2009 07 31 2011 03 30 2011 12 13 2012 05 22 2012 08 15 2012 08 30 2012 11 29 2013 07 08 2015 01 26 24 Herceptin 1 / 46
Trastuzumab Injection Zhusheyong Qutuozhu Dankang DNA ( CHO) 1.1% 20ml L-L-α,α- 20 440mg 21mg/ml HER2 1 HER2 5- HER2 HER2 HER2 IHC3+ IHC2+/FISH+ 2 / 46
440 mg(20 ml)/ 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 3 / 46
90 30 1 EBC 1 LVEF LVEF 44 1 LVEF LVEF 16 LVEF LVEF 10 4 8 LVEF LVEF 15 LVEF 8 3 4 / 46
2 mg/kg6 mg/kg 2 mg/kg :6 mg/kg 4mg/kg8mg/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% 5 / 46
2 8 24 5% / >10% 5 6 / 46
1/10 1/100 <1/10 1/1,000 <1/100 1/10,000 <1/1,000<1/10,000 / 1 * / 7 / 46
* +1 + ( ) 1 +1 + + 8 / 46
* * ADR 2% ADRs SOC + 1 NYHA II IV S3 1% 9 / 46
4% + 9% - 12% 6% 9%+/27% /7% 10%0% + 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 2 1 2 2 NSABP B31 NCCTG N9831 BO16348 LVEF NSABP B31 NCCTG BO16348 N9831 AC-TH AC-T (n=1606) (n=1488) (n=1678) (n=1708) LVEF <50% 22.8%(366) 9.1%(136) 8.6%(144) 2.7%(46) <50% 10% 18.3%(294) 5.4%(81) 7.0%(118) 2.0%(35) <50% 16% 11.7%(188) 2.2%(33) 3.8%(64) 1.2%(20) LVEF 10% <20% 33.4%(536) 18.3%(272) 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% 10 / 46
50% + -------AC T AC T+H T: H 2 BO16348 LVEF 10% 50% ------- 1 0 3/4 CHF 0.3-0.4% 2.0% 3 AC P + + H 11 / 46
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% 12 1 NYHA III-IV 0.6% 3.6 CHF 0.8% 9.8% 8 CHF NYHA III-IV 0.89% 6.35% 70.0% CHF LVEF 50%83.1% 10% 3 4 180 mg/m 2 360 mg/m 2 1.7% BO22227 20.6 0.7% BO18255 / FP / H FP LVEF 64 48 ~90 65 50 ~86 1 LVEF 12 / 46
BO18255 LVEF 3 LVEF BO18255 LVEF : * LVEF 10% <50% / (N = 290) ( ) // (N = 294) ( ) 1.1% 4.6% <50% 1.1% 5.9% * LVEF 10% 50% 11.8% 16.5% * LVEF LVEF FP 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 IRR / IRR/ / IRR IRR IRR 49% 54% 36% 58% IRR 3 5% 7% 5% 6% 13 / 46
IRR 18% 54% 6% 50% IRR 3 0.5% 6% 0.3% 5% BO22227 IRR 37.2% 3 2.0% 4 5 IRR 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% NCI-CTC 4 5 2 vs 0.7 [NCCTG N9831] 2 5 7.1 vs4.5 [NSABP B31] NCI-CTC 3/4 32 vs 22 23 vs 17 14 / 46
SOC 3 1 5 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 BO18255 NCI-CTC AE 3.0 3 FP H FP 3 2 NCI-CTC AE 3.0 3 SOC 15 / 46
FP H FP 1<1 46 vs 30 [H0648g]NCI-CTC 2-5 22 vs 14 [NSABP B31] 3-5 / 3.3 vs 1.4 [NCCTG N9831] 23 vs 17 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 5 2.5 vs 0.1 [NCCTG N9831] / 0.7 0.3 3 1 1 / 16 / 46
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 BO16348 8% BO18255 109 37% 80 (28%) NCI-CTCAE 3.0 FP FP+H 4% 9% 3 7.0% ADA [pcr ] ADA 17 / 46
6 7 18 / 46
(LVEF) CHF [NYHA]II-IV 19 / 46
CHF 28-38 27 27 ECG / MUGA CHF 3 6 24 LVEF 10 50% 3 LVEF LVEF CHF 6-8 HF ACE ARB β MBC EBC EBC 3 6 24 20 / 46
5 LVEF MI CHF NYHA II IV EBC 18 4 > 50 LVEF LVEF < 55% LVEF BMI>25kg/m 2 EBC 180 mg/m 2 360 mg/m 2 65 MUGA LVEF LVEF 3 LVEF 21 / 46
6 LVEF 4 LVEF NSABP B31 16% 136/844 LVEF BO16348 2.6% 44/1678 BO16348 32 CHFNSABP B31 NCCTG N98311 LVEF 50% 8 NSABP B31 NCCTG N9831 * 2% (32/1677) 0.4% (7/1600) BO16348 2% (30/1678) 0.3% (5/1708) *1 9 * I-IV III-IV 22 / 46
H0648g (AC) H0648g 28% 7% 19% 3% 11% 1% 4% 1% H0649g ** 7% N/A 5% N/A * LVEF ** 1 IRR IRR IRR IRR IRR IRR β- / / 23 / 46
440 mg 3 1 IRR NCI CTC 3 4 HER2 HER2 HER2 HER2 HER2 24 / 46
HercepTest TM CONFIRM anti-her-2/neu (4B5) Primary Antibody HER-2/NEU IHC HER2 FISH pharmdx TM INFORM HER2 DNA Probe HER2 DNA Rabbit anti-dnp Antibody DNP INFORM Chromosome 17 Probe 17 DDISH HER2 Probe DDISH HER2 (FISH ) IHC FISH FISH HER2 H0648g IHC FISH 13 NCCTG N9831 BO16348 IHC FISH 10 HER2 HER2 HER2 BO18255 HER2 BO18255 IHC 16 HER2 HER2 HER2 HER2 HER2 IHC HER2 FISH CISH HER2 3+ IHCFISH CISH IHC HER2 0 < 10% 1+ > 10% / 25 / 46
