Microsoft Word - Herceptin IV all_0915-HER-01_CDS 12.0_clean_solvent site of SSF

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1 0915-HER Herceptin Trastuzumab Vial 150 mg Vial 440 mg 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 ) 1

2 2. (MBC) (1) () anthracycline taxane anthracycline taxane (2) paclitaxel docetaxel (3) 3. (mgc) Herceptin capecitabine( 5-fluorouracil) cisplatin HER2 () (1) HER2 () (Validation)(Performance) [(12.3)] (2) HER2 (IHC2+/FISH+ IHC3+) 2 HerceptinHER2 Herceptin (intravenous push or bolus) Herceptin4/90 Herceptin2/ 30 8 /3 6 / 3 6 / Herceptin (disease progression) 2

3 1 Herceptin Herceptin (2 /6 /) Herceptin (2 / 6 /) Herceptin Herceptin 90 (4 /8 /) 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 3

4 Herceptin(disposition) Herceptin Herceptin 3 trastuzumab 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% ) Trastuzumab Herceptin trastuzumab 27 Herceptin anthracycline Herceptin 27 anthracycline anthracylines Herceptin ( anthracycine ) (ECG) 4

5 (MUGA) Herceptin 3 ( )Herceptin 6 24 (LVEF) 10% 50% Herceptin 3 Herceptin ( 6-8 ) Herceptin Herceptin Herceptin Herceptin 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) 5

6 Herceptin taxanes 18 4 (>50 ) (LVEF)(<55%) paclitaxel Herceptin Herceptin Herceptin anthracycline (BMI) - - Herceptin anthracyclines anthracycline doxorubicin 180 mg/m 2 epirubicin 360 mg/m 2 anthracyclines Herceptin - 65 Herceptin MUGALVEF LVEF Herceptin3LVEFHerceptin LVEF Herceptin6LVEF2 Herceptin4LVEF [ (2)] 1 16% (136/844) LVEF Herceptin 3 Herceptin 2.6% (44/1678) 4 TCH AC-TH 2.9%(31/1056) (1.5% 1.4%) 5.7%(61/1068) (1.5% 4.2%) Herceptin 32(12) 6

7 LVEF ( 50%)Herceptin Herceptin 1 CHF Herceptin 1 & 2 a AC b Paclitaxel+Herceptin 2% (32/1677) 0.4% (7/1600) 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 b Anthracycline (doxorubicin) cyclophosphamide 2 a NYHA I-IV NYHA III-IV Herceptin Herceptin 5(AC) b 28% 7% 19% 3% 5 (paclitaxel) 11% 1% 4% 1% 6 c 7% N/A 5% N/A a LVEF b Anthracycline (doxorubicin epirubicin) cyclophosphamide c 1 4Herceptin[(AC-TH0.3% (3/1068) TCH0.2% (2/1056)] NCI-CTC 3/4/HerceptinAC-T () 4.2 ( )[ 5.1)] 7

8 Herceptin diphenhydramine Herceptin Herceptin()Herceptin Herceptin 4.3 Herceptin NCI CTC3-4 () [(5.1)] 4.4 Herceptin [(4.2)] taxane, gemcitabine, vinorelbine Herceptin 4.5 HER2 HER2Herceptin HER2HER2 (IHC)Herceptin (FISH)Herceptin FISHHER2 8

9 HerceptinIHCFISH (5)10IHCFISH (23)8 4.6 (D) Herceptin Herceptin HerceptinHerceptin[ (7.1)] Herceptin/ Herceptin/ () ( 1/10)( 1/100 ~ <1/10)( 1/1,000 ~ <1/100)( 1/10,000 ~ <1/1,000)(<1/10,000)( ) HerceptinHerceptin - H0648g and H0649gHerceptinpaclitaxel - M7700DocetaxelHerceptin - BO16216HER2anastrozole Herceptin - BO16348HER2Herceptin - BO18255HER2Herceptinfluoropyrimidinecisplatin - B-31, N9831doxorubicincyclophosphamide Herceptinpaclitaxel - BCIRG 006doxorubicincyclophosphamide HerceptindocetaxelHerceptindocetaxelcarboplatin - MO16432Herceptin doxorubicinpaclitaxel paclitaxel cyclophosphamide methotrexate 5-fluorouracil 9

