Microsoft Word - Avastin_CDS34.0_CRC TML_0718-AVA-01_clean

0718-AVA-01 Injection Bevacizumab AVASTIN () 0.3-3.2% ( 2.4.1()) 28 28( 2.4.1( )) ( ) (5 ) ( 2.4.1()) 1. 1.1 / ATC Code: L01X C07 1.2 1.3 (i.v. ) ( 2.4.1 ) 1.4 / 1.5 Bevacizumab [(VEGF) ] 1

100 400 4 16 (25 /) 100 100 bevacizumab 400 400 bevacizumab : α,α-trehalose dihydrate, Sodium phosphate monobasic monohydrate, Sodium phosphate dibasic anhydrous, Polysorbate 20, Water for injections 2. 2.1 (mcrc) (bevacizumab) 5-fluorouracil 5-fluorouracil/leucovorin/oxaliplatin fluoropyrimidine (bevacizumab) fluoropyrimidine-irinotecan- fluoropyrimidine-oxaliplatin- : (bevacizumab) (high risk stage II and III adjuvant colon cancer; acc) (mbc) paclitaxel HER2 (-) 1. paclitaxel paclitaxel paclitaxel 2. anthracycline taxane (WHO 4 ) - Temozolomide (Glioblastoma multiforme) (NSCLC) carboplatin paclitaxel 切 2

erlotinib 切 (EGFR) (Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer) carboplatin gemcitabine (Platinum-based) 6 () bevacizumab (VEGF) (VEGF receptor-targeted agents) carboplatin paclitaxel paclitaxel topotecan pegylated liposomal doxorubicin (platinum-based) 6 () 2bevacizumab (VEGF) (VEGF receptor-targeted agents) (Persistent, Recurrent, or Metastatic Cervical Cancer) paclitaxel cisplatin paclitaxel topotecan (platinum therapy) 2.2 ( 4.2 ) 90 60 60 30 2.4.1 () 3

( 2.4.1 ) (mcrc) 5 /() 7.5 /() 10 /()15 / () fluoropyrimidine-irinotecan- fluoropyrimidine-oxaliplatin- 5 /() 7.5 /() (mbc) 10 /() (WHO 4 ) - 10 /() 15 /( ) (NSCLC) NSCLC: carboplatin paclitaxel 六 carboplatin paclitaxel 15 /( ) erlotinib (EGFR) NSCLC : erlotinib EGFR erlotinib 15 /() erlotinib erlotinib erlotinib 4

(Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer) 15 /() carboplatin paclitaxel 六 carboplatin gemcitabine 六 paclitaxel topotecan () pegylated liposomal doxorubicin 10 / ()2 1IV ( 3.1.2 MO22224) topotecan31 515/ ( )3 1IV (3.1.2MO22224) (Cervical Cancer) Paclitaxel cisplatin paclitaxel topotecan ( 3.1.2 GOG-0240 ) 15 /() 2.2.1 2.3 5

2.4 2.4.1 () ( 2.6.1 ) ( 2.6.2 ) (-) ( 2.6.1 ) 2.6.1 () ( 2.6.1 ()) (TE) 4 2.6.1 () ( 2.6.1 ) 3 4 (imaging procedures) ( 2.6.1 ) warfarin 3 ( 2.6.2 ; ) () / ( 2.6 ) 6

/ ( 2.6.1 )/( 1/2 ) ( 2.6.1 ()) ( 2.6.1 () 2.6.2 ) (Posterior Reversible Encephalopathy Syndrome PRES) (Posterior Reversible Encephalopathy Syndrome (PRES)) PRES PRES (MRI) PRES PRES ( 2.6.1 2.6.2 ) (TIA) (MI) 65 2.6 ( ) ( 2.6.1 ) (4 ) 3 ( ) 切 2.6 (CHF) 7

( ) anthracyclines (CHF) () ( ) 28 ( 2.6.1 ( )) ( 2.6.2 ()) 2.6 1.4% 4 ( ) 2.6 () / bevacizumab 切 / 2.5.1 2.6.1 2.4.2 2.4.3 bevacizumab bevacizumab α 2a erlotinib (IFL 5-FU/LV carboplatin/paclitaxel capecitabine doxorubicin ) bevacizumab 8

