2010 02 26 2010 04 10 2010 07 29 2011 03 30 2011 07 25 2011 09 20 2011 12 16 2012 09 17 2013 01 21 2015 07 01 2015 11 25 2016 11 30 2017 05 08 1
, Avastin Bevacizumab Injection Bei Fa Zhu Dankang Zhusheye - VEGF 100 mg 400 mg 4 ml 16 ml25 mg/ ml α,α- 20 ph 5.96.3 5-2
100mg4ml / 100mg 25mg/ml 4ml 400mg16ml / 400mg 25mg/ml 16ml 90 60 60 30 mcrc m-ifl IFL5 mg/kg NSCLC 6 15 mg/kg 3 15mg/kg/q3w 3
Bolus 0.9% 1.4-16.5 mg/ml 5% / ( ) ( ) ( ) ( ) 4 ) ( ) ( PRES ( ) 4
( ) ( 4 ) ( ) ( ) ( ) 5500 ( ) NSCLC/ ( ) ( ) 1 2%NCI-CTC 3-5 10% NCI-CTC 1-5 10% 1%10% 5
6 1. SOC NCI-CTC 3-5 2% 10%
7 - * ** *- - ** 295 AVF3077sNSABP C -08 NCI-CTC 1% 2% 2.7% GOG-0240
8 3.2 X 0.2%-1% 2% - 8.3% 0.9%- GOG -0240 1.8% 1.4% 0.1% < 1% 6 NCI-CTC 3-5 0.4%-6.9% 0-4.5% NSCLC /
NSCLC NSCLC 9% 5% 3-5 2.3%1% / CNS CNS 13 91 3 3.3% 4 96 1 1% 5 800 2 AVF3708g, CNS 2.4%2/841 CNS 3.8%3/791, 2 4 50% NCI-CTC 1 5 42.1% 14% NCI-CTC 3 4 0.4%-17.9% 4 1.0% 4 0.2% 9
PRES III PRES 0.8% PRES - 5.9% 1.7% 0.8% 0.5% 0.5% 1.4% 0.7% AVF2192g 11%11/100 5.8% 6/104 AVF3708g 6.3%5/79 4.8%4/84-2.8%-17.3% 3.2%-15.6% 3-5 7.8% 4.9% 10
GOG-0240 3-5 10.6 5.4 BO21990 35 7.6%8.0% CHF 5 III AVF2119gE2100BO17708AVF3694g AVF3693g 3 3 CHF 3.5% 0.9% AVF3694g 3 3 CHF + 2.9% + 0% CHF 6.2% + 6.0% + CHF / NYHA II-IV CHF CHF / CHF B 300 mg/m 2 CHF / / / R -CHOP R-CHOP CHF R-CHOP III 28 2860 11
60 10%4/40 20%3/15 3-5 1.1% 0.9% AVF3708g, 3.6% 1.3% 3 5 1.6% 0.7%-38% 8.1% 3 4 1.4% 1 2g/24 2 g/24 5% / 3 FSH 30 miu/ml β-hcg BO21990 III 3-5 12
54.4%12.8% 39.1%7.8% 65 65 3-4 AVF2107 65 65 18 18 3 4 2% PT 1.5-1.9 ECL 2233 14 0.63% 14 3 ELISA 13
SOC * ** ) *** **** / / / 4 1,5 1 HR1.8299% CI1.202.76 0.46 /100 / vs. 0.26 /100 / HR1.1199% CI1.01, 1.23 6.33 /100 /vs. 5.64 /100 / / 5 ONJ 14
6 1 HR1.5799% 1.042.37 CI 0.41 /100 /vs. 0.26 /100 / HR1.1199% CI1.01, 1.23 6.03 /100 /vs. 5.51 /100 / 2 3 1.2995% CI1.01 1.66 24.1% vs. 19.0% : * 1 Gower et al.adverse Event Rates Following Intravitreal Injection of Avastin or Lucentis for Treating Age- Related Macular Degeneration ARVO 2011, Poster 6644, Data on file 2 Curtis LH, et al.risks of mortality, myocardial infarction, bleeding, and stroke associated with therapies for age-related macular degeneration.arch Ophthalmol.2010;128(10):1273-1279 3 CATT Research Group, Ranibizumab and Bevacizumab for Neovascular Age-Related Macular Degeneration. 10.1056/NEJMoa1102673 4 5 6 CTC ** 1/10,000 *** 1/10,000 1/1,000 **** 1/100 1/10 15
