Added value of the. in oncology

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1 Added value of the molecular l targeted t agents in oncology Pr Jean-Charles SORIA U981

2 Potential conflict of interest: Occasional honoraria from: Abbott, Amgen, Astellas, Astra Zeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Pfizer, Merck-Serono, MSD, Roche, Sanofi-Aventis

3 Context Epidemiological Financial Regulatory Industrial Topics Therapeutic advances in cancer Incremental advances Emergence of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, Sutent t Perspectives

4 Epidemiological data CANCER France Europe World Incidence Mortality Prevalence Current smokers in France 15 Millions people Males Females 32% 21% IARC 2008; INSERM 2007

5 Epidemiological Context: Cancer Worldwide Burden (2008 Æ 2030) 12.4 million new cases 7.6 million deaths 28 million living g with cancer 26.4 million new cases 17 million deaths 82 million living g with cancer Courtesy of Peter Boyle. IARC 5

6 Cancer = 2 nd cause of expense for chronical diseases for the french healthcare system Cancer is not the leading cause of expense Cardiovascular disease: 17 Mds Cancer : 14 Mds Diabetes : 9 Mds Mean annual Dépenses moyenne expense toute pathologie (all diseases) 8700 = 8700 Cardio- Diabetes Cancer Kidney HIV Rheumatoid Multiple Neurological vascular chronic arthritis sclerosis & muscular disease diseases Source : CNAM previsions (2009) and results (2006)

7 in 2007: Mean annual amount of expense for patients diagnosed with cancer = largely more inferior than those for patients with psychiatric or Alzheimer disease Moderate increase of the amount of expense between 2004 and 2007 = +7,2% as compared with other chronic disease Mean annual al amount of expenses per patient and per disease between een 2004 and 2007: Cardiovascular Cancer Diabetes Psychiatric Respiratory Alzheimer & dementias Source: French healthcare system, 2008

8 Developmental steps of antineoplastics: Discovery Formulation Evaluation of activity (in vitro and in vivo) Pharmacology ~ 7ans ~ 8 ans Toxicology Phase I (dose-finding trial) Phase II (efficacy trial) Phase III (comparison with standard agent trial) Introduction into general medical practice Costs = 1,2 Md USD

9 Several steps are necessary to assess the drug s potentiality The earlier stage it can be used, the greater is the benefit Adjuvant therapy Benefit = months, years, potential for cure (long-term remission) Earlier stages of cancer Benefit = many months L t t di Late stage disease Benefit = weeks, a few months

10 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Incremental advances Emergenec of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

11 In metastatic colorectal setting, incremental survival gains are function of drugs approvals Best supportive care Bolus 5-FU/LV Infusional 5-FU/LV capecitabine 13.2 Irinotecan + bolus 5-FU/LV Irinotecan + infusional 5-FU/LV Bolus 5-FU/LV + oxaliplatin or irinotecan Oxaliplatin + infusional 5-FU/LV (N9741) 19.5 Ii Irinotecan + bolus 5-FU/LV 5FU/LV + bevacizumab b 20.3 Irinotecan (FOLFIRI)/oxaliplatin (FOLFOX) sequencing Irinotecan + bolus 5-FU/LV + bevacizumab Survie globale (mois) Adapted from Grothey A et al. JClin Oncol. 2004;22: ; 09 ; Kalofonos o os HP et al. Ann Oncol. 2005;16: ; 8 ; Venook A. Oncologist. 2005;10:

12 Advances in RH- breast cancer stage IV 50 Objective responses Median overal survival (mois) 50% 50% % 40% 45% 30% % Before First line BSC CMF anthracylin Taxane + Trastuzumab + bevacizumab + Trastuzumab + anthracyclin standard Ct standard Ct standard Ct Second line Third line capecitabine Capecitabine + tratsuzumab Trastuzumab + ChT Capecitabine +/- vinorelbine Capecitabine + lapatinib + + Bottenbal et al JCO 2005; Miller et al NEJM 2007; Slamon et al NEJM 2001; Geyer et al, NEJM 2006; Miles et al, JCO 2008;

13 Added value of antineoplastic drugs in metastatic lung cancer Median overall survival (mois) One-year survival rate(%) 35% 40% 50% 20 25% 15% 10 10%

14 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Incremental advances Emergence of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

15 Molecular targeted agents (MTA) this terminology refers to: therapeutic strategies Treatments directed against molecular targets implicated in tumor growth old example: endocrine therapy

