2006 10 23 2006 11 12 2007 03 22 2007 04 28 2007 05 24 2008 12 09 2009 02 11 2009 03 15 2009 09 08 2010 04 08 2011 04 29 2012 02 27 2012 11 06 2013 12 05 2017 01 17 2017 03 10 2018 07 30 Tarceva Erlotinib Hydrochloride Tablets Yansuan Eluotini Pian N-(3-) -6,7- (2 -) -4-1 35
C 22H 23 N 3 O 4 HCl 429.90 EGFR NSCLC ++ NSCLC 1 100 2 150 NSCLC EGFR 150mg/ 1 2 2 35
ILD - 50mg CYP3A4 CYP3A4 AUC 2/3-4/5 CYP3A4 150mg 450mg CYP3A4 St. John s Wort -Pugh 7-9 3 35
>1.5 x ULN 50-60% NSCLC 300mg 150 1500 150mg 300 100mg 150mg 1228 ADR ADR 10% 3% 1/10 1/100 <1/101/1000 <1 1/10000 <1/1000 <1/10000 NSCLC - NSCLC- EGFR NSCLC 154 III ML20650 (EURTAC) 75 EGFR NSCLC ML20650 80% 57% 1 2 3 9% 4% 4 1% 11% 7% 4 35
YO25121(ENSURE) / EGFR (IIIB/IV )NSCLC110 AE 67.3% 40.9% 10.9% 1 2 7 6.4% 31 2 2 3 4 51 0.9% ALT 9.1% AST 5.5% 6.4% 1 2 1 ENSURE 3% 10% MedDRA N = 110 NCI-CTC N = 104 NCI-CTC % 3 % 4 % % 3 % 4 % 67.3 6.4 0 10.6 1.0 0 40.9 1.8 0 9.6 1.0 0 10.9 0.9 0 0 0 0 2 SAE 3 2.7% 2 [1.8%] 23 IIIMO20981 OPTIMAL, B T4 EGFRNSCLC + 83 88.0% 73/83 98.6% 71/72 1 23 4 12.0% 10/83 2 2.4 ALT/AST 1 1.2 3 4 65.3% 47/ 72 5 35
2 2.4% + 10 13.9% 7 NSCLC III BO18192 SATURN BO25460 IUNO 1532 NSCLC 150mg 2. 4 BO18192 1% <1% BO25460 BO18192 8.3% 3% BO25460 5.6% 2.8% 2 BO18192 SATURN BO25460 IUNO MedDRA BO18192 SATURN * n=433 n=445 BO25460 IUNO * n=322 n=319 % % % % 49.2 5.8 39.4 10.0 3 6.0 0 5.0 1.6 20.3 4.5 24.2 4.4 3 1.8 0 2.5 0.3 ALT AST 2 (>2.5 5.0 x ULN) ALT 2% 1% 3 (>5.0 20.0 x ULN) ALT 1% 0% 2 (>1.5-3.0 x ULN) 3 (>3.0-10.0 x ULN) 4% <1% <1% NSCLC / III BR.21 731 NSCLC 2:1 150mg 75% 54 % 1 2 6 35
3/4 9% 6% 1% 6% 1% BR.21 8 12 3 BR.21 5% 10% * 150mg NSCLC ALT AST 2 ALT >2.5-5.0 4% <1% 3 ALT >5.0-20.0 NSCLC 6578 71%, 3/4 12% 4% 5% 509 7 35
84% 3/4 4% 3 <1% 6 1% - PA.3 569 1:1 100 mg 150 mg IV 1000 mg/m 2 1 1, 8, 15, 22, 29, 36 43 8 2 1, 8 15 4 285 261 100mg 24 150mg 284 260 100mg 24 150mg 150mg 100mg 3/4 5% 10 15 2% 1% 150mg 23 4 5% 10% NCI-CTC 4 PA.3 5% 10% + 1000 mg/m2 IV N=259 + 1000 mg/m2 IV N=256 3 4 3 4 % % % % % % 8 35
