Revisiting JPN

1 13 . Revisiting JPN - . 3.. TKI . - - , 1) 2). 3), 4). 1) , 2) . 3) , 4) .. 06/16/12. P-I/II of IFN- and low dose IL-2 for mRCC. - Overall responses - Response n CR PR MR NC PD rate (%) 95CI . P-I 9 - 4 1 4 - P-II 37 - 8 2 14 13 IL-2 : x 106 Japan reference unit (JRU)/person for 5 days a week (Akaza H. Int. J. Clin. Oncol. 11 434, 2006). IFN 2b and Thalidomide in the treatment of mRCC. Overall survival Time to treatment failure Mos (Hernberg M et al. J Clin Oncol 21:3770,2003). Sorafenib Study 100391 Trial Schema 25% Shrinkage Continue Sorafenib Open Label Sorafenib 12 Week >-25% to <25% Tumor Induction Randomized Assessment 25% Growth Placebo*. Off study Base line 12 wks 24wks * May cross over to Sorafenib (Ratin MJ et al. ASCO, 2004 ). RCC in Hamamatsu Univ. Sch. of Med. Cases M0 M1. 90. 80. (n=1059, ). 70. 60. 50. 40. 30. 20. 10. 0. 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006.

2 RCC in Hamamatsu Univ. Sch. of Med. - OS according to N,M classification - (%). 100 -N- 80. 79. 69 N0 (n=929). 60 -M- 60 (%). p< 30 N1 (n=27). 40 100. 85. 20. 18 18 80 76. 5 p= 66 M0 (n=873). 0. N2 (n=55) 60. 0 5 10 15 20 25 30. (Yrs) 40 p< 16. 20. 3. M1 (n=186). 0. 0 5 10 15 20 25 30. (Yrs).. 1.. 2. Sorafenib . 3. Sunitinib . 4.. 1.. : . - 99 2004 9 - 39. 31. 28. 7 6 5 3 1.. F , 2005 . : . - 88 2004 - . 1417. 1000. 915. 620 583. 500 538 512 505. 0.. (2006 5 ) IMS Lifecycle . BAY43-9006 II . - - 8 ! 140. 120.. 100. 80. 60. 40. 20 . 0. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 ( ). ( , ). Phase II study of Sorafenib in Japan - Best overall response - JAPAN P-II TARGET. n=129 % n=451 %. Complete response 0 1 1. Partial response 19 43 10. Stable disease 93 333 74. Disease progression 13 56 12. Not evaluated 4 18 4. Response rate (Akaza H et al. : Jpn J Clin Oncol 37:753,2007)(Escudier B, et al.)

3 N Eng J Med 356:125,2007). Phase II study of Sorafenib in Japan - PFS at 32 wks ( 95% CI: 25 - 40 wks ) - Proportion of patients progression free RCC Ph-II in Japan Sorafenib in G Ph-III. (TARGET). Placebo in G Ph-III (TARGET). Censored observation 0. 0 2 4 6 8 10 12 14 16 18 20. Time from randomization (months). *Based on investigator assessment (Naito S et al. : 95th JUA annual meeting,2007). Phase II study of Sorafenib in Japan - Adverse events - JAPAN P-II (n=131) TARGET (n=451). Adverse Event (%) Any Grade G3/4 Any Grade G3/4. Cardiac-hypertension 36 (28) 16 (12) 76 (17) 16 (4). Hematologic-decreased Hb 90 (69) 7 (5) 34 (8) 12 (3). Constitutional Fatigue 21(16) 1 (1) 165 (37) 22 (5). Gastrointestinal Diarrhea 45 (34) 1 (1) 195 (43) 11 (2). Anorexia 18 (14) 4 (3) 73 (16) 3 (<1). Dermatologic Rash or desquamation 49 (37) 5 (4) 180 (40) 4 (1). Hand-foot skin reaction 72 (55) 12 (9) 134 (30) 25 (6).

4 Alopecia 14 (11) 0 122 (27) 1 (<1). Pruritus 29 (6) 0 85 (19) 1 (<1). (Akaza H et al. : Jpn J Clin Oncol 37:753,2007)(Escudier B, et al. N Eng J Med 356:125,2007). Phase II study of Sunitinib in Japan - Response rate - JAPAN P-II Motzer P-III. 1st line 2nd line Total Total Best response (%). (n=25) (n=26) (n=51) (n=335). Independent Central Review : CR 0 0 0 0 (0). PR 13 (52) 14 (54) 27 (53) 103 (31). RR 13 (52) 14(54) 27 (53) 103 (31). [95%CI] [ ] [ ] [ ]. (Uemura H et al. : JJCO 40:194,2010) (Motzer RJ, et al. N Eng J Med 356:115,2007). Phase II study of Sunitinib in Japan - PFS - Progression-Free Survival Probability P-II in JAPAN 1st line (n=25) med, mos. P-II in JAPAN 2nd line (n=26) med. P-III by Motzer 1st line (n=335) med. 11mos. 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14. (Mos.). Phase II study of Sunitinib in Japan - Laboratory abnormality(%) - JAPAN P-II (n=51) Motzer P-III (n=375). Grade 3/4 (%) Grade 3/4 (%).

