0314-KAD-01 寧 KADCYLA 100 160 Vial 100 mg Trastuzumab Emtansine Vial 160 mg KADCYLA Trastuzumab Trastuzumab KADCYLA - KADCYLA KADCYLA KADCYLA KADCYLA KADCYLA (2.2 5.1) KADCYLA (LVEF) KADCYLA KADCYLA (2.2 5.2) - KADCYLA - (5.3 8.1 8.5) 1 KADCYLA HER2 trastuzumab taxane : 6 2 2.1 KADCYLA 3.6 mg/kg 3 ( 21 ) 3.6 mg/kg KADCYLA KADCYLA Trastuzumab Trastuzumab KADCYLA [(5.9)] 1
1 90 90 [(5.5)] 30 30 2.2 KADCYLA 3 KADCYLA KADCYLA [(5.5)] 1 5 KADCYLA 1 1 2 3.6 mg/kg 3 mg/kg 2.4 mg/kg [(5.1)] / KADCYLA ( 2 3 ) 2 (AST/ALT) 2 (> 2.5 5 ULN) 3 (> 5 20 ULN) KADCYLA AST/ALT 2 ALT = AST = ULN = 4 (> 20 ULN) KADCYLA 3 2 (> 1.5 3 ULN) KADCYLA 1 3 (> 3 10 ULN) KADCYLA 1 4 (> 10 ULN) KADCYLA 2
> 3 ULN > 2 ULN KADCYLA (Nodular regenerative hyperplasia, NRH) KADCYLA 3
[(5.2)] 4 LVEF 40% CHF LVEF < 40% 45% 10% KADCYLA KADCYLA KADCYLA 3 LVEF LVEF < 40% KADCYLA CHF = LVEF = 3 LVEF LVEF 10% KADCYLA LVEF 40% 45% < 10% KADCYLA 3 LVEF LVEF > 45% KADCYLA [(5.6)] 4 ( < 25,000/mm 3 ) ( 5) 5 3 4 PLT 25,000/mm 3 < 50,000/mm 3 PLT < 25,000/mm 3 KADCYLA 1 ( 75,000/mm 3 ) PLT = [(5.4)] KADCYLA 1 ( 75,000/mm 3 ) (Interstitial lung disease, ILD) KADCYLA [(5.7)] 3 4 KADCYLA 2 2.3 KADCYLA (trastuzumab emtansine) KADCYLA trastuzumab 4
0.2-0.22 (In-line non-protein adsorptive polyethersulfone) KADCYLA KADCYLA ( ) () 5 ml 100 mg KADCYLA 8 ml 160 mg KADCYLA 20 mg/ml KADCYLA 2 C 8 C (36 F 46 F) 24 24 KADCYLA KADCYLA (mg) [ (2.1)] 20 mg/ml KADCYLA 250 ml 0.9% (5%) KADCYLA 2 C 8 C (36 F 46 F) 24 3 100 mg 160 mg trastuzumab emtansine 4 5 5.1 5
KADCYLA [ (6.1)] KADCYLA / 6
KADCYLA KADCYLA 1 B C [ (13.1)]/ KADCYLA [ (2.2)]> 3 ULN > 2 ULN KADCYLA KADCYLA > 2.5 ULN > 1.5 ULN KADCYLA (NRH) ( 884 3 ) 3 NRH 2 ( 1) [ (6.1)] NRH (hepatic parenchyma)nrh NRH NRH NRH KADCYLA 5.2 KADCYLA KADCYLA LVEF < 40% ( 1)KADCYLA 1.8% lapatinib capecitabine 3.3% [ (6.1)] KADCYLA ( 3 ) LVEF LVEF LVEF < 50% KADCYLA LVEF < 40% 40% - 45% 10% KADCYLA 3 LVEF LVEF KADCYLA [ (2.2)] 1 (CHF) 6 [ (13.1)] 5.3 - KADCYLA KADCYLA trastuzumab (KADCYLA ) KADCYLA DM1 - KADCYLA KADCYLA [(8.1)] 7
KADCYLA / 5.4 KADCYLA (ILD) ( ) 0.8% (884 7 ) 1 3 ( 1) 1.2% [ (6.1)] ILD KADCYLA 5.5 (IRR) / trastuzumab KADCYLA KADCYLA 1 KADCYLA ( 1) KADCYLA IRR 1.4% [ (6.1)] 1 IRR KADCYLA IRR KADCYLA [ (2.2)] IRR 1 KADCYLA / 5.6 KADCYLA (884 103 3 884 283 ) 1 2 (< [LLN] 50,000/mm 3 ) 8 0 1 ( 75,000/mm 3 ) KADCYLA (2.2) ( 1)KADCYLA 31.2% lapatinib capecitabine 3.3% [ (6.1)] KADCYLA 3 14.5% lapatinib capecitabine 0.4% KADCYLA 3 45.1% lapatinib capecitabine 1.3% 8
