0814-AVA-03 ( ) Avastin Injection Bevacizumab AVASTIN Avastin () 0.3-2.4% Avastin ( 2.4.1( )) Avastin Avastin/ Avastin 28 Avastin 28 Avastin( 2.4.1( )) Avastin (5 ) Avastin ( 2.4.1( )) 1. 1.1 / ATC Code: L01X C07 1.2 1.3 (i.v. ) Avastin ( 2.4.1 ) 1.4 / 1
1.5 Bevacizumab [(VEGF) ] Avastin 100 400 4 16 (25 /) 100 Avastin 100 bevacizumab 400 Avastin 400 bevacizumab : α,α-trehalose dihydrate, Sodium phosphate monobasic monohydrate, Sodium phosphate dibasic andydrous,polysorbate 20, Water for injections 2. 2.1 (mcrc) Avastin(bevacizumab) irinotecan/5-fluorouracil/leucovorin 5-fluorouracil/leucovorin Avastin 5-fluorouracil/leucovorin/oxaliplatin fluoropyrimidine Avastin Avastin (bevacizumab) fluoropyrimidine-oxaliplatin- Avastin fluoropyrimidine-irinotecan- : Avastin (bevacizumab) (high risk stage II and III adjuvant colon cancer; acc) (mbc) Avastin paclitaxel HER2 (-) 1. Avastin paclitaxel paclitaxel Avastin paclitaxel 2. Avastin anthracycline taxane (WHO 4 ) - Avastin Temozolomide (Glioblastoma multiforme) (NSCLC) 2
Avastin carboplatin paclitaxel 切 (Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer) Avastin carboplatin gemcitabine (Platinum-based) 6 ( ) bevacizumab (VEGF) (VEGF receptor-targeted agents) 2.2 Avastin ( 4.2 ) Avastin Avastin 90 60 60 30 2.4.1 ( ) Avastin Avastin ( 2.4.1 ) (mcrc) Avastin 5 /() Avastin 10 /() 15 / () Avastin Avastin fluoropyrimidine-oxaliplatin- Avastin 5 /( ) 7.5 /() (mbc) Avastin 10 /() Avastin 3
(WHO 4 ) - Avastin 10 /() 15 /( ) Avastin (NSCLC) Avastin carboplatin paclitaxel 六 Avastin carboplatin paclitaxel Avastin 15 /( ) (Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer) Avastin 15 /() Avastin carboplatin gemcitabine 六 Avastin 2.2.1 Avastin Avastin Avastin 2.3 Avastin 2.4 2.4.1 ( ) Avastin ( 2.6.1 ) ( 2.6.2 ) Avastin 2.6.1 () 4
Avastin ( 2.6.1 ()) (TE) 4 Avastin Avastin Avastin 2.6.1 () Avastin ( 2.6.1 ) Avastin 3 4 Avastin (imaging procedures) Avastin ( 2.6.1 ) Avastin Avastin Avastin Avastin Avastin warfarin Avastin 3 ( 2.6.2 ; ) Avastin () / ( 2.6 ) Avastin / ( 2.6.1 )/( 1/2 ) Avastin Avastin Avastin Avastin Avastin ( 2.6.1 ()) Avastin( 2.6.1 () 2.6.2 ) (Posterior Reversible Encephalopathy Syndrome PRES) Avastin (Posterior Reversible Encephalopathy Syndrome (PRES)) PRES 5
PRES (MRI) PRES Avastin PRES Avastin ( 2.6.1 2.6.2 ) Avastin (TIA) (MI) Avastin 65 Avastin Avastin 2.6 Avastin ( ) (4 ) Avastin 3 ( ) 切 2.6 (CHF) Avastin ( ) anthracyclines (CHF) Avastin () Avastin 28 Avastin Avastin Avastin ( 2.6.1 ()) Avastin ( 2.6.2 ) 2.6 6
