2017 3 10 2017 5 26, Zelboraf Vemurafenib film-coated tablets Weimofeini Pian -1- {3-[5-(4- )-1H- [2,3- b] -3- ]-2,4- } - C 23H 18 ClF 2 N 3 O 3 S 489.93 1
CFDA BRAF V600 240 mg CFDA BRAF V600 BRAF 960 mg 240 12 1 2 4 QTc 1 2 480 mg 2
1 CTC-AE a 1 2 960 mg 2 3 1 2 3 AE 0-1 720mg 480mg 2 2 3 AE 0-1 480mg 3 2 3 AE 4 1 4 AE 0-1 480mg 2 4 AE a CTC -AE 4.0 II - QT QTc 2 QT QTc QTc > 500 ms QTc > 500 ms > 60 ms 1 QTc > 500 ms 60 ms QTc500 ms QTc 2 QTc> 500 ms 60 ms QTc 3 QTc > 500 720mg 480mg QTc 500 ms 480mg 480mg 3
ms QTc 60 ms 65 18 ADR 2 BRAF V600 N III NO25026 = 675 BRAF V600 N = 132 II NO22657 III NO25026 2 960 mg 1000 mg/m 2 3 3.1 0.8 II NO22657 960 mg, 5.7 30% 5% 3 cussc 4 4% 3 III II 10% 4
3 10% * III n = 336 n = 287 II n = 132 3 4 3 4 3 4 % % % % % % % % % 37 8-2 - - 54 7-33 3-4 - - 52 3-45 < 1-2 - - 38 - - 23 1-1 - - 32 2-24 1 - < 1 - - 30 - - 9 2 - < 1 - - 21 6-8 - - 3 - - 17 - - 19 - - 1 - - 19 - - 5 < 1 - - - - 13 - - 14 - - 2 - - 10 - - 8 < 1-1 10 2 - - - 53 3-3 < 1-68 8-13 - - 1 - - 24 < 1-18 < 1-6 2-10 - - 8 < 1-4 < 1-12 - - 8 - - 5 < 1-11 < 1-2 < 1 - - - - 10 2-38 2-33 2-57 4-17 < 1-5 < 1-23 - - 19 < 1-9 < 1-19 2-11 < 1-9 < 1-2 - - 35 2-43 2-42 3-5
III n = 336 n = 287 II 3 4 3 4 3 % % % % % % % % n = 132 28 < 1-13 < 1-32 < 1-18 1-26 1-28 2-12 < 1-24 - - 17 - - 23 < 1-10 - - 29 - - 14 - - 3 - - 11 - - 2 - - < 1 - - 11 < 1-21 < 1 - - - - 31 - - 4 % # 24 22 - < 1 < 1-23 23-10 < 1-1 - - 14 - - - 5 3 < 1 1 15 6 4 - - 8 < 1-2 - - 10 < 1-18 - - 8 < 1-23 - - 8 - - 7 - - 15 - - 10 - - - - - 14 - - *MedDRA NCI-CTCAE v 4.0 NCI # 3 III II < 10% Stevens -Johnson 6
VII cuscc 20% SCC- 52% 43% / 7 8 33% 6 960 mg 8 240 mg QT IIQT 132 960 mg QTc 1 3.3 ms 95% 5 15 12.8 ms 95% 14.9 ms ms QTc QTc 12 15 ms 6 QTc 15.1 ms 95% 17.7 ms n = 90 1.5% QTc 500 ms CTCAE 30.8% QTc 7
60 ms QT 960 mg QTcP 60 ms 0.05% 45 kg/m 2 0.2% QTcP 60 ms 0.043% 0.046% QTcP 500 ms 0.05% 1.1% III 3 4 4 4 3/4 * % 3 /4 GGT 11.5 8.6 AST 0.9 0.4 ALT* 2.8 1.9 * 2.9 0.4 * 1.9 - % *ALT 4 5 III 5 % 1 27.9 6.1 13 1.2 1.1 3 0.3 0.4 4 0.9 0.8 % 6 SOC 8
- CMML * # DRESS ^ *n -ras - # k -ras ^ ALT 5 ALP 2 ALT 3 > 2 BRAF V600 9
cuscc 65 6 cuscc 3 CT 6 6 RAS RAS BRAF BRAF BRAF MAP BRAF V600 BRAF 10