10 Herceptin * <1% / / 1 10

11 % 1 * % 11

12 1 1 12

13 1 / 1 * anthracyclineherceptintaxanes HERABO % 1/10Herceptin 13

14 ()(II-IV)Hereptin [(4.1)]trastuzumab 3 (Herceptin)taxane Herceptin3/4() ( %)Herceptintaxane(2.0%) Herceptin (H0648H0649M7700BO1621BO1634BO18255 B-31N9831BCIRG 006MO16432) -/ Herceptin Herceptin Herceptin anthracycline Herceptin 40% ((NCI-CTC) )( 123 ) () Herceptin 1 2 anthracycline trastuzumab docetaxel Herceptin()

15 123(n=3355)(n=3308) trastuzumab Herceptin 3(3)1678Herceptin ( 2180)83%13% 3 3 a MedDRA (v. 7.1) Herceptin1 (n=1678) (n=1708) 64 (4%) 35 (2%) 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%) 15

16 MedDRA (v. 7.1) Herceptin1 (n=1678) (n=1708) 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%) 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 Herceptin (24-80)84%7% 4%(hispanic)4% Herceptin 2%(31%28%)(28%22%)(22%14%) 16

17 (17%15%)(13%7%)(12%4%)/(11%7%) (7%5%)(6%4%)(3.7%1.5%) 2() Herceptin NCI-CTC453-5taxanes2-5( ) Herceptin 2%(11%8.4%)(10%8%)(9%7%) (2.5%0.1%) 4 Herceptin 2124 Herceptin [AC-THn = 1068TCHn = 1056] AC-TH TCH 54 AC-TH 26TCH ( ) TCH CHF (n=235)(n=234) trastuzumab (5) (6n=222)Herceptin (25-77)89% 5%1%5%4/ Herceptin2/Herceptin %9% 352(2136)50( 28-86)100%86%3%3%8% 4/Herceptin2 /Herceptin %16% 4 5%()Herceptin (56) ([%]) a n=352 Herceptin + Paclitaxel n=91 Paclitaxel n=95 Herceptin +AC b n=143 AC b n=135 17

18 a n=352 Herceptin + Paclitaxel n=91 Paclitaxel n=95 Herceptin +AC b n=143 AC b n=

19 a n=352 Herceptin + Paclitaxel n=91 Paclitaxel n=95 Herceptin +AC b n=143 AC b n= < a Herceptin b Anthracycline (doxorubicin epirubicin) cyclophosphamide ToGA(BO18255E)trastuzumabfluoropyrimidinecisplatin (fluoropyrimidinecisplatin)her % / 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) 19

20 165 (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) (LVEF)3 12.6(12.4Herceptin 112.6)12AC- TH23AC-T24126%AC (LVEF<50%ACLVEF 15%) HerceptinHerceptin12 Herceptinpaclitaxel 20

21 paclitaxel3herceptin (612) a (LVEF)( ) 1 2 b AC TH (n=1606) AC T (n=1488) 3 Herceptin (n=1678) (n=1708) LVEF <50% LVEF <50% 22.8% (366) 9.1% (136) 8.6% (144) 2.7% (46) 10% 18.3% (294) 5.4% (81) 7.0% (118) 2.0% (35) 16% 11.7% (188) 2.2% (33) 3.8% (64) 1.2% (20) LVEF <20% and 10% 33.4% (536) 18.3% (272) 22.4% (376) 11.9% (204) 20% 9.2% (148) 2.4% (36) 3.5% (59) 1.2% (21) 4 c TCH 8.5% 5.9% 3.3% 34.5% 6.3% (n=1056) (90) (62) (35) (364) (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 Herceptin 4 b 1 2 doxorubicin cyclophosphamide paclitaxel (AC T) paclitaxel Herceptin (AC TH) c 4 doxorubicin cyclophosphamide docetaxel (AC T) docetaxel Herceptin (AC TH); docetaxel carboplatin Herceptin (TCH) 1 12LVEF 10%50% 21

22 0paclitaxelHerceptin + paclitaxel 2 3LVEF 10%50% 0 3 4LVEF 10%50% 0 (I IVIV)(2) Herceptinanthracyclines 22

23 ToGA fluoropyrimidine/cisplatin(fp) LVEF 64%(48% - 90%)Herceptin + fluoropyrimidine/cisplatin(h+fp) 65%(50%-86%) Herceptin LVEF ToGA LVEF LVEF LVEF * LVEF<50% 10% Fluoropyrimidine/Cisplatin (N = 290) (%) Herceptin Trastuzumab/Fluoropyrimidine/ Cisplatin (N = 294) (%) 1.1% (2/187) 4.6% (11/237) 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()( ) 21%35%Herceptin 1.4%9% 23