5 Hematologic Thrombocytopenia 55 8. Leukopenia 20 5. Neutropenia 53 12. Lymphopenia 33 12. Anemia 8 4. Biochemical Increased lipase 49 16. Increased AST 10 2. Increased ALP 2 3. Increased amylase 12 5.. - - Everolimus IL-2 Sorafenib Temsirolimus Bevacizumab + IFN Axitinib Sunitinib Pazopanib Dec 05 Jan 06 May 07 Mar 09 Jul 09 Oct 09 Jan 12.. Apr 08 Apr 10. IFN Sorafenib Jul 08 Everolimus Sep 10. IL-2 Sunitinib Temsirolimus . MSKCC risk criteria /. setting recommended therapy Pre-treatment IFN (+ low dose IL-2)(Lung). favorable IL-2. or Sunitinib 1st line intermediate Sorafenib Temsirolimus poor Sunitinib Sorafenib cytokine refractory Sunitinib 2nd line TKI refractory Everolimus mTOR inhibitor clinical trial refractory 2010 12 . Approved molecular agents for RCC. Sorafenib 2006 (2008). Sunitinib 2006 (2008). Bevacizumab 2007 - Temsirolimus 2008 (2010). Everolimus 2009 (2010). Pazopanib 2010 no yet Axitinib no yet soon ?

6 23 .. (H23- - -012).. 2. Sorafenib .. - - .. 12 .. 12 . 30 .. , , , , . 1, 3, 6, 9, 12 . , , , , .. [n] 3,418 [n]. 500 3500. 3000. 400. 2500.. 300. 2000. 3 n=2,453. 1500. 200. 1000. 100. 500. 0 0. ' 5 6 7 8 9 10 11 12 ' 2 3 4 5 6 7 8 9 10. 2008 2009 . 3,418 2011 7 31 . 2,453 .. 3,418 . 2011 7 31 * . 2,453 . * . 2,453 . 12 . 2 . 2 . 33 . 9 . 2,407 . 24 . 23 . 14 . 2,346 .. Ph.. Ph.. Ph. 2,407 129 * . 2,407 129 * .. 90-99. 80-89. ( ) ( ) 70-79. 60-69. 50-59. ( ) ( ) 40-49. 30-39. 20-29. 10-19. ECOG-PS. 40 30 20 10 0 0 10 20 30 40. Ph.. [ ] [ ]. 2,407 129 * . 3. ( ). 4 ( ) . 2 Ph.. ( ) 1 2,407 129 * . RCC+. ( ) . 1 ( ) ( ). ( ). 0 ( ) 0. ( ) RCC RCC. ( ) (100%). ( ) ( ). * 129 ITT .. Ph.. Stage TNM . Ph.. 2,407 129 * . II I . ( ) ( ). III .. ( ). Ph.. IV ( ) IV (100%) 2,407 129 * . ( ).. Ph.. 2,407 129 * ( ) (100%). ( ). ( ) (100%). * 129 ITT .. 2,350 2,406 . 200 mg ( ). ( ). 600 mg 400 mg ( ) ( ).

7 ( ). ( ). 800 mg . ( ). ( ) ( ).. 2,407 .. 730 . 730 1,677 . 1,677 . 0% 20% 40% 60% 80% 100%.. 982 1,425 . 0% 20% 40% 60% 80% 100%.. 1,402 1,005 . 0% 20% 40% 60% 80% 100%.. 2,407 .. 12 .. 688 1,719 . 0% 20% 40% 60% 80% 100%.. 12 1,719 . 0 5 10 15. 6 .. 23 . 1 .. 33 . 9 .. 189 .. 952 .. 506 .. 1,719 [ ]. 2 .. 2,407 . [mg]. 800. 700. 600. 500. 400 617 mg 504 mg 493 mg 491 mg 491 mg 300. 200. 100. 0. 0~1 2~3 4~6 7~9 10~12 . n=2,407 n=1,933 n=1,520 n=1,149 n=905. Dose Intensity . [mg]. Dose Intensity [ ] 100. *[ ] 800 [mg/ ]. * .. 2,407 .. 131 .. 0% 20% 40% 60% 80% 100%.. Ph.. Ph.. 646 47. 2,407 131. 2,228 127. * 2,407 .. Ph.. [ ] 2,407 131 [ ]. 70 60 50 40 30 20 10 0 0 10 20 30 40 50 60 70.. [ ]. 70.. 60. 50.. 40.. 30.. 20 .. 10. + .. 0.. 0 50 100 150 200 250 300 350 400.. [ ]. [ ]. 70. 70.. 60. 60. 50.. 50.. 40 40. 30 30.. 20 20.. 10 10.. 0 0. 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400.