Stevens -Johnson DRESS QT II QT QT QT QT QT 3 3 QTc > 500 ms QTc 500 ms CTCAE 3 QT QTc 500 ms 1 2 500 ms 60 ms 11
12 UVA/UVB (SPF 30) 2 ipilimumab I ipilimumab 3 mg/kg 960 mg 720 mg 3 ipilimumab
13 3 >1-1.5 ULN >1.5 3 ULN / 6
/ 18 65 III 336 94 28% 65 65 - CYP1A2 CYP3A4 CYP1A2 CYP3A4 CYP1A2 CYP3A4 CYP1A2 CYP1A2 AUC 2.6 CYP3A4 AUC 39% 2 mg CYP1A2 AUC last AUC inf 4.2 4.7 CYP2D6 AUC 47% CYP2D6 14
S-CYP2C9 S- AUC 18% INR CYP2C8 CYP2C8 CYP2C8 CYP3A4 CYP3A4 CYP3A4 CYP3A4 2 Gy/ P- P-gp BCRP P-gp GO28394 960mg AUC last C max 1.8 1.5 P-gp P-gp BCRP BCRP 15
III 675 II 278 cobas 4800 BRAF V600 BRAF V600 III BRAF V600 1000 2 3 mg/m 675 n = 337n = 338 LDH ECOG 59% 99% 56 28% 65 ECOG 0 1 M1c 66% - OS PFS BORR 2010 12 30 OSp < 0.0001 PFS p < 0.0001 3 2011 3 31 200 78 122 OS 6.2 0.4 13.9 4.5 0.1 11.7 0.44 95% 0.33 0.59 56% 6 Kaplan-Meier K -M 83% 95% 79% 87% 63% 95% 57% 69% OS K-M 95% 9.6 OS 7.9 95% 7.3 9. 6 16
24 OS 2012 12 20 478 242 236 13.4 0.4 33.3 OS K-M 13.6 95% 12.0 15.3 PFS 0.26 95% 0.20 0.33 74% 6 PFS Kaplan-Meier K -M 47% 95% 38% 55% 12% 95% 7% 18% PFS 5.32 95% 4.86 6.57 PFS 1.61 95% 1.58 1.74 CR + PR 48.4% 95% 41.6% 55.2% 5.5% 95% 2.8% 9.3% p < 0.0001 37% 24% RECIST 1.1 LDH ECOG OS PFS 7 1 OS 2 PFS 1 Kaplan-Meier - 2012 12 20 7 BRAF V600 17
N = 337 0.44 95%CI a 0.33 0.59 OS 95%CI b 6 83% 95%CI b 79% 87% OS OS 13.6 95%CI b c 12.0 15.3 a N = 338 7.9 9.6 7.3 9.6 63% 57% 69% 9.7 7.9 12.8 < 0.0001 0.26 95%CI a 0.20 0.33 < 0.0001 PFS 5.32 95%CI b 4.86 6.57 1.61 1.58 1.74 Cox 1 b Kaplan-Meier p d - - - - c d 24 2 Kaplan-Meier - 95% 57% 69% 20.2% 95% 15% 26% 18
NO25026 673 57 BRAF V600K V600K OS PFS II N=132 52 19% 65 61% 99% M1c 61%49% 2 6.87 0.6 11.3 - CR + PR IRC 52% 95% 43% 61% 1.4 75% 1.6 IRC 6.5 95% 5.6 30% RECIST 1.1 95% 9.5 6 77% 95% 70% 85% PFS 6.1 95% 5.5 6.9 6 PFS 52% 95% 43% 61% BRAF V600 II N=146 1 N = 90 2 N = 56 SRT RECIST- 54 26-83 61.6% 135 92.5% 11 7.5% 2 1-5 BORR IRC 1.1 RECIST v1.1 19
BORRDOR PFS OS ORR a n 8 1 n[%] 16 17.8% 95% CI b DOR c n 2 90 10.5 27.3 16 4.6 95% CI d 2.9 6.2 PFS- n e 90 3.7 95% CI 3.6 3.7 PFS - n 90 e 3.7 95% CI d 3.6 4.0 OS 90 56 10 17.9% 8.9 30.4 10 6.6 2.8 10.7 56 3.7 3.6 5.5 56 4.0 3.6 5.5 8.9 9.6 95% CI d 6.1 11.5 6.4 13.9 56 146 26 17.8% 12.0 25.0 a n % b 95%Clopper-Pearson CI c d Kaplan-Meier e 26 5.0 3.7 6.6 146 3.7 3.6 3.7 146 3.7 3.6 4.2 146 9.6 6.9 11.5 YO28390 YO28390 I N=46 BRAF V600 BORR PFS OS 42 4.3% 65 54% M1c 61% ECOG 0 1 67% 11.3 3.3 16.0 20
