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 5 217 1 17 217 3 1 Tarceva Erlotinib Hydrochloride Tablets Yansuan Eluotini Pian N-(3-) -6,7- (2 -) -4-1 34
C 22H 23 N 3 O 4 HCl 429.9 EGFR NSCLC ++ NSCLC 1 1 2 15 NSCLC EGFR 15mg/ 1 2 2 34
ILD - 5mg CYP3A4 CYP3A4 AUC 2/3-4/5 CYP3A4 15mg 45mg CYP3A4 St. John s Wort -Pugh 7-9 3 34
>1.5 x ULN 5-6% NSCLC 3mg 15 15 15mg 3 1mg 15mg 1228 ADR ADR 1% 3% NSCLC - EGFR NSCLC 153 III ML265 (EURTAC) 75 EGFR NSCLC ML265 8% 57% 1 2 3 9% 4% 4 1% 11% 7% YO25121(ENSURE) / EGFR (IIIB/IV 4 34
)NSCLC 11 AE 67.3% 4.9% 1.9% 12 7 6.4% 3 1 2 2 3 45 1.9% ALT 9.1% AST 5.5% 6.4% 12 1 ENSURE 3% 1% MedDRA N = 11 NCI-CTC N = 14 NCI-CTC % 3 % 4 % % 3 % 4 % 67.3 6.4 1.6 1. 4.9 1.8 9.6 1. 1.9.9 2 SAE 3 2.7% 2 [1.8%] 23 IIIMO2981 OPTIMAL, B T4 EGFR NSCLC + 83 88.% 73/83 98.6% 71/72 1 23 4 12.% 1/83 2 2.4 ALT/AST 1 1.2 3 4 65.3% 47/ 72 2 2.4%+ 113.9% 7 NSCLC 5 34
III BO18192 SATURN BO2546 IUNO 1532 NSCLC 15mg 2. IV BO18192 1% <1% BO2546 BO18192 8.3% 3% BO2546 5.6% 2.8% 2 BO18192 SATURN BO2546 IUNO * ALT AST 2 (>2.5 5. x ULN) ALT 2% 1% 3 (>5. 2. x ULN) ALT 1% % 2 (>1.5-3. x ULN) 3 (>3.-1. x ULN) 4% <1% <1% NSCLC / III BR.21 731 NSCLC 2:1 15mg 3 75% 54% I II III/IV 9% 6% 1% 6% 1% BR.21 8 12 6 34
3 BR.21 3% 1% N=485 NCI-CTC N=242 NCI-CTC % III % IV % % III % IV % * 24 4 15 2 52 8 1 38 5 <1 12 12 <1 41 33 17 4 54 33 23 17 11 75 13 12 6 3 2 <1 2 8 <1 52 14 4 45 16 4 11 <1 <1 <1 <1 * 15mg NSCLC ALT AST II ALT >2.5-5. 4% <1% III ALT >5.-2. NSCLC 6578 2 3 35 29 18 24 19 3 7 17 5 4 <1 15 2 <1 2 2 1 11 <1 7 34
71%, III/IV 12% 4% 5% 59 84% III/IV 4% 3 <1% 6 1% 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 4 1% NCI-CTC 8 34
4 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 * 9 34
/ 1 3.9%/ 3 1.2%III IV 11% 9% III IV 5% -CTC III NCI / ALT AST 5 NCI-CTC 5 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 2 3 4 1% 1 34
11 34 INR ALT AST PA3 NSCLC ILD NSCLC / 1% Stevens-Johnson /
65 : Stevens-Johnson / NSCLC EGFR 19 21 L858R EGFR 12 34
NSCLC NSCLC NSCLC.8% 2.5%.4% 32.6% ILD / 3.5%.8% 1.4%.4% 13 34
/ / 6 2.3% / 1 3 1.2% 1 / 6 2.3% 1 / 2.8% / / >5 ULN - Child -Pugh B 15 1 3 1 14 34
1 8 1 8 > 3 ULN > 3 > ULN Child-Pugh A, B C /, Stevens-Johnson /, - INR INR 15 34