* - / 10 4%/ 3 1% 3 4 11% 9% 3 4 5% -CTC 3 NCI / ALT AST 5 NCI-CTC 5 NCI-CTC 100mg + 1000 mg/m 2 IV N=259 NCI CTC + 1000 mg/m 2 IV N=256 NCI CTC 2 3 4 2 3 4 17% 10% <1% 11% 10% 3% ALT 31% 13% <1% 22% 9% 0% AST 24% 10% <1% 19% 9% 0% 9 35
150mg 100mg 150mg 1 2 3 4 1% INR NSAIDs ALT AST PA3 NSCLC ILD NSCLC / 10 35
1% Stevens-Johnson / / 65 : Stevens-Johnson / 11 35
NSCLC EGFR 19 21 L858R EGFR NSCLC NSCLC NSCLC 0.8%NSCLC 0.9% 0.4% 2.5% 0.4% ILD / 12 35
3 0.5% 0.8% 1.4% 0.4% / / 6 2.3% / 1 3 1.2% 1 / 6 2.3% 1 / 2 0.8% / / >5 ULN 13 35
- Child -Pugh B 15 10 30 1 1 8 10 8 > 3 ULN > 3 > ULN Child-Pugh A, B C /, Stevens-Johnson /, - INR INR 14 35
150mg 3 150mg 0.3 0.7 mg/m 2 2 2 18 NSCLC NSCLC 66% 65 34% 65 65 0.78 95% CI: 0.65, 0.95 65 0.88 95% CI: 0.68, 1.15 NSCLC / NSCLC 62% 65 38% 65 15 35
CYP1A1 CYP3A4 CYP2C8 UGT1A1 CYP1A1 CYP 1Al UGT1Al UGT1A1 Gilbert CYP3A4 CYP1A2 CYP1A1 CYP3A4 200mg 2 5 CYP3A4 AUC AUC 86% C max 69% CYP3A4 CYP1A2 AUC C max 39% 17% AUC C max 60% 48% CYP1A2 CYP3A4 CYP3A4 /CYP1A2 CYP3A4 150mg 600mg 1 7 CYP3A4 AUC 69% 450 mg AUC 150 mg 57.5% CYP3A4 + CYP3A4 300 mg 2 450 mg St. Johns Wort 16 35
CYP3A4 CYP3A4 CYP3A4 24% CYP3A4 CYP3A4/2C8 CYP3A4 ph ph ph AUC C max 46% 61% T max 300mg H 2 AUC C max 33% 54% 150mg 2 10 AUC C max 15% 17% H 2 H 2 2 10 P- Pgp / CNS AUC 0-48 10.6% AUC C max CYP1A1 CYP1A2 50-60% 17 35
1000mg 1600mg 200mg 150mg EGFR NSCLC III ML20650 EURTAC EGFR NSCLC NSCLC IIIB IV EGFR 19 21 L858R PCR 1:1 150 mg 4 174 NSCLC 99% 65 51% ECOG 1 53% ECOG 0 33% 93% IV 7% IIIB AJCC 93% 66% 19 34% 21(L858R) PFS 6 18 35
1. ML20650 EURTAC PFS Kaplan-Meier 6 ML20650 EURTAC N = 86 N = 88 PFS 71 (83%) 63 (72%) PFS (95% CI) 10.4 (8.7, 12.9) 5.2 (4.6, 6.0) (95% CI) (1) 0.34 (0.23, 0.49) P ( log-rank ) < 0.001 OS (%) 55 (64%) 54 (61%) OS (95% CI) 22.9 (17.0, 26.8) 19.5 (17.3, 28.4) (95% CI) (1) 0.93 (0.64, 1.35) 19 35
(95% CI) 65% (54.1%, 75.1%) 16% (9.0%, 25.3%) (1) Cox ( ) III YO25121 ENSURE EGFR NSCLC NSCLC IIIB IV EGFR 19 21 L858R cobas 1:1 150 mg 4 + 647 217 107 110 61.3% 38.7% 56 30-78 57.5 33-79 ECOG 0 1 94.4% 93.6% IV 93.5% 90.9% PFS PFS 66% (HR= 0.34 [95 % CI 0.22,0.51], p<0.0001 PFS Kaplan-Meier 2 (n=110) (n=107) PFS 11.0 5.5 CR/PR 62.7% 33.6% p<0.0001 (IRC) PFS 5.6 PFS 11.0 HR= 0.42 [95% CI 0.27,0.66], p=0.0001 IRC PFS 85.6 % HR=0.91 [95% CI: 0.63,1.31], p=0.6073) 20 35
