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 2015 11 04 2016 04 12 2017 05 11 2018 07 04 2018 07 31 24 1 / 45
Herceptin 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 / 45
440 mg(20 ml)/ HER2 4mg/kg 90 2mg/kg 30 3 8mg/kg 6mg/kg 6mg/kg 90 30 8mg/kg 6mg/kg 90 30 1 EBC 1 3 / 45
L LVEF 4 4 1 LVEF LVEF 16% LVEF LVEF 4 8 LVEF LVEF LVEF >8 3 2 mg/kg 6 7 21 4mg/kg 90 7 21 6 mg/kg 21mg/ml, ph 6.0 28 4 / 45
20mL 5 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% / / 5 / 45
5% 1 1/100 <1/10 1/1,000 <1/100 1/10,000 <1/1,000 <1/10,000 1 * / 6 / 45
+1 + ( ) 1 +1 + 7 / 45
8 / 45 * ADR 2% ADRs SOC + 1
NYHA II IV S3 1% 4% + 9% - 12% 6% 9%+ / 27% 7% 10% 0% + 2.2% ( BO16348 12.6 12.4 1 12.6 NSABP B31 NCCTG N9831 AC-T 7.9 AC-TH 8.3 NSABP B31 NCCTG N9831 AC 6% AC (AC LVEF < LLN 16 %) NSABP B31 NCCTG N9831 BO16348 21 2AC -TH 2.0 AC - TH 64.5%90.3% 2 a NSABP B31 NCCTG N9831 BO16348 BCIRG006 LVEF LVEF <50% LVEF LVEF <50% 10% 16% <20% 10% 20% NSABP B31 NCCTG N9831 b c AC TH 23.1% 18.5% 11.2% 37.9% 8.9% n=1856 428 344 208 703 166 AC T 11.7% 7.0% 3.0% 22.1% 3.4% 9 / 45
a n=1170 137 82 35 259 40 BO16348 d 8.6% 7.0% 3.8% 22.4% 3.5% n=1678 144 118 64 376 59 2.7% 2.0% 1.2% 11.9% 1.2% n=1708 46 35 20 204 21 BCIRG006 e TCH 8.5% 5.9% 3.3% 34.5% 6.3% n=1056 90 62 35 364 67 AC TH 17% 13.3% 9.8% 44.3% 13.2% n=1068 182 142 105 473 141 AC T 9.5% 6.6% 3.3% 34% 5.5% n=1050 100 69 35 357 58 NSABP B31 NCCTG N9831 BO16348 BCIRG006 b NSABP B31 NCCTG N9831 AC TH c NSABP B31 NCCTG N9831 AC TH 8.3 d 12.6 e BCIRG006 AC T AC THTCH 10 / 45
1 NSABP B31 NCCTG N9831 LVEF 10% 50% + ---AC T AC T+H T: H 0 + 2 BO16348 LVEF 10% 50% --- 1 0 11 / 45
3 BCIRG006 LVEF 10% 50% 0 3/4 CHF 0.3-0.4% 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 NCI -CTC 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% BO16348 8 CHF NYHA III -IV 0.8% 4.6% 12 / 45
71.4% CHF LVEF 50%79.5% 17% NSABP B-31 NCCTG N9831 AC PH + + 8.1 AC PH 2.0 LVEF 18.5% AC PH LVEF 10%~ 50%AC PH 64.5% 90.3% LVEF MO16432 3 180 mg/m 2 ) 1.7% BO22227 4 300mg/m 2 70 / 0.3% BO18255 / FP / H FP LVEF 64% 48%~90% 65% 50%~86% 1 LVEF 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 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 13 / 45
IRR / 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% BO22227 IRR 37.2% IRR 3 2.0% 4 5 IRR WHO 3 1% WHO 4 WHO 3 4 34% 21% 3 4 32% 22% NCI-CTC 17% NCI-CTC BO16348 0.4% 3 4 0.6% 14 / 45
30%vs21%[BO16348 ] NCI-CTC 2~5 12.3%vs 6.7%[NSABP B31] N9831]H0649g NCI-CTC 3 < 1% BO18255 28% 21% NCI CTC 3/4 12.2% 10.3%,NCI -CTC 4 51.7%vs 0.8% 2 56.4%vs4.3%[NSABP B31] NCI-CTC 3/4 32%vs 22% 17% BO18255 NCI CTC 3/4 36.8% 28.9% 5.1% 2.8% 12% WHO3 4 60% WHO3 4 7% vs 15% WHO3 4 4 18 BO18255 NCI-CTC AE 3.0 3 FP H FP 3% 2% NCI-CTC AE 3.0 3 SOC FP H 1% <1% 15 / 45
