0715-PER-01 0713-PER-01 420 PERJETA Vial 420mg Pertuzumab 000942 - PERJETA PERJETA PERJETA PERJETA - 1 1.1 PERJETA trastuzumabherceptin docetaxel HER2 HER2 1.2 PERJETA trastuzumab docetaxel HER2 2 cm [ ( 14.2 ) ( 2.1 )] PERJETA doxorubicin 6 PERJETA 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 1
trastuzumab docetaxel 30 60 [ (5.3)] (MBC) docetaxel PERJETA docetaxel 75 mg/m 2 3 100 mg/m 2 3 PERJETA 3 6 [ ( 14.2 )] 2 (NEOSPHERE) PERJETA trastuzumab docetaxel 4 fluorouracil epirubicin cyclophosphamide (FEC) 3 3 (TRYPHAENA) FEC 3 PERJETA docetaxel trastuzumab 3 3 (TRYPHAENA) PERJETA docetaxel carboplatin trastuzumab (TCH) 6 ( docetaxel 75 mg/m 2 ) trastuzumab 1 PERJETA 6 anthracycline PERJETA PERJETA doxorubicin 2.2 6 PERJETA 420 mg ( ) 6 PERJETA 840 mg 60 3 30 60 420 mg trastuzumab PERJETA PERJETA Docetaxel docetaxel PERJETA [(5.3)] (LVEF) PERJETA trastuzumab 3 405 LVEF 405-459 10 [(5.2)] 2
LVEF 459 405-459 10 PERJETA 3 PERJETA trastuzumab[ (5.2)] trastuzumab PERJETA docetaxel PERJETA trastuzumab PERJETA Docetaxel docetaxel PERJETA [ (5.3)] / [(5.4)] 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 3
pertuzumab 5 5.1 - 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 2 (NEOSPHERE) trastuzumab docetaxel PERJETA (LVSD) PERJETA trastuzumab docetaxel (LVEF) trastuzumab docetaxel 1.9 LVEF >10 50 PERJETA trastuzumab docetaxel 8.4 PERJETA trastuzumab 0.9 LVSD 3 LVEF 50 3 (TRYPHAENA) PERJETA PERJETA trastuzumab FEC PERJETA trastuzumab docetaxel 6.9 LVEF >10 50 FEC PERJETA trastuzumab docetaxel 16.0 PERJETA TCH 10.5 FEC PERJETA trastuzumab docetaxel 4.0 LVSD PERJETA TCH 1.3 PERJETA trastuzumab FEC PERJETA trastuzumab 4
docetaxel LVEF 50 PERJETA 50 (CHF) trastuzumab < 50 anthracycline > 360 mg/m 2 doxorubicin PERJETA ( 3 ) < 405 405-459 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) PERJETA ( 1.0) 2 (NEOSPHERE) 3 (TRYPHAENA) PERJETA 1 (CLEOPATRA) (NCI - CTCAE 3.0 ) 1 2 PERJETA / 10.8 9.1 (NCI-CTCAE) PERJETA 3-4 / 2 2.5 PERJETA 4 2 PERJETA 60 30 [ (2.2)] 5.4 / 5
1 (CLEOPATRA) PERJETA / 10.8 9.1 (NCI-CTCAE) 3.0 PERJETA 3-4 / 2 2.5 PERJETA 4 2 2 (NEOSPHERE) 3 (TRYPHAENA) / 1 (CLEOPATRA) 2 (NEOSPHERE) 2 PERJETA docetaxel 3 (TRYPHAENA) / PERJETA TCH (13.2) 2.6 NCI-CTCAE ( 3 ) 3 4 PERJETA [ (6)] PERJETA PERJETA [ (4)] 5.45 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)] / [(5.4)] 6.1 1400 PERJETA PERJETA 6
1 804 HER2 PERJETA trastuzumab docetaxel trastuzumab docetaxel PERJETA 18.1 11.8 PERJETA 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) 1 10 PERJETA PERJETA + + trastuzumab + trastuzumab + docetaxel docetaxel / n=407 n=397 3 ~ 4 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 7
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 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 8
docetaxel PERJETA trastuzumab < 10(19.1) (12.8) (11.7) (11.4) (11.1) ( 2 (NEOSPHERE)) 2 (NEOSPHERE) PERJETA trastuzumab docetaxel 4 1 (CLEOPATRA) PERJETA (>30) NCI-CTCAE 3.0 3-4 (>2) 2 2 (NEOSPHERE) PERJETA 2 2(NEOSPHERE) PERJETA 10 PERJETA + / Trastuzumab + docetaxel n=107 trastuzumab + docetaxel n=107 PERJETA + trastuzumab n=108 PERJETA + docetaxel n=108 3 4 3 4 3 4 3 4 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0 9