Bevacizumab α 2a erlotinib ( OSI-420) irinotecan ( SN38) capecitabine oxaliplatin () cisplatin bevacizumab bevacizumab gemcitabine bevacizumab sunitinib malate 19bevacizumab(10mg/kg) sunitinib malate(50 mg) 7 (microangiopathic hemolytic anemia MAHA) MAHA () bevacizumab sunitinib malate( 2.4.1( )) 2.5 2.5.1 ( 3.3.4 ) IgG bevacizumab ( 2.6.2 ()) 6 2.4.1 2.6.1 bevacizumab ( 3.3 ) 295 bevacizumab bevacizumab bevacizumab 2.5.2 Bevacizumab IgG 6 9

2.5.3 18 18 ( 3.3.5 ( )) 2.5.4 2.4.1 2.5.6 2.5.7 2.6 2.6.1 5500 2.6.2 3.1.2 / [ 2.4.1 ()] /[ 2.4.1 ( )] [ 2.4.1 ()] 2%(NCI- CTC 3-5 ) 10%(NCI-CTC 1-5 ) : (( 10%) ( 1% < 10%)) doxorubicin (pegylated liposomal doxorubicin) capecitabine paclitaxel oxaliplatin paclitaxel erlotinib 10

(SOC) NCI-CTC 3-5 ( 2 %) ( 10 % ) () ** 11

* * AVF3077s (NSABP C-08) 295 ** -- () 2.4.1 () 1% 2% 2.7% ( ) (GOG-0240 ) 3.2% () X (free air)() 0.2% - 1% () 2% 12

- 8.2% 0.9% - 2.4.1 () () (GOG-240) 1.8% 1.4% ()( 0.1% to <1%) 六 0.4% 6.9% NCI-CTC 3 5 0 4.5% () () - : /(NSCLC) / () 9.3% 5% 3-5 2.3%1% / [ 2.4.1 ( )] (CNS) 13

(CNS) bevacizumab 13 91 bevacizumab 3 (3.3%)( 4 )96 bevacizumb 1 (1%)( 5 ) ( 800 ) 2 AVF3708g 2.4% (2/84)( 1 ) irinotecan 3.8% (3/79)( 1 2 4 ) 50% NCI-CTC 1 5 () 2.4.1 () JO25567 () 42.1% 14% NCI-CTC 3 4 0.4% 17.9% 4 ( ) 1.0% 0.2% JO25567 bevacizumab erlotinib EGFR NSCLC 77.3% erlotinib 14.3% bevacizumab erlotinib 60.0% 3 erlotinib 11.7% 4 5 ( 2.4.1 ( )) (Posterior Reversible Encephalopathy Syndrome PRES) (0.8%) - 14

5.9% 1.7% 0.8% 0.5%() 2.7% 0.5% 1.4% 0.7% AVF2192g irinotecan 11% (11/100) 5.8% (6/104) AVF3708g irinotecan 6.3% (5/79) 4.8% (4/84) - 2.4.1 () 2.8% 17.3% 3.2% 15.6% bevacizumab ( ) 3-5 7.8% 4.9% (GOG-0240 ) 10.6% bevacizumab 3-4 5.4% 5 (AVF2119g E2100 BO17708 AVF3694g) 3 3.5% 0.9% / 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 15

doxorubicin R-CHOP bevacizumab 2.4.1 () 28 28 60 60 10% (4/40) 20% (3/15) ( 2.4.1 ) 3-5 1.1% 0.9% (AVF3708g) ( 切 ) 3.6% irinotecan 1.3% 2.4.1 () 0.7% 54.7% 8.1% 3 4 ( ) 1.4% 1 2 /24 <2 /24 2.4.1 () 2.6.2 () (anaphylactic) (anaphylactoid-type) (bevacizumab 5%) / 2.4.1 () 2.5.1 () ( 3 FSH 30 miu/mlβ-hcg ) bevacizumab bevacizumabbevacizumab ( 2.4.1 ()) 16

