0318-HER-01 150 440 440 Herceptin Vial 150 mg Vial 440 mg Trastuzumab HERCEPTIN Herceptin( <LVEF>)Herceptinanthracycline Herceptin Herceptin Herceptin Herceptin Herceptin 24 Herceptin Herceptin 1 Herceptin HER2 HER2 amplification 1. (EBC) (1) () (2) doxorubicin cyclophosphamide paclitaxel docetaxel (3) docetaxel carboplatin (4) () (>2 ) 2. (MBC) (1) () anthracycline taxane anthracycline taxane (2) paclitaxel docetaxel 1
(3) 3. (mgc) Herceptin capecitabine( 5-fluorouracil) cisplatin HER2 () (1) HER2 () (Validation)(Performance) [(12.3)] (2) HER2 (IHC2+/FISH+ IHC3+) HER2 HER2 (IHC 0/FISH+: HR 0.92IHC 1+/FISH+: HR 1.24) HER2 (IHC 2+/FISH+: HR 0.75IHC 3+/FISH+: HR 0.58) 2 HerceptinHER2 (Herceptin) Herceptin (trastuzumab) Kadcyla (trastuzumab emtansine) Herceptin (intravenous push or bolus) Herceptin4/90 Herceptin2/ 30 Herceptin 8 /3 6 / 3 6 / 90 30 Herceptin(disease progression) 1 [(12)] Herceptin Herceptin (2 /6 /) 2
7 21 Herceptin Herceptin Herceptin 90 (4 / 8 /) 7 21 Herceptin (2 /6 /) Herceptin Herceptin [(4.2)] Herceptin [(4.1)] Herceptin(LVEF) Herceptin4 LVEF 16% LVEF 10% 4-8LVEF 15% Herceptin LVEF(>8)Herceptin3 Herceptin 2.1 Herceptin(disposition) Herceptin Herceptin 3 trastuzumab 4 3
() 4.1 Herceptin []Herceptin (LVEF) HerceptinHerceptin 4-6Herceptinanthracycline LVEF 16%LVEF 10%Herceptin [(2.)] HerceptinHerceptin Herceptin (CHF) ( [NYHA] II-IV ) Herceptin anthracycline (doxorubicin epirubicin) Herceptin taxane (paclitaxel docetaxel) ( (LVEF) 55% ) Herceptin trastuzumab 7 [(10.2)] Herceptin anthracycline Herceptin 7 anthracycline anthracylines Herceptin ( anthracycine ) (ECG) (MUGA) Herceptin 3 ( )Herceptin 6 24 (LVEF) 10% 50% Herceptin 3 (CHF) Herceptin ( 6-8 ) Herceptin / Herceptin Herceptin 4
β-/(acei) Herceptin Herceptin (MBC) Herceptin anthracyclines anthracyclines Herceptin Herceptin anthracyclines (EBC) Herceptin ( 3 )( 6 24 ) anthracycline Herceptin 5 (MI)( II-IV ) () Herceptin (Adjuvant threatment) Herceptin anthracyclines anthracyclines Herceptin anthracycline (docetaxel carboplatin)herceptin taxanes 18 4 (> 50 ) (LVEF)(< 55%) paclitaxel Herceptin Herceptin Herceptin anthracycline (BMI>25 kg/m 2 ) - - Herceptin anthracyclines anthracycline doxorubicin 180 mg/m 2 epirubicin 360 mg/m 2 anthracyclines Herceptin - 65 5
Herceptin MUGALVEF LVEF Herceptin3LVEFHerceptin LVEF Herceptin6LVEF2 Herceptin4LVEF [(2.2)] 1 (NSABP B31)AC-TH 8.7 15% (158/1031) LVEF Herceptin 3 (BO16348/HERA) Herceptin 2.6% (44/1678) 4 (BCIRG006)TCH AC-TH 2.9% (31/1056) (1.5% 1.4%) 5.7% (61/1068) (1.5% 4.2%) Herceptin 64[(1 (NSABP B31)2 (NCCTG N9831)] 33 24%LVEF ( 50%)1 HerceptinHerceptin 1 CHF d Herceptin 1& 2 a AC b Paclitaxel+Herceptin 3.2% (64/2000) 1.3% (21/1655) 3 Herceptin 2% (30/1678) 0.3% (5/1708) 4 AC b Docetaxel+Herceptin 2% (20/1068) 0.3% (3/1050) 4 Docetaxel+Carboplatin+Herceptin 0.4% (4/1056) 0.3% (3/1050) a 1 2 AC-TH 8.3 b Anthracycline (doxorubicin) cyclophosphamide c d 1NSABP B31 2NCCTG N9831 36/HERA 4BCIRG006 2 a NYHA I-IV NYHA III-IV d Herceptin Herceptin 5(AC) b 28% 7% 19% 3% 5 (paclitaxel) 11% 1% 4% 1% 6 c 7% N/A 5% N/A 6
a LVEF b Anthracycline (doxorubicin epirubicin) cyclophosphamide c 1 d 5H0648g 6H0649g 4 (BCIRG006)Herceptin[(AC-TH0.3% (3/1068)TCH0.2% (2/1056)]NCI-CTC3/4/HerceptinAC- T() 4.2 Herceptin [5] ( ) [(5.1)] Herceptin diphenhydramine Herceptin Herceptin()Herceptin Herceptin 4.3 Herceptin NCI CTC3-4 () [(5.1)] 4.4 Herceptin [(4.2)] 7