KADCYLA KADCYLA [ (2.2)] < 100,000/mm 3 KADCYLA 3 (< 50,000/mm 3 ) 1 ( 75,000/mm 3 ) KADCYLA [ (2.2)] KADCYLA (< 100,000/mm 3 ) 5.7 KADCYLA ( 1 ) (884 14 3 884 196 )( 1)KADCYLA 21.2% lapatinib capecitabine 13.5% [ (6.1)] KADCYLA 3 2.2% lapatinib capecitabine 0.2% 3 4 KADCYLA 2 [ (12.2)] 5.8 HER2 HER2 KADCYLA [ (1) (13.1)]( 1) HER2 Dako Herceptest IHC 3+ Dako HER2 FISH PharmDx (FISH) 2.0 FISH IHC 0 1+ HER2 ( ) 5.9 (Extravasation) KADCYLA 24 KADCYLA 6 [(5.1)] [(5.2)] -[(5.3)] 9
[(5.4)] [(5.5)] [(5.6)] [(5.7)] 6.1 884 HER KADCYLA ( 25%) 884 KADCYLA (ADR) 6 ADR ( 1) HER2 ADR [ (13.1)] KADCYLA lapatinib capecitabine KADCYLA 7.6 lapatinib capecitabine 5.5 5.3 KADCYLA 211 (43.1%) 3 lapatinib capecitabine 289 (59.2%) KADCYLA [ (2.2)] 32 (6.5%) KADCYLA 41 (8.4%) lapatinib 51 (10.5%) capecitabine KADCYLA 80 (16.3%) KADCYLA KADCYLA ( 1% ) 116 (23.7%) KADCYLA KADCYLA ( 1% ) 6 ( 1) KADCYLA (n = 490) ADR 7 KADCYLA ADR ( > 25%) (NCI-CTCAE) ( 3 ) 3 ADR ( > 2%) 10
6 ( 1) KADCYLA (MedDRA) KADCYLA (3.6 mg/kg) n = 490 % (%) 3-4 (%) Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) n = 488 % (%) 3-4 (%) 6.7 2.0 9.0 4.3 14.3 4.1 10.5 2.5 31.2 14.5 3.3 0.4 1.8 0.2 3.3 0.4 3.3 0 2.5 0 3.9 0 3.1 0 4.5 0 0.8 0 3.9 0 2.3 0 9.2 0 11.5 0.4 14.1 0.2 32.6 2.5 16.7 0 4.9 0.2 18.6 0.8 17.6 1.6 19.2 0.8 29.9 4.5 24.1 1.6 79.7 20.7 26.5 0.4 11.1 0 39.8 0.8 45.1 2.5 7.1 0 8.2 0.2 7.6 0 3.1 0 18.6 0.2 8.4 0.4 17.8 0.4 17.6 1.6 36.3 2.5 28.3 3.5 * 0.4 ND 0 0 * 0.4 0.2 0 0 2.2 0 0.8 0 1.4 0 0.2 0 9.4 0.6 3.9 0 4.7 0.4 3.7 0.4 11
(MedDRA) KADCYLA (3.6 mg/kg) n = 490 % Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) n = 488 % 3-4 (%) (%) (%) 3-4 (%) 28.8 8.0 14.3 2.5 10.2 2.7 9.4 4.7 14.1 0.6 3.7 0 19.2 0.6 8.4 0 36.1 1.8 30.5 1.4 8.0 0 4.1 0.2 10.2 0.4 10.7 0.2 21.2 2.2 13.5 0.2 28.2 0.8 14.5 0.8 12.0 0.4 8.6 0.2 1.2 0 0 0 12.0 0.8 8.0 0.4 18.2 0.2 13.1 0.2 22.5 0.2 8.4 0 5.5 0.2 9.2 0 11.6 0 27.5 1.8 5.1 1.2 2.3 0.4 29.8 1.4 15.8 0.8 * ND = 12
7 KADCYLA (3.6 mg/kg) Lapatinib (1250 mg) + Capecitabine (2000 mg/m 2 ) 3 % 4 % % % 3 % 4 % 17 < 1 0 57 2 0 AST 98 7 < 1 65 3 0 ALT 82 5 < 1 54 3 0 83 14 3 21 < 1 < 1 60 4 1 64 3 < 1 39 3 < 1 38 6 2 33 3 0 31 6 < 1 6.2 KADCYLA 6 836 KADCYLA (ATA) KADCYLA 5.3% (44/836) 1 KADCYLA ATA KADCYLA KADCYLA KADCYLA KADCYLA KADCYLA KADCYLA 7 KADCYLA KADCYLA DM1 CYP3A4 CYP3A5 CYP3A4 ( ketoconazole itraconazole clarithromycin atazanavir indinavir nefazodone nelfinavir ritonavir saquinavir telithromycin voriconazole) KADCYLA DM1 CYP3A4 CYP3A4 KADCYLA CYP3A4 ( 3 ) CYP3A4 KADCYLA 8 8.1 D [(5.3)] KADCYLA KADCYLA trastuzumab emtansine 13