Avastin 4 ( ) Avastin 4 Avastin 2.6 () / bevacizumab 切 / 2.5.1 2.6.1 Avastin Avastin 2.4.2 Avastin 2.4.3 bevacizumab Avastin Avastin Avastin α 2a (IFL 5-FU/LV carboplatin/paclitaxel capecitabine doxorubicin ) Avastin Bevacizumab (AVF3135g) bevacizumab irinotecan SN38 NP18587 bevacizumab capecitabine oxaliplatin ((free platinum)(total platinum) ) BO17705 bevacizumab interferon alfa-2a BO17704 bevacizumab cisplatin BO17704 bevacizumab gemicitabine bevacizumab sunitinib malate 19bevacizumab(10mg/kg) sunitinib malate(50 mg) 7 (microangiopathic hemolytic anemia MAHA) MAHA ( ) bevacizumab sunitinib malate ( 2.4.1( )) 7
Avastin 2.5 2.5.1 Avastin ( 3.3.4 ) IgG Avastin Avastin Avastin Avastin 6 2.4.1 2.6.1 bevacizumab ( 3.3 ) 295 bevacizumab bevacizumab bevacizumab 2.5.2 Bevacizumab IgG Avastin Avastin Avastin 6 2.5.3 Avastin 2.5.4 2.4.1 2.5.6 Avastin 2.5.7 Avastin 2.6 2.6.1 Avastin 5000 2.6.2 3.1.2 / 8
[ 2.4.1 ( )] /[ 2.4.1 ( )] [ 2.4.1 ( )] Avastin Avastin Avastin 2% (NCI- CTC 3-5 ) 10% (NCI-CTC 1-5 ) : (( 10%) ( 1% < 10%)) ( capecitabine paclitaxel oxaliplatin ) Avastin Avastin pegylated liposomal doxorubicin : (SOC) NCI-CTC 3-5 ( 2 % ) ( 10 % ) 9
() * * AVF3077s (NSABP C-08) 295 Avastin () 2.4.1 ( ) Avastin 1% 2% 2.7% () 10
Avastin 0.2% - 1% X (free air) () Avastin 2.4.1 ( ) Avastin () Avastin 2% ( )( 0.1% to <1%) Avastin 六 Avastin 0.4% 6.5% NCI-CTC 3 5 0 2.9% Avastin () () - : /(NSCLC) / Avastin Avastin ( )Avastin 9% 5% Avastin 3-5 2.3%1% / [ 2.4.1 ( )] (CNS) 11
(CNS) bevacizumab 13 91 bevacizumab 3 (3.3%)( 4 )96 bevacizumb 1 (1%)( 5 ) ( 800 ) 2 AVF3708g Avastin 2.4% (2/84)( 1 ) Avastin irinotecan 3.8% (3/79)( 1 2 4 ) Avastin Avastin 50% NCI-CTC 1 5 Avastin () 2.4.1 ( ) Avastin () 42.1% 14% Avastin NCI-CTC 3 4 0.4% 17.9% 4 ( ) Avastin 1.0% 0.2% Avastin ( 2.4.1 ( )) Avastin (Posterior Reversible Encephalopathy Syndrome PRES) (0.8%) - Avastin Avastin 3.8% 1.7% Avastin 0.8% 0.5%() Avastin 2.3% 0.5% Avastin 1.4% 0.7% 12
AVF2192g irinotecan Avastin 11% (11/100) 5.8% (6/104) - 2.4.1 ( ) Avastin 2.8% 17.3% 3.2% 15.6% bevacizumab 3-5 7.8% 4.9% Avastin Avastin (AVF2119g E2100 BO17708 AVF3694g)Avastin 3 3.5% 0.9% / Avastin NYHA II IV anthracyclines / ( 2.4.1 ( )) B bevacizumab doxorubicin 300 mg/m 2 rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) bevacizumab R-CHOP bevacizumab doxorubicin R-CHOP bevacizumab 2.4.1 ( ) Avastin Avastin 28 Avastin 28 60 Avastin 60 10% (4/40) 20% (3/15) Avastin 3-5 1.1% 0.9% 13
(AVF3708g) Avastin ( 切 ) 3.6% Avastin irinotecan 1.3% 2.4.1 ( ) 0.7% 38% Avastin 8.1% 3 4 ( ) 1.4% Avastin Avastin Avastin 1 Avastin Avastin 2 /24 Avastin <2 /24 2.4.1 ( ) 2.6.2 () Avastin (anaphylactic) (anaphylactoid-type)avastin (bevacizumab 5%) / 2.4.1 2.5.1 ( 3 FSH 30 miu/mlβ-hcg ) bevacizumab bevacizumabbevacizumab 65 65 Avastin [ 2.4.1 ( ) 2.6.1 () ] 65 3-4 65 Avastin ( 65 ) 2.6.1.1 Avastin Avastin ( 2%) 3 4 (PT)(normalised ratio) 14