CR 52% 95% 37 + PR 67% 1.8 9.1 95% 7.4 46% RECIST 1.1 PFS 8.3 95% 5.7 10.96 PFS 59% 95% 45 % 73 12 PFS 33% 95% 20% 47 % 13.5 95% 12.2 6 89% 95% 80% 98 % 12 65% 95% 51 % 79 % 2014 12 15 1 1 2 2 3 3 13 28.3% 7 15.2% 9 3-4 3 2 3 3 3 33 3 GGT 4 AE 30 65.2% 27 58.7% 25 54.3% 24 52.2% 23 50.0%22 47.8% 17 37.0% 14 30.4% 13 28.3% 12 26.1% - 11 23.9% 10 21.7% 21
BRAF - BRAF V600E CRAF ARAF BRAF SRMS ACK1 MAP4K5 FGR BRAF V600E BRAF BRAF V600E Ames 450mg/kg/ AUC 1.6 0.6 0.3 250mg/kg/ AUC 1.3 450mg/kg/ AUC 0.6 / 3~5% cuscc I III C max C min AUC 0-12hr 62 µg/ml 53 µg/ml 600 µg h/ml 458 C max C min AUC 62 µg/ml 59 µg/ml 734 µg h/ml 7.36 240 960 mg 960 mg 240 mg T max 4 960 mg II 4 1 3.6 µg/ml 15 49.0 µg/ml 5.4 118 µg/ml 960 mg 22
C max AUC 2.5 4.7 T max 4 8 15 80% 2-4 1.13 0.19-1 101% 91 L 64.8% > 99% 14 C- 95% 18 94 % 1% CYP3A4 95% 29.3L/ 31.9% 56.9 5 95 29.8-119.5 CL/F 17% V/F 48% 12 AUC Cmax 792 µg h/ml 67 µg/ml 696 23
µg h/ml 63 µg/ml >30 min ml/ 29 ml/min AST ALT 3 I (YO28390 BRAF V600 20 21 960mg 21 ( 21 AUC 0-8h / 1 AUC 0-8h 17.9) 9 960mg YO29380 NP25163 AUC 0-8h C max 28% 26% 15 9 960mg YO28390 NP25163 a 1 AUC 0-8h (µg h/ml) YO28390 37.5 ± 22.3(59.4) (8.5 93.1,n=20) NP25163 27.0 ± 18.9 (69.9) (2.8 57.7, n=16) 24
C max (µg/ml) 15 AUC 0-8h (µg h/ml) C max (µg/ml) C trough b (µg/ml) 21 AUC 0-8h (µg h/ml) 6.9 ±3.9(55.8) 4.8 ± 3.3 (69.8) (2.4 14.9,n=20) (0.61 10.7, n=16) n/a 392.2 ± 126.4 (32.2) (217.3 575.7, n=11) n/a 61.4 ± 22.8 (37.1) (31.2 106.0, n=11) 63.0 ±23.3(37.0) 55.4 ± 19.2 (34.7) (16.9-106.5,n=19) (29.7-87.8, n=11) 501.3±123.0(24.5) n/a (303.9 701.9,n=19) C max (µg/ml) C trough b (µg/ml) 77.6 ±17.9(23.0) (48.4 107.6,n=19) 72.6±20.0(27.5) (35.7 107.6,n=19) n/a n/a a b ± (CV%), (, n/a = 30 / 56 / 25
36 JX20150212 H20170124 Roche (Schweiz) Pharma AG Sch önmattstrasse 2, 4153 Reinach BL, Switzerland Roche S.p.A. Via Morelli 2, 20090 Segrate (Milano), Italy 1100 021-28922888 021-50801800 8008208780 4008208780 www.roche.com.cn 26