30%[H0648g]NCI -CTC 2-5 / 24.3%vs 13.4%[NSABP B31] 3-5 / 2.9%vs 1.4%[NCCTG N9831] BCIRG006 AC-T TCH [44% AC -TH37% TCH38% AC -T ] NCI-CTC 3-4 [25% AC-TH21% TCH23% AC-T ] NCI-CTC 2 514%vs NCI 5%[NSABP -CTC 3 B31] 5 2 3.4%vs 1%[NCCTG N9831] -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 / 2.6%vs 2.5% 3.7% 2.2 1.5%[NSABP B3 [BCIRG006] 2.1%vs 0%[H0648g] 16 / 45
,NCI -CTC 2 5 6.7% vs 5.4%[NSABP NCI -CTC B31] 3 5 2.2% vs 0%[NCCTG NCI N9831] -CTC 1 4 7% 1%[BO16348] BCIRG006 3-4 [5.7% AC -TH 5.5% TCH vs. 3.0% AC-T] 1-4 [51% -TH 63% AC TCH vs. 43% AC-T] 25% BO18255 109 37% 80 (28%) NCI-CTCAE 3.0 FP +H 4% 9% 3 EBC BO22227 70 10.1% 30/296 30 2 [pcr ] EFS [ ARRs ] 5 17 / 45
18 / 45 6
CHF [NYHA]II- IV CHF 7 7 ECG MUGA CHF 3 6 24 19 / 45
LVEF 10 50% 3 LVEF CHF 6-8 HF ACE ARB β MBC EBC EBC 3 6 24 5 LVEF CHF NYHA II IV EBC 18 4 > 50 LVEF LVEF < 55% LVEF 20 / 45
BMI>25kg/m 2 EBC 180 mg/m 2 360 mg/m 2 65 MUGA LVEF LVEF 3 LVEF 6 LVEF 4 LVEF NSABP B31 AC-TH 15% 158/1031 8.7 LVEF BO16348 12.6 2.6% 44/1678 BCIRG006 TCH 2.9% 31/1056 1.5% 1.4% AC-TH 5.7% 61/1068 1.5% 4.2% 64 NSABP NCCTG B31 N98311 33 24% 7 21 / 45
7 NSABP B31& NCCTG AC b + 3.2% 64/2000 1.3% 21/1655 N9831 a BO16348 d 2% 30/1678 0.3% 5/1708 BCIRG006 AC b + 2% 20/1068 0.3% 3/1050 BCIRG006 + + 0.4% 4/1056 0.3% 3/1050 a NSABP B31 2 AC TH 8.3 b c 1 1 d 12.6 NYHA III & IV BO16348 8 NYHA III IV 0.8% 4.6% 8 a NYHA I-IV NYHA III-IV H0648g AC b 28% 7% 19% 3% H0648g 11% 1% 4% 1% c H0649g 7% N/A 5% N/A a LVEF b c 1 BCIRG006 NCI-CTC 3/4 / AC -TH 0.3% (3/1068) TCH 0.2% (2/1056) AC-T(0 ) IRR IRR IRR IRR IRR IRR 22 / 45
β- / 440 mg 3 1 IRR NCI CTC 3 4 23 / 45
HER2 HER2 HER2 HER2 HER2 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 -DNP anti Antibody DNP INFORM Chromosome 17 Probe 17 DDISH HER2 Probe DDISH HER2 (FISH ) IHC FISH FISH HER2 H0648g IHC FISH 12 NCCTG BO16348 N9831 IHC FISH 9 HER2 HER2 HER2 BO18255 HER2 BO18255 IHC 15 HER2 HER2 HER2 HER2 HER2 HER2 CISH HER2 3+ IHC FISH CISH 24 / 45
IHC 0 < 10% HER2 1+ > 10% / 2+ > 10% 3+ > 10% HER2 17 2 17 HER2 4 FISH 50 % HER2 5 CISH FISH CISH HER2 HER2 HER2 2+ 3+ HER2 HER2 HER2 HER2 HER2 IHC HER2 SISH FISH SISH HER2 HER2 BO18255 IHC3+ FISH HER2 HER2 IHC 3+ IHC 2+ FISH D008548 SISH FISH HER2 >95% IHC ISH HER2 IHC 25 / 45
- - HER2 0 <10% 1+ 10% / / 2+ 10 % 3+ 10% HER2 17 2 SISH FISH 7 7 1 26 / 45
25 HER2 20 50 120 150 IgG 12.5 2 mg/kg 3 18 [H0648g H0649g] [NSABP B31 NCCTG N9831] 386 65 253 133 4 65 27 / 45
1.5 6-α POH DOL 7-- 13- D7D D7D PK 5-FU + NSABP B31 NCCTG N9831 4063 BO16348 3386 BCIRG006 3222 HER2 NSABP B31 NCCTG N9831 HER2 28 / 45
IHC 3 FISH HER2 NCCTG N9831 >100mmHg >200mmHg 1 1 AC + 2 4 21 60 mg/m 2 600 mg/m 2 NSABP B31 80 2 3 175 mg/m mg/m 2 12 NCCTG N9831 4mg/kg 2mg/kg 52 / ER / PR 3752 2.0 AC + DFS OS 4063 8.3 AC + 707 NSABP B31 NCCTG N9831 DFS 49 22-80 6% > 84% 65 7%4% 4% / 90% 38% T1 91% 27%66% 53% ER+ / PR+ 8.3 AC + BO16348 HER2 IHC 3+ FISH LVEF <55% ECG ( > 180 mm Hg > 100 mm Hg) BO16348 HER2 1:1:1 ER+ / PgR+ 8 mg/kg 6 mg/kg 29 / 45