15mg 3 15mg.3.7 mg/m 2 2 18 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 CYP1A1 CYP3A4 CYP2C8 UGT1A1 CYP1A1 CYP 1Al 16 34
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 C max 6% 48% CYP1A2 CYP3A4 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 17 34
ph AUC C max 46% 61% T max 3mg H 2 AUC C max 33% 54% 15mg 2 1 AUC C max 15% 17% H 2 H 2 2 1 P- Pgp / CNS AUC -48 1.6% AUC C max CYP1A1 CYP1A2 5-6% 1mg 16mg 2mg 15mg 18 34
EGFR NSCLC III ML265 EURTAC EGFR NSCLC NSCLC IIIB IV EGFR 19 21 L858R PCR 1:1 15 mg 4 174 NSCLC 99% 65 51%ECOG 1 53% ECOG 33% 93% IV 7% IIIB AJCC 93% 66% 19 34% 21(L858R) PFS 6 1. ML265 EURTAC PFS Kaplan-Meier 6 ML265 EURTAC N = 86 N = 88 PFS 19 34
71 (83%) 63 (72%) PFS (95% CI) 1.4 (8.7, 12.9) 5.2 (4.6, 6.) (95% CI) (1).34 (.23,.49) P ( log-rank ) <.1 OS (%) 55 (64%) 54 (61%) OS (95% CI) 22.9 (17., 26.8) 19.5 (17.3, 28.4) (95% CI) (1).93 (.64, 1.35) (95% CI) 65% (54.1%, 75.1%) 16% (9.%, 25.3%) (1) Cox ( ) III YO25121 ENSURE EGFR NSCLC NSCLC IIIB IV EGFR 19 21 L858R cobas 1:1 15 mg 4 + 647 217 17 11 61.3% 38.7% 56 3-78 57.5 33-79 ECOG 1 94.4% 93.6% IV 93.5% 9.9% PFS PFS 66% (HR=.34 [95 % CI.22,.51], p<.1 PFS Kaplan-Meier 2 (n=11) (n=17) PFS 11. 5.5 CR/PR 62.7% 33.6% p<.1 (IRC) PFS 2 34
5.6 PFS 11. HR=.42 [95% CI.27,.66], p=.1 IRC PFS 85.6 % HR=.91 [95% CI:.63,1.31], p=.673) 2. ENSURE PFS Kaplan-Meier FACT-L ENSURE 175 81% + 7 7 ENSURE ENSURE ENSURE N = 11 N = 17 N = 87 N = 88 PFS HR [95%].34 [.22.51 ].3 [.18.49] 21 34
11. 5.5 11.1 5.7 p <.1 <.1 PFS IRC HR [95%].42 [.27.66 ].38 [.22.64] 11. 5.6 11. 5.6 p.1.1 62.7% 33.6% 69.% 37.5% [95 %]29.8 [15.8, 42.3] 31.47 [16.8, 46.2] HR [95% ].6 [.37,.96].57 [.35,.93] ( ) - 5.5-5.5 (TOI HR [95% ].53 [.35,.82].5 [.32,.78] ( ) 11.1 4.2 11.1 2.9 HR [95% ].67 [.45,1.1].63 [.41,.96] ( ) 8.2 2.9 5.6 2.8 III MO2981 OPTIMAL EGFR NSCLC B NSCLC PCR-DNA EGFR 19 21 L858R 1:1 15 mg 4 + 165 1 1 154 93.3% 154/165 ITT 82 72 ECOG 19 21 22 34
PFS 83.8% (HR=.162 [95 % CI.13,.256], p<.1 PFS Kaplan-Meier 3 (n=83) (n=72) PFS 13.1 4.6 CR/PR 82.9% 36.1% p<.1 HR=1.186 [95% CI:.825,1.76], p=.2663) 3. OPTIMAL PFS Kaplan-Meier 8 OPTIMAL OPTIMAL N = 82 N = 72 PFS HR [95% ].162.13.256 13.1 4.6 p <.1 23 34