taxane, gemcitabine, vinorelbine Herceptin 4.5 HER2 HER2Herceptin HER2HER2 (IHC)Herceptin (FISH)Herceptin FISHHER2 HerceptinIHCFISH [5 (H0648g)]13IHCFISH [2 (NCCTG N9831)3 (BO16348/HERA)]11 4.6 (D) Herceptin Herceptin HerceptinHerceptin[ (7.1)] Herceptin/ 4.7 4.8 (Benzyl alcohol) 440 HerceptinHerceptin Herceptin150 5 Herceptin/ () ( 1/10)( 1/100 ~ <1/10)( 1/1,000 ~ <1/100)( 1/10,000 ~ <1/1,000)(<1/10,000)() 8
HerceptinHerceptin - 56 (H0648gH0649g)Herceptinpaclitaxel - M77001DocetaxelHerceptin - BO16216HER2anastrozole Herceptin - 3 (BO16348/HERA) HER2 Herceptin - 7 (BO18255/TOGA)HER2Herceptinfluoropyrimidinecisplatin - 12 (NSABP B31NCCTG N9831)doxorubicincyclophosphamide Herceptinpaclitaxel - 4 (BCIRG 006)doxorubicincyclophosphamide HerceptindocetaxelHerceptindocetaxelcarboplatin - 8 (MO16432/NOAH)Herceptin doxorubicinpaclitaxel paclitaxel cyclophosphamide methotrexate 5-fluorouracil Herceptin () 9
/ / 1 1 1 1 1 1 * 10
() (2%) 1 1 1 (14%) 1 11
1 (onychoclasis) 1 12
/ 1 * anthracyclineherceptintaxanes (HERABO163481 1%) 1/10Herceptin (II-IV)Hereptin Herceptin (orthopnea)(s3 gallop) [(4.1)] trastuzumab 3( Herceptin)taxaneHerceptin3/4 ()(0.3-0.4%)Herceptintaxane (2.0%) 13
Herceptin (H0648gH0649gM77001BO16216BO16348BO18255B-31 N9831BCIRG 006MO16432) β-/ Herceptin Herceptin Herceptin anthracycline Herceptin 40% ((NCI-CTC) )( 123 ) () Herceptin 1 2 anthracycline trastuzumab docetaxel Herceptin() 5.1 123 (NSABP B31NCCTG N9831BO16348/HERA) (n=3355)(n=3308) trastuzumab Herceptin 33 (BO16348/HERA)1678Herceptin 51183 (BO16348/HERA) 338649(2180)83%13% 3 3(BO16348/HERA) a MedDRA (v. 7.1) Herceptin 1 (n=1678) (n=1708) 64 (4%) 35 (2%) 14
MedDRA (v. 7.1) Herceptin 1 (n=1678) (n=1708) 60 (4%) 29 (2%) 58 (3.5%) 11 (0.6%) 48 (3%) 12 (0.7%) b 40 (3%) 17 (1%) 30 (2%) 5 (0.3%) 9 (0.5%) 4 (0.2%) 5 (0.3%) 0 (0%) 4 (0.2%) 0 (0%) 135 (8%) 43 (3%) 81 (5%) 34 (2%) 70 (4%) 9 (0.5%) 57 (3%) 26 (2%) 46 (3%) 20 (1%) 36 (2%) 6 (0.4%) 32 (2%) 8 (0.5%) 26 (2%) 5 (0.3%) 25 (2%) 1 (0.06%) 4 (0.2%) 0 (0%) 4 (0.2%) 0 (0%) 123 (7%) 16 (1%) 108 (6%) 19 (1%) 58 (3.5%) 10 (0.6%) 33 (2%) 17 (1%) 30 (2%) 9 (0.5%) 29 (2%) 15 (1%) 137 (8%) 98 (6%) 91 (5%) 58 (3%) 63 (4%) 17 (1%) 49 (3%) 26 (2%) 46 (3%) 3 (0.2%) 162 (10%) 49 (3%) 29 (2%) 11 (0.6%) 70 (4%) 10 (.6%) 43 (2%) 0 (0%) 15
MedDRA (v. 7.1) Herceptin 1 (n=1678) (n=1708) 40 (2%) 10 (0.6%) 100 (6%) 6 (0.4%) 79 (5%) 37 (2%) 85 (5%) 0 (0%) 75 (4.5%) 30 (2%) 40 (2%) 3 (0.2%) 1 (.06%) 0 (0%) 135 (8%) 43 (3%) 39 (3%) 13 (0.8%) 10 (0.6%) 1 (0.06%) 4 (0.3%) 0 (0%) a 3/4<1% b 12 (NSABP B31NCCTG N9831)32061635 Herceptin5049.0(24-80) 84%7%4%(hispanic)4% 1 (NSABP B31)33-5 22-52-5 Herceptin 2%(31%28%)(28%22%)(22% 14%)(17%15%)(13%7%)(12%4%)/(11% 7%)(7%5%)(6%4%)(3.7%1.5%) 2 2 (NCCTG N9831)() HerceptinNCI-CTC45 3-5taxanes2-5( )1-52-5 Herceptin 2%(11%8.4%)(10%8%)(9%7%) (2.5%0.1%)2 4 (BCIRG006) Herceptin 2124 Herceptin [AC-THn = 1068TCHn = 1056] AC-TH TCH 54 AC-TH 26TCH 30 3 49 ( 22-74 ) 4(BCIRG006) 16
