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1 내과연수강좌 표적치료제의 허와실 - 항암치료의최신동향- 분당서울대학교병원혈액종양내과이근욱

2 Treatment of Cancer s 1990s 2000s Surgery Radiotherapy Chemotherapy Biologic therapy Gene therapy? Target-based Therapy

3 Most Anticancer Drugs are Not Target-Driven Agents Normal non-proliferating cell Normal Proliferating cell Cancer cell

4 Ideal Anticancer Drug Should be Target or Context-Driven Therapy Molecular target-driven Context-driven ` Normal non-proliferating cell Normal Proliferating cell Cancer cell

5 Common Strategies of Target-Based Drugs R R Antibody-Based Membrane K K ATP Small Molecule Inhibitor Lung Prostate Breast Ovary Gastric Colon

6 Molecular targeted therapies BCR-ABL TKI: Imatinib (Glivec EGFR antagonist - TKI: Imatinib (Glivec TM TM ) TKI: Gefitinib [Iressa TM ], Erlotinib [Tarceva TM ] - mab: mab: Cetuximab [Erbitux TM TM ] Proteosome inhibitor: Bortezomib [Velcade Bortezomib [Velcade TM HER2 antagonist: Trastuzumab [Herceptin Trastuzumab [Herceptin TM VEGF antagonist: Bevacizumab [Avastin 등등. Bevacizumab [Avastin TM TM ] TM ] TM ]

7 Tamoxifen 표적치료제의효시 유방암에서 tamoxifen의치료효과는종양내호르몬수용체의유무에따라예측할수있다. ER+, PR+: 반응율 74% ER-, PR-: 반응율 10%

8 Imatinib (Gleevec) 만성골수성백혈병 (CML) 위장관간질성종양 (GIST)

9 Philadelphia Chromosome in CML STI571 P P P P P P ATP Bcr/Abl P P P P P P P substrate P P P STI Crk1-p Bcr/Abl ATP substrate Crk1 p62dok STAT5 Leukemogenesis

10 Gastrointestinal Stromal Tumor (GIST) 기존에 leiomyosarcoma 또는 leiomyoma로분류 KIT 또는 PDGFRα의활성화로인해발병 Interstitial cells of Cajal(ICC) 이종양의기원 KIT 단백면역화학염색 : 95~100% 위, 상부소장에서주로발생하나, 평활근을갖는모든위장관에서발생가능 / 종종 omentum, mesentery 및 peritoneum 에서도발생

11 Imatinib in GIST - Overall Survival - Median FU : 760 days Verweij J et al. Lancet 2004(364)

12 Rituximab (Mabthera (Mabthera ) in BB-cell Lymphoma AntiAnti -CD20 mab

13 NEJM 2002

14 EGFR Family and Ligands EGF TGFα Amphiregulin β-cellulin HB-EGF Epiregulin? Heregulins NRG2 NRG3 Heregulins β-cellulin Cysteine-rich domains Tyrosine kinase domain C-terminus ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4

15 Discovery of HER2 Slamon DJ et al, Science 1987;235:

16 Normal HER2 gene amplification (+)

17 HER2 Signal Transduction Pathway

18 Trastuzumab (Herceptin TM ) : Humanized Anti-HER2 Antibody Targets HER2 protein 95% human, 5% murine - Decreases potential of immunogenicity. - Increases potential for recruiting immune effector mechanisms.

19 TM ) Trastuzumab (Herceptin TM - Metastatic Breast Cancer - Marty M et al, J Clin Oncol 2005

20 전이성유방암 = 만성질환? At least in endocrine-responsive responsive disease Hormone-refractory refractory disease Median survival: less than 2 years even with chemotherapy Optimal use of chemotherapy Combination (A+B C+D) Sequential single agent (A B C D) A+B >A? A+B> A B?

21 NSABP B-31/N Adjuvant therapy - AC TH % AC T 87% 75% 85% 67% N Events AC T AC TH HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831

23 Targeting EGFR

24 EGFR Family and Ligands EGF TGFα Amphiregulin β-cellulin HB-EGF Epiregulin? Heregulins NRG2 NRG3 Heregulins β-cellulin Cysteine-rich domains Tyrosine kinase domain C-terminus ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4

25 Epidermal Growth Factor Receptor (EGFR) EGFR pathway: 상피암의발병과진행에중요한역할 EGFR activation: 세포증식, 혈관형성, 침범및전이에관여 High expression of EGFR: 다양한암에서확인됨 & 진행된질병 / 불량한예후 / 항암치료대한내성등과관련된것으로알려져있음 Colorectal cancer (CRC) - EGFR expression : 25-77% - EGFR 이발현된경우더 aggressive 하고예후가나쁘다.

27 Cetuximab (Erbitux) IgG1 (chimerized antibody) 150 kda Exclusive for EGFR and its heterodimers Stimulates Rc internalization Blocks Rc dimerization, TK phosphorylation, signal transduction

28 2 nd -line therapy in metastatic CRC -BOND study - Cunningham D et al. New Engl J Med 2004

29 Cunningham D et al. New Engl J Med 2004

30 ERBITUX + RT in locally advanced SCCHN : phase III study Stratified by KPS Nodal involvement Tumor stage RT fractionation Stage III and IV non metastatic SCCHN (n=424) R RT (n=213) ERBITUX + RT (n=211) ERBITUX initial dose (400 mg/m 2 ) 1 week before RT ERBITUX (250 mg/m 2 ) + RT (weeks 2 8) b Primary endpoint: duration of locoregional control Secondary endpoints: OS, PFS, RR, and safety Bonner J, et al. N Engl J Med 2006;354:

31 survival (%) Overall Phase III study: overall survival Survival rate 3-year ERBITUX + RT RT p-value 55% 45% 0.05 ERBITUX + RT (n=211) RT (n=213) Months Hazard ratio = 0.74 (95% CI: ) Log-rank p=0.03 Bonner J, et al. N Engl J Med 2006;354:

32 Targeting Angiogenesis

33 Angiogenesis

34 Angiogenesis is highly dependent upon the VEGF pathway PIGF = Placenta Growth Factor

Bevacizumab (Avastin) Binds VEGFA and its isoforms T 1/2 = 17-21 days Bevacizumab increases survival when

35 Bevacizumab (Avastin) Binds VEGFA and its isoforms T 1/2 = days Bevacizumab increases survival when added to chemotherapy in first-line treatment - Breast cancer - Colorectal cancer (CRC) - NSCLC (Non-squamous)

36 Metastatic CRC - First-line Treatment (AVF2107g) - Hurwitz H et al. New Engl J Med 2004

37 Advances in the treatment of metastatic CRC Best supportive care 5-FU Irinotecan Xeloda Oxaliplatin Avastin and other MoAbs Months Median overall survival

38 Targeted Therapy in Renal Cell Carcinoma Sorafenib (NEXAVAR ) 2nd-line Sunitinib (SUTENE ) 1st-line Sorafenib Sunitinib

39 표적치료제 (Targeted agents) 정의 : 특정분자표적에작용하는약제 (?)

40 Metabolism of 5-FU & 5-FU analogues

41 Targets of Imatinib Imatinib Bcr/Abl TK c-kit TK PDGFR TK CML Gastrointestinal stromal tumor (GIST)

42 Bevacizumab : Non-squamous NSCLC Sandler et al. ASCO 2005

43 Sorafenib in HCC: SHARP trial Llovet et al. ASCO 2007

44 Efficacy of ZD1839 (Iressa, Gefitinib) in Refractory NSCLC IDEAL-1 IDEAL-2 ZD1839 (mg/d) ZD1839 (mg/d) RR (%) Symptom Improvement Rate (%) Disease control rate (%) OS (months)

47 Tsao et al. New Engl J Med 2005

48 Erlotinib (Tarceva TM ) - NCIC CTG BR.21 trial (NSCLC) PFS OS Shepherd FA et al. ASCO 2004

전이성대장암 : 1 차치료 (Cetuximab) PFS estimat te 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 8.0 mo ERBITUX + FOLFIRI (n=599) FOLFIRI (n=599) HR 0.851 [ 95% CI 0.726 0.998]; p=0.

49 전이성대장암 : 1 차치료 (Cetuximab) PFS estimat te mo ERBITUX + FOLFIRI (n=599) FOLFIRI (n=599) HR [ 95% CI ]; p= % risk reduction for progression 8.9 mo 1-year PFS rate: 23% vs. 34% 48% CRYSTAL study Progression-free survival time (months) Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000)

50 강 O 분 (F/47): Stage IV Colon Cancer Avastin + FOLFOX #

51 강 O 분 (F/47): Stage IV Colon Cancer Off Chemotherapy

52 Withdrawal of anti-vegf therapy results in vessel regrowth CD31 Untreated AG , 7 d Withdrawal, 2 d Withdrawal, 7 d RIP-Tag2 Continue anti-angiogenic therapy to avoid vessel regrowth Mancuso, et al. J Clin Invest 2006

54 Bevacizumab (Avastin ) Trastuzumab (Herceptin ) Cetuximab (Erbitux ) Rituximab (Mabthera ) Gefitinib (Iressa ) Erlotinib (Tarceva ) Sorafenib (Nexavar ) 60kg, BSA 1.6 기준 단위당비용 630,000 /100mgv 670,000 /150mgv 270,000 /100mgv 1,260,000 /500mgv 51,800 /250mgt 68,500 /150mgt 28,500 /200mgt 1달사용비용 보험적용 3,780,000 비보험 2,680,000 4,320,000 비보험 2,100,000 보험 ( 전이성 ) 비보험 ( 재발방지 ) 보험 (DLBCL) 비보험 (DLBCL 외림프종 ) 1,554,000 보험 ( 폐암 ) 2,055,000 3,420,000 보험 ( 폐암 ) 비보험 ( 췌장암 ) 보험 ( 신장암 ) 비보험 ( 간암 )

55 EGFR mutation is not only predictive, but also prognostic for survival in gefitinib-treated treated NSCLC Mutation (+) Proportion event free Mutation (+) Mutation (-) Proportion event free Mutation (-) 0.0 p* < Time-to-progression (months) 0.0 p* < Overall survival (months) HR : 0.23 (95%CI ) HR : 0.16 (95% CI ) Han & Kim et al. J Clin Oncol 2005:23;

56 EGFR Mutations & Clinical Features

58 표적치료제 (Targeted agents) 정의 : 특정분자표적에작용하는약제 : 치료효과를예측할수있는생물학적지표 ( 예측인자, predictive marker) 가있어야함

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<B0E6C8F1B4EBB3BBB0FA20C0D3BBF3B0ADC1C E687770> 2012 개원의와함께하는임상강좌 경희대학교의과대학종양혈액내과학교실 백선경 한국인사망원인 평균수명까지생존시암발생확률 길라잡이 : 개정된가이드라인을중심으로 History of anti-cancer chemotherapy Chabner BA & Roberts TG Jr. Nat Rev 2005 Use standard therapies 2012 개원의와함께하는임상강좌