420 PERJETA Vial 420mg Pertuzumab 000942 - PERJETA - 1 PERJETA Herceptin docetaxel HER2 HER2 2 2.1 PERJETA 840 mg 60 3 420 mg 30 60 trastuzumab PERJETA trastuzumab 8 mg/kg 90 3 6 mg/kg 30 90 PERJETA trastuzumab docetaxel PERJETA trastuzumab Docetaxel PERJETA trastuzumab PERJETA trastuzumab docetaxel 30 60 [ (5.3)] 2.2 6 PERJETA 420 mg ( ) 6 PERJETA 840 mg 60 3 30 60 420 mg PERJETA [(5.3)] (LVEF) PERJETA trastuzumab 3 40% 1
LVEF 40% - 45% 10% [(5.2)] LVEF 45% 40-45% 10% PERJETA 3 PERJETA trastuzumab[ (5.2)] trastuzumab PERJETA docetaxel PERJETA trastuzumab PERJETA Docetaxel docetaxel 2.3 PERJETA PERJETA 250 ml 0.9%(PVC) (non-pvc polyolefin) 2 C - 8 C 24 0.9%(5%) 3 PERJETA (pertuzumab) 420 mg/14 ml (30 mg/ml) 4 pertuzumab 5 5.1-2
PERJETA (cynomolgus monkey) pertuzumab - PERJETA [ (8.1)] PERJETA - PERJETA PERJETA 5.2 HER2 ( PERJETA ) trastuzumab docetaxel PERJETA trastuzumab docetaxel (LVSD) (LVEF) [ (13.1)] PERJETA 4.4% 8.3% PERJETA ( ) 1.0% 1.8% [ (6.1)] anthracyclines PERJETA 50% (CHF) trastuzumab < 50% anthracycline > 360 mg/m 2 doxorubicin PERJETA ( 3 ) < 40% 40% - 45% 10% PERJETA trastuzumab 3 PERJETA trastuzumab [ (2.2)] 5.3 / PERJETA [ (6.1)] (anaphylactic reaction) PERJETA trastuzumab docetaxel PERJETA PERJETA PERJETA 13.0% 9.8% 1% 3-4 ( 1.0%) 3
PERJETA ( 1.0%) PERJETA / 10.8% 9.1% (NCI-CTCAE) PERJETA 3-4 / 2% 2.5% PERJETA 4 2 PERJETA 60 30 [ (2.2)] 5.4 HER2 HER2 PERJETA [(1) (13)] HER2 Dako Herceptest IHC 3+ Dako HER2 FISH PharmDx (FISH) 2.0 FISH IHC HER2 ( ) 6 -[(5.1)] [(5.2)] / [(5.3)] 6.1 1400 PERJETA PERJETA 1 804 HER2 PERJETA trastuzumab docetaxel trastuzumab docetaxel PERJETA 18.1 11.8 PERJETA 4
trastuzumab PERJETA 6.1% 5.3% PERJETA docetaxel 23.6% 23.2% 1 PERJETA 10% PERJETA trastuzumab docetaxel (> 30%) NCI-CTCAE 3-4 (> 2%) pertuzumab (26%) (12%) 5
1 10% PERJETA / PERJETA + trastuzumab + docetaxel % n=407 % 3 ~ 4 % + trastuzumab + docetaxel % n=397 % 3 ~ 4 % 37.6 2.2 36.8 3.3 26.0 2.5 30.2 1.5 23.1 0.5 30.0 0.8 27.8 1.5 19.9 1.0 18.7 1.2 17.9 0.5 60.9 0.0 60.5 0.3 33.7 0.7 24.2 0.8 22.9 1.2 22.9 0.3 14.0 0.0 10.1 0.0 10.6 0.0 4.3 0.0 66.8 7.9 46.3 5.0 42.3 1.2 41.6 0.5 24.1 1.5 23.9 1.5 15.0 0.0 24.9 1.0 18.9 0.5 15.4 0.3 52.8 48.9 49.6 45.8 23.1 2.5 18.9 3.5 18.2 12.3 20.4 14.6 * 13.8 13.0 7.6 7.3 32.4 3.2 33.8 2.0 20.9 1.2 16.9 0.5 18.4 0.0 15.6 0.0 12.5 0.5 12.1 0.0 22.9 1.0 23.9 0.8 6
15.5 0.2 16.1 0.8 16.7 0.7 13.4 0.0 11.8 0.0 12.8 0.3 14.0 1.0 15.6 2.0 29.2 1.7 26.4 1.5 14.0 0.0 13.9 0.0 13.3 0.0 13.4 0.0 * PERJETA < 10% (PERJETA 7.1% 3.5%) (PERJETA 5.2% 5.8%) (PERJETA 4.4% 8.3%) (CHF) (PERJETA 1.0% 1.8%) (PERJETA 10.1% 8.6%) Docetaxel PERJETA Trastuzumab docetaxel PERJETA trastuzumab < 10%(19.1%) (12.8%) (11.7%) (11.4%) (11.1%) 6.2 PERJETA PERJETA PERJETA 2.8% (11/386) 6.2% (23/372) PERJETA 34 (ATA)/ (anaphylactic/hypersensitivity reactions) ATA pertuzumab pertuzumab trastuzumab pertuzumab 7