12 3 (NSABP B31NCCTG N9831 BO16348/HERA) TCH CHF (n=235)(n = 234) trastuzumab [5 (H0648g)] [6 (H0649g)n=222]Herceptin4 56 4645 (H0648g)52(25-77) 89%5%1%5%4 /Herceptin2/ Herceptin 6 1258%9% 352[2136 (H0649g)] 50(28-86)100%86%3%3% 8%4/Herceptin 2/Herceptin 6 1231% 16% 4 5%()Herceptin (56) (H0648g H0649g) ([%]) a n=352 Herceptin + Paclitaxel n=91 Paclitaxel n=95 Herceptin +AC b n=143 AC b n=135 47 61 62 57 42 42 62 57 54 55 36 49 23 56 34 32 41 4 35 11 26 36 28 44 31 22 34 22 23 18 22 34 30 27 15 20 47 27 47 31 10 12 5 12 6 6 13 3 9 4 3 8 2 4 2 5 12 4 10 5 7 11 1 28 7 33 51 9 76 77 25 45 29 45 26 17
Herceptin + Paclitaxel n=91 Paclitaxel n=95 Herceptin +AC b n=143 AC b n=135 a n=352 23 37 28 53 49 8 14 11 18 9 14 24 16 31 26 4 14 9 36 26 3 24 17 52 34 10 22 20 20 17 8 10 8 11 5 7 24 18 7 7 6 37 21 8 9 14 25 13 29 15 13 22 24 24 18 9 48 39 17 11 6 12 13 20 12 2 23 16 2 2 1 13 5 4 4 26 41 22 43 29 22 27 26 42 25 14 22 5 22 16 12 22 14 30 18 9 21 7 13 6 18 38 18 27 17 2 12 3 7 9 2 11 3 3 < 1 5 18 14 13 7 a Herceptin 4 213 6 (H0649g) b Anthracycline (doxorubicin epirubicin) cyclophosphamide 7 (BO18255/TOGA)trastuzumabfluoropyrimidinecisplatin HER2 5 18
5 ( 10%) / Fluoropyrimidine/Cisplatin (N = 290) N (%) Herceptin Trastuzumab/Fluoropyrimidine/ Cisplatin (N = 294) N (%) 184 (63) 197 (67) 134 (46) 147 (50) 80 (28) 109 (37) 93 (32) 75 (26) 43 (15) 72 (24) 42 (14) 46 (16) 165 (57) 157 (53) 61 (21) 81 (28) 33 (11) 47 (16) 82 (28) 102 (35) 53 (18) 55 (19) 36 (12) 54 (18) 18 (6) 37 (13) 133 (46) 135 (46) 64 (22) 75 (26) 27 (9) 32 (11) 40 (14) 69 (23) 39 (13) 47 (16) 28 (10) 34 (12) 28 (10) 31 (11) 28 (10) 14 (5) 17 (6) 37 (13) 19
(LVEF)3 (BO16348/ HERA)12.6(12.4Herceptin 112.6) 12 (NSABP B31NCCTG N9831)AC-T7.9AC-TH8.3 12 (NSABP B31NCCTG N9831)6%AC (LVEF(LLN)ACLVEF 16%) HerceptinHerceptin12 (NSABP B31NCCTG N9831)Herceptinpaclitaxel paclitaxel3 (BO16348/HERA) Herceptin(612) BO16348 8 Herceptin 1 (CHF) ( III -IV ) 0.8% 4.6% Herceptin (H0648gH0649gM77001BO16216BO16348BO18255 B31N9831BCIRG 006MO16432) β-/ Herceptin Herceptin 71.4% Herceptin (CHF) ( LVEF 50%)79.5% Herceptin NSABP B31 NCCTG N9831 (CHF) ACTH 64.5% 90.3% LVEF 6 a 1234 (NSABP B31NCCTG N9831BO16348/HERABCIRG006) (LVEF)() LVEF <50% LVEF LVEF <50% 10% 16% <20% and 10% 20% 1 2 bc (NSABP B31 NCCTG N9831) AC TH (n=1856) 23.1% (428) 18.5% (344) 11.2% (208) 37.9% (703) 8.9% (166) AC T (n=1170) 11.7% (137) 7.0% (82) 3.0% (35) 22.1% (259) 3.4% (40) 3 (BO16348/HERA) Herceptin (n=1678) 8.6% (144) 7.0% (118) 3.8% (64) 22.4% (376) 3.5% (59) (n=1708) 2.7% 2.0% 1.2% 11.9% 1.2% 20
(46) (35) (20) (204) (21) 4 d (BCIRG006) c TCH (n=1056) 8.5% (90) 5.9% (62) 3.3% (35) 34.5% (364) 6.3% (67) AC TH (n=1068) 17% (182) 13.3% (142) 9.8% (105) 44.3% (473) 13.2% (141) AC T (n=1050) 9.5% (100) 6.6% (69) 3.3% (35) 34% (357) 5.5% (58) a 12 3 (NSABP B31, NCCTG N9831 BO16348/HERA) Herceptin 4 (BCIRG006) b 1 2 (NSABP B31 NCCTG N9831) doxorubicin cyclophosphamide paclitaxel (AC T) paclitaxel Herceptin (AC TH) c 1 2 AC-TH 8.3 d 4 (BCIRG006) doxorubicin cyclophosphamide docetaxel (AC T) docetaxel Herceptin (AC TH); docetaxel carboplatin Herceptin (TCH) 1 12 (NSABP B31 NCCTG N9831)LVEF 10% 50% 0 paclitaxel Herceptin + paclitaxel 2 3 (BO16348/HERA)LVEF 10% 50% 21
0 3 4 (BCIRG006)LVEF 10% 50% 0 (EBC) - 8 (MO16432/NOAH)Herceptin ( 3 doxorubicin 180 mg/m 2 ) Herceptin 1.7% 22