2.6.2 : (SOC) (* ()( 2.4 2.6.1 ) ()( 2.4 ) () 2.4 2.6.1 () ( () () () () () / // /( 2.4.1 ( ) 2.6.1 ()) 4 ( ) 1,5 ( ) 1 Avastin Avastin ( HR: 1.82; 99% CI: 1.20, 2.76) ( 100 0.46 ; 100 0.26 ) ( HR: 1.11; 99% CI: 1.01, 1.23) ( 100 6.33 ; 100 5.64 ) 5 Avastin 15
() 1 Avastin Avastin ( HR: 1.57; 99% CI: 1.04, 2.37) ( 100 0.41 ; 100 0.26 ) ( HR: 1.11; 99% CI: 1.01, 1.23) ( 100 6.03 ; 100 5.51 ) 2 Avastin 3 Avastin (: 1.29; 95% CI: 1.01, 1.66) ( 24.1%; 19.0%) /. Avastin (osteonecrosis of the jaw; ONJ) () ( 2.4.1 ( )) * 1 Gower et at. 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/NEJMoz1102673 4 (meningoencephalitis) 5 2.7 (20 / ) 16
3. 3.1 3.1.1 Avastin(bevacizumab) (VEGF) Bevacizumab (framework regions) VEGF (antigen binding regions) Bevacizumab gentamicin Gentamicin 0.35 ppm Bevacizumab 214 149,000 daltons Avastin VEGF Flt-1 KDR VEGF bevacizumab 3.1.2 / mcrc Avastin fluoropyrimidine Avastin ( 2 5 /) Avastin AVF2107g irinotecan/bolus 5-fluorouracil/leucovorin(IFL ) 4 6 AVF0780g bolus 5-fluorouracil/leucovorin (5-FU/LV) 6 8 (Roswell Park ) AVF2192g irinotecan bolus 5- fluorouracil/leucovorin(5-fu/lv) 6 8 (Roswell Park ) Avastin Avastin (E3200) Avastin Avastin (ML18147) Avastin FOLFOX-4(5FU/LV/Oxaliplatin) fluoroprymidine/irinotecan fluoroprymidine/oxaliplatin E3200 Avastin 10 / ( ) leucovorin 5- fluorouracil( ) oxaliplatin(folfox-4) ML18147 Avastin Avastin 5.0 / () Avastin 7.5 /() fluoropyrimidine/irinotecan fluoropyrimidine/oxaliplatin irinotecan oxaliplatin irinotecan oxaliplatin 17
AVF2107g Avastin IFL 813 IFL + ( ) IFL + Avastin( 5 /) 110 bolus 5-FU/LV + Avastin( ) Avastin IFL Avastin IFL ()Avastin AVF2107g IFL + AVF2107g IFL + Avastin a 411 402 ( ) 15.6 20.3 95% 14.29 16.99 18.46 24.18 (Hazard ratio) b 0.660 (p- = 0.00004) ( ) 6.2 10.6 0.54 (p- < 0.00001) 34.8% 44.8% a 2 5 / b (p- = 0.0036) (5-FU/LV + Avastin) 110 18.3 8.8 AVF2192g Avastin 5-FU/Leucovorin irinotecan 105 5-FU/LV + 104 5-FU/LV Avastin ( 2 5 /) Avastin 5 / 5-FU/LV 5-FU/LV 18
ECOG E3200 Avastin 10 / leucovorin 5-fluorouracil() oxaliplatin (FOLFOX- 4) ( ) FOLFOX-4 () 829 (292 FOLFOX-4 293 Avastin + FOLFOX-4 244 Avastin ) FOLFOX-4 Avastin ( ) E3200 FOLFOX-4 FOLFOX-4 + Avastin Oxaliplatin Leucovorin 5-Fluorouracil 85 / 2 200 / 2 400 / 600 / 22 Avastin 5 / IV 30-90 5-Fluorouracil: leucovorin Oxaliplatin Leucovorin 5-fluorouracil / FOLFOX-4 E3200 E3200 FOLFOX- FOLFOX-4 4 + Avastin a 292 293 ( ) 10.8 13.0 95% 10.12 11.86 12.09 14.03 b 0.751 (p = 0.0012) ( ) 4.5 7.5 0.518 (p < 0.0001) 8.6 % 22.2 % 19