(GOG-0240) paclitaxel topotecan24% 3-5 paclitaxel topotecan13% 65 65 [ 2.4.1 () 2.6.1 () ] 65 3-4 ( AVF2107) 65 ( 65 ) 2.6.1.1 ( 2%) 3 4 (PT)(normalised ratio) ( 1.5-1.9 ) 2.6.2 (SOC) (* bevacizumab ( 2.5.1 ( )) ( ** )( 2.4 2.6.1 ) ( *** )( 2.4 ) ( ) 2.4 2.6.1 () 17

( () (****) () () () /// /( 2.4.1 () 2.6.1 ( )) 4 () 1,5 () 1 ( 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 ( ) 1 ( HR: 1.57; 99% CI: 1.04, 2.37) 18

( 100 0.41 ; 100 0.26 ) ( HR: 1.11; 99% CI: 1.01, 1.23) ( 100 6.03 ; 100 5.51 ) 2 3 (: 1.29; 95% CI: 1.01, 1.66) ( 24.1%; 19.0%) (osteonecrosis of the jaw; ONJ) ( 2.5.3 ) 6 () ( 2.4.1 ( )) * 1 Gower et at. Adverse Event Rates Following Intravitreal Injection of 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 6 CTC ** (<1/10,000) *** ( 1/10,000 <1/1,000) **** ( 1/100 <1/10) 2.7 (20 /()) 19

3. 3.1 3.1.1 (bevacizumab) (VEGF) Bevacizumab (framework regions) VEGF (antigen binding regions) Bevacizumab gentamicin Gentamicin 0.35 ppm Bevacizumab 214 149,000 daltons VEGF Flt-1 KDR VEGF bevacizumab 3.1.2 / mcrc fluoropyrimidine ( 2 5 /) 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 ) (NO16966) (E3200) (ML18147) FOLFOX-4(5FU/LV/Oxaliplatin) XELOX (capecitabine/oxaliplatin) fluoroprymidine/irinotecan fluoroprymidine/oxaliplatin NO16966 7.5 /() capecitabine oxaliplatin (XELOX) 5 /() leucovorin 5-fluorouracil ( ) oxaliplatin (FOLFOX-4) 20

E3200 10 / ( ) leucovorin 5- fluorouracil( ) oxaliplatin(folfox-4) ML18147 5.0 / () 7.5 /() fluoropyrimidine/irinotecan fluoropyrimidine/oxaliplatin irinotecan oxaliplatin irinotecan oxaliplatin AVF2107g IFL 813 IFL +() IFL + ( 5 /) 110 bolus 5-FU/LV + () IFL IFL () AVF2107g IFL + AVF2107g IFL + 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 + ) 110 18.3 8.8 AVF2192g 21

5-FU/Leucovorin irinotecan 105 5-FU/LV + 104 5-FU/LV + ( 2 5 /) 5 / 5-FU/LV 5-FU/LV NO16966 bevacizumab 7.5 / capecitabine oxaliplatin XELOX 5 / leucovorin 5-fluorouracil ( ) oxaliplatin (FOLFOX-4) XELOX FOLFOX-4 2 x 2 XELOX + FOLFOX-4 + XELOX + FOLFOX-4 + 350 NO16966 mcrc FOLFOX-4 FOLFOX-4 + XELOX XELOX+ Oxaliplatin Leucovorin 5-Fluorouracil Oxaliplatin Capecitabine 85 / 2 200 / 2 400 / 600 / 22 Oxaliplatin Leucovorin 5-fluorouracil / 5 mg/kg IV 30-90 min FOLFOX-4 130 / 2 1000 / Oxaliplatin Capecitabine 7.5 mg/kg IV 30-90 min 5-Fluorouracil leucovorin XELOX 22