BO22227 Herceptin ( 4 epirubicin 300 mg/m 2 ) 40 Herceptin 0% (I IVIV)(2) Herceptinanthracyclines 7 (BO18255/TOGA)fluoropyrimidine/cisplatin (FP) LVEF 64% (48%-90%)Herceptin + fluoropyrimidine/cisplatin (H+FP) 65% (50%-86%) Herceptin LVEF 7 (BO18255/TOGA) LVEF LVEF LVEF Fluoropyrimidine/Cisplatin (N = 290) (%) Herceptin Trastuzumab/Fluoropyrimidine/ Cisplatin (N = 294) (%) * LVEF<50% 1.1% (2/187) 4.6% (11/237) 10% LVEF<50% 1.1% (2/190) 5.9% (14/239) * LVEF 50% 10% 11.8% (22/187) 16.5% (39/237) *(FP n = 187 H +FP n = 237) Fluoropyrimidine/Cisplatin (N = 290) (%) Herceptin Trastuzumab/Fluoropyrimidine/ Cisplatin (N = 294) (%) 6% 6% NCI CTCAE v3.0 *3% **1% * 9 9 ** 4 5 Herceptin40% acetaminophendiphenhydraminemeperidine( Herceptin)<1% Herceptin()( ) 23
21%35%Herceptin 1.4%9% -(BO22227) 37.2%32.0% 45 Herceptin( 30%21% [5 (H0648g)NCI CTC2-5(12.5%6.6% [1 (NSABP B31)])(0.1%0 [2 (NCCTG N9831)]) Herceptin[6 (H0649g)]NCI- CTC3< 1% Herceptin NCI CTC4-5(2%0.7% [2 (NCCTG N9831)])2-5(7.1%4.5% [1 (NSABP B31)]) HerceptinNCI-CTC 3/4(32%22%)(23% 17%) () 3 () 1% Fluoropyrimidine/Cisplatin (N = 290) (%) Herceptin Trastuzumab/Fluoropyrimidine/ Cisplatin (N = 294) (%) 30% 27% 10% 12% 3% 5% 3% 5% FP NCI CTCAE v3.0 3 ()(SOC) 38% FP + H 40% Herceptin(46%30% [5 (H0648g)])NCI-CTC2-5/(22%14% [1 24
(NSABP B31)])3-5/(3.3%1.4% [2 (NCCTG N9831)]) 4 (BCIRG006) Herceptin AC-T ( TCH ) [44% (AC-TH)37% (TCH)38% (AC-T)] NCI-CTC 3-4 [25% (AC-TH)21% (TCH)23% (AC-T)] HerceptinNCI-CTC 2-5(14%5% [ 1 (NSABP B31)])NCI-CTC3-5 2(3.4%1% [2 (NCCTG N9831)]) (NCI-CTC2-5 12%4% [1 (NSABP B31)]NCI-CTC2-52.5%0.1% [2 (NCCTG N9831)] Herceptin/0.7% 0.3%Herceptin3(1 )1 3 (BO16348/HERA)Herceptin4 Herceptin (4.4) / 4Herceptin (3.0%1.3% [1 (NSABP B31)]3.7% 2.2% [4 (BCIRG006)]2.1%0% [5 (H0648g)]) HerceptinNCI-CTC2-5( 6.2%4.8% [1 (NSABP B31)]NCI-CTC3-5(1.6%0% [2 (NCCTG N9831)]1-4(7%1% [3 (BO16348/HERA)] 4 (BCIRG006)Hercepatin3-4[5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T]1-4[51% AC-TH, 63% TCH vs. 43% AC-T] Herceptin27% 25
3 (BO16348)8%Herceptin1 7 (BO18255/TOGA)Herceptin 109 (37%) 80 (28%) NCI-CTCAE v3.0 FP 3 () 4%FP+H 9% Hercpetin Herceptin418 7 (BO18255/TOGA) Herceptin NCI-CTCAE(v 3.0) 3 () 3% FP 2% NCI-CTCAE(v 3.0) 3 ()(SOC) (Herceptin 1%vs. FP <1%) 5.2 HAHA -8.1% (24/296) Herceptin trastuzumab () Herceptin 24 2 trastuzumab Herceptin [(pcr)][(irr) ] () Herceptin 5.3 Herceptin [(4.2)] 26
[(4.6)] 6 Herceptin Trastuzumab BO15935 M77004 HER2 MBC trastuzumab ( 8 mg/kg 4 mg/kg 3 6 mg/kg 1 2 mg/kg ) paclitaxel doxorubicin ( 6-α hydroxylpaclitaxel, POH doxorubicinol, DOL) trastuzumab doxorubicin (7-deoxy-13 dihydro-doxorubicinone, D7D) D7D JP16003 HER2 MBC Herceptin ( 4 mg/kg 2 mg/kg ) docetaxel (60 mg/m 2 ) trastuzumab docetaxel JP19959 BO18255 27
(ToGA) capecitabine cisplatin Herceptin cisplatin cisplatin Herceptin capecitabine ( 5-FU) Herceptin capecitabine capecitabine capecitabine Herceptin cisplatin H4613g/GO01305 HER2 trastuzumab carboplatin trastuzumab Herceptin ( 4 mg/kg 2 mg/kg ) trastuzumab HER2 MBC ( JP16003) docetaxel trastuzumab II (BO15935 M77004) III (H0648g) Herceptin paclitaxel II Herceptin (W016229 MO16982) HER2 MBC trastuzumab paclitaxel trastuzumab M77004 HER2 MBC Herceptinpaclitaxel doxorubicin Herceptin (H0649g) anthracycline cyclophosphamide paclitaxel ( H0648g) trastuzumab doxorubicin paclitaxel trastuzumab H4613g/GO01305 carboplatin trastuzumab carboplatin trastuzumab anastrozole trastuzumab 7 7.1 D [(4.6)] Herceptin Herceptin HerceptinHerceptin Herceptin Herceptin Herceptin Herceptin/ Herceptin (IV) Herceptin (2/)25trastuzumab 28
