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 24 1 / 52
Herceptin Trastuzumab Injection Zhusheyong Qutuozhu Dankang DNA ( CHO) 1.1% 20ml L - L-α,α 20 440mg 21mg/ml HER2 1 HER2 5- HER2 2 / 52
HER2 HER2 IHC3+IHC2+/FISH+ 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 3 / 52
8mg/kg 6mg/kg 90 30 1 EBC 1 LVE LVEF 4 1 LVEF LVEF 16 LVEF LVEF 10 48 LVEF LVEF 15 LVEF 8 3 4 / 52
2 6 mg/kg mg/kg 7 21 4mg/kg8mg/kg 90 7 21 2 mg/kg 6 mg/kg 21mg/ml, ph 6.0 28 20ml 5 4mg/kg 1 2mg/kg 5 / 52
= Kg 4mg/Kg 2mg/Kg 21mg/ml 8mg/kg 3 6mg/kg = Kg 8mg/Kg 6mg/Kg 21mg/ml 250ml 0.9% 5% 28 24 5% / / 6 / 52
5 1/10 1/100 <1/10 1/1,000 <1/100 1/10,000 <1/1,000 <1/10,000 1 * / 7 / 52
* +1 + () 1 +1 + + 8 / 52
9 / 52 *
* ADR 2% ADRs SOC + 1 NYHA IIIV 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-T 7.9 AC -TH 8.3 NSABP B31 NCCTG N9831 AC 6% AC (AC LVEF < LLN 16 %) NSABP B31 NCCTG N9831 BO16348 2 1 2 AC-TH 2.0 AC - TH 64.5% 10 / 52
90.3% 2 a NSABP B31NCCTG N9831 BO16348 BCIRG006 LVEF LVEF <50% LVEF LVEF <50% 16% <20% 10% 10% 20% NSABP B31 NCCTG N9831 bc 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% 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 a 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 B31NCCTG N9831 BO16348 BCIRG006 b NSABP B31 NCCTG N9831 AC TH c NSABP B31 NCCTG N9831 AC TH 8.3 d 12.6 11 / 52
e BCIRG006 AC T AC THTCH 1 NSABP B31 NCCTG N9831 LVEF 10% 50% + -------AC T AC T+H T: H 2 BO16348 LVEF 10% 50% ------- 1 12 / 52
0 3 BCIRG006LVEF 10% 50% 0 3/4 CHF 0.3-0.4% 2.0% 3 ACP + + H 3.2% ACP 0.8%5 5.5 ACD + ACDH + + DCarbH LVEF 1.0%2.3%1.1% CHFNCI -CTC 3-4 AC DACDHDCarbH 5 0.6%1.9%0.4%ACDDCarbH ACDDCarbH ACDH 13 / 52
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 -IV III 0.8% 4.6% 71.4 % CHF LVEF 50%79.5% 17% NSABP B-31 NCCTG N9831 ACPH + + 8.1 ACPH 2.0 LVEF 18.5%ACPH LVEF 10%~ 50% ACPH 64.5% 90.3% LVEF MO16432 ( 3 180 mg/m 2 ) 1.7% BO22227 4 300mg/m 2 40 0% BO18255 / FP / H FP LVEF 64 48~ 90 65 50 ~86 1 LVEF BO18255 LVEF 3 LVEF BO18255 14 / 52
LVEF : * LVEF 10% <50% / (N = 290) ( ) / (N = 294) ( ) 1.1% 4.6% <50% 1.1% 5.9% * LVEF 10% 11.8% 16.5% 50% * LVEF LVEF F n=187 HFPn=237 4 BO18255 / (N = 290) ( ) 6% 6% / (N = 294) ( ) 3 NCI CTCAE 3.0 *3% **1% * 9 9 ** 4 5 IRR/ IRR/ / IRR IRR IRR 49%54% 36%58% IRR3 5%7% 5%6% IRR 18%54% 6%50% IRR 3 0.5%6% 0.3%5% 15 / 52
BO22227 IRR 37.2% IRR3 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 12.3 vs6.7[ NSABP B31]0.1 vs0[ncctg N9831] H0649g NCI-CTC 3 < BO18255 1% 28%21%NCI CTC 3/4 12.2%10.3% NCI-CTC 451.7 vs 0.8[NCCTG N9831] 25 6.4vs 4.3[ NSABP B31] NCI-CTC 3/4 32vs 22 vs 17 BO18255 16 / 52
NCI 3/4 CTC 36.8% 28.9% 5.1%2.8% 12% WHO 3 4 60% WHO 3 4 7 vs 15 WHO 3 4 4 18 BO18255 NCI-CTC AE3.0 3 FPH FP 3 2 NCI-CTC AE3.0 3 SOC FPH 1 <1 46vs 30 [H0648g]NCI -CTC 2-5 / vs13.4 [NSABP B31] 3-5 / 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 ] 17 / 52
NCI-CTC 25 14vs 5[ NSABP B31]NCI-CTC 35 2 3.4vs 1[NCCTG N9831] NCI -CTC 25 12vs 4[ NSABP B31]NCI -CTC 252.5 vs 0.1[NCCTG N9831] / 0.7 0.3 3 1 1 / 2.6 vs 1.5[NSABP B31]2.5%3.7% vs 2.2 [BCIRG006] 2.1vs 0[H0648g] NCI-CTC 25 6.7vs 5.4[ NSABP B31]NCI-CTC 35 18 / 52
