Download Is there a role for EGFR Tyrosine Kinase Inhibitors in recurrent

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
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 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
 Thank you very much for your attention