HER2HER2 (20-50) (120-150)trastuzumab[(11.2)] Herceptin Herceptin 7[ (10.2)]HerceptinHerceptin Herceptin7 7.2 HerceptinIgG (2/)12.5Herceptin trastuzumabtrastuzumab3 trastuzumab Herceptin trastuzumab 7.3 Herceptin 7.4 36865()Herceptin (253133 )5612 4Herceptin Herceptin Herceptin (ORRTTPOSDFS)<65 7.5 trastuzumab 8 10/ 9 29
Herceptin (trastuzumab)igg1 kappa 2(HER2)Trastuzumab gentamicin() gentamicin Herceptin() Herceptin trastuzumab α,α-trehalose dihydrate L-histidine HCl L- histidine20 (USP)Hercetpin 44020(BWFISWFI) 21trastuzumabpH6 10 10.1 HER2 (c-erbb2)185 kda Herceptin HER215%-20%HER2 BO18255IHC3+FISH+ HER222.1% Herceptin(ADCC) HER2HerceptinADCC HER2 10.2 Trastuzumab Herceptin trastuzumab 10500Herceptin 10500 212Trastuzumab(44/) (500)377/ 4/2/ 6(1-32)1632trastuzumab 79/123/ 8/ 6/trastuzumab16( 11-23)637trastuzumab 63/216/ 64% (286/447)HER2 ()1880/(11/) 30
trastuzumab( 2.0/dL) anthracyclinecyclophosphamidetrastuzumabpaclitaxel trastuzumab1.5herceptin paclitaxeldocetaxelpaclitaxeldoxorubicinher2+ Herceptin 8/6/1 18(1)21Cmax225 /Cmin68.9/ 8/36 /trastuzumab( > 75/)(< 25/) BO18255/TOGA trastuzumab8/6 /() 26AUC(3) 1213/Cmax132/Cmin 27.6/ HER2() 18IIIIII Herceptin1,582trastuzumab trastuzumab (/[MBC/EBC]) 0.127 /(AGC)0.176/ (Vmax)8.81 /Michaelis-Menten(Km)8.92/ 2.62 3.63 (CmaxCmin)(595)7 (1) 8 () 7 (IV) 1 ( 5 95 ) C N min C max AUC (µg/ml) (µg/ml) (µg.day/ml) 8mg/kg + 1195 29.4 178 1373 MBC/EBC 6mg/kg q3w (5.859.5) (117291) (7362245) 31
4mg/kg + 2mg/kg qw AGC MBC/EBC 274 23.1 (6.150.3) 1195 37.7 (12.370.9) 132 (84.2225) 88.3 (58144) 1109 (5881938) 1066 (5861754) 8 Herceptin (IV) ( 5 95 ) C N min,ss C max,ss AUC ss (µg/ml) (µg/ml) (µg.day/ml) CL (L/day) () 8mg/kg + 6mg/kg q3w 4mg/kg + 2mg/kg qw MBC/ EBC 1195 AGC 274 MBC/ EBC 1195 47.4 (5115) 32.9 (6.188.9) 66.1 (14.9142) 179 (107309) 131 (72.5251) 109 (51.0209) 1794 (6733618) 1338 (5572875) 1765 (6473578) 12 9 12 0.173 0.283 0.189 0.337 0.201 0.244 Trastuzumab trastuzumab 95% trastuzumab 7 <1 µg/ml ( C min,ss 3% 97%) 11 11.1 Herceptin Amestrastuzumab 5000/ 118/Herceptin (2/)25Herceptin trastuzumab 11.2 () (2/)25Herceptin HER2HER2 (20-50)(120-150)Herceptin 32
12 12.1 4063[12 (NSABP B31 NCCTG N9831)] 3386 [ 3 (BO16348/HERA)] 3222 [ 4 (BCIRG006)]HerceptinHER2 12 (NSABP B31NCCTG N9831)HER2(3+ IHC)(FISH)HER2 [2 (NCCTG N9831)][ 1 (NSABP B31)] X( >100 mmhg>200 mmhg) (1:1)doxorubicincyclophosphamide paclitaxel (AC paclitaxel)paclitaxelherceptin (AC paclitaxel+ Herceptin) doxorubicin 60/cyclophosphamide 600/ 211 (NSABP B31)(80/) 3(175/)paclitaxel2 (NCCTG N9831) paclitaxelpaclitaxel4/herceptin 2/52 LVEF/Herceptin[(2.)] ER+() PR+ (DFS ) 3752AC paclitaxel+ Herceptin (DFS) 2 4063 AC paclitaxel+ Herceptin8.3707 (OS)1 (NSABP B31)2 (NCCTG N9831) DFS49(22-806% > 65) 84%7%4%4%/ 90%38%T191% 27%66%53%ER+() PR+ AC paclitaxel+ Herceptin8.3 3 (BO16348/HERA)12Herceptin HER2() 2 Herceptin1HerceptinHerceptin 8/Herceptin6/1 2 33