2. ENSURE PFS Kaplan-Meier FACT-L ENSURE 175 81% + 7 7 ENSURE ENSURE ENSURE N = 110 N = 107 N = 87 N = 88 PFS HR [95%] 0.34 [0.22 0.51 ] 0.30 [0.18 0.49] 11.0 5.5 11.1 5.7 p < 0.0001 < 0.0001 PFS IRC HR [95%] 0.42 [0.27 0.66 ] 0.38 [0.22 0.64] 11.0 5.6 11.0 5.6 21 35
p 0.0001 0.0001 62.7% 33.6% 69.0% 37.5% [95 %]29.08 [15.8, 42.3] 31.47 [16.8, 46.2] HR [95% ] 0.60 [0.37, 0.96] 0.57 [0.35, 0.93] ( ) - 5.5-5.5 (TOI HR [95% ] 0.53 [0.35,0.82] 0.50 [0.32, 0.78] ( ) 11.1 4.2 11.1 2.9 HR [95% ] 0.67 [0.45,1.01] 0.63 [0.41, 0.96] ( ) 8.2 2.9 5.6 2.8 III MO20981 OPTIMAL EGFR NSCLC B NSCLC PCR-DNA EGFR 19 21 L858R 1:1 150 mg 4 + 165 10 1 154 93.3% 154/165 ITT 82 72 ECOG 19 21 PFS 83.8%(HR= 0.164 [95 % CI 0.105,0.256], p<0.0001 PFS Kaplan-Meier 3 (n=8 2) (n=72) PFS 22 35
13.7 4.6 CR/PR 82.9% 36.1% p<0.0001 HR=1.186 [95% CI: 0.825,1.706], p=0.2663) 3. OPTIMAL PFS Kaplan-Meier 8 OPTIMAL OPTIMAL N = 82 N = 72 PFS HR [95% ] 0.164 0.105 0.256 13.7 4.6 p < 0.0001 68 26 % 82.9 36.1 p < 0.0001 OPTIMAL + 74 54 + FACL-L TOI LCS P <0.0001 23 35
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(3.01-14.85) <0.0001 TOI 74 54 20 ( 27.0%) 40 ( 74.1%) 54 ( 73.0%) 14 ( 25.9%) 8.07(3.57-18.26) <0.0001 LCS 74 54 17 ( 23.0%) 37 ( 68.5%) 57 ( 77.0%) 17 ( 31.5%) 7.54(3.38-16.85) <0.0001 NSCLC BO18192 SATURN 26 889 NSCLC 1:1 150 mg 438 451 EGFR IHC PFS BO18192 SATURN PFS HR= 0.0001 0.71 p< OS HR= 0.81 p=0.0088 EGFR n=49 PFS HR= 0.10 95 CI 0.04,0.25 p<0.0001hr 0.83 95 CI 0.34,2.02 EGFR 67 EGFR-TKI EGFR 24 35
n=388 PFS HR 0.78 95 CI 0.63,0.96 p=0.0185 HR 0.77 95 CI 0.61,0.97 p=0.0243 [82 93] EGFR 1921 4 L858R 643 NSCLCBO25460 IUNO 1:1 150mg EGFR HR= 95% 1.02 CI 0.85, 1.22 p=0.82 PFS HR=0.94 95 CI 0.80,1.11 p=0.48 BO25460 IUNO EGFR NSCLC / NSC BR.21 7312 1150mg CR+PR PFS OS 17 1/2 326EGFR 10 2/3 1/4 ECOG PS 2 9% PS 3 50% 3/4 10 N=488 N=243 n % n % 173 35 83 34 315 65 160 66 25 35
