Tyrosine Kinase Inhibitor. June-Won Cheong

Transcription

1 Tyrosine Kinase Inhibitor June-Won Cheong Yonsei University College of Medicine

2 Part I Protein Kinases

3 Cellular communication Signal transduction pathways 3 stages of cell signalling reception transduction response G-protein -linked receptor Protein Kinase receptor

4 Protein Kinases Tyrosine Kinases Serine/threonine Kinases ABL Abelson PKC Protein kinase C KITR c-kit receptor CDK Cyclin-dep. kinase PDGFR PLT-derived-GF receptor MKK1 Mitogen-act. PK kinase 1 EGFR Epidermal-GF receptor RAF Rapidly accelerated fibrosarcoma ERB2R Erb2 receptor CHK1 Checkpoint kinase 1 VEGFR Vascular-endothelial GF receptor mtor Mammalian Target of rapamycin FGFR Fibroblast-GF receptor ROCK RHO-dep. PK NGFR Nerve-GF receptor p38/sapk2a P38/Stress-act. PK2a MLK Mixed-lineage PK

5 Protein Kinases as a Target PKs in a cell Upstream/downstream of relevant oncogenes or tumor suppressor genes Commonality & diversity among ATP-binding sites of PKs Possibility of a step-wise concept validation at the biochemical, cellular & intact animal level as proof of concept in the clinic

6 Protein Kinases & Cancer Overexpression of GFRs EGFR,HER2,HER3,HER4 HER3 HER4 in breast, ovary, lung, H&N and glioblastoma FGFR in lung, ovary and breast PDGFR in glioblastoma IGF-1R in solid tumors Overexpression of GFs TGF-α in carcinoma overexpressing the EGFR PDGF-BB expression in glioblastoma VEGF expression for neo-vascularization (angiogenesis g and metastasis) Altered PK levels and/or activities Bcr-Abl in CML (95%), ALL (15%) c-met in renal carcinoma c-kit in gastric cancers (GIST) Cancers with Onc Ras have deregulated PKC, Raf-kinase (bladder, colon, lung, breast) Deregulation of cell cycle by CdKs

7 Protein Kinase

8 Protein Kinase Inhibitor; PKI Isoquinoline sulfonamides From 1 st PKI (Naphthalene sulfonamide) camp- & cgmp-dept. PKI Hidaka H et al. Biochemistry 1984;23:5036

9 Protein Kinase Inhibitor; PKI Staurosporine Antifungal agent (1977) From Streptomyces Indolocarbazole product Nanomolar inhibitor of PKC K252, CEP-1347, UCN-01, PKC412, etc Tamaoki T et al. Biochem Biophys Res Commun 1986;135:397 Kase H et al. J Antibiot 1986;39:1059

10 Protein Kinase Inhibitor; PKI Knighton DR et al. Science 1991;253:407/414

11 Part II Tyrosine Kinases TKI &

12 Tyrosine Kinases

13

14 Important discoveries in TK Hunter T. Curr Opin Cell Biol 2009;21:140

15 TKI discovery Target TK Inhibitor Company *Bcr-Abl, c-kit, PDGFR STI 571 (Imatinib, GLIVEC) Novartis *, CSF-1R, EPHA4R AMN107 (Nilotinib, ib TASIGNA) Novartis *, SRC, EPHR BMS (Dasatinib, SPRYCEL) BMS *, SRC SKI 606 (Bosutinib) Wyeth-Ayerst EGFR ZD1839 (Gefitinib, IRRESA) AstraZeneca EGFR OSI 774(Erlotinib,TARCEVA) OSI Pharmaceuticals EGFR, ERB2R PKI 166 Novartis EGFR, ERB2R CI 1033 (Canertinib) Pfizer EGFR, ERB2R EKB 569 Wyeth-Ayerst EGFR, ERB2R GW (Lapatinib, TYKERB) GlaxoSmithKline VEGFR PTK 787 Novartis VEGFR ZK Schering-Plough VEGFR SU 5416 (TSU-16) Sugen/Pharmacia Upjohn VEGFR, EGFR ZD 6474 (Vandetanib, ZACTIMA) AstraZeneca VEGFR, FGFR, PDGFR SU 11248(Sorafenib, SUTENT) Pfizer VEGFR, FGFR, PDGFR SU 6668 (TSU-68) Pharmacia Corp. bfgfr PD Pfizer NGFR CEP 2583 Cephalon

16 Tyrosine Kinase Inhibitor; TKI Investigation of catalytic mechanism of EGFR Structure-based searching & discovery of a potent inhibitor Crystallization ti process PD EGFR inhibitor Ward WH et al. Biochem Pharmacol 1994;48:659 Fry DW et al. Science 1994;265:1093 AG1478 EGF-dept. activation of Src-family TK inhibitor Osherov N et al. Eur J Biochem 1994;225:1047

