >65 84 7 4 4 / 90 38 T1 91 27 66 53 ER / PR 53 BO16348 HER2 IHC 3+ FISH LVEF <55% ECG ( > 180 mm Hg > 100 mm Hg) 4 1:1 (n 1 (n = 1693) = 1693) ER / PgR 8 mg/kg 3 6 mg/kg 52 NSABP B31 NCCTG N9831 3386 49 21 80 83% 13% 94% 50% ER / PgR 57% 32% 11% 96% (1055/1098 ) 1098 49% 543 ER PgR 47% (512) ER / PgR 2 cm 2 3 < 35 94% NSABP B31 NCCTG N9831 DFS 3 NSABP B31 NCCTG N9831 BO16348 DFS 10NSABP B31 NCCTG N9831 30 / 44
/ / BO16348 / / 65 10 NSABP B31 NCCTG N9831 BO16348 NSABP B31 NCCTG N9831 BO16348 AC AC + (n = 1872) (n = 1880) (n = 1693) (n = 1693) DFS 133 261 127 219 (95% CI) 0.048 a 0.54 0.39, 0.59 (0.44, 0.67) p <0.0001 b <0.0001 c 62 92 31 40 95% CI 0.67 0.75 a COX p NS d NS d CI b c d NS 3 ITT NSABP B31 NCCTG N9831 31 / 44
NCCTG N9831 BO16348 HER2 DFS 11 NCCTG N9831 IHC 3+/FISH+ 81% BO16348 IHC 3+/FISH FISH +/IHC DFS 11 NCCTG N9831 BO16348 HER2 / NCCTG N9831 BO16348 DFS / DFS HER2 * (95% CI) (95% CI) IHC 3+ FISH (+) 1170 FISH ( ) 51 FISH 51 IHC < 3+ / FISH (+) 174 0.42 (0.27, 0.64) 0.71 (0.04, 11.79) 0.69 (0.09, 5.14) 1.01 (0.18, 5.65) 91 0.56 (0.13, 2.50) 8 ---- 2258 299 ^ IHC / FISH (+) ---- ---- 724 *HercepTest IHC Path Vysion FISH ^ BO16348 IHC2+ 0.53 (0.41, 0.69) 0.53 (0.20, 1.42) 0.59 (0.38, 0.93) BO16348 122 54 1 68 122 46 26 67 92% 50% 40% 10% 41% 91% 26% BO16348 DFS 1 2 81.4% 92.9% 1 (HR 0.29, 95% CI 0.08-1.08, p=0.0489) BO16348 12 32 / 44
12 BO16348 BO16348 (n = 68) (n = 54) DFS 3 8 (95% CI) 0.29 (0.08, 1.08) p 0.0489 a OS 1 3 95% CI 0.30 p a b NS= NS b (H0648g n=469) H0649g n=222 2 HER2 2 3 HER2 0 3 H0648g H0648g 469 IHC CTA 0 1+ 2+ 3+, 3+ 2+ 3+ 33 4 mg/kg 2 mg/kg 175mg/m 2 3 21 1 6 AC 60 mg/m 2 75mg/m 2 600 mg/m 2 21 1 6 65 33 / 44
ORR 13 AC b,c 13 H0648g AC AC + (n=235) (n = 234) + (n = 92) (n=96) + AC a (n=143) (n=138) TTP 7.2 4.5 6.7 2.5 7.6 5.7 95% 6.9, 8.2 4.3, 4.9 5.2, 9.9 2.0, 4.3 7.2, 9.1 4.6, 7.1 p d < 0.0001 < 0.0001 0.002 b 45 29 38 15 50 38 95% 39, 51 23, 35 28, 48 8, 22 42, 58 30, 46 p e <0.001 <0.001 0.10 8.3 5.8 8.3 4.3 8.4 6.4 b,c ( ) 25%, 75% 5.5, 14.8 3.9, 8.5 5.1,11.0 3.7, 7.4 5.8, 14.8 4.5, 8.5 c ( ) 25.1 20.3 22.1 18.4 26.8 21.4 95% 22.2, 29.5 16.8, 24.2 16.9, 28.6 12.7, 24.4 23.3, 32.9 18.3, 26.6 p d 0.05 0.17 0.16 a AC= ( ) b c Kaplan-Meier d e χ 2 H0648g HER2 14 34 / 44
14 H0648g HER2 HER2 ** ** (N) (95% CI) (95% CI) CTA 2+ or 3+ 469 0.49 (0.40, 0.61) 0.80 (0.64, 1.00) FISH (+)* 325 0.44 (0.34, 0.57) 0.70 (0.53,0.91) FISH (-)* 126 0.62 (0.42, 0.94) 1.06 (0.70,1.63) CTA 2+ 120 0.76 (0.50, 1.15) 1.26 (0.82,1.94) FISH (+) 32 0.54 (0.21, 1.35) 1.31 (0.53, 3.27) FISH (-) 83 0.77 (0.48,1.25) 1.11 (0.68, 1.82) CTA 3+ 349 0.42 (0.33, 0.54) 0.70 (0.51,0.90) FISH (+) 293 0.42 (0.32, 0.55) 0.67 (0.51,0.89) FISH (-) 43 0.43 (0.20, 0.94) 0.88 (0.39, 1.98) * 469 451 FISH ** H0649g H0649g HER2 1 2 222 66 68 2 25 4mg/kg 2 mg/kg ORR 14 2 12 CTA 3+ 18 CTA 2+ 6 (1:1) III BO18255 5-FU HER2 594 314 53% 351 35 / 44