3HER2(3+IHC) (FISH) T1c LVEF<55% (>180 mm Hg>100 mm Hg) (1:1) (n=1693)herceptin1(n=1693) ER+() PgR+ 8/Herceptin 36/52 (DFS)12 (NSABP B31NCCTG N9831) 338649(21-80)83% 13%94%50%ER+ () PgR+57%32%11% 96% (1055/1098)109849% (543) ER PgR 47% (512)ER/ PgR+ 22-3<3594% anthracycline 4 (BCIRG006) HER2 ( FISH+) ER/PR > 2 <35 2 3 CHF (> 100 ) T4 N2 N3 M1 (1:1:1) doxorubicin cyclophosphamide docetaxel (AC T) doxorubicin cyclophosphamide docetaxel Herceptin (AC TH) docetaxel carboplatin Herceptin (TCH) AC-T AC-TH doxorubicin 60 / cyclophosphamide 600 / 3 docetaxel 100 / 3 TCH docetaxel 75 / carboplatin ( 6 // AUC 30 60 ) 3 6 T TC Herceptin ( 4 / 2 /) 3 (6 /) 52 ER+() PR+(DFS) 3222 49 ( 22-74 6% 65 ) 54% ER+() PR+ 71% 34
12 (NSABP B31NCCTG N9831)3 (BO16348/HERA)4 (BCIRG006) DFS12 (NSABP B31NCCTG N9831) 3 (BO16348/HERA) OS912 (NSABP B31NCCTG N9831) AC TH 2DFS48.3OS54 (BCIRG006)DFS64DFS (/)>65 12OS0.64 (95%: 0.55, 0.74)8.3[AC TH] AC TH86.9%AC T79.4%12OS OS(grade) /50 (n = 2197)OS0.65 (95%: 0.52, 0.81)>50 (n = 1866)OS0.63 (95%: 0.51, 0.78)(ER+/PR+) (n = 2223)OS0.63 (95%: 0.51, 0.78)(ER-/PR-) (n = 1830)OS 0.64 (95%: 0.52, 0.80)>2(n = 2448)OS 0.67 (95%: 0.56, 0.80) 9 [1+2 (NSABP B31NCCTG N9831)3 (BO16348/HERA)4 (BCIRG006)] DFS (95% CI) OS DFS p p 1 + 2 a (NSABP B31 NCCTG N9831) e AC TH (n = 1872) b (n = 2031) c 133 b 0.48 b,d (0.39, 0.59) p=< 0.0001 e 289 c AC T (n = 1880) b (n = 2032) c 261 b 418 c 3 (BO16348/HERA) Herceptin 127 0.54 (0.44, 0.67) (n =1693 ) p< 0.0001 f 219 40 (n = 1693) 4 (BCIRG006) h TCH (n=1075) AC TH (n=1074) 134 121 0.67 (0.54 0.84) 56 p=0.0006 e,i 0.60 (0.48 0.76) 49 p=< 0.0001 e,i 0.64 c,d (0.55, 0.74) P<0.0001 e 0.75 p=ns g 35
AC T 180 80 (n=1073) CI = a 1 2 (NSABP B31 NCCTG N9831) doxorubicin cyclophosphamide paclitaxel (AC T) paclitaxel Herceptin (AC TH) b AC TH DFS 2 c 707 OS (AC TH 8.3 ) d Cox paclitaxel e f g NS= h 4 (BCIRG006) doxorubicin and cyclophosphamide docetaxel (AC T) docetaxel Herceptin (AC TH); docetaxel carboplatin Herceptin (TCH) i alpha 0.025 10 [3 (BO16348/HERA)]12*8** 12 8 N=1693 N= 1697*** Herceptin 1 N = 1693 Herceptin 1 N = 1702*** - 219 (12.9%) 127 (7.5%) 570 (33.6%) 471 (27.7%) - 1474 (87.1%) 1566 (92.5%) 1127 (66.4%) 1231 (72.3%) P- < 0.0001 < 0.0001 0.54 0.76-208 (12.3%) 113 (6.7%) 506 (29.8%) 399 (23.4%) - 1485 (87.7%) 1580 (93.3%) 1191 (70.2%) 1303 (76.6%) P- < 0.0001 < 0.0001 0.51 0.73-184 (10.9%) 99 (5.8%) 488 (28.8%) 399 (23.4%) - 1508 (89.1%) 1594 (94.6%) 1209 (71.2%) 1303 (76.6%) P- < 0.0001 < 0.0001 0.50 0.76 () - 40 (2.4%) 31 (1.8%) 350 (20.6%) 278 (16.3%) - 1653 (97.6%) 1662 (98.2%) 1347 (79.4%) 1424 (83.7%) P- 0.24 0.0005 0.75 0.76 * 1 (DFS) **( 52% Herceptin ) *** 12 36
1 Herceptin 12 (DFS)(HR) 0.54 (95% CI 0.44, 0.67) Herceptin 2 7.6 (85.8% 78.2%) 8 1 Herceptin 24%(HR = 0.76, 95% CI 0.67, 0.86) 1 Herceptin 8 6.4 Herceptin 1 [2 1 (ITT) HR = 0.99 (95% CI: 0.87, 1.13)p = 0.90 HR = 0.98 (0.83, 1.15); p = 0.78]2 (8.1% 1 4.6%) 1 (16.3%)2 3 4 (20.4%) NSABP B31 NCCTG N9831 HER2 HER2 > 1 > 2 Herceptin paclitaxel AC Paclitaxel Paclitaxel - 80 mg/m 2 12 Paclitaxel - 175 mg/m 2 3 4 11 DFS (NSABP B31 NCCTG N9831 )* AC P (1679 ) AC PH (1672 ) AC P P AC P (95%) (%) 261 (15.5) 133 (8.0) < 0.0001 0.48 (0.39, 0.59) (%) 193 (11.5) 96 (5.7) < 0.0001 0.47 (0.37, 0.60) () (%) 92 (5.5) 62 (3.7) 0.014** 0.67 (0.48, 0.92) A: doxorubicin; C: cyclophosphamide; P: paclitaxel; H: trastuzumab * ACP ACPH 1.8 2.0 ** ACPH ACP OS p 15 B-31 N9831 2006 2 4 Genentech, Inc (DFS)paclitaxel Herceptin 52% AC PH (Herceptin) AC P 11.8% (87.2% 75.4%) 37