68 26 % 82.9 36.1 p <.1 OPTIMAL + 74 54 + FACL-L TOI LCS P <.1 9 OPTIMAL Logistic Regression + OR 95 CI P FACT-L 74 54 19 ( 25.7%) 37 ( 68.5%) 55 ( 74.3%) 17 ( 31.5%) 6.69(3.1-14.85) <.1 TOI 74 54 2 ( 27.%) 4 ( 74.1%) 54 ( 73.%) 14 ( 25.9%) 8.7(3.57-18.26) <.1 LCS 74 54 17 ( 23.%) 37 ( 68.5%) 57 ( 77.%) 17 ( 31.5%) 7.54(3.38-16.85) <.1 NSCLC BO18192 SATURN 26 889 NSCLC 1:1 15 mg 438 451 EGFR IHC 24 34
PFS BO18192 SATURN PFS HR=.1.71 p< OS HR=.81 p=.88 EGFR n=49 PFS HR=.1 95 CI.4,.25 p<.1hr.83 95 CI.34,2.2 EGFR 67 EGFR-TKI EGFR n=388pfs HR.78 95 CI.63,.96 p=.185 HR.77 95 CI.61,.97 p=.243 [82 93] EGFR 1921 4 L858R 643 NSCLCBO2546 IUNO 1:1 15mg EGFR HR= 95% 1.2 CI.85, 1.22 p=.82 PFS HR=.94 95 CI.8,1.11 p=.48 BO2546 IUNOEGFR NSCLC / NSCLC BR.21 731 2 1 15mg 488 243 OS CR+PR PFS OS 17 1/2 326 EGFR 1 2/3 1/4 ECOG PS 2 9% ECOG PS 3 5% 3/4 1 N=488 N=243 n % n % 25 34
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 49 144 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 26 34
* 454 93 224 92 34 7 19 8 * 11 11 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 8.9%.9% <.1 3 CR+PR 34.3 15.9 1 ECOG COX 2 ECOG Log-Rank 3 Fisher's 4 Kaplan-Meier OS PFS ECOG Log-Rank 4. Kaplan-Meier HR ECOG COX P ECOG Log-Rank 27 34
5 EGFR HR=.68 HR=.42 5. 28 34
5 HR HR 95%CI N HR 95%CI HR 1. EGFR 326 45% EGFR III MO22162 CURRENTS 38 NSCLC 3 mg 15 mg 3 mg PFS 7. 6.86 EGFR NSCLC 1 NSCLC + N=526+ N=58 EGFR / I HER1 EGFR EGFR EGFR EGFR EGFR EGFR EGFR ATP EGFR 29 / 34
ALT AST UV 6 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 3 / 34
CYP1A1 CYP3A4 CYP1A1 1B1 3 1 O- 2 3 O- OSI-42 OSI-413 <1 % 1mg 91% 83% 1% 8%.3% 591 36.2 7-8 24% 291 NSCLC AAG Child -Pugh 7-9 -Pugh 7-9 AUC -t C max 27 ng h/ml 85 ng/ml 31 / 34
293 ng h/ml 19 ng/ml C max 9% 15mg C max 156 ng/ml 689 ng/ml 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 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 1.22 µg/ml n=17 CYP3A4 CYP3A4 CYP3A4 AUC 2/3 CYP3A4 3 AUC 2/3 Ib 32 / 34
11% 2515-3 PVC 1 3 / 15 3 / 7 / 36 JX211234 1 1 H216392 2 15 H217143 Roche Registration Limited 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 33 / 34
11 21 28922888 8-82-878, 4-82-878 http://www.roche.com.cn 34 / 34