16 - TE 4 3 4, 3 3 / / /1/2
17 PRES PRES / PRES PRES PRES PRES TIAMI 65 4 3
CHF CHF CHF CHF AVF3694g + + CHF AVF3694g AVF3693g CHF 3 3 28 4 1.4% 18
19 / / IgG 6 295 IgG
6 PK α-2a IFL, -FU/LV 5 / AVF3135g SN38 NP18587 BO17705 α-2a BO17704 BO17704 2 10mg/kg 50mg 19 7 20
MAHA PRES BO21990 921 III 20 2 mg/kg mcrc 5 mg/kg 2 AVF2107g 5-/ IFL 4 6 AVF0780g 5-/ 5- FU/LV, 6 8 Roswell Park AVF2192g 5-/ 5 -FU/LV, 6 8 Roswell Park NO16966 21
E3200 ML18147 FOLFOX-45FU /LV/ XELOX / / NO16966 7.5 mg/kg 3 XELOX 5mg/kg 2 5-5-FOLFOX -4 E3200 10mg/kg 2 5- FOLFOX -4 ML18147: 5.0 mg/kg/ 27.5 3/ mg/kg/ AVF2107g III IFL 813 IFL1 IFL 5 mg/kg 2 2 3 110 5-FU/LV 3 IFL 3 IFL 2 2. AVF2107g AVF2107g 1 IFL 2 a IFL 411 402 15.6 20.3 22
95%CI 14.29-16.99 18.46-24.18 b 0.660 p 0.00004 6.2 10.6 0.54 p<0.0001 % 34.8% 44.8% a 5 mg/kg 2 b p<0.0036 3 5 -FU/LV 110 18.3 8.8 AVF2192g II 5-FU/LV 5-FU/LV104 5-FU/LV 5 mg/kg 2 5-FU/LV 5 mg/kg 2 5-FU/LV NO16966 III 7.5 mg/kg 3 XELOX 5 mg/kg 2 5-FU 5-FU FOLFOX - 4 I XELOX FOLFOX-4 4 2 2 II XELOX FOLFOX-4 XELOX FOLFOX -4 3 II II 350 3. NO16966 mcrc 23
FOLFOX-4 85 mg/m 2 IV 2h 1 FOLFOX-4 200 mg/m 2 IV 2h 1 2 XELOX XELOX 5-400 mg/m 2 IV 1 2 600 mg/m 2 IV 22h 5 mg/kg IV 3090 min 5- IV / FOLFOX-4 2 130 mg/m 2 IV 2h 1 1000 mg/m 2 2 1 7.5 mg/kg IV 30 90 min XELOX 3 5- XELOX FOLFOX-4 XELOX i XELOX FOLFOX-4 ii 4 IRC 4 4. ITT NO16966 FOLFOX-4 FOLFOX-4 XELOX XELOX + + n=701 n=699 P 24
** 8.0 9.4 0.0023 97.5% CI a 0.83 0.72 0.95 ** 7.9 10.4 <0.0001 97.5% CI 0.63 0.52-0.75 ** 8.5 11.0 <0.0001 97.5% CI 0.70 0.58-0.83 %** 49.2% 46.5%,%** 37.5% 37.5% * 19.9 21.2 0.0769 97.5% CI 0.89 0.76-1.03 * 2007 1 31 ** 2006 1 31 a ECOG E3200 III 10 mg/kg 5-5-FOLFOX -4 2 FOLFOX-4 NO16966 3 FOLFOX -4 292 FOLFOX-4 293 244 FOLFOX-4 5 5. E3200 E3200 FOLFOX-4 FOLFOX-4 292 293 10.8 13.0 95%CI 10.12-11.86 12.09-14.03 b 0.751 p 0.0012 25
4.5 7.5 0.518 p <0.0001 % 8.6% 22.2% a 10 mg/kg 2 b p <0.0001 FOLFOX-4 FOLFOX-4 ML18147 III 5.0 mg/kg 2 7.5 mg/kg 3 3 mcrc 1:1 // ± OS 820 ITT 6 6. ML18147 ML18147 / / / / + a 410 409 9.8 11.2 95% 9-11 10-12 0.81 p = 0.0062 4.1 5.7 26
ORR a 2.5 mg/kg/ 0.68 p < 0.0001 3.9% 5.4% p = 0.3113 acc BO17920 3 III 2.5 mg/kg / 2 FOLFOX-4 3 XELOX-4 FOLFOX-4 3451 2 3 3 FOLFOX-4+ 1.1795%CI 0.98-1.39 XELOX-4+ 1.0795%CI 0.90-1.28 BO20696 BO20696 5 mg/kg 2 6 PFS OR R, OS, DoR 214 1:2 /5 -FU/LV m-ifl /5 - FU/LV + m-ifl 1 10 FAS, N=203 7 7. BO20696 m-ifl + m-ifl 27