a 10 / (p < 0.0001) b Avastin FOLFOX-4 FOLFOX-4 Avastin ML18147 Avastin 5.0 /() Avastin 7.5 /() fluoropyrimidine fluoropyrimidine Avastin ( : Avastin 2.1 ) Avastin 3 1:1 fluoropyrimidine/oxaliplatin fluoropyrimidine/irinotecan ( ) Avastin (overall survival; OS) 820 Fluoropyrimidine Avastin Avastin (ITT=819) ( 六 ) 六 ML18147 ML18147 Fluoropyrimidine/irinotecan Fluoropyrimidine/oxaplatin Fluoropyrimidine/irinotecan Fluoropyrimidine/oxaplatin + Avastin a 410 409 ( ) 9.8 11.2 (95%) 0.81 (0.69, 0.94) (p =0.0062) 20
( ) 4.1 5.7 (95%) 0.68 (0.59, 0.78) (p <0.0001) 3.9% 5.4% (p =0.3113) 2 5.0 mg/kg 3 7.5 mg/kg (Adjuvant Colon Cancer; acc) BO17920 3451 FOLFOX4 XELOX 2.5 mg/kg/week Avastin FOLFOX4 Avastin Avastin (n=2867) Avastin (disease free survival; DFS) FOLFOX4 + Avastin DFS 1.17 (95% CI: 0.98-1.39) XELOX + Avastin 1.07 (95% CI: 0.90-1.28) mbc ECOG E2100 E2100 Avastin paclitaxel ( ) taxane 12 paclitaxel (90 / ) Avastin (10 / ) Avastin (PFS) 21
722 HER2 (90%) (8%) HER2 (2%) HER2 trastuzumab (65%) 19% taxanes 49% anthracyclines E2100 *, Paclitaxel (n=354) Paclitaxel/Avastin (n=368) Paclitaxel (n=354) Paclitaxel/Avastin (n=368) ( ) 5.8 11.4 5.8 11.3 0.421 0.483 (95% ) (0.343 ; 0.516) (0.385 ; 0.607) p <0.0001 <0.0001 ( ), Paclitaxel (n=273) Paclitaxel/Avastin (n=252) Paclitaxel (n=243) Paclitaxel/Avastin (n=229) (%) 23.4 48.0 22.2 49.8 p <0.0001 <0.0001 * Paclitaxel (n=354) Paclitaxel/Avastin (n=368) ( ) 24.8 26.5 (95% ) 0.869 (0.722 ; 1.046) p 0.1374 (NSCLC) E4599Avastin carboplatin paclitaxel (NSCLC) E4599 Avastin ( IIIb) 878 paclitaxel carboplatin(pc)( paclitaxel 200 /carboplatin AUC = 6.0(PC) 六 )PC Avastin( 15 /)carboplatin-paclitaxel 六 22
Avastin + carboplatin-paclitaxel Avastin Avastin 32.2% (136/422) 7-12 Avastin 21.1% (89/422) 13 Avastin E4599 Carboplatin / Paclitaxel Carboplatin/ Paclitaxel + Avastin 15 / 444 434 ( ) 10.3 12.3 0.80 (p=0.003) 95% CI (0.69, 0.93) ( ) 4.8 6.4 0.65 (p<0.0001) 95% CI (0.56, 0.76) (%) 12.9 29.0 (p<0.0001) WHO 4 - AVF3708g (AVF3708g) Avastin ( Avastin 8 ) temozolomide (1 1) Avastin (10 / ) Avastin irinotecan (125 / 340 / ) (IRF) 6 (PFS)(ORR) 23
AVF3708g Avastin Avastin + Irinotecan 85 82 Inv IRF Inv IRF 6 95% CI (Inv) 97.5% CI (IRF) 43.6% (33.0, 54.3) - 42.6% - (29.6, 55.5) 57.9% (46.6, 69.2) - 50.3% - (36.8, 63.9) 95% CI (Inv) 97.5% CI (IRF) 41.2% (30.6, 52.3) - 28.2% - (18.5, 40.3) 51.2% (39.9, 62.4) - 37.8% - (26.5, 50.8) ( ) (95% CI) 4.2 (3.0, 6.9) 4.2 (2.9, 5.8) 6.8 (5.0, 8.2) 5.6 (4.4, 6.2) ( ) (95% CI) 8.1 (5.5, *) 5.6 (3.0, 5.8) 8.3 (5.5, *) 4.3 (4.2, *) ( ) (95% CI) 9.3 (8.2, *) 8.8 (7.8, *) ORR MacDonald Inv = IRF = * AVF3708g IRF 六 (p< 0.0001) Avastin 42.6% Avastin irinotecan 50.3%( Avastin 43.6% Avastin irinotecan 57.9%) (p< 0.0001)Avastin 28.2% Avastin irinotecan 37.8%( Avastin 41.2% Avastin irinotecan 51.2%) ( ) bevacizumab ( 24 ) 24 Karnofsky (KPS) (Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer) 24
