2008.8.31. 내과연수강좌 표적치료제의 허와실 - 항암치료의최신동향- 분당서울대학교병원혈액종양내과이근욱
Treatment of Cancer 1890-1980s 1990s 2000s Surgery Radiotherapy Chemotherapy Biologic therapy Gene therapy? Target-based Therapy
Most Anticancer Drugs are Not Target-Driven Agents Normal non-proliferating cell Normal Proliferating cell Cancer cell
Ideal Anticancer Drug Should be Target or Context-Driven Therapy Molecular target-driven Context-driven ` Normal non-proliferating cell Normal Proliferating cell Cancer cell
Common Strategies of Target-Based Drugs R R Antibody-Based Membrane K K ATP Small Molecule Inhibitor Lung Prostate Breast Ovary Gastric Colon
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 ]
Tamoxifen 표적치료제의효시 유방암에서 tamoxifen의치료효과는종양내호르몬수용체의유무에따라예측할수있다. ER+, PR+: 반응율 74% ER-, PR-: 반응율 10%
Imatinib (Gleevec) 만성골수성백혈병 (CML) 위장관간질성종양 (GIST)
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 STI571 - + Crk1-p Bcr/Abl ATP substrate Crk1 p62dok STAT5 Leukemogenesis
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
Imatinib in GIST - Overall Survival - Median FU : 760 days Verweij J et al. Lancet 2004(364)
Rituximab (Mabthera (Mabthera ) in BB-cell Lymphoma AntiAnti -CD20 mab
NEJM 2002
EGFR Family and Ligands EGF TGFα Amphiregulin β-cellulin HB-EGF Epiregulin? Heregulins NRG2 NRG3 Heregulins β-cellulin 100 44 36 48 Cysteine-rich domains Tyrosine kinase domain 100 82 59 79 C-terminus 100 33 24 28 ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4
Discovery of HER2 Slamon DJ et al, Science 1987;235:177-182182
Normal HER2 gene amplification (+)
HER2 Signal Transduction Pathway
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.
TM ) Trastuzumab (Herceptin TM - Metastatic Breast Cancer - Marty M et al, J Clin Oncol 2005
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?
NSABP B-31/N9831 - Adjuvant therapy - AC TH % AC T 87% 75% 85% 67% N Events AC T 1679 261 AC TH 1672 134 HR=0.48, 2P=3x10-12 Years From Randomization B31/N9831
Targeting EGFR
EGFR Family and Ligands EGF TGFα Amphiregulin β-cellulin HB-EGF Epiregulin? Heregulins NRG2 NRG3 Heregulins β-cellulin 100 44 36 48 Cysteine-rich domains Tyrosine kinase domain 100 82 59 79 C-terminus 100 33 24 28 ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4
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.
Cetuximab (Erbitux) IgG1 (chimerized antibody) 150 kda Exclusive for EGFR and its heterodimers Stimulates Rc internalization Blocks Rc dimerization, TK phosphorylation, signal transduction
2 nd -line therapy in metastatic CRC -BOND study - Cunningham D et al. New Engl J Med 2004
Cunningham D et al. New Engl J Med 2004
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;354:567 578
survival (%) Overall 100 80 60 40 20 Phase III study: overall survival Survival rate 3-year 29.3 49.0 ERBITUX + RT RT p-value 55% 45% 0.05 ERBITUX + RT (n=211) RT (n=213) 0 0 10 20 30 40 50 60 70 Months Hazard ratio = 0.74 (95% CI: 0.57 0.97) Log-rank p=0.03 Bonner J, et al. N Engl J Med 2006;354:567 578
Targeting Angiogenesis
Angiogenesis
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 added to chemotherapy in first-line treatment - Breast cancer - Colorectal cancer (CRC) - NSCLC (Non-squamous)
Metastatic CRC - First-line Treatment (AVF2107g) - Hurwitz H et al. New Engl J Med 2004
Advances in the treatment of metastatic CRC 1980 1985 1990 1995 2000 2005 2010 Best supportive care 5-FU 35 30 25 Irinotecan Xeloda Oxaliplatin Avastin and other MoAbs Months 20 15 10 5 Median overall survival 0 1980 1985 1990 1995 2000 2005 2010
Targeted Therapy in Renal Cell Carcinoma Sorafenib (NEXAVAR ) 2nd-line Sunitinib (SUTENE ) 1st-line Sorafenib Sunitinib
표적치료제 (Targeted agents) 정의 : 특정분자표적에작용하는약제 (?)
Metabolism of 5-FU & 5-FU analogues
Targets of Imatinib Imatinib Bcr/Abl TK c-kit TK PDGFR TK CML Gastrointestinal stromal tumor (GIST)
Bevacizumab : Non-squamous NSCLC Sandler et al. ASCO 2005
Sorafenib in HCC: SHARP trial Llovet et al. ASCO 2007
Efficacy of ZD1839 (Iressa, Gefitinib) in Refractory NSCLC IDEAL-1 IDEAL-2 ZD1839 (mg/d) ZD1839 (mg/d) 250 500 250 500 RR (%) 18.4 19.0 11.8 8.8 Symptom Improvement Rate (%) 40.3 37.0 43.1 35.1 Disease control rate (%) 54.4 51.4 42.2 36.0 OS (months) 7.6 8.0 6.5 5.9
Tsao et al. New Engl J Med 2005
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=0.0479 15% risk reduction for progression 8.9 mo 1-year PFS rate: 23% vs. 34% 48% 0.2 0.1 0.0 CRYSTAL study 0 2 4 6 8 10 12 14 16 18 20 Progression-free survival time (months) Van Cutsem E, et al. ASCO 2007 (Abstract No. 4000)
강 O 분 (F/47): Stage IV Colon Cancer Avastin + FOLFOX # 12 2006.8. 2007.5.
강 O 분 (F/47): Stage IV Colon Cancer Off Chemotherapy 2007.5. 2007.4.
Withdrawal of anti-vegf therapy results in vessel regrowth CD31 Untreated AG-013736, 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
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 )
EGFR mutation is not only predictive, but also prognostic for survival in gefitinib-treated treated NSCLC 1.0 1.0 Mutation (+) Proportion event free 0.8 0.6 0.4 0.2 Mutation (+) Mutation (-) Proportion event free 0.8 0.6 0.4 0.2 Mutation (-) 0.0 p* < 0.001 0 4 8 12 16 20 24 28 Time-to-progression (months) 0.0 p* < 0.001 0 4 8 12 16 20 24 28 32 Overall survival (months) HR : 0.23 (95%CI 0.093-0.57) HR : 0.16 (95% CI 0.046-0.52) Han & Kim et al. J Clin Oncol 2005:23;2493-2501
EGFR Mutations & Clinical Features
표적치료제 (Targeted agents) 정의 : 특정분자표적에작용하는약제 : 치료효과를예측할수있는생물학적지표 ( 예측인자, predictive marker) 가있어야함