DFS NSABP B31 NCCTG N9831 12.6 DFS n =1693 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% DFS 8 [ ITT = 0.99 95% 0.87 1.13p CI = 0.90 OS =0.98 0.83 1.15p = 0.78] BCIRG006 BCIRG006 HER2 FISH+ ER/PR >2 < cm35 / 2 3 4 > 100 mmhg T4 N2 N3 M1 1:1:1 -T AC-TH TCHAC -T AC-TH 3 60 mg/m 2 600 mg/m 2 3 100 mg/m 2 TCH 3 75 mg/m 2 AUC 6 mg/ml/min 30-60 4 mg/kg 2 mg/kg T TC 3 6 mg/kg 52 / PR+ 30 / 45
DFS 3222 49 22-74 6% 65 54% ER+ / PR+ 71% DFS NSABP B31 NCCTG N9831 BO16348 BCIRG006 OS NSABP B31 NCCTG N9831 BO16348 9 NSABP B31 NCCTG N9831 2.0 AC TH 4 8.3 AC TH 5 BCIRG006 6 DFS / >65 NSABP B31 NCCTG N9831 OS 0.64 95% CI:0.55 0.74 8.3 [AC TH] AC TH 86.9% AC T 79.4% NSABP B31 NCCTG N9831 OS / OS 50 n=2197 OS 0.65 95% CI:0.52 0.81 >50 n=1866 OS 0.63 95% CI:0.51 0.78 ER / PR n=2223 0.63 95% CI:0.51 0.78ER / PR n=1830 0.64 95% CI:0.52 0.80. 2 cm n=1604 0.52 95% CI:0.39 0.71 >2 cm n=2448 0.67 95% CI:0.56 0.80 31 / 45
9 NSABP B31 NCCTG N9831 BO16348 BCIRG006 DFS DFS OS OS p 95% CI p NSABP B31 NCCTG N9831 a AC TH 133 b 0.48 b,d 289c 0 64 c,d n =1872 b 0.39, 0.59 0.55, 0.74 n = 2031 c p< 0.0001 e p< 0.0001 e AC T 261 b 418 c n = 1880 b n = 2032 c BO16348 f 127 0.54 31 0.75 0.44, 0.67 p=ns h n =1693 p< 0.0001 g 219 40 n = 1693 BCIRG006 i TCH 134 0.67 56 n=1075 0.54-0.84 p=0.0006 e, j AC TH 121 0.60 49 n=1074 0.48-0.76 p< 0.0001 e,i AC T 180 80 n=1073 CI = a NSABP B31 NCCTG N9831 AC TH b AC TH 2.0 DFS c 707 AC TH 8.3 OS d Cox e f 12.6 DFS g h NS= i BCIRG006 AC AC THTCH j α 0.025 32 / 45
4 NSABP B31 NCCTG N9831 5 NSABP B31 NCCTG N9831 6 33 / 45
BCIRG006 HER2 NCCTG N9831 BO16348 DFS 10 NCCTG N9831 IHC 3+/FISH+ 81% BO16348 IHC 3+/FISH FISH +/IHC DFS 10 NCCTG N9831 BO16348 HER2 NCCTG N9831 BO16348 c a HER2 DFS DFS 95% CI 95% CI IHC 3+ FISH + 1170 0.42 0.27, 0.64 91 0.56 0.13, 2.50 FISH - 51 0.71 0.04, 11.79 8 FISH 51 0.69 0.09, 5.14 2258 0.53 0.41, 0.69 IHC < 3+ / FISH + 174 1.01 0.18, 5.65 299 b 0.53 0.20, 1.42 IHC / FISH + 724 0.59 0.38, 0.93 a HercepTest IHC PathVysion FISH HER2/CEP17 2.0 b BO16348 IHC 2+ c 12.6 BO16348 122 54 1 68 122 46 26 67 50% 40% 10% 34 / 45
41% 91% BO16348 DFS 1 2 81.4% 92.9% 1 (HR 0.29, 95% CI 0.08-1.08, p=0.0489) BO16348 11 11 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 NS b a b NS= (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 60 mg/m 2 75mg/m 2 600 mg/m 2 21 1 6 65% 35 / 45
ORR 12 AC 12 H0648g AC AC + + + AC a (n=235) (n = 234) (n = 92) (n=96) (n=143) (n=138) b,c TTP 7.2 4.5 6.7 2.5 7.6 5.7 95% 7, 8 4, 5 5, 10 2, 4 7, 9 5, 7 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%6, 15 4, 8 5, 11 4, 7 6, 15 4, 8 ( ) c 25.1 20.3 22.1 18.4 26.8 21.4 95% 22, 30 17, 24 17, 29 13, 24 23, 33 18, 27 P d 0.05 0.17 0.16 a AC= ( ) b c Kaplan-Meier d e χ 2 H0648g HER2 3 13 13 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) 36 / 45