XELOX FOLFOX-4 FOLFOX-4 XELOX i) XELOX FOLFOX-4 ii) (ITT) IRCon-treatment (ITT) NO16966 FOLFOX-4 XELOX + (n=701) FOLFOX-4 XELOX + Bevacizumab (n=699) ** 8.0 9.4 0.0023 (97.5%) a 0.83 (0.72 0.95) (on treatment)** (97.5%) 0.63 (0.52-0.75) P 7.9 10.4 <0.0001 ()** 8.5 11.0 <0.0001 (97.5%) 0.70 (0.58-0.83) ()** 49.2% 46.5% ()** 37.5% 37.5% * 19.9 21.2 0.0769 (97.5%) 0.89 (0.76-1.03) * 2007 1 31 ** 2006 1 31 a ECOG E3200 10 / leucovorin 5-fluorouracil() oxaliplatin (FOLFOX- 4)() FOLFOX-4 NO16966 23

() 829 (292 FOLFOX-4 293 + FOLFOX-4 244 ) FOLFOX-4 ( 六 ) 六 E3200 E3200 FOLFOX- FOLFOX-4 4 + 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 % a 10 / b (p < 0.0001) FOLFOX-4 FOLFOX-4 ML18147 5.0 /() 7.5 /() fluoropyrimidine fluoropyrimidine ( : 2.1 ) 3 1:1 fluoropyrimidine/oxaliplatin fluoropyrimidine/irinotecan ( ) (overall survival; OS) 24

820 Fluoropyrimidine (ITT=819) () ML18147 Fluoropyrimidine/irinotecan Fluoropyrimidine/oxaliplatin ML18147 Fluoropyrimidine/irinotecan Fluoropyrimidine/oxaliplatin + a 410 409 ( ) 9.8 11.2 (95%) 0.81 (0.69, 0.94) (p =0.0062) ( ) 4.1 5.7 (95%) 0.68 (0.59, 0.78) (p <0.0001) 3.9% 5.4% a 2 5.0 mg/kg 3 7.5 mg/kg (p =0.3113) (Adjuvant Colon Cancer; acc) BO17920 3451 FOLFOX4 XELOX 2.5 mg/kg/week 25

FOLFOX4 (n=2867) (disease free survival; DFS) FOLFOX4 + DFS 1.17 (95% CI: 0.98-1.39) XELOX + 1.07 (95% CI: 0.90-1.28) mbc ECOG E2100 E2100 paclitaxel ( ) taxane 12 paclitaxel (90 / ) (10 / ) (PFS) 722 HER2 (90%)(8%) HER2 (2%) HER2 trastuzumab (65%) 19% taxanes 49% anthracyclines E2100 *, Paclitaxel (n=354) Paclitaxel/ (n=368) Paclitaxel (n=354) Paclitaxel/ (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 (), 26

Paclitaxel (n=273) Paclitaxel/ (n=252) Paclitaxel (n=243) Paclitaxel/ (n=229) (%) 23.4 48.0 22.2 49.8 p <0.0001 <0.0001 * Paclitaxel (n=354) Paclitaxel/ (n=368) ( ) 24.8 26.5 (95% ) 0.869 (0.722 ; 1.046) p 0.1374 (NSCLC) E4599 carboplatin paclitaxel (NSCLC) E4599 ( IIIb) 878 paclitaxel carboplatin(pc)( paclitaxel 200 /carboplatin AUC = 6.0(PC) 六 )PC ( 15 /)carboplatin-paclitaxel 六 + carboplatin-paclitaxel 32.2% (136/422) 7-12 21.1% (89/422) 13 E4599 Carboplatin / Paclitaxel Carboplatin/ Paclitaxel + 15 / 444 434 ( ) 10.3 12.3 0.80 (p=0.003) 95% CI (0.69, 0.93) 27

( ) 4.8 6.4 0.65 (p<0.0001) 95% CI (0.56, 0.76) (%) 12.9 29.0 (p<0.0001) YO25404: NSCLC YO25404 切 Bevacizumab carboplatin paclitaxel (CP) III CP (carboplatin AUC = 6.0 paclitaxel 175 mg/m 2 IV ) 3 1 6 CP Bevacizumab 15 mg/kg 3 1 IV 六 CP 3 Bevacizumab Bevacizumab 78% (107/138) 7 Bevacizumab 57% (78/138) 7 YO25404 Carboplatin/ Paclitaxel + Carboplatin/ Paclitaxel + Bevacizumab 15 mg/kg 3 138 138 () 6.5 9.2 0.4 (p<0.0001) 95% CI (0.29, 0.54) * () 26.3 54.4 28

