Targeted therapy Effecitiviteit, bijwerkingen en kosten Pax Willemse Afdeling Medische Oncologie UMCG, Groningen

Mustard gas BARI, ITALY

Achilleshiel? Normale cellen hebben meerdere pathways nodig. Tumorcellen zijn afhankelijk van 1 of 2 pathways. = de Achilleshiel voor therapeutisch targeten van pathways, die geactiveerd zijn door oncogenen. Weinstein Science 297;64-64:2002 Downward Nature 439,274-275:2006

Cancer cells acquire a number of traits which can potentially be used for targeted therapy Hanahan, Weinberg, Cell 2000

IJsberg

Pharmaceutical Research 1975-1995 phase I cancer studies 280 new agents,10% approved by FDA Now: 395 anticancer drugs in clinical development phase 282 phase III trials of molecular targeted agents 34 phase III trials classic cytotoxic agents

Drug-types and targets Mab’s: monoclonal antibodies Nib‘s: (tyrosine) kinase inhibitors Targets C-kit: imatinib EGF receptor pathways EGFR1 & EGFR2=HER2/neu Angiogenese: VEGF

Nibs & Mabs Imatinib Sunitinib Sorafenib Erlotinib Bevacizumab Cetuximab Trastuzumab

Angiogenic switch

Angiogenic balance or switch Tumor angiogenesis Angiogenic balance or switch

results in abnormal blood vessels VEGF overproduction results in abnormal blood vessels

Geregistreerde targeted Mab’s cetuximab = EGFR1 antilichaam bevazuzimab = VEGF antilichaam trastuzumab = HER2-neu antilichaam rituximab = CD 20 Al alemtuzumab = CD 53 Al denusomab = RANKL

Geregistreerde targeted Nib’s (lapatinib) = EGFR2 tyrosine-kinase remmer (gefitinib) = EGFR1 tyrosine-kinase remmer erlotinib = EGFR1 tyrosine-kinase remmer imatinib mesylate = c-kit kinase remmer sorafenib = multi-targeted kinase remmer sunitinib = same bortezomib = proteasome inhibitor The ubiquitin-proteasome pathway (UPP) is the major non-lysosomal proteolytic system in the cytosol and nucleus of all eukaryotic cells. Bortezomib (also known as PS-341 and Velcade) is a proteasome inhibitor, a novel class of cancer therapies. Bortezomib blocks multi-ubiquitinated protein degradation by inhibiting 26S proteasome activity, including regulating cell cycle, anti-apoptosis, and inflammation, as well as immune surveillance. In multiple myeloma (MM) cells, bortezomib directly induces cell stress response followed by activation of c-Jun NH(2) terminal kinase (JNK)/stress-activated protein kinase (SAPK), and triggers caspase-dependent apoptosis of tumor cells. Recent clinical studies demonstrated that bortezomib had remarkable anti-tumor activity in refractory and relapsed MM, providing the basis to approval by FDA. Its anti-tumor activities earlier in the course, in combination therapies, and in other malignancies is ongoing.

Imatinib en GIST: Problemen bloeding oedeem comedicatie! (CYP 3A4, 2D6) grote OK’s behandeling in centrum! Probleem: resistentie tegen imatinib

Sunitinib (SU11248, Sutent) FDA Januari 2006: Geregistreerd voor GIST & niercelcarcinoom EMEA: recent goedgekeurd

sunitinib als patienten resistant tegen imatinib FDG-PET bij GIST met sunitinib als patienten resistant tegen imatinib Dileo et al, ASCO 2005

Remming VEGF signaal

Fase 2 studies Sunitinib voor niercelcarcinoom

Behandeling gerelateerde adverse events, grade 2&3 Studie 1 Studie 2 Moeheid 38% 22% Diarrhee 24% 16% Misselijkheid 19% 13% Stomatitis 19% 14% Dermatitis 8% 11% Afname LVEF 11% 5% Hypertenise 5% 14%

Epitheliale receptor (HER) familie

Aangrijpingspunt erlotinib en cetuximab

Er waren eens 2 EGFR inhibitoren ….

Erlotinib EMEA registratie Na falen chemotherapie NSCLC Pancreascarcinoom + gemcitabine

Respons / benefit Meer responses in Niet-rokers East-Asian descent Vrouwen Adenocarcinoom Mutaties in het kinasedomein van de EGFR Slechter effect als K-RAS mutatie in tumor 10%

Cetuximab Colon: EMEA: als EGFR1 expresssie en falen op irinotecan bij gemetastaseerd coloncarcinoom BOM 2004: onvoldoende meerwaarde Hoofd-hals: EMEA: Toegevoegd aan radiotherapie

Skin rash, marker clinical benefit Acneiform hyperkeratotic rash

Failures of targeted drugs Metalloproteinase inhibitors pancreas carcinoma SCLC EGFR tyrosine kinase inhibitors (gefitinib = Iressa) first line NSCLC

Reasons for failure complex tumors heterogeneity of tumors subpopulations complex tumors connections with other pathways downstream effectors for each pathway

Budgettaire bijwerkingen

Budgettaire bijwerkingen

You’ll never believe it, but…. Nature Medicine 2007 US $ 100.000,- voor 1 jaar Avastin bij NSCLC Winst: 2 maanden toename mediane overleving 16% toename van verkoop oncolytica in 2005 US $ 1.100 M verkoop van Avastin in 2005 US $ 69 M in stocks in 2005 uitgekeerd aan Arthur Levinson, Chairman Genentech

Commissie Beoordeling Nieuwe Oncologische Middelen (CieBOM)  Doel: beoordeling van de klinische waarde van nieuwe, geneesmiddelen, behandelmethoden en -indicaties op het gebied van de Medische Oncologie  

Commissie Beoordeling Nieuwe Oncologische Middelen (CieBOM)    …. anderzijds stelt de Ziekenfondswet dat voor vergoeding in aanmerkingen komen: ‘behandelingen die in de kring der beroepsgenoten gebruikelijk en aanvaard zijn, en voldoende bewezen in wetenschappelijk onderzoek’ …. ‘de gelddiscussie komt voortdurend naar ons toe, die kunnen we niet terzijde schuiven. Alleen kijken naar medische criteria is anno 2000 naïef’

Conclusions targeted drugs 1 Toxicity may be severe and specific: e.g. Skin for EGFR (cetuximab, erlotinib) - Heart for HER2 (trastuzumab) - Bone marrow for c-kit (imatinib) Wound healing/epistaxis/HT (avastin)

Conclusions targeted drugs 2 The tumor is not the only target!! Most drugs are not tumor-specific Drug interaction may be a problem e.g. CYP 3A4 for imatinib Selection of sensitive tumors or specific mutations still elusive Targeted drugs are new and expensive

Conclusions targeted drugs 3 Therefore..... Targeted drugs should be prescribed by targeted physicians, who are competent and dedicated

Thank you for your attention