26 1 23 26 11 12 27 3 22 27 4 28 27 5 24 28 12 9 29 2 11 29 3 15 29 9 8 21 4 8 211 4 29 212 2 27 212 11 6 213 12 5 Tarceva Erlotinib Hydrochloride Tablets Yansuan Eluotini Pian N-(3-)-6,7- (2- )-4- C 22 H 23 N 3 O 4 HCl 429.9 1 33
NSCLC + + NSCLC 4 BO18192 [ ] EGFR 1 1 2 15 15mg/ 1 2 ILD - 2 33
5mg CYP3A4 TAO CYP3A4 AUC 2/3-4/5 CYP3A4 15mg 45mg CYP3A4 St. John s Wort Child-Pugh 7-9 >1.5 x ULN 5-6% NSCLC 3mg >14 3 33
12 15mg 3 1mg 15mg 1228 ADR ADR 1% 3% NSCLC - NSCLC III BO18192 889 NSCLC 15mg 49% 2% I/II III 6% 1.8% IV 1% <1% 8.3% 3% 66% 81% 1 NCI-CTC 3. 15 mg 3% 3% 1 3% 3% MedDRA N = 433 N = 445 NCI-CTC NCI-CTC % III % IV % % III % IV % 4 33
49.2 6. 5.8 2.3 1.8 4.5 9. 1.8 5.8 1.1 9.2 <1 4.9 <1 7.4 <1 2.7 6.2 <1 4.6 <1 1.1 4.4 <1 3.9 <1 <1 3.9 <1 ALT AST II (>2.5 5. x ULN) ALT 2% 1% III (>5. 2. x ULN) ALT 1% % II (>1.5-3. x ULN) III (>3.-1. x ULN) 4% <1%<1% NSCLC / III BR.21 731 NSCLC 2:1 15mg 2 75% 54% I II III/IV 9% 6% 1% 6% 1% BR.21 8 12 2 BR.21 3% 1% N=485 N=242 NCI-CTC NCI-CTC % III % IV % % III % IV % * 24 4 15 2 52 8 1 38 5 <1 5 33
12 12 <1 2 3 <1 41 33 17 4 11 35 29 15 2 11 54 33 6 3 <1 18 24 <1 2 23 2 <1 19 2 17 <1 3 11 2 <1 7 1 <1 75 13 12 8 <1 <1 17 5 4 52 14 4 45 16 4 * 15mg NSCLC ALT AST II ALT >2.5-5.ULN 4% <1% III ALT >5.-2.ULN NSCLC TRUST 6578 71%, III/IV 12% 4% 5% 59 84% III/IV 4% 3 <1% 6 1% 154 III ML265 75 EGFR NSCLC ML265 8% 57% I II III 9% 4% IV 1% 6 33
11% 7% PA.3 569 1:1 1 mg 15 mg IV 1 mg/m 2 1 1, 8, 15, 22, 29, 36 43 8 2 1, 8 15 4 285 261 1mg 24 15mg 284 26 1mg 24 15mg 15mg 1mg III/IV 5% 1 15 2% 1% 15mg 23 3 1mg 1% NCI-CTC 7 33
3 1mg + 1% + 1 mg/m 2 IV N=259 + 1 mg/m 2 IV N=256 NCI CTC NCI CTC % III % IV % % III % IV % 73 14 2 7 13 2 69 5 3 1 6 7 58 7 52 6 <1 52 5 <1 48 5 <1 36 2 46 9 <1 45 12 <1 42 7 <1 41 4 <1 39 2 29 <1 * 39 13 3 3 9 2 37 3 <1 36 2 <1 36 3 3 4 31 3 1 34 5 1 25 4 <1 23 2 24 5 <1 23 5 22 <1 12 21 1 2 <1 19 2 14 <1 17 <1 13 <1 16 11 15 <1 13 <1 15 <1 1 15 <1 16 <1 14 11 13 1 11 <1 13 1 <1 1 <1 13 9 <1 12 9 * / 1 3.9% / 3 1.2% III IV 11% 9% 8 33
