2018 08 12, Alecensa Alectinib Hydrochloride Capsules Yansuan Alaitini Jiaonang 9--6,6- -8-[4- -4-G -1- ]-11--6,11--5H- [b]-3- C 30 H 35 ClN 4 O 2 519.08 E172 E172FD&C 2 E132 1-150mg ALE150 mg 1 / 20
ALK 150 mg 161.33 mg ALK 600 mg 4 150 mg 1200 mg 6 150 mg 300 mg 1 1 600 mg 450 mg 300 mg 2 / 20
2 CTCAE ILD / 3 ALT AST >5 ULN 2 ULN 2 ALT AST 3 ULN 2 ULN 3 ULN ILD/ 1 3 ULN 1 1.5xULN 1 3 1.5xULN 1 4 1 60 bpm 2 3 a 1 60 bpm 1 60 bpm 1 4 a CPK 5 ULN 1 60 bpm 1 3 / 20
CPK 10 ULN CPK 5 ULN 2.5 ULN 2.5 ULN1 ALT = AST = CPK = ULN = CTCAE=NCI a 60bpm <18 65 Child-Pugh A Child-Pugh B Child- Pugh C 450 mg 900 mg 928 203 II NP28761 NP28673 253 ALK 600 mg 11 0-35 III BO28984 152 ALK 600 mg 17.9 20%36% 34% 31% 22% 21% 20% 20% 3 II NP28761 NP28673 III BO28984 ADR MedDRA 4 / 20
1/10 1/100 < 1/10 1/1000 < 1/100 1/10000 < 1/1000 < 1/10000 3 IINP28761 NP28673IIIBO28984 MedDRA N=253 NP28761 NP28673 N=152 BO28984 % 3 4% 36 0 22 0.7 # 18 1.2 13 0.4 #1 3.3 # 0 # 2 34 0.8 3 31 1.2 13 3.6 4 20 0.7 # 12 0.7 # #5 3.3 # 0.7 # 6 21 # 3.3 # AST 16 5.3 # ALT 15 # 4.6 # 7 0.8 0.8 8 20 # 4.6 # 9 12 0 5 / 20
10 11 # 0 # 9.9 # 0.7 # 7.9 # 1.3 # * # 2.6 # 2.6 # * / 1.3 # 0.4 * 5 # BO28984 / N=152 ( # NP28761 NP28673 / N=253 ) BO28984 NP28761 NP28673 1 2 3 4 5 6 7 1 MedDRA 1 4 AST ALT 8 9 10 III BO28984 II NP28761 NP28673 ILD / / NP28761 NP28673 BO28984 405 1 0.2% 3 III BO28984 3 4 / 2.0% NP28761 NP28673 BO28984 15% 14% AST ALT 1 2 3.7% 3 AST ALT 3 1.5% 3.0% 2.2% 1.2% 1.2% 1.5% AST ALT 2 3-4 AST/ALT 1 6 / 20
4 2 III BO28984 5% 3 4 ALT AST 15% 11% NP28761 NP28673 BO28984 18% 1 2 3.2% 3 3 5.2% 1.5% III BO28984 3 4 3.3% 1 0.2% ALT AST 3 ULN 2 ULN ALT AST NP28761 NP28673 BO28984 8.9% 1 2 3 365 66 18% 50 / III BO28984 15% 50 / 20% CPK NP28761 NP28673 BO28984 28% 22% 7.4% 1 2 3 0.7% 3 2 0.5% 362 CPK 43% CPK 3 CPK 3.7% 3 CPK 14 3.2% CPK CPK III BO28984 2.6% 1.3% 3 CPK 3 CPK 27.5 369 35% 19% 16% 11% 3 0.7% 0.5% 0.2% NP28761 NP28673 BO28984 / 21 1 III BO28984 1 0.2% 4 3 4 7 / 20
3.3% 3.3% 2.0% 4 II NP28761 NP28673 III BO28984 4 N= 250* N=152 # % 3 4 % ** 38 # 3.4 # AST 53* 6.2 # ALT 40 # 6.1 # 46* 5.0* 53 # 5.5 # 62 # 6.8 # AST ALT NCI CTCAE * NP28761 NP28673 3 N=219 ** ULN CTCAE # BO28984 / ALT N=147 AST N=145 N=146 5 II NP28761 NP28673 7.5% ILD / / / 8 / 20
