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1 Introduction to Medical Oncology and Molecularly Targeted Therapy 서울대학교의과대학내과학교실분당서울대학교병원혈액종양내과 김유정 연도별성별암발생자수추이 70 분당서울대학교병원

2 제 8 회분당서울대학교병원내과연수강좌 2012 평균수명까지생존시암발생확률, 2009 주요암종발생분율, 2009 분당서울대학교병원 71

3 성별주요암종발생분율, 2009 성별 5 년생존율추이 : 모든암 72 분당서울대학교병원

4 제 8 회분당서울대학교병원내과연수강좌 2012 주요암의 5 년생존율국제비교 암환자의진단및평가 Pathologic diagnosis Staging Biologic behavior of cancer Estrogen receptor (ER) HER2 Patient s performance status 분당서울대학교병원 73

5 치료방침의결정 국소질환 (locoregional disease): I-III 기 국소치료 ( 수술, 방사선치료 ) 보조요법 ( 방사선치료, 항암화학요법 ) 전신질환 (systemic disease): 보통 IV 기 전신치료 ( 항암화학요법 ) 다학제적접근 (Multidisciplinary approach) 74 분당서울대학교병원

6 제 8 회분당서울대학교병원내과연수강좌 2012 What is Medical Oncology? Subspecialty of internal medicine that cares for and designs treatment approaches to patients with cancer, in conjunction with surgical and Radiation oncologists. The core skills of the medical oncologist include the use of drugs (chemotherapy) that may have a beneficial effect on the natural history of the patient's illness or favorably influence the patient's quality of life. 전이성 / 재발성암의임상경과 Metastatic or recurrent cancer 항암화학요법 질병진행 항암화학요법영구중단 말기 1 st line chemotherapy 2 nd line chemotherapy Death 분당서울대학교병원 75

항암치료의결정 Benefit 항암효과생명연장증상완화 Response Risk 부작용경제적손실 Toxicity ECOG Performance Status Grade ECOG 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in

7 항암치료의결정 Benefit 항암효과생명연장증상완화 Response Risk 부작용경제적손실 Toxicity ECOG Performance Status Grade ECOG 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead 76 분당서울대학교병원

8 제 8 회분당서울대학교병원내과연수강좌 2012 Response Evaluation History of Cancer Treatment 1950 s: Surgery 1960 s: Radiation Therapy 1970 s: Chemotherapy 1980 s: Immunotherapy 1990 s: Gene Therapy 2000 s: Molecularly Targeted Therapy 분당서울대학교병원 77

9 Conventional Cytotoxic Agents Direct DNA-interacting agents Alkylating agents Platinum Antitumor antibiotics Topoisomerase interactive agents Cyclophosphamide Melphalan, Temozolomide Cisplatin, carboplatin, oxaliplatin Bleomycin, mitomycin C Anthracyclines, Etoposide Camptothecins (irinotecan etc.) Indirect DNA-interacting agents Antimetabolites Antimicrotubule agents Antifolic acids Pyrimidine analogues (5-FU etc.) Purine analogues Vinca alkaloids Taxanes (paclitaxel, docetaxel) Miscellaneous agents L-asparaginase Translating research into cancer therapies Growth factor receptors and signal transduction Improved genetic and molecular techniques Tumor suppressor genes and oncogenes Angiogenesis and metastasis Innovative cancer therapies Apoptosis and cell cycle control Molecular Targets 78 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Molecularly Targeted Agents Rituximab (Mabthera ): CD 20 MAb (monoclonal antibody) NHL (B-cell lymphoma) Trastuzumab (Herceptin ): HER2 (c-erbb2) MAb Breast ca, AGC

10 제 8 회분당서울대학교병원내과연수강좌 2012 Molecularly Targeted Agents Rituximab (Mabthera ): CD 20 MAb (monoclonal antibody) NHL (B-cell lymphoma) Trastuzumab (Herceptin ): HER2 (c-erbb2) MAb Breast ca, AGC Cetuximab (Erbitux ): EGFR MAb Colorectal ca, NSCLC Bevacizumab (Avastin ): VEGF MAb Colorectal ca, NSCLC, Breast ca, Glioblastoma Imatinib (Glivec, Gleevec ): bcr/abl, c-kit, PDGFR tyrosine kinase inhibitor CML, GIST, idiopathic hypereosinophilic syndrome, dermatofibrosarcoma protuberans Gefitinib (Iressa ): EGFR tyrosine kinase inhibitor (TKI) NSCLC Erlotinib (Tarceva TM ): EGFR TKI NSCLC, pancreatic ca Crizotinib (Xalkori ): ALK inhibitor NSCLC Sunitinib (Sutent, Sutene ): VEGFR, PDGFR, c-kit inhibitor Sorafenib (Nexavar ): Raf, VEGFR, PDGFR inhibitor 분당서울대학교병원 79