2.2vs 0[NCCTG N9831]NCI-CTC 14 7vs 1 [BO16348] BCIRG006 3-4 [5.7% AC-TH 5.5% TCH vs. 3.0% AC-T]1-4 [51% -TH AC63% TCH vs. 43% AC-T] 25 BO18255 109 37% 80 (28%) NCI-CTCAE 3.0 FP FP+H 4%9% 3 EBC 8.1%24/296 24 2 [pcr] ARRs 5 19 / 52
20 / 52 6
21 / 52 ( CHF [NYHA]II -IV CHF
7 7 ECG/ MUGA CHF 3 6 24 LVEF 10 50% 3 LVEF CHF 6-8 HF ACEARB β MBC EBC EBC 3 6 24 5 LVEF 22 / 52
CHF NYHA IV II 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 6 LVEF 4 LVEF 23 / 52
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% 50% 7 7 NSABP B31& AC b + 3.2%64/2000 c 1.3% 21/1655 NCCTG 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 24 / 52
NYHA I-IV NYHA III-IV H0648g 28% 7% 19% 3% AC b 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)TCH0.2%(2/1056) AC-T(0 ) IRR IRR IRR IRR IRR IRR β- / 25 / 52
/ 440 mg 3 1 IRR NCI CTC 34 26 / 52
HER2 HER2 HER2 HER2 HER2 HercepTest TM CONFIRM anti-her-2/neu (4B5) Primary AntibodyHER -2/NEU IHC HER2 FISH pharmdx TM INFORM HER2 DNA ProbeHER2 DNA Rabbit anti-dnp AntibodyDNP INFORM Chromosome 17 Probe 17 DDISH HER2 ProbeDDISH HER2 (FISH ) IHC FISH FISH HER2 H0648g IHC FISH 12 NCCTG N9831 BO16348IHC FISH 9 HER2 HER2 HER2 BO18255 HER2 BO18255 IHC 15 HER2 HER2 HER2 HER2 HER2 IHC HER2 CISH HER2 3+ IHC FISH CISH 27 / 52
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 2+3+ HER2 HER2 HER2 HER2 HER2 IHC HER2 SISH FISH SISH HER2 HER2 BO18255IHC3+ FISH HER2 HER2 IHC 3+ IHC 2+ FISH 28 / 52
D008548 SISH FISH HER2>95% IHC ISHHER2 IHC - - HER2 0 <10% 1+ 10%/ / 2+ 10 % 3+ 10% HER2 17 2 SISH FISH 7 7 29 / 52
1 2mg/kg 25, HER2 2050 120150 IgG 12.5 2 mg/kg 3 18 30 / 52
[H0648g H0649g][NSABP B31 NCCTG N9831] 386 65 253 133 4 65 1.5 6-α POH DOL 7- -13- D7D D7D PK 5-FU 31 / 52
+ + 10 mg/kg NSABP B31 NCCTG N9831 4063 BO16348 3386 BCIRG006 3222 HER2 NSABP B31 NCCTG N9831 HER2 IHC 3 FISH HER2 NCCTG N9831 NSABP B31 >100mmHg >200mmHg 11 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 4mg/kg 2mg/kg 52 32 / 52
/ ER /PR DFS 3752 2.0 AC + DFS OS 4063 8.3 AC + 707 NSABP B31 NCCTG N9831 DFS 49 22-80 6% > 65 84%7% 4% 4%/ 90% 38% T191%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 DFS NSABP B31 NCCTG N9831 33 / 52
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 < 94% 35 DFS 8 [ITT DFS= 0.9995% 0.87 1.13 CI p = 0.90 OS=0.980.831.15 p 0.78] BCIRG006 BCIRG006 HER2 FISH+ ER/PR >2 < cm35 / 2 3 3 4 > 100 mmhg T4 N2 N3 M1 1:1:1 -T AC-TH 34 / 52
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 T TC 3 6 52mg/kg ER+/ PR+ 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 ACTH 4 8.3 ACTH 5 BCIRG006 6 DFS / />65 NSABP B31 NCCTG N9831 OS 0.6495% CI:0.550.74 8.3 [ACTH] ACTH 86.9%ACT 79.4% NSABP B31 NCCTG N9831 OS / OS 50 n=2197 OS 0.6595% CI:0.52 0.81>50 n=1866 OS 0.6395% CI:0.51 0.78 ER / PR n=222 0.6395% CI:0.510.78 ER / PR n=1830 0.64 95% CI:0.52 0.80 2 n=1604 cm 0.5295% CI:0.39 0.71>2 cm n=2448 35 / 52
0.6795% CI:0.560.80 9 NSABP B31 NCCTG N9831 NSABP B31 NCCTG N9831 a BO16348 BCIRG006 DFS DFS OS OS p 95% CI p ACTH 133 b 0.48 b,d 289 c 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 ACT 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 ACTH 121 0.60 49 n=1074 0.48-0.76 p< 0.0001 e,i ACT 180 80 n=1073 CI = a b c d e f g h i NSABP B31 NCCTG N9831 T ACTH AC TH 2.0 DFS 707 AC TH 8.3 OS Cox 12.6 DFS NS= BCIRG006 AC 36 / 52