24 Herceptin( 30%21% [5])NCI CTC2-5(12.5%6.6% [1]) (0.1%0 [2]) Herceptin(6)NCI-CTC3<1% Herceptin NCI CTC4-5(2%0.7% [2]) 2-5(7.1%4.5 % [1]) HerceptinNCI-CTC3/4 (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])NCI-CTC2-5/(22%14% [1]) 24

25 3-5/(3.3%1.4% [2]) 4 Herceptin AC-T ( TCH ) [44% (AC-TH)37% (TCH)38% (AC-T)] NCI-CTC 3-4 [25% (AC-TH)21% (TCH)23% (AC-T)] Herceptin (23%17%) HerceptinNCI-CTC 2-5(14%5% [1])NCI-CTC3-5 2(3.4%1% [2]) (NCI-CTC2-512%4% [1]NCI-CTC2-52.5%0.1% [2]) Herceptin/0.7% 0.3%Herceptin3(1 )1 3Herceptin4 Herceptin (4.4) / 4Herceptin (3.0%1.3% [1] 3.7% 2.2% [4]2.1%0% [5]) HerceptinNCI-CTC2-5( 6.2%4.8% [1])NCI-CTC3-5(1.6%0% [2])1-4(7% 1% [3])4Hercepatin3-4 [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T]1-4[51% AC-TH, 63% TCH vs. 43% AC-T]Herceptin25% 25

26 ToGA Herceptin 109 (37%) 80 (28%)( ) NCI-CTCAE v3.0 FP 3 () 4%FP+H 9% Hercpetin Herceptin418 ToGA Herceptin NCI-CTCAE(v 3.0) 3 () 3% FP 2% NCI-CTCAE(v 3.0) 3 ()(SOC) (Herceptin 1%vs. FP <1%) (ELISA)Herceptin (HAHA) HAHA () Herceptin 5.3 Herceptin 26

27 [(4.2)] [(4.6)] 6 paclitaxelherceptintrastuzumab1.5[ (10.2)] docetaxelpaclitaxelherceptin M77004BO15935 JP16003 paclitaxeldocetaxel doxorubicin Herceptin Herceptin JP19959 cisplatincapecitabine Herceptin D [(4.6)] Herceptin Herceptin HerceptinHerceptin Herceptin Herceptin Herceptin Herceptin/ Herceptin (IV) Herceptin (2/)25trastuzumab HER2HER2 (20-50) ( )trastuzumab[ (11.2)] 27

28 Herceptin Herceptin HerceptinIgG (2/)12.5Herceptin trastuzumabtrastuzumab3 trastuzumab Herceptin trastuzumab 7.3 Herceptin ()Herceptin ( )5612 4Herceptin Herceptin Herceptin (ORRTTPOSDFS)<65 8 8/ 9 Herceptin (trastuzumab)igg1 kappa 2(HER2)Trastuzumab 28

29 gentamicin() gentamicin Herceptin() Herceptintrastuzumabα,α-trehalose dihydratel-histidine HClL-histidine20 (USP)Hercetpin 44020(BWFI SWFI)21trastuzumabpH HER2 (c-erbb2)185 kda Herceptin HER2 Herceptin(ADCC) HER2HerceptinADCC HER Trastuzumab Herceptin trastuzumab 10500Herceptin Trastuzumab(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/) 29

30 trastuzumab( 2.0/dL) anthracyclinecyclophosphamidetrastuzumabpaclitaxel trastuzumab1.5herceptin paclitaxeldocetaxelpaclitaxeldoxorubicinher2+ Herceptin 8 / 3 6 / trastuzumab( > 75 /)(<25 /) BO18255 trastuzumab 8 / 6 /() 26 AUC ( 3 ) 1213 / Cmax 132 / Cmin 27.6 / HER2 () Herceptin Amestrastuzumab 5000/ 118/Herceptin (2/)25trastuzumab trastuzumab 11.2 () 30