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% 351 184 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 37 / 45
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% 7% / 2% log-rank OS 351 OS 0.0193 OS 14 7 14 ( ) (%) 95% CI ( ) 95% CI p *, (%) 95% CI ( ) 95% CI * 0.0193 BO18255 ITT FC FC + H N=296 N=298 184 (62.2%) 11.0 (9.4, 12.5) 227 (76.7%) 11.7 (10.3, 13.0) 0.73 (0.60, 0.91) 0.0038 0.80 (0.67, 0.97) 167 (56.0%) 13.5 (11.7, 15.7) 221 (74.2%) 13.1 (11.9, 15.1) 38 / 45
7 HER2 FISH IHC 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) 15 39 / 45
15 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) (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) (95% CI) 0.78 (0.55, 1.10) FISH+ or FISH-/IHC3+ c /n (%) OS ( ) 95% CI ( ) (N=294) 104/143 (73%) 13.2 (11.5 15.2) (95% CI) 0.66 (0.50, 0.87) 56/62 (90%) 8.3 (6.2, 10.7) 64/80 (80%) 12.3 (9.5, 15.7) 96/151 (64%) 18.0 (15.5, 21.2) 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 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] 16 16 FAS 40 / 45
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 ## = = Kaplan-Meier 8 4 8 Kaplan-Meier FAS PFS TTP 17 17 FAS / // N = 36 N = 48 41 / 45
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%) 13 (100.0%) 16 (100.0%) 4.5 5.8 HR 95% CI 0.56[0.23 ; 1.35] HER2 HER2 FP 34 FP+H 28 HER2 IHC 2+/FISH+ IHC 3+ HER2 FP H 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 HER2 HER2 42 / 45
Ames 5000μg/mL 118mg/kg 2mg/kg 25 18 I II III 1582 - MBC/EBC 0.127 L/ 0.176 L/ Vmax 8.81 mg/ Km 8.92 mg/l 2.62 LAGC 3.63 L 18 1 19 3-95th PK Cmax Cmin 18 1 5 th - 95 th N C min µg/ml C max µg/ml AUC µg. /ml 8mg/kg + 6mg/kg MBC/EBC 1195 29.4 5.8-59.5 178 117-291 1373 736-2245 3 AGC 274 23.1 6.1-50.3 132 84.2-225 1109 588-1938 4mg/kg + 2mg/kg MBC/EBC 1195 37.7 12.3 70.9-88.3 58 144-1066 586 1754-43 / 45
19 AGC 5 th - 95 th 8mg/kg + 6mg/kg 3 4mg/kg + 2mg/kg MBC/ EBC N C min,ss (µg/ml) 1195 47.4 (5-115) AGC 274 32.9 (6.1-88.9) MBC/ EBC 1195 66.1 (14.9-142) C max,ss (µg/ml) 179 (107-309) 131 (72.5-251) 109 (51.0-209) AUC ss (µg. /ml) 1794 (673-3618) 1338 (557-2875) 1765 (647-3578) CL (L/ ( ) ) 12 0.173-0.283 9 0.189-0.337 12 0.201-0.244 2 8 2 8 28 28 1 0.9% 2 8 24 2 8 44 / 45
1 / 1.1% 20ml 2 8 36 JS20170037 S20181016, S20181017 J20180073 Roche Pharma (Schweiz) Ltd. Schoenmattstrasse 2, 4153 Reinach, Switzerland Genentech Inc. 4625 NE Brookwood Parkway Hillsboro, OR 9332 97124- USA F. -La Roche Ltd. Hoffmann Wurmisweg 4303 Kaiseraugst Switzerland 1100 201203 021 28922888 021 50801800 800-820-8780 400-820-8780 9:00-18:00 http://www.roche.com.cn 45 / 45