11 Clinical Trials in Oncology Development of a new drug 새로운항암제가임상에서사용되기까지의과정 Phase I trial Phase II trial Phase III trial Phase IV trial 약물의독성평가 약물의효능평가 기존치료또는무치료와비교한치료효과평가 Post-marketing surveillance Dose-limiting toxicity (DLT) 를찾아 maximal tolerated dose (MTD) 결정 Pharmocokinetic analysis 다른치료가불가능한 refractory patient 대상 MTD 또는 MTD 보다약간낮은용량사용 특정암에서약물의치료효능평가 Primary endpoint : Response rate Toxicity profile 평가 Measurable disease 가있는일정한환자군 (homogeneous group) 대상 Active agent : phase II trial 에서 20-25% 이상의 RR 를보이고, reversible non-lifethreatening toxicity 를보이는약제 Active agent 를 standard therapy 또는 no therapy (placebo) 와비교하는 two arm study Randomized controlled trial 로보통이전에치료받지않은환자를대상으로시행 Primary endpoint : OS, TTP, PFS 실제임상에서쓰이는중에발생한예상치못했던부작용이나지연성부작용, 새로운적응증을확인하는과정 Intergration into primary treatment 80 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 Molecularly Targeted Therapy I. Targeting signal transduction pathway 1. Extracellular targeting: Monoclonal antibodies 2.

12 제 8 회분당서울대학교병원내과연수강좌 2012 Molecularly Targeted Therapy I. Targeting signal transduction pathway 1. Extracellular targeting: Monoclonal antibodies 2. Intracellular targeting: Small molecules - Receptor tyrosine kinase inhibitors (TKI) - Non-receptor TKI -mtorinhibitor, etc. II. Targeting angiogenesis III. Other agents Signal Transduction Pathway Receptor tyrosine kinase (RTK) 분당서울대학교병원 81

13 Recepetor Tyrosine Kinase Initiates 2 major signal transduction pathways Ras/MAP kinase pathway Cell Proliferation PI3K/Akt pathway, STAT pathway Cell Survival Regulate cellular proliferation, survival, differentiation, function, and motility. Constitutively activated by Chromosomal translocation Mutation Overexpression RTK Targeting Monoclonal Antibodies Receptor tyrosine kinase of HER family Cetuximab Trastuzumab (EGFR or ErbB family) Ligand-binding domain Tyrosine-kinase (TK) domain HER1 (=EGFR) HER2 HER3 HER4 82 분당서울대학교병원

14 제 8 회분당서울대학교병원내과연수강좌 2012 Trastuzumab (Herceptin ) Humanized anti-her2 monoclonal Ab Ix: Breast cancer with HER2 overexpression/amplification Tumor type Bladder Pancreas Breast Lung(NSCLC) Ovary Colorectum Renal Head and neck Gastric Esophageal Frequency of Her2 Overexpression(%) Data Series Literature range <HER2 overexpression> Prognostic value aggressive disease poor clinical outcome Predictive value relative sensitivity to anthracycline-based regimens decreased sensitivity to tamoxifen and CMF Pivotal Phase III trial in MBC (2001) Slamon DJ, et al. N Engl J Med 2001;344(11): 분당서울대학교병원 83

Adjuvant phase III trials (2005-2006) Imatinib

15 Adjuvant phase III trials ( ) Imatinib (Glivec, Gleevec, STI 571) competitive inhibitor of the ATP binding site of the BCR/ABL, c-kit, PDGF RTKs Ix: CML, GIST, idiopathic hypereosinophilic syndrome 84 분당서울대학교병원