PERJETA 7 pertuzumab trastuzumab pertuzumab docetaxel 8 8.1 D PERJETA PERJETA PERJETA (trimester) (cynomolgus monkey) pertuzumab (C max ) 2.5 20 - PERJETA PERJETA 19 30-150 mg/kg pertuzumab 2 10-100 mg/kg C max 2.5-20 Pertuzumab 19 50 ( ) 25 70 2 10 30 100 mg/kg pertuzumab ( C max 2.5-20 ) - 33 50 85% 100 pertuzumab pertuzumab 100 29% - 40% 8.3 PERJETA IgG PERJETA PERJETA [(5.1) (11.2)] 8
8.4 PERJETA 8.5 PERJETA 402 60 (15%) 65 5 (1%) 75 PERJETA < 65 (n = 306) 65 (n = 175) pertuzumab 8.6 PERJETA - PERJETA PERJETA 6 8.7 ( [CLcr] 60-90 ml/min) (CLcr 30-60 ml/min) PERJETA (CLcr 30 ml/min) [ (11.2)] 8.8 pertuzumab 9 PERJETA 10 Pertuzumab (HER2) ( II) Pertuzumab (DNA) ( ) gentamicin gentamicin Pertuzumab 148 kda PERJETA 420 mg pertuzumab 30 mg/ml L-histidine Glacial Acetic Acid Sucrose Polysorbate 20 9
11 11.1 Pertuzumab (HER2) ( II) HER2 (HER)( EGFR HER3 HER4) (ligand-dependent heterodimerization)pertuzumab [ (Mitogen-activated protein, MAP) 3 (phosphoinositide 3-kinase, PI3K)] (ligand-initiated intracellular signaling) pertuzumab (antibody-dependent cell-mediated cytotoxicity, ADCC) pertuzumab pertuzumab trastuzumab HER2 11.2 Pertuzumab 2-25 mg/kg ( 481 ) pertuzumab (CL) 0.24 L/day 18 840 mg 3 420 mg pertuzumab () (baseline serum albumin)(lean body weight) 37 pertuzumab trastuzumab pertuzumab docetaxel PERJETA (CLcr 60-90 ml/min n = 200) (CLcr 30-60 ml/min n = 71) pertuzumab (CLcr 90 ml/min n = 200) CLcr (27-244 ml/min) CLcr pertuzumab 11.3 20 HER2 840 mg 3 420 mg pertuzumab QTc Fridericia QT ( 20 ms) QTc ( 10 ms) 10
12 12.1 pertuzumab pertuzumab pertuzumab pertuzumab 6 13 13.1 808 HER2 HER2 IHC 3+ FISH 2.0 1:1 trastuzumab docetaxel PERJETA trastuzumab docetaxel (/ HER2 ) ( ) 12 (disease free interval) PERJETA 840 mg 3 420 mg Trastuzumab 8 mg/kg 3 6 mg/kg PERJETA trastuzumab Docetaxel 75 mg/m 2 3 6 docetaxel 100 mg/m 2 16.2 PERJETA 19.9 (IRF)(PFS) PFS 18 ( )(OS) PFS ( ) (ORR) 54 ( 22-89 ) 59% 32% 4% 2 17% 14% 38%31% ( 48% 50%) (78%) (22%) HER2 ( 47% PERJETA 46%) 45% 11% 11% trastuzumab IRF PFS PERJETA [ (HR)= 0.62 95%(CI) 0.51, 0.75 p < 0.0001] 11
PFS 6.1 (PERJETA PFS 18.5 12.4 ) ( 1) PFS IRF PFS (< 65 65 ) / HER2 ( ) / trastuzumab ( )(n = 408) 0.55 (95% CI 0.42, 0.72)(n = 388) 0.72 (95% CI 0.55, 0.95) (n = 178) 0.96 (95% CI 0.61, 1.52) PFS 165 (23.6%) PERJETA (17.2%) OS OS 1 2 OS OS [ = 0.66 (95% CI 0.52, 0.84) p=0.0008] 2 2 OS IRF PFS [ = 1.42 (95% CI 0.71, 2.84)] 12
() 2 PERJETA + trastuzumab + docetaxel n=402 + trastuzumab + docetaxel n=406 (95% ) p ( ) ( 2 ) 191 (47.5%) 18.5 242 (59.6%) 12.4 0.62 (0.51, 0.75) < 0.0001 ( ) 113 (28.1%) NR 154 (37.9%) 37.6 0.66 (0.52, 0.84) 0.0008* (ORR ) 343 336 (CR + PR) 275 (80.2%) 233 (69.3%) (CR) 19 (5.5%) 14 (4.2%) (PR) 256 (74.6%) 219 (65.2%) ( ) 20.2 12.5 95% 10.8% (4.2%, 17.5%) 0.0011 * 2 p ( 0.739 p 0.0138) NR = CI = 13
1 IRF Kaplan-Meier 2 Kaplan-Meier 14
14 / 14.1 PERJETA 420 mg/14 ml (30 mg/ml) 2 C-8 C (36 F-46 F) 15 PERJETA - [(5.1)(8.1)] PERJETA PERJETA 6 [(5.1) (8.6)] PERJETA PERJETA [(8.3)] 14 100 Ref: US PI_201304 05.13-PER-3-A-01 Roche Diagnostics GmbH Sandhofer Strasse 116, D-68305 Mannheim, Germany F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland. 3 134 9 (02)27153111 15