8 2,342 .. 34 222 .. 527 1,216 343 . 0% 20% 40% 60% 80% 100%.. Progression Free Survival . 2,342 .. 100. 75. 197 . [ 95 Cl 188 - 208 ]. 50. 25. 0. 0 50 100 150 200 250 300 350 400.. Overall Survival . 2,346 . 1 .. 100.. 95 Cl - . 75. 50. 25. 0. 0 50 100 150 200 250 300 350 400.. Overall Survival . - n=2,346 - - n=2,346 - . 100 100.. 75 75.. 50 50. 25 25. (n=1,951) (n=1,822). (n=395) (n=524). 0 0. 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400.. Overall Survival . n=2,294 CRP [mg/L] n=1,743 .. 100 100.. 75 75 .. 50 50.. 25 25. 1 (n=896). (n=606). 1 3 (n=327). (n=1,688) 3 (n=547). 0 0. 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400.. MSKCC 1999 n=1,843 n=2,346 .. 100 100.. 75. 800mg 75.. 50 50 800mg . 25 25. (n=382) 800 mg (n=1,883). (n=1,350). 800 mg (n=463). (n=111). 0 0. 0 50 100 150 200 250 300 350 400 0 50 100 150 200 250 300 350 400.. mg .. 5 .. 2,407.

9 10 .. 90 . 21 .. 2,346 .. 197 . 95 CI 188-208 . 1 . 95 CI .. 3. Sunitinib .. - - .. RCC . RCC . 1 . 2 . 3 .. 20 6 13 .. 24 24 2 .. 1,673 1,671 . 1,435 .. 1,673 . 2 .. 1 . 1 . 1,671 . 236 .. 6 . 230 . 1,435 .. n=1,671.. 421 . 737 .. 934 . 1,250 . m2 . 45 125( ) 8( ). 45 55 215( ) 135( ). 55 65 599( ) 470( ). 65 75 498 617( ). 75 214 260( ). 20 181( ). 0 200 400 600 0 200 400 600 800 .. n=1,671.. 12 .. 1,173( 95( ) ). 183 15( ).. 1,476 187( ). 0 500 1,000 1,500 .. 1,089( ). 0 7( ). 520( ). 1 36( ). 288( ) 2 29( ). 139( ) 3 111( ). 602( ) 4 1,459( ). 29( ). 0 500 1,000 1,500 . 0 400 800 1,200 1,600( .. 24 .. 100. 1,671 . 90 24 80.. 70. 60. 50. 40. 30. 20. 10. 0. 7 14 21 28 35 49 56 63 70 77 91 98 105 112 119 140 147 154 161. 0 42 84 126 133 168 .. 1,671 972 . 50mg .. 25mg . 50mg 1,308 843 ( ) 395 ( ) 405 ( ) 42 ( ) 1 ( ). 218 112 ( ) 100 ) 12 ( ) 0 ( ). 25mg 130 18 ( ) 18 ) 0 ( ). 15 0 0 ( ) 0 ( ) 0 ( ) 0 ( ).

10 / 40% 1 .. / .. 6 1,670 268 41 ( ) 179 ( ) 49 ( ) 13 ( ) 26 ( ). 6 12 1,391 222 77 ( ) 97 ( ) 44 ( ) 15 ( ) 31 ( ). 12 18 1,157 153 69 ( ) 54 ( ) 25 ( ) 7 ( ) 15 ( ). 18 24 995 134 57 ( ) 45 ( ) 34 ( ) 8 ( ) 19 ( ). 24 48 617 164 85 ( ) 54 ( ) 25 ( ) 13 ( ) 18 ( ). 48 72 162 38 25 ( ) 13 ( ) 7 ( ) 1 ( ) 0 ( ). 72 96 52 17 13 ( ) 1 ( ) 0 (0) 2 ( ) 3 ( ). 96 8 1 1 ( ) 0 ( ) 0 ( ) 0 ( ) 0 ( ). 1,671 997 368 ( ) 443 ( ) 184 ( ) 59 ( ) 112 ( ). -RCC - .. 100 (1,594). 80. (1,019).. 60. (616) (593) (584) 40 (547). (281) (271) (234). 20 (224) (211) (193). 0. PT . CTCAE 3 . -RCC - CTCAE . 3 50/51 .. 100 n=1,671. 80 (1,163).. 60. 40 (574). 20 (169) (168) (131) (93) (83) (79) (76) (57) (53) (24) (24). 0. PT . CTCAE 3 28/51 . 26/51 20/51 17/51 . 12/51 .. 4 . 5 6 4 .. 100. 1,671 . 90 607 . 80 CTCAE 3 90 . 70.. 60. 50. 40. 30. 20. 10. 0. 168 . 7 14 21 28 35 49 56 63 70 77 91 98 105 112 119 133 140 147 154 161.