16 Cell biology in 1979 Cell Nucleus? Cytoplasm

17 Cell biology in the 2000 Hanahan D,Weinberg RA, Cell,2000

18 Therapeutical progress in oncology overview of the molecular tageted agents in 2011 Anti-HER Tarceva (erlotinib), Iressa (gefitinib): lung cancer, pancreatic cancer Erbitux (cetuximab): colorectal cancer, head and neck cancer Panitumumab (Vectibix): colorectal cancer Lapatinib: breast cancer More than 500 drugs Herceptin (trastuzumab): breast and gastric cancer under investigation Anti-angiogenics Nexavar (sorafenib): renal cell carcinoma, hepatocarcinoma Sutent (sunitinib): renal cell carcinoma, GIST Avastin (bevacizumab): colorectal cancer, lung cancer, breast, ovarian cancer Autres Glivec (imatinib): GIST, CML Rituxan (rituximab): B Cell Lymphoma Sprycel (dasatinib): CML Afinitor (everolimus): renal cell carcinoma, NE of the pancreas Torisel (temsirolimus): renal cell carcinoma, mantle cell lymphoma

19 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Incremental advances Emergence of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

20 MTA oncolo ogy se of MTA in Pat tients (% %) 50 MTA 40 Surgery + CT RT ± CT Best supportive care + CT U 0 Localised Regional Distant RT = radiotherapy CT = chemotherapy

21 Importance of the biomarkers when prescribing MTA MTA should be delivered only to patients whose tumor express the target Situations in current practice: Optimal situations (precription directed by biomarkers) HER2 & Herceptin (trastuzumab) CD20 & Rituxan (rituximab) EGFR mutation & Iressa (gefitinib) Intermediate situations EGFR mutation & Tarceva (erlotinib) RAS Mutation & Erbitux (cetuximab) or Vectibix (panitumumab) HER2 & Tykerb (lapatinib) KIT mutation & Gleevec (imatinib) Sub-optimal situations, ti (prescription without t biomarker) All the antiangiogenic drugs (avastin, sutent, nexavar) mtor inhibitors (afinitor, torisel)

22 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Advances step by step Emergence of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

23 Mechanism of action of Trastuzumab Trastuzumab HER2 receptor Subdomain IV of HER2 Trastuzumab continually suppresses HER2 activity Flags cells for destruction by the immune system (ADCC) Prevents HER2 activation by ECD shedding

24 Trastuzumab: incremental integration in the therapeutic arsenal against HER2+ cancers adjuvant BC Phase III mbc 1 st line various combinations Phase III Phase III Gastric Cancer Approval EU/US Phase II Phase III Approval US/EU mbc 1 st line Phase II Phase III Approval US/EU mbc 2 nd line Phase I Phase II Phase III Approval US/EU 91/ / /10

25 Added-value of MTA Trastuzumab and Early Breast Cancer Systematic decrease of the mortality risk ( one third decrease in all studies) Overall survival benefit Median follow-up, years HERA CTx H 1 year 2 B-31 / N9831 AC PH 3 BCIRG 006 AC DH 3 BCIRG 006 DCarboH 3 0 Favours 1 Favours no 2 Herceptin Herceptin Hazard ratio Slamon et al 2006; Perez et al 2007; Smith et al 2007

26 Added-value of MTA Trastuzumab and Early Breast Cancer 28,000 patients projection upon a 10 year period in the five leading european countries No. of patients prevented from developing metastases Patients, n 20,000 18,000 Herceptin introduced Incidence of MBC without following Herceptin introduction of Herceptin 16,000 14,000 12,000 27,737 10, Year MBC, metastatic breast cancer Weisgerber-Kriegl et al 2008

27 Trastuzumab and Metastatic breast cancer significative majoration of overall survival with first line metastatic breast cancer H0648g (IHC 3+) M77001 BCIRG 007 US Oncology (IHC 3+) P alone PH D alone DH DCarboH DH PCarboH H Median survival (months) P = paclitaxel; H = trastuzumab D = docetaxel; Carbo = carboplatin Smith, et al. Anticancer Drugs 2001; Marty, et al. JCO 2005 Robert, et al. JCO 2006; Pegram, et al. ASCO 2007

28 Trastuzumab completely reversed the poor prognosis associated with HER2+ metastatic breast cancer Overall survival probab ility HER2 HER2+/no trastuzumab u ab HER2+/trastuzumab Months from diagnosis Dawood, et al. ASCO 2008

29 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Advances step by step Emergence of molecular targeted agents (MTA) To measure the target of MTA remains problematic Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

30 CD20 antigen specific biomarker of B lymphocytes» 297 AA phosphoprotein (33 35 kd) Extra-cellular domain» Restricted to the B lineage Expression in > 95% lymphomatous cells Absence of expression in stem cells, in B progenitors or in mature B plasmocytes Transmembrane domain» Absence of rapid modulation during the binding with the anti-cd20 antibody Cytoplasm

31 Rituximab chimeric i (murine human) monoclonal l antibody directed d against CD20 antigen Variable domain (Fab) = (murine part)» directed against CD20 antigen Constant domain (Fc) = (human part) lgg1» prolonged half-life as compared to fully murine antibody» initiate early effectors of the immune response» Limits the generation of anti-chimeric antibodies (HACA) Mc Laughlin P et al. J Clin Oncol 1998 ; 16(8) :