10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0 12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0 2 (NEOSPHERE) <10 PERJETA (Ptz = pertuzumab T = trastuzumab D = docetaxel) ( T + D 6.5 Ptz + T + D 2.8 Ptz + T 4.6 Ptz + D 8.5) ( T + D 6.5 Ptz + T + D 8.4 Ptz + T 0.0 Ptz + D 7.4) ( T + D 1.9 Ptz + T + D 5.6 Ptz + T 5.6 Ptz + D 5.3) ( T + D 3.7 Ptz + T + D 2.8 Ptz + T 5.6 Ptz + D 3.2) ( T + D 2.8 Ptz + T + D 4.7 Ptz + T 1.9 Ptz + D 7.4) ( T + D 3.7 Ptz + T + D 4.7 Ptz + T 2.8 Ptz + D 2.1) ( T + D 0.9 Ptz + T + D 2.8 Ptz + T 0.0 Ptz + D 1.1) (CHF) ( Ptz + T 0.9 T + D Ptz + T + D Ptz + D 0.0) ( T + D 1.9 Ptz + T + D 3.7 Ptz + T 0.9 Ptz + D 4.3) ( 3 (TRYPHAENA)) 3 (TRYPHAENA) FEC 3 PERJETA trastuzumab docetaxel 3 (>30) NCI-CTCAE 3 3-4 (> 2) PERJETA docetaxel, carboplatin trastuzumab (TCH) 6 (>30) NCI-CTCAE 3 3-4 (> 2) 10
ALT FEC PERJETA trastuzumab docetaxel 6.7 PERJETA TCH 7.9 3 3 (TRYPHAENA) PERJETA 3 3 (TRYPHAENA) PERJETA 10 / PERJETA + trastuzumab + FEC PERJETA + trastuzumab + docetaxel n = 72 3 4 FEC PERJETA + trastuzumab + docetaxel n = 75 3 4 PERJETA + TCH n = 76 3 4 36.1 0.0 36.0 0.0 42.1 3.9 9.7 0.0 14.7 1.3 13.2 1.3 11.1 0.0 4.0 0.0 9.2 0.0 23.6 0.0 20.0 0.0 17.1 1.3 16.7 0.0 9.3 0.0 15.8 0.0 48.6 0.0 52.0 0.0 55.3 0.0 19.4 0.0 10.7 0.0 21.1 1.3 5.6 0.0 9.3 0.0 10.5 0.0 6.9 0.0 10.7 0.0 7.9 0.0 61.1 4.2 61.3 5.3 72.4 11.8 25.0 1.4 8 0.0 22.4 0.0 52.8 0.0 53.3 2.7 44.7 0.0 40.3 0.0 36.0 2.7 39.5 5.3 18.1 0.0 22.7 0.0 15.8 0.0 13.9 0.0 17.3 0.0 11.8 0.0 51.4 47.2 46.7 42.7 48.7 46.1 19.4 1.4 9.3 4.0 38.2 17.1 22.2 19.4 16.0 12.0 17.1 11.8 18.1 18.1 9.3 9.3 17.1 17.1 6.9 0.0 1.3 0.0 30.3 11.8 11
9.7 2.8 1.3 0.0 11.8 2.6 5.6 0.0 1.3 0.0 10.5 0.0 22.2 0.0 14.7 0.0 17.1 0.0 11.1 0.0 13.3 0.0 21.1 0.0 8.3 0.0 8.0 1.3 15.8 0.0 16.7 0.0 10.7 1.3 10.5 0.0 11.1 0.0 12.0 0.0 6.6 0.0 9.7 0.0 5.3 0.0 11.8 0.0 12.5 0.0 8.0 2.7 10.5 1.3 11.1 0.0 10.7 0.0 15.8 1.3 8.3 0.0 6.7 0.0 11.8 0.0 20.8 0.0 10.7 0.0 21.1 0.0 12.5 0.0 5.3 0.0 7.9 0.0 11.1 0.0 13.3 0.0 21.1 0.0 ALT 6.9 0.0 2.7 0.0 10.5 3.9 FEC = 5-fluorouracil epirubicin cyclophosphamide TCH = docetaxel carboplatin trastuzumab 3 (TRYPHAENA) < 10 (Ptz = pertuzumab T = trastuzumab D = docetaxel FEC = fluorouracil epirubicin cyclophosphamide TCH = docetaxel carboplatin trastuzumab) ( Ptz + T + FEC/Ptz + T + D 9.7 FEC/Ptz + T + D 6.7 Ptz + TCH 9.2)( Ptz + T + FEC/Ptz + T + D 0 FEC/Ptz + T + D Ptz + TCH 1.3)( Ptz + T + FEC/Ptz + T + D 2.8 FEC/Ptz + T + D 4.0 Ptz + TCH 3.9) ( Ptz + T + FEC/Ptz + T + D 8.3 FEC/Ptz + T + D 4.0 Ptz + TCH 2.6)( Ptz + T + FEC/Ptz + T + D 6.9 FEC/Ptz + T + D 6.7 Ptz + TCH 7.9) ( Ptz + T + FEC/Ptz + T + D 1.4 FEC/Ptz + T + D Ptz + TCH 0) ( Ptz + T + FEC/PTZ + T + D 5.6 FEC/Ptz + T + D 4.0 Ptz + TCH 2.6) (CHF) ( FEC/Ptz + T + D 2.7 Ptz + T + FEC/Ptz + T + D Ptz + TCH 0) 12
6.2 PERJETA PERJETA PERJETA 2.8 (11/386) 6.2 (23/372) PERJETA 34 (ATA)/ (anaphylactic/hypersensitivity reactions) ATA pertuzumab pertuzumab trastuzumab pertuzumab 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 13
