2017 3 10 2017 5 26 2017 11 29 2018 7 24, 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 / 27
CFDA BRAF V600 240 mg CFDA BRAF V600 BRAF 960 mg 240 12 1 2 4 QTc 1 2 480 mg 2 / 27
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 / 27
ms QTc 60 ms 65 18 18 6300 ADR 2 BRAF V600 N III NO25026 = 675 BRAF V600 N = 132 II N P22657 III NO25026 2 960 mg 1000 mg/m 2 3 6.6 0.8 II NP22657 960 mg, 5.7 ADR 30% 4 / 27
5% 3 ADR cuscc- GGT 4 4% NO25026 7 % NP22657 3% 3 ADR ADR MedDRA ADR 1/100 <1/101/1,000 <1/100 1/10,000 <1/1,000 <1/10,000 3 * ADR n=336 n=132 3 3 % % % % 43 9 55 8 40 4 54 4 48 <1 40-26 1 33 2 29 2 31-10 3 21 6 13-20 - 24-21 - 18-11 - 10 <1 11 2 10 <1 10-5 <1 2 - <1-2 - 2 <1 3 - Stevens-Johnson <1 <1 - - <1 <1 - - 56 6 70 9 5 / 27
ADR % n=336 n=132 3 % % 3 % 15 1 27 2 23 <1 11-13 <1 12-16 <1 13 <1 4 <1 11 2 <1 <1 <1-47 3 60 4 15 <1 27-22 <1 20 2 15 <1 2-39 2 45 3 37 2 32 <1 22 2 33 2 16 <1 18-34 2 31 <1 16-11 - 4-11 <1 12 <1 10 - VII <1-3 <1 29 <1 33 - # 20 20 26 26 11 11 5 5 14 <1 15-3 3 8 8 6 / 27
ADR % n=336 n=132 3 % % 3 % QT 4-3 - - - <1 <1 3 <1 5 - <1-2 - GGT 7 4 17 7 23 1 23-10 1 11 <1 15-17 - 1 <1 2-17 <1 17-8 <1 11 <1 *MedDRA NCI-CTCAE v 4.0 NCI # 3 4 GGT 4% cuscc 20% SCC- 43% 7 / 27
cuscc 7.1 8.1 33% 6 960 mg 8 240 mg QT IIQT 132 960 m 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 95% ms 17.7 msn = 90 1.5% QTc 500 ms CTCAE 30.8% QTc 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 NO25026 3 4 4 4 3/4 * % 8 / 27 3 /4 GGT 11.5 8.6 AST 0.9 0.4 ALT* 2.8 1.9 * 2.9 0.4 * 1.9 - %
*ALT 5 III 5 % 1 27.9 6.1 1 3 1.2 1.1 3 0.3 0.4 4 0.9 0.8 % 6 SOC 6 % 9 / 27 <1 <1 N/A CMML 1,2 1,3 N/A N/A 1 DRESS N/A <1 N/A N/A N/A 1 * 2 n -ras -
#3 k -ras ^ 4 ALT 5 ALP 2 ALT 3 > 2 BRAF V600 cuscc 65 10 / 27
6 cuscc 3 CT 6 6 RAS RAS BRAF BRAF BRAF MAP BRAF V600 BRAF 11 / 27
Stevens -Johnson DRESS QT QT QT QT QT QT 3 3 QTc > 500 ms QTc 500 ms CTCAE 3 QT QTc 500 ms 1 2 QTc 500 ms 60 ms UVA/UVB (SPF 30) 12 / 27
2 ipilimumab I ipilimumab 3 mg/kg 960 mg 720 mg 3 ipilimumab 3 13 / 27
14 / 27 >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 S-CYP2C9 S- AUC 18% INR 15 / 27
CYP2C8 CYP2C8 CYP2C8 CYP3A4 CYP3A4 CYP3A4 CYP3A4 AUC 960 mg 40% 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 16 / 27
III 675 II 278 cobas 4800 BRAF V600 BRAF V600 III BRAF V600 1000 2 3 mg/m 675 n n = 337 = 338 LDH ECOG 99% 56 28% 65 ECOG 0 1 M1c 66% - OSPFS 2010 12 30 OS p < 0.0001PFS 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 24 OS 2012 17 / 27
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 48.4% 95% 41.6% 55.2%5.5% 95% 2.8% 9.3%p 37% < 0.0001 24% RECIST 1.1 LDH ECOG OS PFS 7 1 OS 2 PFS 1 Kaplan-Meier - 2012 12 20 7 BRAF V600 p d 18 / 27
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 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 a Cox 1 b Kaplan-Meier c 24 d - - - - 2 Kaplan-Meier - 63.4% 95% 57% 69% 20.2% 95% 15% 26% NO25026 673 57 BRAF V600K V600K 19 / 27
OS PFS II N=132 52 19% 65 61% 99% M1c 61%49% 2 6.87 0.6 11.3 - CR + PR 52% 95% 43% 61% 1.4 75% 1.6 IRC 6.5 95% 5.6 30% RECIST 1.1 15.9 95% 11.2 19.3 6 77% 95% 69% 84% 1 58% 95% 48% 66% PFS 6.1 95% 5.5 6.96 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 1.1 RECIST v1.1 BORR DOR PFS OS 20 / 27
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 26 5.0 3.7 6.6 a n % b 95%Clopper-Pearson CI c d Kaplan-Meier e 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 5 M1c 61% ECOG 0 1 67% 11.3 3.3 16.0 CR 52% 95%37% + PR 67% 1.8 9.1 95% 21 / 27
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% BRAF - BRAF V600E CRAF ARAF BRAF SRMS ACK1 MAP4K5 FGR BRAF V600E BRAF BRAF V600E 22 / 27
Ames 450mg/kg/ AUC 1.6 0.6 0.4 250mg/kg/ AUC 1.7 450mg/kg/ AUC 0.7 / 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 240mg 4 T max 4 960 mg II 4 1 3.6 µg/ml 15 49.0 µg/ml 5.4 118 µg/ml 960 mg C max AUC 2.5 4.6-5.1 T max 4 7.5 15 80% 2-4 1.13 23 / 27
0.19-1 101% 91 L 64.8% > 99% 14 C- 95% 18 1% CYP3A4 95% CYP3A4 AUC 960 mg 40% CYP3A4 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 µg h/ml 63 µg/ml 6 15-17 IIIC IV BRAF V600 24 / 27
>30 min ml/ 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) C max (µg/ml) YO28390 37.5 ± 22.3(59.4) (8.5 93.1,n=20) 6.9 ±3.9(55.8) (2.4 14.9,n=20) NP25163 27.0 ± 18.9 (69.9) (2.8 57.7, n=16) 4.8 ± 3.3 (69.8) (0.61 10.7, n=16) 25 / 27
15 AUC 0-8h (µg h/ml) C max (µg/ml) C trough b (µg/ml) 21 AUC 0-8h (µg h/ml) 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 / 36 26 / 27
JX20150212 H20170124 Roche Registration GmbH Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany Delpharm Milano S.r.l. Via Carnevale 1, 20090 Segrate (MI), Italy 1100 021-28922888 021-50801800 8008208780 4008208780 www.roche.com.cn 27 / 27