16 제 8 회분당서울대학교병원내과연수강좌 2012 Gefitinib (Iressa, ZD1839) competitive inhibitor of the ATP binding site of the EGFR tyrosine kinase Ix : NSCLC Failure of large scaled randomized phase III trials INTACT 1, 2 trial: 1 st line Iressa combined with chemotherapy (1: GP, 2: TC) ISEL trial: 2 nd line Iressa, OS 5.6 mo vs. 5.1 mo (not significant) (FDA approval June, 2003 FDA restriction June, 2005 rapid withdrawal from US market) Erlotinib (Tarceva ) competitive inhibitor of the ATP binding site of the EGFR tyrosine kinase Ix: NSCLC, pancreatic cancer Limited success of large scaled randomized phase III trials TRIBUTE, TALENT: 1 st line Tarceva combined with chemotherapy failed to show survival benefit BR.21 trial: 2 nd line Tarceva, OS 6.7 mo vs. 4.7 mo, p<0.001 (FDA approval Nov, 2004 for 2 nd line CRx in NSCLC) 분당서울대학교병원 85

mutations EGFR amplification/high polysomy (FISH+) EGFR IHC+

17 Predictors of Response to EGFR TKI Clinical Predictors Female Never-smoker Adenocarcinoma Asian Molecular Predictors EGFR mutations EGFR amplification/high polysomy (FISH+) EGFR IHC+ (via AKT/STAT) (via MAPK/ERK) EGFR mutation and response to TKI 86 분당서울대학교병원

제 8 회분당서울대학교병원내과연수강좌 2012 New drugs targeting the VEGF pathway Anti-VEGF antibodies Bevacizumab VEGF Soluble VEGF receptors VEGF-Trap Anti-VEGFR antibodies IMC-1121 P P P P VEGFR-1 P P P P VEGFR-2

18 제 8 회분당서울대학교병원내과연수강좌 2012 New drugs targeting the VEGF pathway Anti-VEGF antibodies Bevacizumab VEGF Soluble VEGF receptors VEGF-Trap Anti-VEGFR antibodies IMC-1121 P P P P VEGFR-1 P P P P VEGFR-2 Endothelial cell VEGF: vascular endothelial growth factor Small-molecule VEGFR inhibitors Sunitinib, Sorafenib Bevacizumab (Avastin ) Anti-VEGF monoclonal antibody Ix: colorectal cancer, NSCLC, RCC, glioma VEGF secretion Tumour Bevacizumab VEGF complexes No binding VEGFR-1&2 No angiogenesis 분당서울대학교병원 87

19 Bevacizumab in Colorectal Cancer PFS A Phase III trial, metastatic, 1 st line IFL (Irinotecan/5-FU/LV)+ placebo vs. IFL + bevacizumab OS Hurwitz H, et al. N Engl J Med 2004;350: Commonly Prescribed Targeted Agents Cancer Type 폐암유방암위암대장암간암림프종신장암뇌종양 (glioblastoma) 위장관기질종양 (GIST) Targeted Agents Gefitinib (Iressa ), Erlotinib (Tarceva TM ), Bevacizumab (Avastin ), Cetuximab (Erbitux ), Crizotinib (Xalkori ) Trastuzumab (Herceptin ), Lapatinib (Tykerb ) Trastuzumab (Herceptin ) Bevacizumab (Avastin ), Cetuximab (Erbitux ) Sorafenib (Nexavar ) Rituximab (Mabthera ) Sunitinib (Sutene ), Sorafenib (Nexavar ), Pazopanib (Votrient ), Everolimus (Afinitor ), Bevacizumab (Avastin ), Temsirolimus (Torisel ) Bevacizumab (Avastin ) Imatinib (Glivec ), Sunitinib (Sutene ) 88 분당서울대학교병원

20 제 8 회분당서울대학교병원내과연수강좌 2012 Major Problems Selecting an optimal patient Overcoming resistance Cost-effectiveness Future Directions Identifying predictive biomarkers of response and resistance Identification of new drugs and new targets Selecting optimal dose and schedule Exploring optimal combination with conventional chemotherapy and/or radiation therapy Exploring optimal combinations of molecularly targeted agents 분당서울대학교병원 89

21 Best clinical practice might be selecting a best clinical trial for the patient, during our journey toward a genuine tailored therapy 90 분당서울대학교병원

<B0E6C8F1B4EBB3BBB0FA20C0D3BBF3B0ADC1C E687770>

<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