/ ALT AST 5 ULN 3 ULN 3 3 3-4 AST/ALT 1 ALT AST 3 ULN 2 ULN ALT AST 3 3 2 CPK 3 CPK 3 II NP28761 NP28673 3 CPK 14 III BO28984 3 CPK 27.5 CPK CPK NP28761 NP28673 BO28984 3 1.7% 0.5% 3.2%3 3.7 0.5 14.7 4 3 1.5 ULN 2 7 A UVA / B UVBSPF 50 9 / 20
- - 3 3 3-10 / 20
18 CYP M4 CYP1A2 CYP2B6 CYP2C9 CYP2C19 CYP2D6 M4 CYP3A4 CYP3A4 CYP2B6 ALK - CYP3A CYP3A CYP2C8 PBPK CYP2C8 P-gp BCRP M4 P-P-gpBCRP P-gp BCRP 2 P-gp BCRP CYP3A4 M4 CYP3A 40%~50% M4 ALK CYP3A 600 mg CYP3A 600 mg M4 / [90%] C max 0.96 [0.88~1.05] AUC inf 0.82 [0.74~0.90] CYP3A CYP3A 11 / 20
400 mg CYP3A 300 mg M4 / [90%] C max 0.93 [0.81~1.08] AUC inf 1.36 [1.24 ~1.49] CYP3A ph ph 40 mg - M4 ph H2 P-gp M4 BCRP OATP 1B1/B3 M4 P-gp P-gp P-gp M4 NP28761 NP28673 BO28984 ALK III BO28984 Ventana ALK D5F3IHC ALK III 303 151 152 600 mg ECOG PS 0/1 2 RECIST 1.1 PFS 58 54 55% 58%55% 54%61% 65%93% ECOG PS 0 1 93%97% IV 96%90% 94%40% 38% 17% 14% 12 / 20
5 Kaplan-Meier 1 5 BO28984 N=151 N=152 17.6 (: 0.3 27.0) 18.6 (: 0.5 29.0) PFS INV % [95% CI] HR [95% CI] p # PFS IRC * % [95% CI] HR [95% CI] p # IRC *, ** 102 (68%) 11.1 [9.1; 13.1] 92 (61%) 10.4 [7.7; 14.6] 0.47 [0.34, 0.65] p <0.0001 0.50 [0.36; 0.70] p < 0.0001 62 (41%) NE [17.7; NE] 63 (41%) 25.7 [19.9; NE] % 68 (45%) 18 (12%) HR [95% CI] p # 0.16 [0.10; 0.28] p < 0.0001 CNS 12 % [95% 41.4% [33.2; 49.4] 9.4% [5.4; 14.7] CI] ORR INV * % CR % 114 (75.5%) 2 (1.3%) 126 (82.9%) 6 (3.9%) DOR[95 % CI] 11.1 [7.9; 13.0] NE [NE; NE] CNSCNS-ORR (IRC) CNS% N=22 11 (50.0%) N=21 17 (81.0%) CNS-CR% 1 (5%) 8 (38%) 5.5 [2.1, 17.3] 17.3 [14.8, NE] CNS-DOR[95% CI] CNS CNS-ORR IRC CNS% CNS-CR % N=58 15 (25.9%) 5 9% 3.7 [3.2, 6.8] N=64 38 (59.4%) 29 45% NE [17.3, NE] CNS-DOR[95% CI] * # ** CNS CI = CNS = CR = DOR = HR = IRC = INV = NE = ORR = PFS = CNS HR=0.40 95% CI 0.25-0.64 PFS 95% CI 9.2-NE PFS = 7.4 95% CI 6.6-9.6 CNS HR = 0.51 95% CI 0.33-0.80 PFS 95% CI NE-NE PFS = 14.8 95% CI 10.8-20.3 13 / 20
1 BO28984 PFS Kaplan Meier % 0.47 (95% 0.34-0.65) P < 0.0001(log-rank ) ALK I/II NP28673 NP28761 NP28673 NP28673 I/II ALK 138 II 600 mg IRC RECIST 1.1ORR IRC RECIST 1.1 ORR ORR 35% ALK 67%26% 56% 52 70%90.6% ECOG 0 1 9.4% 2 99% IV 61% 96% 20% 80% NP28761 NP28761 I/II ALK 14 / 20