17 Tyrosine Kinase Inhibitor; TKI 4-(Phenylamino)pyrrolopyrimidines By pharmacophore model of ATP binding site EGFR TKI Traxler P et al. J Med Chem 1996;39:2285 PKI166 By optiminization process EGFR/erbB-2 TKI Traxler P et al. Clin Cancer Res 1999;5:3750s

18 Tyrosine Kinase Inhibitor; TKI Folia Pharmacol Jpn. 2003;122:482

19 Part III Individual TKIs

20 Imatinib, Glivec Standard Frontline Tx for CML ; IRIS study Imatinib R A N n = 553 D O M I Z + E IFN-α Ara-C n = 553 Crossover for: Crossover Lack of response Loss of response Intolerance of treatment Reluctance to continue IFN O Brien SG et al. N Engl J Med 2003;348:994

21 Imatinib, Glivec Standard Frontline Tx for CML ; IRIS study O Brien SG et al. N Engl J Med 2003;348:994

22 Imatinib, Glivec Standard Frontline Tx for CML ; IRIS study MCyR PFS O Brien SG et al. N Engl J Med 2003;348:994

23 Imatinib, Glivec Standard Frontline Tx for CML ; IRIS study 7 yrs after All randomized to imatinib (n= 553; 100%) Still receiving study imatinib (n = 332; 60%) Discontinued study imatinib* (n = 221; 40%) In CCR (n = 317; 57%) No CCR (n = 15; 3%) Safety (n = 43; 8%) Efficacy (n = 82; 15%) Other (n = 96; 17%) Alive Dead Alive Dead Alive Dead (n = 17; (n = 26; (n = 52; (n = 30; (n = 81; (n = 15; 40%) 60%) 63%) 37%) 84%) 16%) O Brien SG et al. Blood 2008;112: Abstract 186.

24 Imatinib, Glivec Standard Frontline Tx for CML ; IRIS study 7 yrs after ut Event % Witho Survival: deaths associated with CML Overall Survival Estimated OS at 7 years is 86% (94% considering only CML-related deaths) O Brien SG et al. Blood 2008;112: Abstract year after random.

25 Imatinib, Glivec Standard Frontline Tx for CML ; IRIS study 7 yrs after 100 % of Available Samples BCR-ABL% (IS) 0.1% 0.01% Sample Analysis Time Points (months) Hughes et al. Blood 2008;112: Abstract 334.

26 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response Time Failure Suboptimal Response Warnings Dx 3 m No HR < CHR 6 m No CHR or CyR < PCyR High risk Del9q+ Additional ch somal abnls in Ph+ cells 12 m < PCyR PCyR < < CCyR Any MR < MMR 18 m < CCyR < MMR Any time Loss of CHR Loss of CCyR Mutation with high insensitivity to Glivec Additional ch somal abnls in Ph+ cells Loss of MMR Mutation with low insensitivity to Glivec Increase in BCR- ABL level Other ch somal abnls in Ph-cells Baccarani M et al. Blood 2006;108:1809.

27 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response % CCyR >6 months s(n=81) ( ) Suboptimal 60 (n=19) (n=16) 30 Failure (n=16) Months since randomization CyR at 6 months (Ph+) 1-35% 66-95% 36-65% >95% Druker et al. Blood 2003; 102: Abstract 634

28 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response % Wit thout Ev vent BCR-ABL % (IS) at 18 months 0.1% (n = 164) >0.1-1% (n = 47) 20 >1-10% (n = 25) 10 >10% (n = 13) % P = % 62% 58% Hughes et al. Blood 2008;112: Abstract 334.

29 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response Standard Frontline Tx for CML ; AP and BC patients Overall CyR 48% Overall CyR 17% PFS Palandri F et al. Haematologica 2009;94:205 Palandri F et al. Haematologica 2008;93:1792

30 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response Standard Frontline Tx for CML ; AP and BC patients Standard Frontline Tx for CML ; Bcr/Abl mutations 20% Data from the GIMEMA CML WP on 655 imatinib-resistant patients 15% 10% 5% Catalytic Activation P-loop domain loop L248V G250E Q252R/H V289A M343T D276G E281A/K M351T T277A E279K E255K/V E292V T315I Y253F/H F311L/I F317L F359V/I E355G/D H396R/P L364I L387M/F L384M F382L S417Y/F V379I E453G/K E459K/Q A380T F486S

31 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response Standard Frontline Tx for CML ; AP and BC patients Standard Frontline Tx for CML ; Bcr/Abl mutations. 2 nd generation TKIs Nilotinib Dasatinib Bosutinib

32 Imatinib Nilotinib Dasatinib Bosutinib

33 Potency & Selectivity of TKIs Imatinib: PDGFR > Kit > BcrAbl > Src (Phos IC 50 ) 72 nm 99 nm 192 nm >1000 nm Dasatinib: Src > BcrAbl > PDGFR > Kit (Phos IC 50 ) 0.1 nm 1.8 nm 2.9 nm 18 nm Nilotinib: BcrAbl > PDGFR > Kit > Src (Phos IC 50 ) 19 nm 75 nm 209 nm >1000 nm Mestan J et al. Blood. 2004;104: Abstract Weisberg E et al. Cancer Cell 2005;7:129.