707 NSABP B31 NCCTG N9831 OS AC PH 8.3 AC PH AC P OS ( HR=0.6495% CI [0.55, 0.74] p < 0.0001)8 AC PH AC P 86.9% 79.4% 7.4% (95% CI 4.9%, 10.0%) NSABP B- 31 NCCTG N9831 OS 12 NSABP B31 NCCTG N9831 AC P (2032 ) AC PH (2031 ) ACP p ACP (95% CI) (OS ) (%) 418 (20.6%) 289 (14.2%) < 0.0001 0.64 (0.55, 0.74) AdoxorubicinCcyclophosphamidePpaclitaxelHtrastuzumab 4 [12 (NSABP B31NCCTG N9831)] 5 [ 1 2 (NSABP B31 NCCTG N9831)] 38
39
6 [4 (BCIRG006)] 23 (NCCTG N9831 BO16348/HERA) HER2 DFS112 (NCCTG N9831)IHC 3+/FISH+ 81% 3 (BO16348/HERA) IHC 3+/FISHFISH+/IHCDFS 13 23 (NCCTG N9831/BO16348/HERA)HER2 2 (NCCTG N9831) 3 (BO16348/HERA) HER2 a DFS (95% CI) DFS (95% CI) IHC 3+ FISH(+) 1170 0.42 (0.27, 0.64) 91 0.56 (0.13, 2.50) FISH (-) 51 0.71 8 ---- (0.04, 11.79) FISH 51 0.69 (0.09, 5.14) 2258 0.53 (0.41, 0.69) IHC<3+/ FISH(+) 174 1.01 (0.18, 5.65) 299 b 0.53 (0.20, 1.42) IHC / ---- ------ 724 0.59 40
FISH(+) (0.38, 0.93) a HercepTestIHCPathVysionFISH b 3 (BO16348/HERA)IHC 2+ 8 (MO16432/NOAH) Herceptin anthracycline taxane (AP+H P+H CMF+H Herceptin 1 ) () HER+ Herceptin 8 (MO16432/NOAH)Herceptin 10 Herceptin ()( 17 Herceptin) Doxorubicin 60 / paclitaxel 150 / Herceptin ( 8 / 6 /) 3 3 Paclitaxel 175 / Herceptin 6 / 3 4 8 cyclophosphamide+methotrexate 5-fluorouracil (CMF) 4 3 3 Herceptin 4 () Herceptin 3 Herceptin 8 (MO16432/NOAH) Herceptin 3.8 8 (MO16432/NOAH) + Herceptin (n=115) (n=116) (95% CI) 46 59 0.65 (0.44, 0.96) * (95% CI) 40% (31.0, 49.6) * 20.7% (13.7, 29.2) p=0.0275 P=0.0014 Herceptin 3 13 (65% vs 52%) 12.2 (5 (H0648g)n = 469) [6 (H0649g)n = 222] HerceptinHER2 41
23(03) [5 (H0648g)] 5 (H0648g)469 IHC (CTA) 01+2+3+3+2+3+ (33%) HerceptinHerceptin4/ 2/anthracycline paclitaxel (213175 /6)anthracyclinecyclophosphamide (ACdoxorubicin 60/epirubicin 75/600/ cyclophosphamide216) 65%Herceptin Herceptin (ORR) Herceptin(12)Herceptin paclitaxelherceptinac paclitaxel 14 5 (H0648g) Paclitaxel AC Herceptin + (n=235) (n=234) Herceptin + Paclitaxel (n=92) Paclitaxel (n=96) Herceptin +AC a (n=143) AC (n=138) TTP () b,c 7.2 4.5 6.7 2.5 7.6 5.7 95% CI 7, 8 4, 5 5, 10 2, 4 7, 9 5, 7 p d <0.0001 <0.0001 <0.002 b 45 29 38 15 50 38 95% CI 39, 51 23, 35 28, 48 8, 22 42, 58 30, 46 p e <0.001 <0.001 0.10 () b,c 42
25%, 75% 6, 15 4, 8 5, 11 4, 7 6, 15 4, 8 () c 25.1 20.3 22.1 18.4 26.8 21.4 95% CI 22, 30 17, 24 17, 29 13, 24 23, 33 18, 27 p d 0.05 0.17 0.16 a AC = Anthracycline (doxorubicinepirubicin)cyclophosphamide b c Kaplan-Meier d e χ2 5 (H0648g)HER2 (3+)(15) 15 5 (H0648g)HER2 HER2 (N) b (95% CI) b (95% CI) CTA 2+ 3+ 469 0.49 (0.40, 0.61) 0.80 (0.64, 1.00) FISH (+) a 325 0.44 (0.34, 0.57) 0.70 (0.53, 0.91) FISH (-) a 126 0.62 (0.42, 0.94) 1.06 (0.70, 1.63) CTA 2+ 120 0.76 (0.50, 1.15) 1.26 (0.82, 1.94) FISH (+) 32 0.54 (0.21, 1.35) 1.31 (0.53, 3.27) FISH (-) 83 0.77 (0.48, 1.25) 1.11 (0.68, 1.82) CTA 3+ 349 0.42 (0.33, 0.54) 0.70 (0.51, 0.90) FISH (+) 293 0.42 (0.32, 0.55) 0.67 (0.51, 0.89) FISH (-) 43 0.43 (0.20, 0.94) 0.88 (0.39, 1.98) a 469451FISH b Herceptin [6 (H0649g)] HER2 [6 (H0649g)] Herceptin22266% 68%25% 4/ 2/Herceptin ORR (+ )14%2%12% CTA 3+ 18%CTA 2+6% 43