87 II 600 mg IRC RECIST 1.1 ORR ORR 35% ALK 84%8% 55% 54 62%89.7% ECOG 0 1 10.3% 2 99% IV 60% 94% 26% 74% 6 NP28673 NP28761 CNS 7 6 NP28673 NP28761 NP28673 N=138 NP28761 N=87 21 (: 1 30) 17 (: 1 29) RE ORR IRC % [95% CI] ORR IRC % [95% CI DOR IRC % [95% CI] PFS IRC % [95% CI] N = 122 a 62 (50.8%) [41.6, 60.0] N = 96 43 (44.8%) [34.6, 55.3] N = 62 36 (58.1%) 15.2 [11.2, 24.9] N = 138 98 (71.0%) 8.9 [5.6, 12.8] N = 67 b 35 (52.2%) [39.7, 64.6] N = 35 20 (57.1%) 14.9 [6.9, NE] N = 87 58 (66.7%) 8.2 [6.3, 12.6] CI = DOR = IRC = NE = ORR = PFS= RE = a IRC 16 IRC b IRC 20 IRC NP28673 NP28761 ORR ECOG CNS 15 / 20
7 NP28673 NP28761 CNS CNS NP28673 NP28761 CNS CNS ORR IRC %95% CI 600 mg N = 50 32 (64.0%) [49.2, 77.1] 11 (22.0%) 21 (42.0%) CNS DOR IRC % 95% CI N = 32 18 (56.3%) 11.1 [7.6 NE] CI= DOR= IRC=ORR=NE= BO28984 BO28984 43 18 25 10 19 14 PFS IRC CNS 13 ALK RET ALK STAT3 PI3K/AKT M4 ALK M4 ALK 10-60 AUC AUC 20-120 20-30 AUC /ALP 16 / 20
// / AUC 2.6 0.5 4.5 Ames CHL 2.7 AUC - - 27mg/kg/ AUC 0-24h,ss 2.9 3/6-3 - 27mg/kg/ AUC 0-24h,ss 4.5-9mg/kg/ AUC 0-24h,ss 2.7 200 400nm UVA 24 CNS- 0.9 1.5 17 / 20
ALK M4 C max C min AUC 0-12hr % 665 ng/ml 44.3% 572 ng/ml 47.8% 7430 ng*h/ml 45.7%M4 C max C min AUC 0-12hr % 246 ng/ml 45.4%222 ng/ml 46.6% 2810 ng*h/ml 45.9% ALK 600 mg 4 6 600 mg 7 600 mg 5.6 300 900 mg 36.9% 90% CI 33.9%, 40.3% 600 mg 3 M4 [90% CI] C max 3.31 [2.79 ~3.93] AUC inf 3.11 [2.73 ~3.55] M4 >99% M4-2.64 2.50 V ss 475 L CYP3A4 M4 CYP 40%-50% M4 M4 76% / 0.399 14 C 97.8%95.6%-100%0.46%0.30%- 0.60% 84% 5.8% M4 CL/F 81.9 L/ 32.5 M4 217 L/ 30.7 18 / 20
21-83 M4 < 0.2% / M4 ULN AST ULN 1.0 1.5 ULN AST ULN AST ULN M4 Child-Pugh B 300 mg M4 / [90%] C max 1.16 [0.786 1.72] AUC inf 1.36 [0.947 1.96] Child- Pugh C 300 mg M4 / [90%] C max 0.981 [0.517 1.86] AUC inf 1.76 [0.984 3.15] 20 M4 600mg 600mg M4 I/II NP28763 30 / 19 / 20
224 /56 4 36 H20180047 Roche Registration GmbH Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany Excella GmbH & Co. KG Nürnberger Strasse 12, 90537 Feucht, Germany Delpharm Milano S.r.l. Via Carnevale 1, 20090 Segrate (MI), Italy 1100 021-28922888 021-50801800 8008208780 4008208780 www.roche.com.cn 20 / 20