(p<0.0001) 95% CI (16.9, 39.3) () 17.7 24.3 0.68 (p=0.0154) 95%CI (0.50, 0.93) * YO25404 : () 3 Bevacizumab + CP (+CP 62% v.s. Bevacizumab + CP 67%) Bevacizumab ( AESI) () (+CP 15.0% v.s. Bevacizumab + CP 19%) Bevacizumab Bevacizumab () Bevacizumab + CP ( + CP 23% v.s. Bevacizumab + CP 49%) ()Bevacizumab 3 Bevacizumab + CP ( + CP 2% v.s. Bevacizumab + CP 11%) 3 ( + CP 2% v.s. Bevacizumab + CP 5%) YO25404 Bevacizumab + CP NSCLC Bevacizumab JO25567 JO25567 II IIIB/IV EGFR NSCLC bevacizumab erlotinib 29

(PFS) FACT-L ( ) EGFR 154 erlotinib + bevacizumab [ erlotinib 150 mg + bevacizumab (15 mg/kg IV 3 )] erlotinib ( 150 mg)(pd) PD erlotinib + bevacizumab JO25567 Erlotinib N = 77 # Erlotinib + Bevacizumab N = 75 # PFS^ ( ) 9.7 16.0 HR (95% CI) p () p 0.54 (0.36; 0.79) 0.0015 63.6% (49) 69.3% (52) 0.4951 ( ) 9.3 13.3 HR (95% CI) p 0.68 (0.43; 1.10) 0.118 p 88.3% 98.7% 0.0177 * ( ) 48.5 48.4 HR (95% CI) p # 154 0.91 (0.56; 1.46) 0.6838 ^() * 2015 10 28 OS 45% OS CIHR Cox NR JO25567 FACT-L (TOI) FACT- L (LCS)(HRQoL) FACT-L 30

erlotinib + bevacizumab bevacizumab erlotinib WHO 4 - AVF3708g (AVF3708g) ( 8 ) temozolomide (1 1) (10 / ) irinotecan (125 / 340 / ) (IRF) 6 (PFS)(ORR) AVF3708g + 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, *) 31

( ) (95% CI) 9.3 (8.2, *) 8.8 (7.8, *) ORR MacDonald Inv = IRF = * AVF3708g IRF 六 (p< 0.0001) 42.6% irinotecan 50.3%( 43.6% irinotecan 57.9%) (p< 0.0001) 28.2% irinotecan 37.8%( 41.2% irinotecan 51.2%) () bevacizumab ( 24 ) 24 Karnofsky (KPS) (Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer) GOG-0213 GOG-0213 carboplatin paclitaxel carboplatin paclitaxel 673 : CP : Carboplatin (AUC5) paclitaxel (175 mg/m 2 IV 3 ) 3 6 8 CPB : Carboplatin (AUC5) paclitaxel (175 mg/m 2 IV 3 ) (15 mg/kg) 3 6 8 (15 mg/kg 3 ) (OS) (PFS) (ORR) GOG-0213 (OS) CP (n=336) CPB (n=337) 32

OS ( ) 37.3 42.6 (95% CI) 0.823 (CI: 0.680, 0.996) P 0.0447 (PFS) CP (n=336) CPB (n=337) PFS ( ) 10.2 13.8 (95% CI) 0.613 (CI: 0.521, 0.721) P <0.0001 (CR, PR) (%) CP* (n=336) CPB* (n=337) 159 (55.6%) 213 (77.7%) P <0.0001 *(ITT) 15 mg/kg (carboplatin paclitaxel) 6 8 carboplatin paclitaxel (OS) AVF4095g (AVF4095g) bevacizumab carboplatin gemcitabine carboplatin gemcitabine 6 bevacizumab 484 : Carboplatin (AUC4) gemcitabine (1000 mg/m 2 8 ) 3 6 10 ( 3 ) 33