PERJETA IgG PERJETA PERJETA [(5.1) (11.2)] 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 11 11.1 Pertuzumab (HER2) ( II) HER2 (HER)( 14
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) 12 12.1 pertuzumab pertuzumab pertuzumab pertuzumab 6 13 13.1 15
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 3831 ( 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] 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 16
1 2 OS OS [ = 0.66 (95 CI 0.52, 0.84) p=0.0008] 24 2 OS IRF PFS [ = 1.42 (95 CI 0.71, 2.84)] () 24 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 = 17
1 IRF Kaplan-Meier 2 Kaplan-Meier 18
13.2 2 (NEOSPHERE) 2 (NEOSPHERE) 417 HER2 (T2-4d)HER2 (IHC) 3 + (FISH) 2.0 4 1 Trastuzumab docetaxel PERJETA trastuzumab docetaxel PERJETA trastuzumab PERJETA docetaxel ( ) (ER) (PgR) PERJETA 840 mg 3 420 mg 4 Trastuzumab 8 mg/kg 3 6 mg/kg 4 Docetaxel 75 mg/m 2 3 4 docetaxel 100 mg/m 2 3 5-fluorouracil (600 mg/m 2 ) epirubicin (90 mg/m 2 ) cyclophosphamide (600 mg/m 2 ) (FEC) 3 trastuzumab 3 1 PERJETA trastuzumab FEC docetaxel 3 4 (pcr) (ypt0/is) (US FDA) pcr (ypt0/is ypn0) ( 49-50 [71]) 732 61 ( ER / PgR ) 5 US FDA trastuzumab docetaxel PERJETA trastuzumab docetaxel pcr PERJETA pcr 5 2 (NEOSPHERE) / H+T Ptz+H+T Ptz+H Ptz+T (ITT) N=107 N=107 N=107 N=96 pcr 1 n () [95] 2 23 (21.5) [14.1, 30.5] p- ( CMHSimes ) 3 42 (39.3) [30.0, 49.2] 0.0063 ( H + T) 12 (11.2) [5.9, 18.8] 0.0223 ( H + T) 17 (17.7) [10.7, 26.8] 0.0018 ( Ptz + H + T) N=50 N=50 N=51 4 N=46 19
6 pcr 1 n () [95] 2 (12.0) [4.5, 24.3] 11 (22.0) [11.5, 36.0] 1 (2.0) [0.1, 10.5] 4 (8.7) [2.4, 20.8] N=57 N=57 N=55 4 N=50 17 pcr 1 n () [95] 2 (29.8) [18.4, 43.4] T = docetaxel Ptz = PERJETA H = trastuzumab 1 ypt0/is ypn0 ( ) 31 (54.4) [40.7, 67.6] 11 (20.0) [10.4, 33.0] 2 Pearson-Clopper 95 3 Cochran-Mantel-Haenszel (CMH) Simes p 4 1 pcr 13 (26.0) [14.6, 40.3] 3 (TRYPHAENA) 225 HER2 ( PERJETA) HER2 (IHC) 3 + (FISH) 2.0 3 1 3 FEC 3 docetaxel PERJETA trastuzumab 3 FEC 3 PERJETA docetaxel trastuzumab 6 PERJETA docetaxel carboplatin trastuzumab (TCH) ( ) (ER) (PgR) PERJETA 840 mg 3 420 mg Trastuzumab 8 mg/kg 3 6 mg/kg 5-Fluorouracil (500 mg/m 2 ) epirubicin (100 mg/m 2 ) cyclophosphamide (600 mg/m 2 ) 3 3 PERJETA trastuzumab docetaxel FEC docetaxel 75 mg/m 2 3 3 docetaxel 100 mg/m 2 PERJETA TCH docetaxel 75 mg/m 2 ( ) carboplatin (AUC 6) 3 6 trastuzumab 1 (trastuzumab 3 ) ( 49-50 [76]) 625 69 ER / PgR PERJETA trastuzumab FEC PERJETA trastuzumab docetaxel FEC PERJETA trastuzumab docetaxel 20
PERJETA TCH pcr (ypt0/is ypn0) 56.2 (95 CI 44.1 67.8) 54.7 (95 CI 42.7 66.2) 63.6 (95 CI 51.9 74.3) pcr pcr 41.0 (95 CI 25.6 57.9) 45.7 (95 CI 28.8 63.4) 47.5 (95 CI 31.5 63.9) 73.5 (95 CI 55.6 87.1) 62.5 (95 CI 45.8 77.3) 81.1 (95 CI 64.8 92.0) 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_20130420130930 05.13-PER-3-A-0103.14-PER-3B01 Roche Diagnostics GmbH Sandhofer Strasse 116, D-68305 Mannheim, Germany F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland. 3 134 9 21
(02)27153111 22