<65 299 61 153 63 65 189 39 90 37 379 78 188 77 18 4 12 5 63 13 28 12 28 6 15 6 ECOG * 0 64 13 34 14 1 256 52 132 54 2 126 26 56 23 3 42 9 21 9 6 <5% 320 66 166 68 5-10% 96 20 36 15 >10% 52 11 29 12 20 4 12 5 104 21 42 17 358 73 187 77 26 5 14 6 246 50 119 49 144 30 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 40 96 40 PD 101 21 51 21 SD 191 39 96 40 * 1 243 50 121 50 2 238 49 119 49 3 7 1 3 1 * 454 93 224 92 34 7 19 8 26 35
* 11 11 1 95%p 6.7 4.7 0.73 0.61-0.86 <0.001 2 1 31.2% 21.5% 9.9 7.9 0.59 0.50-0.70 <0.001 2 8.9% 0.9% <0.001 3 CR+PR 34.3 15.9 1 ECOG COX 2 ECOG Log-Rank 3 Fisher's Kaplan-MeierOS PFS ECOG Log -Rank 4. Kaplan-Meier 27 35
HR ECOG COX P ECOG Rank 5 HR=0.68 HR=0.42 28 35
5. 5 HR HR 95%CI N HR 95%CI HR 1.00 EGFR 326 45% EGFR IIIMO22162 CURRENTS 38 NSCLC 29 35
150 mg 300 mgpfs EGFR NSCLC 1000 NSCLC + N=526+ N=580 EGFR / I HER1 EGFR EGFR EGFR 19 21 L858R EGFR EGFR EGFR EGFR EGFR ATP EGFR ALT AST UV Ames 30 / 35
150mg /d AUC 3 / 30mg/m 2 /d 60mg/m 2 /d 0.3 0.7 600mg/m 2 /d 150mg/d 3 60mg/m 2 /d 150mg/d 0.7 60mg/kg/d 150mg/d 10 10mg/kg/d 2 5mg/kg/d 150mg 60% 4 100% 93% α1 AAG 232 4 3 NSCLC, 1 150 mg 9 1,185 ng/g 63% 5-161% 160 ng/g 113% 88-130% 95% alpha-1 AAG P450 CYP3A4 CYP1A2 CYP1A1 CYP3A4 CYP1A1 31 / 35
1B1 3 1 O- 2 3 O- OSI-420 OSI-413 <10 % 100mg 91% 83% 1% 8% 0.3% 591 36.2 7-8 24% 291 NSCLC AAG Child -Pugh 7-9 -Pugh 7-9 AUC 0-t C max 27000 ng h/ml 805 ng/ml 29300 ng h/ml 1090 ng/ml C max 32 / 35
9% 150mg C max 1056 ng/ml 689 ng/ml 65.2% 95% CI: 44.3-95.9, p=0.031 AUC 0-inf 18726 ng h/ml 6718 ng h/ml 35.9% 95% CI: 23.7-54.3, p<0.0001 C 24h 288 ng/ml 34.8 12.1% 95% CI: 4.82-30.2, p=0.0001 16 CYP1A1 CYP1A2 III NSCLC BR.21 0.65 µg/ml n=16 1/2 1.28 µg/ml n=108 24% NSCLC I 150mg 300mg 1.22 µg/ml n=17 CYP3A4 CYP3A4 CYP3A4 AUC 2/3 CYP3A4 3 AUC 2/3 Ib 11% 33 / 35
2515-30 / PVC 100 30 / 150 30 / 7 / 36 JX20110234 1 100 H20160392 2 150 H20170143 Roche Registration GmbH Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany Delpharm Milano S.r.l. Via Carnevale 1, 20090 Segrate (MI), Italy 34 / 35
F. Hoffmann -La Roche Ltd. Wurmisweg, 4303 Kaiseraugst, Switzerland 1100 021 28922888 800-820-8780, 400-820-8780 http://www.roche.com.cn 35 / 35