32 Rituximab its clinical developement completely changed strategies in treating ti hematologic malignancies i ASMR notable follicular NHL stage III IV pivotal trial ASMR II ASMR I Maintenancerelapse /refractory follicular NHL responding to the induction with/without Mabthera (EORTC 20981) follicular NHL stage III IV Induction 1st line Associated with CVP (M39021) ASMR I Maintenance 1st line NHL follicular (PRIMA Q1 2010) Follicular lymphoma stage III IV 1st line, associated with chemotherapy (GLSG 00, OSHO 39, FL2000) ASMR I Diffuse large B cell lymphoma associated with CHOP (LNH98.5) ASMR: in process CLL 1st line Associated with chemotherapy (CLL8) ASMR in process CLL relapse/refractory LNH: non hodgkin lymphoma LLC: chronic lymphoid leukemia Associated with CT (REACH) ASMR: clinical added value (french healthcare scoring sytem: I, major added value V, absence of added value)

33 Rituximab and lymphomas historical break in the disease specific mortality 15 Cisplatin Etoposide Fludarabine Rituximab (1978) (1983) (1991) (1997) Rate per 100 0,000* ,6% / year LNH mortality (SEER Program, USA) -2,8% / year Molina A, et al. Ann Rev Med 2008; 59: *Age adjusted to 2000 US standard population

34 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Advances step by step Emergence of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

35 Added value of gleevec in the treatment of GIST 1) Revolution in metastatic GISTs: Overal survival increased three times Low toxicity rate, Occupational reintegration 2) necessity of a long term treatment 3) decrease of the relapse risk in adjuvant However, relapses might be delayed Long terme treatment for high risk of relapse adjuvant situations 4) better selection of the patients suitable for imatinib in 4) better selection of the patients suitable for imatinib in adjuvant setting (KIT mutation driven strategy)

36 Overall survival Historical i comparison Glivec Doxorubin-basedbased ABL Poof of the concept (months) O N Number of patients at risk : Treatment KIT PDGFR

37 Kinase Mutations in GISTs Wild-type PDGFRA Exon 9 Exon 18 KIT Exon 11 Heinrich et al. J Clin Oncol 21: , 4349, 2003 Agaram et al. Genes, Chromosomes & Cancer 47: , 859, 2008 Agaimy et al. J Clin Pathol 2009;62: , 616, 2009

38 Phase III Trials Genotype and PFS SWOG S0033 EORTC/ISG/AGITG Heinrich et al. J Clin Onc 2008, 26(33): Debiec-Rychter et al. Eur J Cancer 2006, 42(8):

39 Context Epidemiological Financial Regulatory Industrial Plan Therapeutic advances in cancer Advances step by step Emergence of molecular targeted agents (MTA) The use of MTA and the problematic of biomarkers Added value of MTA Herceptin Mabthera Gleevec Tarceva/Iressa Erbitux Avastin, sutent t Perspectives

40 Perspectives MTA are progressively integrated to therapeutic strategies in oncology Such integration starts in the metastatic setting and is then being expanded to other situations MTA result in major added value in adjuvant setting in few tumor types (e.g. HER2 + Breast cancer and Trastuzumab) Some MTA deepely changed tumors natural history: Rituximab and B lymphomas Trastuzumab and HER2+ Breast Cancers Gleevec and CML or GIST Antiangiogenics g and Renal cell carcinoma MTA represent 0,6% of the total amont of the french healthcare system expenses

41 Perspectives MTA also highlight biology in vivo since these drugs modulate transversal biological process. The use MTA expands beyond the oncology field Rituximab and auto-imune pathologies Antiangiogenics and ARMD The MTA pricing should be based on the clinical added value produced rather than on the «succes storys» of this class of agents With the exception of severe pathologies in which few weeks or months gains represents true advances( e.g. pancreatic cancer, lung cancer, glioblastoma) MTA are always tested at first in metastatic setting

42 phase II trial testing Rituximab in type I diabetes (NEJM 26 nov 2009)

43 Vestibular schwannomas cause hearing loss in neurofibromatosis type 2 Avastin led to tumour shrinkage, with associated decreases in vascular permeability and blood flow hearing was improved in four of seven evaluable patients Plotkin, et al. NEJM 2009

44 Antiangiogenic drugs Aptamer Anti-VEGF/ Macugen Baseline 20/63 ( 60 letters) Year 1 20/40 (70 letters) Year 2 20/20 (84 letters)

45 The last wave of MTA reinforces the global positive trend Tumor type with oncogenic addiction e.g. Hedgehog inhibitors in BCC (PTCH mutations), B RAF inhibitors in melanoma (B RAF mutations), ALK inhibitors in NSCLC (ALK translocation) i.e. superstars!» (New Engl J. Med 2010)» (New Engl J. Med 2010)