184 62.2% 167 56.0% vs. vs. ECOG 0 1 vs. 2 vs. 5- HER2 FISH+ HER2 IHC 3+ LVEF > 50% 8 mg/kg 6 mg/kg3 1 80 mg/m 2 IV 2 3 6 1000 mg/m 2 2000 mg/m 2 14 21 6 1 5 CIV 5-800 mg/m 2 / 3 6 60 21 83 76% 53% 38% 5% 5% / 91% ECOG PS 0 1 82% 18% 23% 7% /2% log-rank OS 351 OS 0.0193 OS 15 4 15 BO18255 ITT FC N=296 FC + H N=298 ( ) (%) 95% CI ( ) 95% CI p *, 184 (62.2%) 167 (56.0%) 11.0 13.5 (9.4, 12.5) (11.7, 15.7) 0.73 (0.60, 0.91) 0.0038 (%) 227 (76.7%) 11.7 221 (74.2%) 13.1 36 / 44
95% CI () (10.3, 13.0) (11.9, 15.1) 95% CI * 0.0193 0.80 (0.67, 0.97) 4 ToGA HER2 FISH IHC OS HER2 (IHC FISH+ 2+ IHC 3+) 16 11.8 HR 0.65 (95 % CI 0.51-0.83) 7.6 5.5 HR 0.64 (95 % CI 0.51-0.79) 16 37 / 44
16 HER2 FC (N= 296) a FC+H (N=298) b FISH+ / IHC 0, 1+ (N=133) /n (%) OS ( ) 95% CI ( ) 57/71 (80%) 8.8 (6.4, 11.7) 56/62 (90%) 8.3 (6.2, 10.7) (95% CI) 1.33 (0.92, 1.92) FISH+ / IHC2+ (N=160) /n (%) OS ( ) 95% CI ( ) 65/80 (81%) 10.8 (6.8, 12.8) 64/80 (80%) 12.3 (9.5, 15.7) (95% CI) 0.78 (0.55, 1.10) FISH+ or FISH-/IHC3+ c (N=294) /n (%) OS ( ) 95% CI ( ) 104/143 (73%) 13.2 (11.5 15.2) 96/151 (64%) 18.0 (15.5, 21.2) (95% CI) 0.66 (0.50, 0.87) a FC FISH+ IHC b 5 FISH+ IHC c 6 10 FISH - IHC3+ 8 8 FISH IHC 3+ 2009 1 7 15 614 HER2 HER2 22.7HER2 85 36 49 95 80 80 ECOG 0 1 1 38 / 44
HER2 12.6 vs 9.7 ) FP H 28% HR 0.72; 95% CI [0.40 1.29]) BO18255 13.8 vs 11.1 HR 0.74; 95% CI [0.60 0.91] 17 17 FAS / N=48 / / N=36 28 (58.3%) 19 (52.8%) * 20 (41.7%) 17 (47.2%) # 9.7 12.6 95% CI# [6 ; 18] [10 ; 18] 0.72 95% CI [0.40 ; 1.29] 5- FU * # Kaplan-Meier ## = = FAS Kaplan-Meier 5 4 5 Kaplan-Meier FAS 39 / 44
PFS TTP 18 18 FAS / N = 48 / / N = 36 5.5 6.8 HR 95% CI 0.69[0.41 ; 1.15] 5.7 7.2 HR 95% CI 0.67[0.39 ; 1.15] 2 (4.2%) 2 (5.6%) 14 (29.2%) 11 (30.6%) 13 (27.1%) 13 (36.1%) 9 (18.8%) 5 (13.9%) 10 (20.8%) 5 (13.9%) CR + PR 16 (33.3%) 13 (36.1%) CR + PR + SD 29 (60.4 ) 26 (72.2 ) 16 (100.0%) 13 (100.0%) 4.5 5.8 HR 95% CI 0.56[0.23 ; 1.35] 40 / 44
HER2 HER2 FP 34 FP+H 28 HER2 IHC 2+/FISH+ IHC 3+ HER2 FP H FP 16 9.7 HR 0.55 95 CI [0.26; 1.18] HER2 BO18255 [ ] -2(HER2)IgG 1 HER2 HER2 C-erbB2 185kDa 25%~30% HER2 HER2 HER2 HER2 HER2 ADCC HER2 HER2 Ames 5000μg/mL 118mg/kg 2mg/kg 25 [ ] 41 / 44
10 50 100 250 500mg 1 28 38 25 175 5 25 175 5 I II III 3 AUC 1677mg d/l 1793 mg d/l 104 mg/l 189 mg/l 64.9 47.3 mg/l 8 mg/kg 6 mg/kg 3 NCA 13 37 63 mg/l CL 68 kg 0.241 d/l Vc Vp 3.02 2.68 HER2 HER2 64 % 286/447 1880 ng/ml =11 ng/ml 42 / 44
6 III BO18255 8 mg/kg 6 3 26 AUC3 1213mg d/l C max 128 mg/l C min 27.6mg/L HER2 [ ] 2 8 2 8 28 28 0.9% 2 8 24 30 24 2 8 [ ] 1 / 1.1% 20ml 43 / 44
[ ] 2 8 36 [ ] JS20090127 [ ] S20110007 S20110008 J20110020 [ ] Roche Pharma (Schweiz) Ltd. Schoenmattstrasse 2, 4153 Reinach, Switzerland Genentech, Inc. South San Francisco, CA 94080, U.S.A. F. La Roche Hoffmann- Ltd. Grenzacherstrasse 124, CH 4070 Basel, Switzerland 1100 201203 021 28922888 021 50801800 800-820-8780 400-820-8780 9 00 17 00 http://www.roche.com.cn 44 / 44