Herceptin 1 N=105 Herceptin 2 N=72 Herceptin paclitaxel 3 N=32 (95%CI) 24% 27% 59% Herceptin Docetaxel 4 N=110 73% (63-81) 13.4 (2.1-55.1) (15-35) (14-43) (41-76) ()( 10.1 7.9 10.5 ) (2.8-35.6) (2.1-18.8) (1.8-21) TTP()(95%CI) 3.4 7.7 12.2 13.6 (2.8-4.1) (4.2-8.3) (6.2-ne) (11-16) ne ne ne 47.3 ()(95%CI) (32-ne) TTP = (time to progression)"ne" 1. WO16229 8 / 6 / 2. MO16982 6 / 6 / 3. BO15935 4. MO16419 Herceptin anastrozole Herceptin anastrozole HER2 ([ER]/ [PR])Herceptin anastrozole anastrozole (4.8 vs 2.4 ) (16.5% vs 6.7%)(42.7% vs 27.9%) (4.8 vs 2.4 ) 4.6 anastrozole Herceptin Herceptin anastrozole 52% anastrozole 45% 12.3 7 (BO18255/TOGA) 16 HER2 (curative therapy)/ Herceptin capecitabine/5-fu+cisplatin Capecitabine 1000 mg/m 2 14 6 5-FU 800 mg/m 2 /day 5 6 Cisplatin 80 mg/m 2 (Day 1) 6 349 182 (62.8%) 167 (56.8%) capecitabine/5-fu + cisplatin Herceptin + capecitabine/5-fu + cisplatin (p = 0.0046 Log-Rank test)capecitabine/5-fu + cisplatin 44
11.1 Herceptin + capecitabine/5-fu + cisplatin 13.8 capecitabine/5-fu Herceptin 26%(Hazard Ratio [HR] = 0.74 95% CI [0.60-0.91]) HerceptinHER2(IHC 2+/FISH+IHC 3+/ FISH)HER2 capecitabine/5-fu + cisplatinherceptin + capecitabine/5-fu + cisplatin 11.8 16HR 0.65(95%CI 0.51-0.83)5.57.6 HR 0.64 (95% CI 0.51-0.79)IHC2+/FISH+HR0.75(95% CI 0.51-1.11)IHC3+/FISH+HR0.58 (95% CI 0.41-0.81) SISHFISHHER2 (>95%) ()HER2 (IHC2+/FISH+ IHC3+/ FISH ) Herceptin+capecitabine/5-FU+cisplatin 19.0 capecitabine/5-fu+cisplatin 14.2 HR0.69 (95% CI 0.48-1.00) Herceptin ECOG PS=2 (HR 0.9695% CI 0.51-1.79) non-measurable (HR 1.78 95% CI 0.87-3.66)locally advanced disease (HR 1.2095% CI 0.29-4.97) 16 7 (BO18255/TOGA)* FP FP+H HR (95% CI) P N = 290 N = 294 () 11.1 13.8 0.74 (0.60-0.91) 0.0046 () 5.5 6.7 0.71 (0.59-0.85) 0.0002 () 5.6 7.1 0.70 (0.58-0.85) 0.0003 % 34.5% 47.3% 1.70 a (1.22, 2.38) 0.0017 () 4.8 6.9 0.54 (0.40-0.73) < 0.0001 FPFluoropyrimidine/cisplatin FP+HFluoropyrimidine/cisplatin + Herceptin a (odds ratio) 13 13.1 2-8 (EXP) 440 440Herceptin2-8 2828 45
[(4.8)]Herceptin HerceptinHerceptin 150 () 2 C - 8 C 48 2-824 ( 0.9%) 2 C - 8 C 24 Herceptin 2 C - 8 C 24 13.2 440Herceptin201.1% 21/trastuzumabpH6.0 150Herceptin7.2() Herceptin Herceptin - 440 1) 20Herceptin 2)! - 150 1) 7.2Herceptin 2)! 5Herceptin 4/trastuzumab2/trastuzumab 46
() ( 4 / 2 /) () 21 (/) 8 / trastuzumab 3 1 6 / trastuzumab () ( 8 /6/) () 21 (/) 0.9%2505% dextrose(13.3) 2824 (13.1) / () / / 13.3 Herceptin(polyvinylchloride)(polyethylene) (polypropylene) 5% dextrose Herceptin 14 150 100 440 10020 47
CDS 17.0_US PI 2014 3 EMA SmPC 2015 11 08.15-HER-3B01 150 000790 (1)Roche Diagnostics GmbH Sandhofer Strasse 116, D-68305 Mannheim, Germany (2)Genentech Inc. 4625 NE Brookwood Parkway, Hillsboro Oregon, 97124 USA. F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland 440 000625 Made for F. Hoffmann-La Roche Ltd. CH-4070 Basel, Switzerland by Genentech Inc. 1 DNA Way, South San Francisco, USA F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland Hoffmann-La Roche Ltd. CH-4070 Basel, Switzerland 440 000961 Genentech Inc. 4625 NE Brookwood Parkway, Hillsboro Oregon, 97124 USA F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland 3 134 9 (02)27153111 HERCEPTIN 48