AVF4095g (AVF4095g) Avastin bevacizumab carboplatin gemcitabine Avastin Avastin carboplatin gemcitabine 6 bevacizumab 484 : Carboplatin (AUC4) gemcitabine (1000 mg/m 2 8 ) 3 6 10 ( 3 ) Carboplatin (AUC4, ) gemcitabine (1000 mg/m 2 8 ) Avastin (15 mg/kg) 3 6 10 Avastin (15 mg/kg 3 ) RECIST (modified RECIST 1.0) AVF4095g +C/G Avastin + C/G +C/G Avastin + C/G (n = 242) (n = 242) (n = 242) (n = 242) PFS ( ) 8.4 12.4 8.6 12.3 (95% CI) 0.524 [0.425, 0.645] 0.480 [0.377, 0.613] P <0.0001 <0.0001 25
PFS ( ) 8.4 12.4 8.6 12.3 (95% CI) 0.484 [0.388, 0.605] 0.451 [0.351, 0.580] P <0.0001 <0.0001 +C/G Avastin + C/G +C/G Avastin + C/G (n = 242) (n = 242) (n = 242) (n = 242) 57.4% 78.5% 53.7% 74.8% P <0.0001 <0.0001 +C/G (n = 242) Avastin + C/G (n = 242) OS ( ) 32.9 33.6 (95% CI) 0.950 [0.771, 1.176] P 0.6479 +C/G (n = 242) Avastin+C/G (n = 242) 6-12 (n=202) 8.0 11.9 (95% CI) 0.41 (0.29-0.58) 26
12 (n=282) 9.7 12.4 (95% CI) 0.55 (0.41-0.73) 3.2 Bevacizumab (solid tumors) 0.1-10 / 3-20 / (q2w) (q3w) 5 /(q2w) 15 / (q3w) bevacizumab bevacizumab bevacizumab (disposition) (Vc) bevacizumab ( bevacizumab (bevacizumab [ 59 5 95 37 76 ] bevacizumab 30% 7% 3.2.1 Vc (central volume) 2.73 3.28 IgGs bevacizumab Vp (peripheral volume) 1.69 2.35 Vc 20% 3.2.2 Bevacizumab 125 I-bevacizumab VEGF IgG Bevacizumab IgG IgG FcRn 3.2.3 Bevacizumab 1.5 10 // 0.188 0.220 / bevacizumab 17% 18 20 27
3.2.4 bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab 3.3 3.3.1 Avastin 3.3.2 Avastin 3.3.3 Avastin cynomolgus Avastin cynomolgus 13 26 4 2 bevacizumab 50 / bevacizumab 3.3.4 Avastin 10-100 / 3.3.5 (Physeal) cynomolgus 26 Avastin 0.8 28
Avastin Avastin 5 Avastin 2 50 / 2 (re-epithelialisation) 2 10 / Avastin 2 / Avastin 0.5 2 / 0.5 / Avastin cynomolgus Avastin 切 cynomolgus Avastin 26 100 / Avastin( 80 ) Avastin cisplatin cynomolgus 10 / 50 / Avastin 26 cynomolgus 50 / Avastin cynomolgus 26 Avastin Avastin 29
4. 4.1 Avastin (EXP) 2 C-8 C Avastin 0.9% 2-30 C 48 2-8 C 24 4.2 Avastin ( ) (intravenous push or bolus) Avastin bevacizumab 0.9% bevacizumab 1.4 16.5 / Avastin Avastin (polyvinyl chloride)(polyolefin) (5%) Avastin / 4.3 100 /4 ; 400 /16 100 30
2013 8 CDS28.0 0714-AVA-3-B01 000807 : : Roche Diagnostics GmbH : Sandhoferstrasse 116, D-68305, Mannheim, Germany : : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland ( ) 000874 : : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland 3 134 9 (02)27153111 Avastin 31