34 Nilotinib, as a Second Tx for CP pts % Patients, % % 59% 56% 65% 44% 41% 51% n Overall No BL CHR Overall Imatinib- Resistant Imatinib- Intolerant Overall Imatinib- Resistant 95 Imatinib- Intolerant CHR MCyR CCyR Patients with a minimum follow-up of 24 months Kantarjian HM, et al. J Clin Oncol. 2009;27(15S): Abstract 7029.

35 Nilotinib, as a Second Tx for CP pts 100 PFS 89% 84% 78% % Without Prog gression or Death Number of patients = 189 Number failed = 35 = Censored observations Months Since MCyR Kantarjian HM, et al. Blood. 2008;112: Abstract 3238.

36 % Alive Nilotinib, as a Second Tx for CP pts OS 95% 87% Number of patients = 321 Number failed = 44 = censored observations Months Since Start of Treatment 87% of patients were estimated to be alive on nilotinib at 24 months Kantarjian HM, et al. J Clin Oncol. 2009;27(15S): Abstract 7029.

37 Dasatinib, as a Second Tx for CP pts For imatinib-resistant or intolerant CML-CP pts. Prior imatinib mg (48%), 600 mg (52%) Non-Hema SE(G3,4): 3% Hema SE(G3,4): 22-49% MCyR PFS Hochhaus A et al. Blood 2007;109:2303

38 Dasatinib, as a Second Tx for CP pts CHR MCyR CCyR % mg 70 mg 140 mg 50 mg Once Daily BID Once Daily BID Shah NP, et al. Blood. 2008;112: Abstract 3225.

39 Dasatinib, as a Second Tx for CP pts % % With hout Loss s of MCyR month response rates MCyR CCyR 62% 53% Months since MCyR 369 of 387 patients evaluable for molecular response Shah NP, et al. Blood. 2008;112: Abstract 3225.

40 Dasatinib, as a Second Tx for CP pts % 94% OS % 80% PFS % Months Shah NP, et al. Blood. 2008;112: Abstract 3225.

41 Nilotinib/Dasatinib, AEs Dasatinib 70 mg BID, Nilotinib 400 mg BID Dasatinib Nilotinib Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Myelotoxicity (Thrombocytopenia & Neutropenia) Pleural Effusion (Peripheral Edema) 26 (29) 9 (1) 1 (6) 1 (0) Bleeding Hyperglycemia Lipase elevation Stone RM, et al. Blood. 2007;110: Abstract 734 / Kantarjian HM, et al. Blood. 2007;110: Abstract 735.

42 Nilotinib/Dasatinib, CP as a Second Tx for 2yr% Nilotinib Dasatinib CHR MCyR CCyR DMCyR D.MCyR PFS 80 OS 87 94

43 Nilotinib/Dasatinib, AP as a Second Tx for 2yr% Nilotinib Dasatinib CHR MCyR CCyR DMC D.MCyR 66 (after MCyR) 75 (after MCyR) PFS 55 OS 66 le Coutre PD, et al. J Clin Oncol. 2009;27(15S): Abstract 7057 / Kantarjian HM, et al. Blood. 15 April Epub ahead of print.

44 Dasatinib, as a Second Tx for BC pts 116 imatinib-resistant or intolerant CML-BC pts. Non-Hema SE(G3,4): 0-24% Hema SE(G3,4): 12-14% MHR PFS Cortes J et al. Blood 2007;109:3207

45 Dasatinib for nilotinib-resistant Pts For imatinib & nilotinib-resistant Ph(+) leukemia N= 13 (CP 1, AP 9, BC 3) Bcr-Abl mutation 100% 140 mg/d (twice daily) Median Tx duration: 4 months (1-10) OR: 57% CHR: 43% CyR: 30% Quintas-Cardama A et al. Blood 2006;109:497

46 Nilotinib for Dasatinib-resistant Pts % % % CHR MCyR CCyR Giles F et al. Blood 2008;112:1110

47 Mutations recovered after TKI therapy * * Imatinib Dasatinib Nilotinib * * % 10 * * 5 0 * * * G250E Y253F/H E255G/K V299L F311I/L T315I F317L/V M351T E355G/A F359C/V H396P/R BCR/ABL Mutation * T315I & F359V recovered after treatment with bosutinib * Jabbour E, et al. Blood. 2006;108: Abstract 750.