Carboplatin (AUC4, ) gemcitabine (1000 mg/m 2 8 ) (15 mg/kg) 3 6 10 (15 mg/kg 3 ) RECIST (modified RECIST 1.0) AVF4095g +C/G + C/G +C/G + 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 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 + C/G +C/G + C/G (n = 242) (n = 242) (n = 242) (n = 242) 57.4% 78.5% 53.7% 74.8% 34

P <0.0001 <0.0001 +C/G (n = 242) + C/G (n = 242) OS ( ) 32.9 33.6 (95% CI) 0.950 [0.771, 1.176] P 0.6479 +C/G (n = 242) +C/G (n = 242) 6-12 (n=202) 8.0 11.9 (95% CI) 0.41 (0.29-0.58) 12 (n=282) 9.7 12.4 (95% CI) 0.55 (0.41-0.73) MO22224 (AURELIA) MO22224 bevacizumab bevacizumab (CT+BV)(CT) 3 361 (paclitaxel topotecan PLD) bevacizumab 35

CT ( ) o 4 1 8 15 22 paclitaxel 80 mg/m 2 1 o 4 1 8 15 Topotecan 4 mg/m 2 30 3 1-5 1.25 mg/m 2 30 o 4 1 1 mg/min PLD 40 mg/m 2 1 1 CT+BV ( bevacizumab) o 2 bevacizumab 10 mg/kg ( 3 1-5 topotecan 1.25 mg/m 2 3 bevacizumab 15 mg/kg) 4 612 FIGO Stage IIIC Stage IV ECOG (PS) 0 (CT: 56.4% vs. CT + BV: 61.2%) ECOG PS 1 2 CT38.7% 5.0%CT+BV29.8% 9.0% 29.3% 61.0 (25-84 ) 16 (4.4%) 75CT 8.8%CT+BV43.6% (Grade 2-3 ) CT2.4CT+BV5.265 CT8.8%CT+BV50.0% 6565 0.47 (95% CI: 0.35, 0.62) 0.45 (95% CI: 0.31, 0.67) 六 六 MO22224 (AURELIA) * CT (n=182) CT+BV (n=179) ( ) 3.4 6.7 (95% CI) 0.379 [0.296, 0.485] P <0.0001 ** CT CT+BV 36

(n=144) (N=142) ( ) 18 (12.5%) 40 (28.2%) P 0.0007 ()*** CT (n=182) CT+BV (n=179) OS ( ) 13.3 16.6 (95% CI) 0.870 (0.678, 1.116) P 0.2711 * 切 2011 11 14 ** *** 266 OS 73.7% (paclitaxel, topotecan or PLD) bevacizumab 10 mg/kg (31 51.25 mg/m 2 topotecan bevacizumab15mg/kg 3) bevacizumab (paclitaxel, topotecan and PLD) CT CT+BV Paclitaxel n=115 () 3.9 9.2 (95% CI) 0.47 [0.31, 0.72] () 13.2 22.4 (95% CI) 0.64 [0.41, 0.99] Topotecan n=120 () 2.1 6.2 (95% CI) 0.28 [0.18, 0.44] () 13.3 13.8 (95% CI) 1.07 [0.70, 1.63] PLD n=126 () 3.5 5.1 (95% CI) 0.53 [0.36, 0.77] () 14.1 13.7 (95% CI) 0.91 [0.61, 1.35] 37

(Cervical Cancer) GOG-0240 bevacizumab (paclitaxel cisplatin paclitaxeltopotecan) 4 III (GOG-0240) 452 1 paclitaxel 135 mg/m 2 24 2 cisplatin 50 mg/m 2 3 (q3w) 1 paclitaxel 175 mg/m 2 3 2 cisplatin 50 mg/m 2 3 (q3w) 1 paclitaxel 175 mg/m 2 3 1 cisplatin 50 mg/m 2 3 (q3w) 1 paclitaxel 135 mg/m 2 24 2 cisplatin 50 mg/m 2 2 bevacizumab 15 mg/kg 3 (q3w) 1 paclitaxel 175 mg/m 2 3 2 cisplatin 50 mg/m 2 2 bevacizumab 15 mg/kg 3 (q3w) 1 paclitaxel 175 mg/m 2 3 1 cisplatin 50 mg/m 2 1 bevacizumab 15 mg/kg 3 (q3w) 1 paclitaxel 175 mg/m 2 3 1-3 topotecan 0.75 mg/m 2 30 3 (q3w) 1 paclitaxel 175 mg/m 2 3 1-3 topotecan 0.75 mg/m 2 30 1 bevacizumab 15 mg/kg 3 (q3w) / bevacizumab 38