j AC THTCH α 0.025 37 / 52
4 NSABP B31 NCCTG N9831 5 NSABP B31 NCCTG N9831 6 BCIRG006 38 / 52
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 IHC 3+ 95% CI 95% CI 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 FISHHER2/CEP17 2.0 b BO16348 IHC 2+ c 12.6 39 / 52
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 11 40 / 52
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 a b NS= NS b (H0648gn=469) H0649gn=222 2 HER2 2 3 HER2 03 H0648g H0648g 469 IHC CTA 01+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 41 / 52
ORR 12 AC b,c TTP 12 H0648g AC AC + (n=235) (n = 234) + (n = 92) (n=96) + AC a (n=143) (n=138) 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 42 / 52
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) 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 43 / 52
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 2183 76% 53% 38% 5% 5%/ 91%ECOG PS 0 182% 18% 23% 7% /2% log-rank OS 351 OS 0.0193 OS 14 7 14 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 44 / 52
95% CI (10.3, 13.0) (11.9, 15.1) 0.80 (0.67, 0.97) * 0.0193 7 ToG 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) 15 45 / 52
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 (11.515.2) (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 95 80 80 ECOG 01 1 46 / 52
HER2 12.6 vs 9.7 ) FPH 28%HR 0.72; 95% CI [0.401.29]) BO18255 13.8 vs 11.1 HR 0.74; 95% CI [0.600.91] 16 16 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 8 4 8 Kaplan-Meier FAS 47 / 52
PFS TTP 17 17 FAS / N = 48 // N = 36 5.5 6.8 HR95% CI 0.69[0.41 ; 1.15] 5.7 7.2 HR95% 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 HR95% CI 0.56[0.23 ; 1.35] 48 / 52
HER2 HER2 FP 34 FP+H 28 HER2 IHC 2+/FISH+IHC 3+ HER2 FPH 16 9.7 HR 0.5595CI [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 49 / 52
18 III III 1582-0.127 L/0.176 L/ max 8.81 mg/ Km 8.92 mg/l 2.62 AGC 3.63 L 18 1 19 3 5 th - 95 th PK C max C min 18 1 5 th - 95 th N C min µg/ml C max µg/ml AUC µg./ml 8mg/kg + 6mg/kg 3 4mg/kg + 2mg/kg MBC/EBC 1195 29.4 5.8 59.5 - AGC 274 23.1 6.1 50.3 - MBC/EBC 1195 37.7 12.3 70.9-178 117 291-132 84.2 225-88.3 58 144-1373 736 2245-1109 588 1938-1066 586 1754-19 AGC 5 th - 95 th N C min,ss C max,ss AUC ss (µg/ml) (µg/ml) (µg./ml) CL (L/ () ) 8mg/kg + 6mg/kg MBC/ EBC 1195 47.4 (5-115) 3 AGC 274 32.9 179 (107-309) 131 1794 (673-3618) 1338 12 0.173-0.283 9 0.189-0.337 (6.1-88.9) (72.5-251) (557-2875) 4mg/kg + MBC/ 2mg/kg EBC 1195 66.1 (14.9-142) 109 (51.0-209) 1765 (647-3578) 12 0.201-0.244 50 / 52
28 28 28 28 1 0.9% 28 24 28 1 / 1.1% 20ml 2836 51 / 52
JS20140045 S20150067 S20160056 J20170037 Roche Pharma (Schweiz) Ltd. Schoenmattstrasse 2, 4153 Reinach, Switzerland Genentech Inc. South San Francisco, CA 94080, USA F. Hoffmann -La Roche Ltd. Wurmisweg4303 Kaiseraugst Switzerland 1100 201203 02128922888 02150801800 800-820-8780400-820-8780 http://www.roche.com.cn 52 / 52