2+ > 10% 3+ > 10% HER2 17 217HER2 4 FISH 50 %HER2 5 CISH FISH CISH HER2 HER2 HER2 2+3+ HER2 HER2 HER2 HER2 HER2 IHC HER2 SISHFISH SISH HER2 HER2 BO18255 IHC3+ FISH HER2 HER2 IHC 3+IHC 2+FISH D008548SISH FISH HER2 >95% IHC ISHHER2 IHC - - HER2 26 / 46
0 <10% 1+ 10% / 2+ 10 % 3+ 10% / HER2 17 2SISH FISH 7 1 27 / 46
2mg/kg 25 HER2 HER2 20 50 120 150 IgG 12.5 2 mg/kg 3 18 [H0648g H0649g] [NSABP B31 NCCTG N9831] 386 65 253 133 4 28 / 46
65 [ ] 1.5 HER2 BO15935 M77004 8 mg/kg 4 mg/kg IV 6 mg/kg q3w 2 mg/kg q1w IV 6- POH DOL 7--13- D7D D7D JP16003 HER2- MBC 4mg/kg IV 2mg/kg IV 60mg/m 2 JP19959 BO18255 PK 5-FU + + 29 / 46
4 mg/kg /2 mg/kg q1w IV HER2- MBC JP16003 HER2- MBC II BO15935 M77004 III H0648g II W016229 MO16982 >10 mg/kg 2 3752 [NSABP B31 NCCTG N9831] HER2 3386 BO16348 NSABP B31 NCCTG N9831 HER2 IHC 3FISH HER2 NCCTG N9831NSABP B31 >100mmHg >200mmHg 1 1 AC 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 30 / 46
4mg/kg 2mg/kg 52 / ER / PR DFS 3752 NSABP B31 NCCTG N9831 49 22 80 6 >65 847 4 4 / 90 38 T1 91 27 66 53 ER / PR 53 BO16348 HER2 IHC 3+ FISH T1c LVEF <55% ECG ( > 180 mm Hg > 100 mm Hg) 4 1:1 (n = 1693) 1 (n = 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 31 / 46
94% NSABP B31 NCCTG N9831 DFS 3 NSABP B31 NCCTG N9831 BO16348 DFS 10 NSABP B31 NCCTG N9831 / / BO16348 / / 65 10 NSABP B31 NCCTG N9831 BO16348 NSABP B31 NCCTG N9831 AC + (n = 1872) AC (n = 1880) (n = 1693) BO16348 (n = 1693) 133 261 127 219 DFS 0.048 a 0.54 (95% CI) 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 p NS d NS d CI a COX b c d NS 3 ITT 32 / 46
NSABP B31 NCCTG N9831 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 HER2 * DFS (95% CI) / DFS (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 0.53 (0.41, 0.69) 0.53 (0.20, 1.42) 0.59 (0.38, 0.93) 33 / 46
^ BO16348 IHC2+ 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 34 / 46
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 35 / 46
ORR 13 AC 13 H0648g AC + (n=235) (n = 234) + (n = 92) (n=96) + AC a (n=143) AC (n=138) TTP b,c 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 ( ) b,c 8.3 5.8 8.3 4.3 8.4 6.4 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 3 14 36 / 46
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 6668 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 37 / 46
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/kg 3 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 (%) 95% CI ( ) 227 (76.7%) 11.7 221 (74.2%) 13.1 38 / 46
95% CI (10.3, 13.0) (11.9, 15.1) 0.80 (0.67, 0.97) * 0.0193 4 ToGA HER2 FISHIHC OS HER2 (IHC 2+ FISH+ 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 39 / 46
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 22.7 HER2 85 36 49 ECOG 95 80 80 ECOG 0 1 1 40 / 46
HER2 12.6 vs 9.7 ) FP H FP 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 41 / 46
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] 42 / 46
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 p185 HER2 HER2 HER2 C-erbB2 185kDa 25%~30% HER2 HER2 HER2 HER2 HER2 ADCC ADCC HER2 HER2 Ames 5000μg/mL 118mg/kg 2mg/kg 25 43 / 46
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 mg/l 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 44 / 46
6 III BO18255 8 mg/kg 6 mg/kg 3 26 AUC 3 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 45 / 46
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. Hoffmann-La Roche Ltd. Grenzacherstrasse 124, CH 4070 Basel, Switzerland 1100 201203 021 28922888 021 50801800 800-820-8780 400-820-8780 9 0017 00 http://www.roche.com.cn 46 / 46