III IV 5% NCI-CTC III / ALT AST 4 NCI-CTC 4 NCI-CTC 1mg + 1 mg/m 2 IV N=259 NCI CTC + 1 mg/m 2 IV N=256 NCI CTC II III IV II III IV 17% 1% <1% 11% 1% 3% ALT 31% 13% <1% 22% 9% % AST 24% 1% <1% 19% 9% % 15mg 1mg 15mg 1/1 1/1, <1/1 1/1,, <1/1 1/1,, <1/1 <1/1, 1 2 3 1% INR 9 33
ALT AST PA3 NSCLC ILD NSCLC / 1% Stevens-Johnson / / 65 1 33
: / Stevens-Johnson / NSCLC NSCLC.8% 2.5%.4% 32 1.1% 11 33
ILD / / / 6 2.3% / 1 / 3 1.2% 1 / 6 2.3% 1 / / 2.8% 12 33
/ >3 ULN />5 ULN - Child-Pugh B 15 1 3 1 1 8 1 8 > 3 ULN > 3 ULN > ULN Child-Pugh A, B C NSAIDs /, Stevens-Johnson /, / 13 33
- INR INR Lapp - D 15mg 3 / 15mg.3.7 mg/m 2 2 14 33
NSCLC NSCLC 66% 65 34% 65 65.78 95% CI:.65,.95 65.88 95% CI:.68, 1.15 NSCLC / NSCLC 62% 65 38% 65 53% 65 47% 65 CYP1A1 CYP3A4 CYP2C8 UGT1A1 CYP1A1 CYP 1Al UGT1Al UGT1A1 Gilbert CYP3A4 CYP1A2 CYP1A1 CYP3A4 2mg 2 5 CYP3A4 AUC AUC 86% C max 69% CYP3A4 CYP1A2 AUC C max 39% 17% AUC Cmax 6% 48% CYP1A2 CYP3A4 15 33
CYP3A4 /CYP1A2 CYP3A4 15mg 6mg 1 7 CYP3A4 AUC 69% 45 mg AUC 15 mg 57.5% CYP3A4 + CYP3A4 3 mg 2 45 mg St. Johns Wort CYP3A4 CYP3A4 CYP3A4 24% CYP3A4 CYP3A4/2C8 CYP3A4 ph ph ph AUC C max 46% 61% T max 3mg H2 AUC Cmax 33% 54% 15mg 2 1 AUC Cmax 15% 17%H2 H2 2 1 P- (Pgp) Pgp / CNS 16 33
AUC -48 1.6% AUC Cmax CYP1A1 CYP1A2 5-6% 1mg 16mg 2mg 15mg NSCLC BO18192 26 889 NSCLC 1:1 15 mg 438 451 EGFR IHC PFS 5 N=438 N=451 17 33
N (%) N (%) 117 (27%) 113 (25%) 321 (73%) 338 (75%) 65 148 (34%) 151 (33%) < 65 29 (66%) 3 (67%) NSCLC III B 116 (26%) 19 (24%) IV 322 (74%) 342 (76%) 37 (84%) 376 (83%) 3 (<1%) 1 (<1%) 62 (14%) 69 (15%) 3 (<1%) 5 (1%) ECOG 135 (31%) 145 (32%) 1 33 (69%) 36 (68%) EGFR IHC 38 (7%) 313 (69%) 62 (14%) 59 (13%) 16 (4%) 24 (5%) 52 (12%) 55 (12%) 166 (38%) 194 (43%) 25 (47%) 198 (44%) 21 (5%) 24 (5%) 46 (11%) 35 (8%) 239 (55%) 254 (56%) 77 (18%) 75 (17%) 122 (28%) 122 (27%) 18 33
= 1 - ITT n=889pfs PFS.71 95% CI,.62-.82 p<.l PFS 22.4 16. PFS EGFR IHC n=621 PFS.69 95% CI,.58-.82 p<.1 PFS 22.8.1-78.9 16.2.1-88.16 27% 16% OS.81 95% CI,.7-.95 p=.88 12. 11.1 Kaplan Meier EGFRn =49, PFS HR=.1, 95% CI,.4-.25 p<.1 EGFR PFS HR.78 95% CI,.63-.96 p=.l85 OS HR.77 95% CI,.61-.97 p=.243 OS.77 95% CI:.61,.97.86 95% CI:.68, 1.1 1 Kaplan Meier ITT 19 33