31 (2/)25Herceptin HER2HER2 ( 20-50)( )Herceptin (12) 3386(3)3222 (4)HerceptinHER2 12HER2(3+IHC) (FISH)HER2 (2)(1) X (>100 mmhg>200 mmhg) (1:1)doxorubicincyclophosphamide paclitaxel (AC paclitaxel) paclitaxel Herceptin (AC paclitaxel+herceptin)doxorubicin 60/ cyclophosphamide 600/211 (80/)3(175/)paclitaxel2 paclitaxel paclitaxel 4 / Herceptin2/52 LVEF/Herceptin[ (2)]ER+() PR+ (DFS ) (22-806% >65)84%7%4%4% /90% 38%T191%27%66% 53%ER+() PR+53% paclitaxel3paclitaxel 3HER2(3+IHC) (FISH) T1c LVEF<55% (>180 mm Hg>100 mm Hg) 31

32 (1:1) (n=1693)herceptin1(n=1693) ER+() PgR+ 8/Herceptin 36/52 (DFS) (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 HER2 ( FISH+) ER/PR > 2 < 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 ) 3 6 T TC Herceptin ( 4 / 2 /) 3 (6 /) 52 ER+() PR+(DFS) ( % 65 ) 54% ER+() PR+ 71% 1234DFS712DFS4 4DFS54 (/)>65 32

33 7 (1+234) e AC TH (n =1872) AC T (n = 1880) 3 Herceptin (n =1693 ) (n = 1693) DFS 133 (95% CI) p 0.48 a (0.39, 0.59) p=< b (0.44, 0.67) p=< c p 0.67 p=ns d 0.75 p=ns d 4 f TCH (n=1075) AC TH (n=1074) ( ) 56 p= b,g 0.60 ( ) 49 p=< b,g AC T (n=1073) CI = a Cox paclitaxel b c d NS= e 1 2 doxorubicin cyclophosphamide paclitaxel (AC T) or paclitaxel Herceptin (AC TH) f 4 doxorubicin and cyclophosphamide docetaxel (AC T) docetaxel Herceptin (AC TH); docetaxel carboplatin Herceptin (TCH) g alpha

34 4 (12) 5 ( 4) 23HER2 DFS82 IHC 3+/FISH+ 81% 3IHC 3+/FISHFISH +/IHC DFS 34

35 8 23HER2 HER2 a IHC 3+ FISH(+) (0.27, 0.64) FISH (-) (0.04, 11.79) FISH (0.09, 5.14) IHC<3+/ FISH(+) IHC / FISH(+) 2 3 DFS DFS (95% CI) (95% CI) (0.18, 5.65) (0.13, 2.50) (0.41, 0.69) 299 b 0.53 (0.20, 1.42) (0.38, 0.93) a HercepTestIHCPathVysionFISH b 3IHC 2+ MO16432 Herceptin anthracycline taxane Herceptin () HER2+ Herceptin MO16432 Herceptin 10 Herceptin ()( 17 Herceptin) Doxorubicin 60 / paclitaxel 150 / Herceptin ( 8 / 6 /) 3 3 Paclitaxel 175 / Herceptin 6 / cyclophosphamide+methotrexate 5-fluorouracil (CMF) Herceptin 4 35

36 Herceptin 3 Herceptin MO16432 Herceptin 3.8 MO Herceptin (n=115) (n=116) (95% CI) (0.44, 0.96) p= * (95% CI) 40% (31.0, 49.6) 20.7% (13.7, 29.2) P= Herceptin 3 13 (65% vs 52%) 12.2 (5n=469) (6n=222)Herceptin HER2 23 (03) (5) 5469 IHC (CTA) (33%) HerceptinHerceptin4/ 2/anthracycline paclitaxel (213175/ 6)anthracyclinecyclophosphamide (ACdoxorubicin 60/epirubicin 75/600/ cyclophosphamide216) 65%Herceptin 36

37 Herceptin (ORR) Herceptin(9)Herceptin paclitaxelherceptinac paclitaxel 9 5 Herceptin + (n=235) Paclitaxel AC (n=234) Herceptin + Paclitaxel (n=92) Paclitaxel (n=96) Herceptin +AC a (n=143) AC (n=138) TTP () b,c % CI 7, 8 4, 5 5, 10 2, 4 7, 9 5, 7 p d < < <0.002 b % CI 39, 51 23, 35 28, 48 8, 22 42, 58 30, 46 p e <0.001 < () b,c 25%, 75% 6, 15 4, 8 5, 11 4, 7 6, 15 4, 8 () c % CI 22, 30 17, 24 17, 29 13, 24 23, 33 18, 27 p d a AC = Anthracycline (doxorubicinepirubicin)cyclophosphamide b c Kaplan-Meier d e χ2 37

