Is there a role for EGFR Tyrosine Kinase Inhibitors in recurrent glioblastoma? Juan M Sepúlveda Sánchez Neurooncology Unit Hospital Universitario 12 de Octubre. Madrid
Topics 1.-EGFR pathway as a potential target in GBM treatment 2.-EGFR alterations in GBM 3.-Gefintinib and Erlotinib clinical trials in GBM 4.-New EGFR tyrosine kinase inhibitors 5.-Ongoing trials with EGFR TK inhibitors 6.-Conclusions
EGFR as a potential target EGFR is a member of HER (ErbB) family of receptor tyrosine kinases EGFR is a common genetically altered gene in human cancer: Gene amplification (lung cancer, colorectal, head and neck) Mutations (Lung cancer) 30-45% of GBMs exhibit EGFR gene amplification Different classes of EGFR somatic mutations have been identified in GBM Most common EGFR mutation: EGFRvIII Much higher incidence of EGFR alterations in primary GBM Different anti-egfr drugs are being used successfully in lung, head and neck, and colorectal cancers
HER FAMILY OF RECEPTORS
HER FAMILY OF RECEPTORS
HER receptors activation In order to convert extracellular signals into intracellular signals, HER family receptors must be activated in a multistep process HER receptor binds its associated ligand Conformation changes from closed to open HER2 has no ligands -> always exists in open conformation HER receptor in open conformation is available for dimerization After dimerization Transactivation Intracellular Tyrosine-Kinase domains of the two receptors are phosphorilated
HER FAMILY OF RECEPTORS
HER1, Erb-b1, EGFR
Receptor Internalization
Targeted therapies
EGFR alterations in GBM 40-50% of GBMs exhibit EGFR gene amplification Most common EGFR mutation: EGFRvIII EGFRvIII is present in 41% of GBMs with EGFR amplification Small proportion of GBMs (5%) may express EGFRvIII without concomitant EGFR gene amplification Much higher incidence of EGFR amp in primary GBM Krishnan S et al. Front Biosci 2003;8:1-13 Barker FG et al. Int J Radiat Oncol Biol Phys 2001;51:410-418
EGFR: Other Mutations Point mutations within the EGFR kinase domain (common in NSCLC) rarely been identified in GBM 17% GBM show exon deletion mutations of the Cterminal domain of EGFR associated with EGFR amplification Limited data about HER2, HER3 y HER4 Cho J, at el. Clin Cancer Res 2011; Epub.
EGFR alterations in GBM Over-expression of ligand also has been noted in GBM: EGF EGF-HB (Heparin-Binding EGF) TGF Autocrine loops may contribute to malignant progression Tang P, et al. J Neurooncol 35, 303 314 Mishima K, at al. Acta Neuropathol (Berl) 96, 322 328
EGFRvIII Delection of exons 2 to 7 of the EGFR gene In-frame delection of 267 aminoacids of the extracellular domain of the receptor EGFRvIII is unable to bind ligand EGFR signaling is constistutively active EGFRvIII is co-expressed with EGFRwt
EGFRvIII
EGFRvIII Has been clinically correlated with Enhanced tumour cell growth Cell invasion Radiation resistance Huang HS, et al. J Biol Chem 1997;272: 2927 35 Prigent SA, et al. J Biol Chem 1996;271:25639 45
EGFRvIII- mediated tumorigencity EGFRvIII Tyrosine Kinase is constitutively active Binding of ligand to EGFRwt results in rapid internalization of the receptor, followed by dephosphorylation and degradation of the receptor EGFRvIII internalization is slow because it dose not bind ligand Huang HS, et al. J Biol Chem 1997;272: 2927 35
EGFRvIII- mediated tumorigencity EGFRvIII induces the expression of: EGF-HB TGF-alfa Other mitogens: MAP4K4, EPHA2 receptor, IL-8 Autocrine loop generated by EGFRvIII mediated by EGF-HB and TGF-A Hatanpaa KJ, et al. Neoplasia 2010;12: 675
EGFR pathway in GBM Mellinhoff 2005