48 2 nd generation TKIs Randomized Trials for Frontline Tx Study Imatinib 2 nd TKI No. of Pts Year started USA-SWOG 400/800 Dasatinib Novartis 400 Nilotinib Wyeth 400 Bosutinib 2007

49 Nilotinib, as a frontline Tx 50% 80% 90% 83% 98% 97% CCyR 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% High Risk (n=10) Non-High Risk (n=63) < CCyR Months Rosti G, et al, Presented at: 14 th Congress of the EHA; 2009: Berlin, Germany. Abstract 1090.

50 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Nilotinib, as a frontline Tx 3% 21% 52% 66% 73% 85% MMR < MMR NE Months Rosti G, et al, Presented at: 14 th Congress of the EHA; 2009: Berlin, Germany. Abstract 1090.

51 Dasatinib, as a frontline Tx Respon nse N = 48 N = 43 N = 37 N = 32 N = 25 N = CCyR PCyR Pe ercenta ge with Months on Therapy Cortes J, et al. Blood. 2008;112: Abstract 446.

52 Dasatinib, as a frontline Tx e with Re esponse Pe ercentag % MMR % CMR Months N Cortes et al. Blood 2008;112: Abstract 182.

53 Nilotinib/Dasatinib, CP as a Frontline Tx for 1yr% Nilotinib Dasatinib CCyR* MMR * Imatinib: 74% 2 nd generation TKIs can improve outcome of pts with early CP-CML Responses with nilotinib/dasatinib are better & faster than imatinib Nilotinib is better tolerated and more selective than dasatinib

54 More approved TKIs. Bcr-Abl ATP-Binding Abl & Src T315I-Active Nonkinase Inhibition Imatinib Dasatinib MK AAG Nilotinib Bosutinib KW-2449 HDAC INNO-406 XL228 DAC AT9283 HHT PHA

55 CASE 1 68/F, CML-CP in Jan Frontline Tx: Imatinib 400 mg/d. At 12 months of Tx: CCyR After 2 month, WBC 25,000/ul & 15 % basophils, BM: Blast 16%. What step would you take next? Continue imatinib at 400 mg/day Increase the dose of imatinib to 800 mg/day Switch therapy to a 2 nd generation TKI Recommend immediate allohsct

56 Imatinib, Glivec Standard Frontline Tx for CML ; Failure / Suboptimal Response Time Failure Suboptimal Response Warnings Dx 3 m No HR < CHR 6 m No CHR or CyR < PCyR High risk Del9q+ Additional ch somal abnls in Ph+ cells 12 m < PCyR PCyR < < CCyR Any MR < MMR 18 m < CCyR < MMR Any time Loss of CHR Loss of CCyR Mutation with high insensitivity to Glivec Additional ch somal abnls in Ph+ cells Loss of MMR Mutation with low insensitivity to Glivec Increase in BCR- ABL level Other ch somal abnls in Ph-cells Baccarani M et al. Blood 2006;108:1809.

57 CASE 1 68/F, CML-CP in Jan Frontline Tx: Imatinib 400 mg/d. At 12 months of Tx: CCyR After 2 month, WBC 25,000/ul & 15 % basophils, BM: Blast 16%. What step would you take next? X Continue imatinib at 400 mg/day Y Increase the dose of imatinib to 800 mg/day Z Switch therapy to a 2nd generation TKI [ Recommend immediate allohsct Pt shows imatinib failure after optimal response Y than Z

58 CASE 2 44/F, CML-CP, with sibling HLA matched donor Frontline Tx: Imatinib 400 mg/d. Grade 2 fluid retentions Ph(+) metaphases in BM: 30% at 6 months 50% at 12 months Imatinib plasma level: adequate & No mutations What step would you take next? Increase the dose of imatinib to 800 mg/day Switch therapy to nilotinib 400 mg twice daily Switch therapy to dasatinib 100 mg daily Recommend immediate allohsct

59 CASE 2 44/F, CML-CP, with sibling HLA matched donor Frontline Tx: Imatinib 400 mg/d. Grade 2 fluid retentions Ph(+) metaphases in BM: 30% at 6 months 50% at 12 months Imatinib plasma level: adequate & No mutations What step would you take next? X Increase the dose of imatinib to 800 mg/day Y Switch therapy to nilotinib 400 mg twice daily Z Switch therapy to dasatinib 100 mg daily [ Recommend immediate allohsct Pt shows imatinib failure after optimal response Y than Z or X

60 Thanks