HR Cox - SD n=487 PFS HR.68 95% CI,.56-.83 p<.1 12.1 11.3 OS HR.72 95% CI,.59-.89 p =.19 OS 11.99.6 HR.67, 95% CI,.48-.92 HR.76, 95% CI.59-1. EGFR HR.48, 95%.14-1.62 EGFR HR.65, 95% CI.48-.87 - SATURN SATURN ITT 72% 66%28% 17% 15% 6 6 ITT (n=438) (n=451) 71% 72% * 63% 66% ** 28% 28% ** 2% 17% ** 8% 9% ** 8% 15% ** 2% 6% * ** SATURN ITT 67 SATURN 438 67 2 33
SATURN NSCLC BR.21 731 2 1 15mg 488 243 OS CR+PR PFS OS 17 1/2 326 EGFR 7 2/3 1/4 ECOG PS 2 9% ECOG PS 3 5% 3/4 7 N=488 N=243 n % n % 173 35 83 34 315 65 16 66 <65 299 61 153 63 65 189 39 9 37 379 78 188 77 18 4 12 5 63 13 28 12 28 6 15 6 ECOG * 64 13 34 14 1 256 52 132 54 2 126 26 56 23 3 42 9 21 9 6 <5% 32 66 166 68 5-1% 96 2 36 15 >1% 52 11 29 12 2 4 12 5 14 21 42 17 358 73 187 77 26 5 14 6 246 5 119 49 21 33
144 3 78 32 41 8 23 9 11 2 2 <1 46 9 21 9 <6 63 13 34 14 6-12 157 32 85 35 >12 268 55 124 51 * CR/PR 196 4 96 4 PD 11 21 51 21 SD 191 39 96 4 * 1 243 5 121 5 2 238 49 119 49 3 7 1 3 1 * 454 93 224 92 34 7 19 8 * 8 8 1 95% p 6.7 4.7.73.61-.86 <.1 2 1 31.2% 21.5% 9.9 7.9.59.5-.7 <.1 2 CR+PR 8.9%.9% <.1 3 34.3 15.9 1 ECOG COX 2 ECOG Log-Rank 3 Fisher's 2 Kaplan-Meier OS PFS ECOG Log-Rank 22 33
2 Kaplan-Meier 4.7 N=488 6.7 N=243 HR ECOG COX P ECOG Log-Rank 3 EGFR HR=.68HR=.42 23 33
3 N HR 95% CI : 731.76.6.9 PS 1 486.73.6.9 PS 2 3 245.77.6 1. 475.76.6.9 256.8.6 1.1 <65 452.75.6.9 65 279.79.6 1. 365.71.6.9 222.67.5.9 144 1.4.7 1.5 <5% 486.77.6.9 5 1% 132.63.4 1. >1% 81.7.4 1.1 146.42.3.6 / 545.87.7 1. 1 364.76.6 1. 2 2 367.75.6 1. 678.72.6.9 53 1.41.7 2.7 267.74.6 1. 464.78.6 1. : CR/PR 292.67.5.9 : SD 287.83.6 1.1 : PD 152.85.6 1.2 <6 97.68.4 1.1 6 12 242.87.7 1.2 >12 392.75.6.9 EGFR 185.68.5.9 EGFR 141.93.6 1.4 EGFR 45.77.6 1. 567.79.6 1. 91.61.4 1. IV 329.92.7 1.2 <IV 42.65.5.8 3 HR HR 95% CI N HR 95%CI HR 1. NSCLC EGFR EGFR 326 45% EGFR EGFR EGFR EGFR EGFR 1% EGFR EGFR pharmdx TM 1% 24 33
N=68pharmDx EGFR N=185 HR=.68 95% CI=.49-.94 4 EGFR N=45 HR=.77 95% CI=.61-.98 6 EGFR N=141 HR=.93 95% CI=.63-1.36 5 EGFR EGFR NSCLC EGFR EGFR N=41 HR=.28 95% CI=.13-.61 EGFR EGFR EGFR 11.3% EGFR 9.5% EGFR 3.8% EGFR HR=.49 95% CI=.35-.68 EGFR HR=.6 95% CI=.47-.75 EGFR HR=.8 95% CI=.55-1.16 4 EGFR N=117 25 33