KADCYLA 2 (trastuzumab DM1) KADCYLA KADCYLA KADCYLA 1 KADCYLA 6 trastuzumab trastuzumab trastuzumab trastuzumab trastuzumab emtansine KADCYLA DM1 (microtubule) DM1 25 mg/kg ( 7 ) trastuzumab trastuzumab (placental barrier) trastuzumab 33% 25% 8.2 KADCYLA IgG 25 mg/kg ( KADCYLA 7 ) trastuzumab ( 0.3%) KADCYLA KADCYLA [(5.3)] 8.3 KADCYLA 8.4 ( 1) 495 KADCYLA [ (13.1)] 65 (13%) 65 11 (2%) 75 65 (2 n = 138) (PFS) (OS) 1.06 (95% CI 0.68 1.66) 1.05 (95% CI 0.58 1.91) 14
trastuzumab emtansine [(11.2)] 8.5 KADCYLA - KADCYLA KADCYLA 6 8.6 KADCYLA 3 ([CLcr] 60 89 ml/min) (CLcr 30 59 ml/min) KADCYLA (CLcr 30 ml/min) [ (11.2)] 8.7 DM1 CYP3A4/5 trastuzumab emtansine (conjugate) 9 KADCYLA KADCYLA () 2 (4 ) 6 mg/kg KADCYLA 3 KADCYLA 10 KADCYLA (trastuzumab emtansine) HER2 (ADC) HER2 IgG1 (trastuzumab) MCC (4-[N-maleimidomethyl] cyclohexane-1-carboxylate) DM1 ( maytansine ) (covalently linked) Emtansine MCC-DM1 (complex) trastuzumab () (DM1 MCC) Trastuzumab emtansine 3.5 DM1 Trastuzumab emtansine 15
MCC n ~ 3.5 DM1/Mab DM1 + MCC emtansine trastuzumab (Mab) n 3.5 DM1 KADCYLA (trastuzumab emtansine) 100 mg 160 mg trastuzumab emtansine trastuzumab emtansine (20 mg/ml) 20 [0.02% (w/v)] (sodium succinate) (10 mm) [6% (w/v)] 5.0 1.026 g/ml 20 mg/ml trastuzumab emtansine 11 11.1 Trastuzumab emtansine HER2 HER2 IgG1 (trastuzumab) DM1 HER2 IV trastuzumab emtansine DM1 DM1 (tubulin) trastuzumab emtansine trastuzumab HER2 HER2 HER2 11.2 1 5 trastuzumab emtansine (ADC) KADCYLA (first-order elimination) (two-compartment model) ADC - ADC ( trastuzumab) DM1 KADCYLA ADC DM1 (C max ) 1 KADCYLA ADC DM1 1 Cmax ( ) 83.4 (16.5) μg/ml 4.61 (1.61) ng/ml 16
93% DM1 DM1 P-glycoprotein (P-gp) ADC 3.13 L KADCYLA DM1 CYP3A4/5 DM1 CYP450 trastuzumab emtansine MCC-DM1 Lys-MCC-DM1 DM1 KADCYLA ADC 0.68 L/day (t1/2) 4 3 KADCYLA (n = 671) (RECIST) HER2 (ECD) AST trastuzumab trastuzumab emtansine KADCYLA 3 3.6 mg/kg 668 ( [CL cr 30-59 ml/min n = 53] [CL cr 60-89 ml/min n = 254] )(CL cr 90 ml/min n = 361) ADC (CL cr < 30 ml/min) [(8.6)] (< 65 [n = 577] 65-75 [n = 78] > 75 [n = 16]) ( [n = 73] [n = 598]) trastuzumab emtansine 11.3 51 HER2 KADCYLA ( 3 3.6 mg/kg) QTc QT ( > 20 ms) 12 12.1 trastuzumab emtansine (rat bone marrow micronucleus assay) KADCYLA DM1 DM1 (aneugenic)(clastogenic) (Ames)DM1 (mutagenic) 17