46 (: 20-83) 48.0 (: 22-85) 9.3% 65 7.5% 452 ( 80.0% 75.3%) ( 67.1% 69.6%)/ ( 83.6% 82.8%) 1-2 ( 72.0% 76.2%) ( 50.2% 56.4%) 6 ( 72.5% 64.4%) (OS) (PFS) (ORR) GOG-0240 (225 ) + (227 ) 6 ( ) 1 12.9 16.8 [95% ] 0.74 [0.58;0.94] (p 5 = 0.0132) 7 ( ) 1 13.3 16.8 [95% ] 0.76 [0.62;0.94] (p 5,8 = 0.0126) 6 ( ) 1 6.0 8.3 [95% ] 0.66 [0.54;0.81] (p 5 = <0.0001) 6 ( 2 ) 76 (33.8 %) 103 (45.4 %) 95% 3 [27.6; 40.4] [38.8; 52.1] 11.60 95% 4 [2.4; 20.8] p () 0.0117 39

1 Kaplan-Meier 2 ; 3 Pearson-Clopper 95% 4 Hauck-Anderson 95% 5 () 6 切 2012 12 12 7 切 2014 3 7 8 P GOG-0240 1 (95% ) 2 (95% ) Cisplatin + Paclitaxel 0.72 (0.51, 1.02) (17.5 vs. 14.3 ; p=0.0609) 0.75 (0.55, 1.01) (17.5 vs. 15.0 ; p=0.0584) Topotecan + Paclitaxel 0.76 (0.55, 1.06) (14.9 vs. 11.9 ; p=0.1061) 0.79 (0.59, 1.07) (16.2 vs. 12.0 ; p=0.1342) Topotecan + Paclitaxel Cisplatin + Paclitaxel 1.15 (0.82, 1.61) (14.9 vs. 17.5 ; p=0.4146) No 1.13 (0.81, 1.57) (11.9 vs. 14.3 ; p=0.4825) 1.15 (0.85, 1.56) (16.2 vs. 17.5 ; p=0.3769) 1.08 (0.80, 1.45) (12.0 vs. 15.0 ; p=0.6267) 1 切 2012 12 12 7 切 2014 3 7 P 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 ] 40

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 3.2.4 bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab bevacizumab 3.3 3.3.1 41

3.3.2 3.3.3 cynomolgus cynomolgus 13 26 4 2 bevacizumab 50 / bevacizumab 3.3.4 10-100 / 2.5.1 2.6.2 () 3.3.5 (Physeal) cynomolgus 26 0.8 2.5.3 2.6.2 () 5 2 50 / 2 (re-epithelialisation) 2 10 / 2 / 0.5 2 / 0.5 / cynomolgus 切 42

cynomolgus 26 100 / ( 80 ) cisplatin cynomolgus 10 / 50 / 26 cynomolgus 50 / cynomolgus 26 4. 4.1 (EXP) 2 C-8 C 0.9% 2-30 C 48 2-8 C 24 43

4.2 ( ) (intravenous push or bolus) bevacizumab 0.9% bevacizumab 1.4 16.5 / (polyvinyl chloride)(polyolefin) (5%) / 4.3 100 /4 ; 400 /16 100 2016 6 CDS34.0 03.18-AVA-3B01 000807 (1): : Roche Diagnostics GmbH : Sandhoferstrasse 116, D-68305, Mannheim, Germany : : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland (2) : 44

: Genentech Inc. : 4625 NW Brookwood, Parkway, Hillsboro, OR 97124, USA : : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland (3) : : F. Hoffmann-La Roche Ltd. : Wurmisweg, CH-4303, Kaiseraugst, Switzerland 3 134 9 (02)27153111 45