N=127 5 EGFR N=93 N=48 6 EGFR N=278 NSCLC TRUST 15mg 29 2 24 6586 519 ECOG 1 / 13% 9 26 33
9 TRUST TRUST: TRUST: N=519 N=6586 n % n % 57 63 296 57 3978 6 223 43 268 4 ECOG 94 18 1473 22 1 321 62 358 53 2 81 16 1236 19 3 23 4 36 5 III B 92 18 1377 21 IV 427 82 519 79 381 73 3594 55 2 4 373 6 3 <1 382 6 95 18 1555 24 2 4 679 1 1 <1 872 13 32 58 3225 49 216 42 2432 37 57 <1 284 55 25 3 235 45 4572 69 13% 69% 3.25 8.15 12% 68% 3.15 8.87 9% 67% 3.18 7.29 26.6% 54.7% 81.3% 6.44 15.37 27 33
1 TRUST TRUST 15.37 8.15 15.34 8.87 15.51 7.29 TTP 6.44 3.25 5.71 3.15 7.31 3.18 27% 13% 28% 12% 25% 9% 81% 69% 8% 68% 83% 67% NSCLC 1 NSCLC +N=526 + N=58 NSCLC 73% 27% [ OS HR=.88 95% CI:.74-1.5 OS HR=.64 95% CI:.46-.91 ] NSCLC / / NSCLC 65% 35% [ OS HR=.76 95% CI:.6-.9 OS HR=.8 95% CI:.6-1.1 ] 28 33
NSCLC 84% 15% [ OS HR=.86 95% CI:.73-1.1 OS HR=.66 95% CI:.42-1.5 ] NSCLC / / NSCLC 78% 13% [ OS HR=.79 95% CI:.6-1. OS HR=.61 95% CI:.4-1. ] EGFR / I HER1 EGFR EGFR EGFR / ALT AST UV 6 29 33
15mg AUC 3 / AUC / 3mg/m 2 /d 6mg/m 2 /d mg/m 2.3-.7 15mg 6% 4 1% 93% α1 AAG 232 4 3 NSCLC, 1 15 mg 9 1,185 ng/g 63% 5-161% 16 ng/g 113% 88-13% 95% alpha-1 AAG P45 CYP3A4 CYP1A2 CYP1A1 CYP3A4 CYP1A1 1B1 3 1 O- 23 O- OSI-42 OSI-413 <1 % 1mg 91% 83% 1% 8%.3% 591 36.2 3 33
7-8 24% 291 NSCLC AAG Child-Pugh 7-9 Child-Pugh 7-9 AUC -t Cmax 27 ng.h/ml 85 ng/ml 293 ng.h/ml 19 ng/ml Cmax 9% 15mg Cmax 156 ng/ml 689 ng/ml 31 33
65.2% 95% CI: 44.3-95.9, p=.31 AUC -inf 18726 ng.h/ml 6718 ng h/ml 35.9% 95% CI: 23.7-54.3, p<.1 C 24h 288 ng/ml 34.8 ng/ml 12.1% 95% CI: 4.82-3.2, p=.1 / 16 CYP1A1 CYP1A2 III NSCLC BR.21.65 µg/ml n=16 1/2 1.28 µg/ml n=18 24% NSCLC I 15mg 3mg 3mg 1.22 µg/ml n=17 CYP3A4 CYP3A4 CYP3A4 AUC 2/3 CYP3A4 3 AUC 2/3 Ib 11% 2515-3 PVC 3 / 32 33
36 JX211234 1 1 H21214 2 15 H21212 Roche Registration Ltd. 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Roche S.p.A. Via Morelli 2, 29 Segrate (Milano), Italy F. Hoffmann-La Roche Ltd. Wurmisweg, 433 Kaiseraugst, Switzerland 11 21 28922888 8-82-878 http://www.roche.com.cn 33 33