KADCYLA trastuzumab emtansine (60 mg/kg AUC [ ] 4 ) (seminiferous tubule) 30 mg/kg ( AUC 7 ) 3 trastuzumab emtansine 12 ( 4 ) 12.2 / 30 mg/kg ( AUC 7 ) trastuzumab emtansine (Schwann cell) (dorsal funiculus) DM1 [(5.7)] 13 13.1 991 HER2 KADCYLA taxane trastuzumab 6 HER2 IHC 3+ FISH 2.0 (1:1) lapatinib capecitabine KADCYLA () (0-1 > 1) KADCYLA 21 1 3.6 mg/kg KADCYLA Lapatinib 21 1 1250 mg/day lapatinib 21 1-14 2 1000 mg/m 2 capecitabine KADCYLA lapatinib capecitabine KADCYLA 5.7 ( 0-28.4) lapatinib 4.9 ( 0-30.8) capecitabine 4.8 ( 0-30.4) (PFS [IRC] )(OS) PFS ( ) PFS ()(ORR) 53 ( 24-84 ) 74% 18% 5% 5 27% 32% 16% ( 55% 43%) (68%)(33%) (< 3: 61% 3: 37%) 18
(88%)12% 6 trastuzumab 85% trastuzumab 99% taxane 61% anthracycline 3 44.4% 44.8%/ lapatinib capecitabine KADCYLA IRC (PFS)[ (HR) = 0.65 95%(CI) 0.55 0.77 p < 0.0001] KADCYLA lapatinib capecitabine PFS 3.2 PFS 9.6 6.4 8 1 PFS IRC PFS PFS 223 lapatinib capecitabine (26%) KADCYLA 19% OS 2 331 KADCYLA (HR = 0.68 95% CI 0.55 0.85 p = 0.0006)(HR = 0.73 p = 0.0037) OS KADCYLA 30.9 lapatinib capecitabine 25.1 8 2 KADCYLA PFS OS (n = 426) PFS OS 0.56 (95% CI 0.44 0.72) 0.75 (95% CI 0.54 1.03)(n = 545) PFS OS 0.72 (95% CI 0.58 0.91) 0.62 (95% CI 0.46 0.85) (n = 205) IRC PFS OS 0.91 (95% CI 0.59 1.42) 0.96 (95% CI 0.54 1.68) 0.62 (95% CI 0.52 0.75) 0.65 (95% CI 0.51 0.82) 65 (n = 853)PFS OS 0.62 (95% CI 0.52 0.74) 0.66 (95% CI 0.52 0.83) 65 (n = 138)PFS OS 1.06 (95% CI 0.68 1.66) 1.05 (95% CI 0.58 1.91) 19
8 1 () KADCYLA N = 495 Lapatinib + Capecitabine N = 496 (%) 265 (53.5%) 304 (61.3%) PFS ( ) 9.6 6.4 (*) 0.650 95% CI (0.549, 0.771) p ([Log-Rank] *) ** < 0.0001 (%) 149 (30.1%) 182 (36.7%) ( ) 30.9 25.1 (*) 0.682 95% CI (0.548, 0849) p ([Log-Rank]*) 0.0006 (ORR ) 397 389 OR (%) 173 (43.6%) 120 (30.8%) (95% CI) 12.7% (6.0, 19.4) ( ) OR 173 120 (95% CI) 12.6 (8.4, 20.8) 6.5 (5.5, 7.2) PFSOR * () (0-1 > 1) ** 331 OS 2 20
1 1 IRC Kaplan-Meier Lap + Cap T-DM1 ( ) 6.4 9.6 0.650 (95%) (0.549, 0.771) (Log-Rank) <0.001 p Lap + Cap (n = 496) T-DM1 (n = 495) Lap + Cap T-DM1 ( ) T-DM1 trastuzumab emtansine Lap lapatinib Cap capecitabine IRC Cox p (Log-Rank) 2 1 Kaplan-Meier Lap + Cap T-DM1 ( ) 25.1 30.9 0.682 (95%) (0.549, 0.849) (Log-Rank) 0.0006 p Lap + Cap (n = 496) T-DM1 (n = 495) Lap + Cap T-DM1 ( ) T-DM1 trastuzumab emtansine Lap lapatinib Cap capecitabine Cox p (Log-Rank) 14 / 14.1 / 21
KADCYLA (trastuzumab emtansine) 100 160 2 C-8 C (36 F-46 F) 14.2 100 160 100 000949 Ref. USPI_Aug13, EMA SPC_Nov13 and CDS 3.0 12.13-KAD-3B01 DSM Pharmaceuticals, Inc. 5900 Martin Luther King Jr. Highway Greenville, NC 27834, USA. F. Hoffmann-La Roche Ltd. Wurmisweg CH-4303 Kaiseraugst Switzerland. 3 134 9 (02)27153111 22