38 5HER2(3+) (10) 10 5HER2 HER2 (N) b (95% CI) b (95% CI) CTA (0.40, 0.61) 0.80 (0.64, 1.00) FISH (+) a (0.34, 0.57) 0.70 (0.53, 0.91) FISH (-) a (0.42, 0.94) 1.06 (0.70, 1.63) CTA (0.50, 1.15) 1.26 (0.82, 1.94) FISH (+) (0.21, 1.35) 1.31 (0.53, 3.27) FISH (-) (0.48, 1.25) 1.11 (0.68, 1.82) CTA (0.33, 0.54) 0.70 (0.51, 0.90) FISH (+) (0.32, 0.55) 0.67 (0.51, 0.89) FISH (-) (0.20, 0.94) 0.88 (0.39, 1.98) a FISH b Herceptin (6) HER2 (6) Herceptin22266% 68%25% 4/ 2/Herceptin ORR (+ )14%2%12% CTA 3+ 18%CTA 2+6% Herceptin 1 N=105 Herceptin 2 N=72 Herceptin paclitaxel 3 N=32 Herceptin Docetaxel 4 N=110 38

39 95%CI 24% (15-35) 27% (14-43) 59% (41-76) 73% (63-81) 10.1 ( ) 7.9 ( ) 10.5 (1.8-21) 13.4 ( ) TTP 95%CI 3.4 ( ) 7.7 ( ) 12.2 (6.2-ne) 13.6 (11-16) 95%CI ne ne ne 47.3 (32-ne) TTP = (time to progression)"ne" 1. WO / 6 / 2. MO / 6 / 3. BO 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 ToGA 11HER2 (curative therapy)/ Herceptin capecitabine/5- FU+cisplatin Capecitabine 1000 mg/m FU 800 mg/m 2 /day 5 6 Cisplatin 80 mg/m 2 (Day 1) (62.8%) 167 (56.8%) capecitabine/5-fu + cisplatin Herceptin + capecitabine/5-fu + cisplatin (p = Log-Rank test)capecitabine/5-fu + cisplatin 11.1 Herceptin + capecitabine/5-fu + cisplatin

40 capecitabine/5-fu Herceptin 26%(Hazard Ratio [HR] = % CI [ ]) HerceptinHER2(IHC 2+/FISH+IHC 3+/ FISH)HER2 capecitabine/5-fu + cisplatinherceptin + capecitabine/5-fu + cisplatin HR %CI ) HR 0.64 (95% CI )IHC2+/FISH+HR0.75(95% CI )IHC3+/FISH+HR0.58 (95% CI ) SISHFISHHER2 (95%) ()HER2 (IHC2+/FISH+ IHC3+/ FISH ) Herceptin+capecitabine/5-FU+cisplatin 19.0 capecitabine/5-fu+cisplatin 14.2 HR0.69 (95% CI ) Herceptin ECOG PS=2 (HR % CI ) non-measurable (HR % CI )locally advanced disease (HR % CI ) 11 BO18255 * FP N = 290 FP+H N = 294 HR (95% CI) P ( ) ( ) ( ) % 34.5% 47.3% 1.70 a (1.22, 2.38) ( ) < FPFluoropyrimidine/cisplatin FP+HFluoropyrimidine/cisplatin + Herceptin a odds ratio

41 2-8 (EXP) Herceptin () 2 C - 8 C () ( 0.9%) Herceptin Herceptin201.1% 21/trastuzumabpH Herceptin7.2() Herceptin Herceptin ) 20Herceptin 41

42 2)! ) 7.2Herceptin 2)! 5Herceptin 4/trastuzumab2/trastuzumab () ( 4 / 2 /) () 21 (/) 8 / trastuzumab / trastuzumab () ( 8 / 6 /) () 21 (/) 0.9%2505% dextrose(13.3) 2824 (13.1) / 13.3 Herceptin(polyvinylchloride)(polyethylene) (polypropylene) 5% dextrose Herceptin 42

43 Ref: US EMA / CDS 11.0/ HER-3-B Roche Diagnistics GmbH. Sandhofer Strasse 116, D-68305, Mannheim, Germany. F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland 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 F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland Genentech Inc NW Brookwood Parkway, Hillsboro Oregon, USA. F. Hoffmann-La Roche Ltd. Wurmisweg, CH-4303 Kaiseraugst, Switzerland (02)

44 HERCEPTIN 44