EGFR TKI Gefitinib (IRESSA, Astra Zeneca) Erlotinib (TARCEVA, Genentech) Small molecules EGFR Tyrosine Kinase inhibitors They bind in a reversible fashion to the ATP binding site of the receptor Active in NSCLC with mutations in the TK domain
EGFR Inhibition
Clinical Trials Recurrent GBM Medscape
Clinical Trials. First line RT + TMZ + Erlotinib Phase I/IIa N= 97 OS = 15,3 months PFS = 7,2 months Ref: Brown PD, et al. J Clin Oncol. 2008;26:5603 5609 Phase II N= 65 OS = 19,3 months PFS = 8 months Prognostic Factor: MGMT and PTEN Ref: Prados MD, et al. J Clin Oncol. 2009;27:579 584
Biomarkers of response Erlotinib and Gefitinib High levels of EGFR and active AKT Phase I trial (Haas-Kogan DA, et al. J Natl Cancer Inst. 2005) EGFRvIII and PTEN Retrospective analysis from patients treated at UCLA (Mellinhoff IK, et al. NEJM 2005)
Biomarkers of response Erlotinib and Gefitinib The markers proposed (EGFRvIII and PTEN) could not be confirmed in subsequet trials included a randomized phase II trial Van Den Bent MJ, at al. JCO 2009 EGFRvIII and PTEN could be prognostic factors?
Gefitinib and Erlotinib in GBM Little activity in GBM despite the solid rationale Reasons for the unexpected low response rate 1. The drug does not reach the tumor 2.- EGFR is not dephosphorylated by the drug 3.- Downstream signaling is independent of EGFR 4.- Drugs have been tested in unselected population
2nd Generation of EGFR TKI Irreversible binding to EGFR Multi HER inhibitors EGFR and HER2 (BIBW2992 = Afatinib) EGFR, HER2, HER4 (PF 299804 = Dacomitinib) Active in gefitinib or erlotinib-resistant NSCLC
Trials ongoing BIBW2992 (Afatinib) BIBW 2992 in recurrent GBM BIBW + TMZ BIBW + RT + TMZ
PF 299804 PF-299804 is a highly selective, pan-her irreversible small molecule inhibitor of most HER family of tyrosine kinases HER1 (EGFR): IC50 6 nm HER2 (ErbB2): IC50 46 nm HER4 (ErbB4): IC50 74 nm EGFRvIII inhibition No activity against panel of other tyrosine or serine threonine kinases
PF 299804 Second generation EGFR TKIs (PF-299804) vs. 1st generation (erlotinib and gefitinib): PF-00299804 is Irreversible vs. gefitinib and erlotinib as a reversible PF-00299804 is a pan-her inhibitor vs. gefitinib and erlotinib as a mono-her inhibitors PF299804 is active in erlotinib and gefitinib-resistant NSCLC PF00299804 has shown preclinical activity in EGFR wild type and mutant disease including EGFRvIII and shows higher potency for EGFRvIII inhibition PF-00299804 appears to have greater potential for blood brain barrier penetration PF-00299804 unlikely to interfere with enzyme-inducing antiepileptic drug therapy
PF 299804 Clinical trials ongoing Haga clic para modificar el estilo de texto del patrón Segundo nivel Tercer nivel Cuarto nivel Quinto nivel
GEINO-11 Open-label Phase 2 trial Experimental Drug: PF 299804 2 cohorts of adult patients with recurrent GBM with EGFR gene amplification or EGFRvIII mutation Cohort A will include 32 patients at first recurrence with EGFRVIII mutations. Cohort B will include 32 patients at first recurrence with EGFR gene amplification but no EGFRVIII mutation Patients will receive continuous daily dose of PF-00299 (45 mg daily) until disease progression, unacceptable toxicity or study end.
CONCLUSIONS Biology supports use of EGFR TKIs ~50% of GBM tumors are amplified for EGFR Predictor of poor prognosis Of EGFR amplified tumors, 50% express EGFRvIII Activity with EGFR TKIs has been modest to date in GBM: First generation reversible EGFR inhibitors including gefitinib and erlotinib showed limited activity for several reasons but mainly because these agents were tested in an unselected population. 2nd generation EGFR could improve results based on their pharmacokinetic and pharmacodynamic properties
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