m-ifl + m-ifl 64 139 4.2 8.3 95%CI 3.7-4.9 7.4-8.9 p Log-Rank <0.001 0.44 95%CI 0.31-0.63 13.4 18.7 95%CI 9.7-17.2 15.8-19.6 p Log-Rank 0.014 0.62 95%CI 0.41-0.95 % 17.2% 35.3% 95%CI 8.4-27.7% 27.5-43.5% p Pearson 0.013 m-ifl: 125 mg/m 2 90 20 mg/m 2 1-2 5 500 mg/m 2 6-8 1 4 6 1 ITT N=214 PP, N=171 FAS : N=211, 3 3 3 1/2 3 3 1 98.6% 97.2% 3-5 61.4% 68.8% 28
13/70, 18.6% 14/141, 9.9% 3 2.1% 1 1.4% NSCLC E4599BO17704YO25404 NSCLC E4599 E4599 NSCLC 200 mg/m 2 AUC = 6.0 CP 3 1 6 CP 15 mg/kg 3 1 6 - + 3 32.2%136/422 7~12 21.1%89/422 13 13 8 8. E4599 1 2 / + / 15 mg/kg q3w 444 434 10.3 12.3 0.80 (p=0.003) 95% CI (0.69, 0.93) 29
4.8 6.4 0.65 (p<0.0001) 95% CI (0.56, 0.76) 12.9 29.0 (p<0.0001) BO17704 BO17704 III + NSCLC 3 1 80 mg/m 2 1 8 1250 mg/m 2 CG 6 7.5 15 mg/kg 3 1 3 94%277/296 7 ( 62%) 9 9. BO17704 / + / + 7.5 mg/kg q3w 347 345 351 6.1 6.7 (p = 0.0026) 0.75 [0.62;0.91] 20.1% 34.1% (p< 0.0001) 13.1 13.6 (p = 0.4203) 0.93 [0.78; 1.11] / + 15 mg/kg q3w 6.5 (p = 0.0301) 0.82 [0.68;0.98] 30.4% (p=0.0023) 13.4 (p = 0.7613) 1.03 [0.86, 1.23] 30
YO25404 YO25404 III NSCLC + CP+ CP CP AUC = 6.0 175 mg/m 2 3 1 6 CP 15 mg/kg 3 1 6 3 78%107/138 7 78/138 7 10 10. YO25404 1 / + 2 / + 15 mg/kg q3w 138 138 6.5 9.2 p<0.0001 0.4 [0.29, 0.54] 26.3 54.4 p<0.0001 17.7 24.3 p=0.0154 0.68 [0.50,0.93] CP NSCLC +CP 3 +CP 60.9% vs +CP 66.7% 31
AE [AESI] 15.0% vs. +CP 18.4% +CP +CP 23.3% vs. + CP 45.4% 1 2 +CP 3 2.3% vs. + 9.9% CP 3 +CP 0.8% vs. +CP 2.1% YO25404 26 0.8 26 100 mg/kg 80 10 mg/kg 50 mg/kg 26 / 32
26 2-50 mg/kg 2 mg/kg 10 mg/kg 2 mg/kg 0.52 mg/kg 0.5 mg/kg 5 50 mg/kg 33
13 26 / 4 2 50 mg/kg 10-100 mg/kg VEGF VEGF DNA 0.35 ppm 214 149,000 VEGF Flt -1 KDR VEGF VEGF 10 90 110 mg/kg 34
Vc 2.73L 3.28L IgG Vp 1.69L 2.35L Vc 20% IV 125 I- VEGF IgG IgG IgG FcRn 0.188 0.220 L/ 17% 18 20 BP20689 35
I 5mg/kg, 15mg/kg 10mg/kg 39 5-15mg/kg 5mg/kg 0.85, 1.01 1.2110mg/kg 0.97, 1.01 1.0215mg/kg 1.01, 1.01 1.01 5mg/kg 10mg/kg PK 3mg/kg 10mg/kg I AVF0737g PK 11 11. AVF0737g BP20689 PK AVF0737g BP20689 mg/kg ml/day/kg ml/kg 3 3.65 41.4 10 2.75 43.5 5 3.41 41.1 10 3.16 41.0 2 8 2 30 0.9% 48 2 8 24 36
1 / 24 JS20160090 100mg4ml / S20170035 400mg16ml / S20170036 Roche (Schweiz) Pharma Ltd. Schoenmattstrasse 2, 4153 Reinach, Switzerland Roche Diagnostics GmbH Sandhofer Strasse 116, 68305 Mannheim, Germany F. Hoffmann-La Roche Ltd. Wurmisweg, 4303 Kaiseraugst, Switzerland 1100 37
021-28922888 021-50801800 8008208780 4008208780 9:00-18:00 www.roche.com.cn 38