Two small molecule EGFR tyrosine kinase inhibitors have been developed, erlotinib (Tarceva
®, OSI-774, Genentech, Inc, CA, USA) and gefitinib (Iressa
®, ZD1839, AstraZeneca, DE, USA) that have been evaluated for GBM treatment, Table
1. However, monotherapy with neither drug had a clear benefit of prolonged survival. A randomised, controlled phase II study by the European Organisation for Research and Treatment of Cancer (EORTC) failed to show improved radiographic responses or survival benefit of erlotinib. The progression free survival (PFS) was 11.4% for erlotinib
versus 24% (temozolomide/carmustine) in 110 patients with progressive GBM [
34]. It has previously been reported that GBM patients exhibiting amplification or over-expression of EGFR responded better to erlotinib than patients with normal EGFR levels [
35]. The response was however, highly dependent on low levels of AKT activation. This is supported by the finding that co-expression of wild-type (wt) PTEN with EGFRvIII predicted radiographic responses in patients treated with gefitinib or erlotinib [
36], indicating that when AKT phosphorylation is a direct result of increased EGFR activity, treatment with EGFR inhibitors might result in better clinical responses. However, the EORTC study [
34] found neither the expression of EGFR, EGFRvIII nor PTEN to be correlated with a survival advantage, and actually both progression free survival and overall survival was worse for the patients exhibiting EGFRvIII treated with erlotinib. The association of particular mutations in the EGFR kinase regions with improved clinical and radiographic responses after gefitinib treatment previously reported in lung cancer patients [
37] has not been demonstrated in GBM patients [
38]. However, a phase I study of 83 glioma patients treated with either erlotinib alone or in combination with temozolomide, showed that 5 GBM patients (median age 50.2 years) had stable disease that lasted longer than 12 weeks (4 treated with erlotinib alone and 1 treated with erlotinib in combination with temozolomide). Of these patients 3 had PFS greater than 6 months [
39]. A small phase II, single institution study of erlotinib plus temozolmide before and after radiation in 65 patients with newly diagnosed GBM and gliosarcoma and stratified for MGMT promoter methylation, showed an increased median survival of 19.3 months compared to 14.1 months of historical controls [
40]. They found a survival benefit for patients whose tumours were both MGMT promoter hypermethylated and PTEN positive indicating that lack of survival signalling benefits therapy response in the absence of DNA repair. Another phase I/II study (N0177) comparing erlotinib combined with temozolomide and radiotherapy for 97 newly diagnosed GBM patients achieved no additional benefit for erlotinib in the combination compared to historical, EORTC 26981 as control studies [
41]. Similarly, A phase II study of 27 GBM patients receiving similar doses of erlotinib in combination with radiotherapy and temozolomide had to be terminated prematurely after accrual of 27 of 30 patients due to lack of efficacy and unacceptable toxicity [
42]. Sources of discrepancies among these studies include technical variability of EGFR biomarker assessment. In many studies, biopsy samples obtained at the time of primary surgery are used to characterise EGFR levels but the molecular characteristics of the tumour after recurrence are not always the same. Unfortunately, it is often not feasible to obtain new biopsies from recurrent GBM patients, rendering this a persistent challenge in targeted therapies. Although EGFR is important for activation of PI3K/AKT, numerous other RTK are co-activated in GBM cells [
43], [
44], [
45] and treatment with single tyrosine kinase inhibitors like erlotinib may not be sufficient to decrease survival signalling. It has been demonstrated that PDGFR and c-MET receptors are engaged after EGFR inhibition and maintain downstream pathway activation [
46]. This suggests that carefully designed inhibitor combinations with limited toxicity profiles and maximal additive or synergistic effects may provide more beneficial therapeutic effects [
47]. Another source for antagonism is that EGFR inhibitors cause G1 cell cycle arrest, making cells less sensitive to the cell cycle dependent effects of radiotherapy and temozolomide. Temozolomide causes cell cycle arrest in G2-M [
48], so erlotinib and gefitinib prevent cells from progressing beyond G1 and may therefore compromise the activity of other cell cycle-specific agents. The EORTC study [
34] included a randomised control arm of patients treated with either BCNU or temozolomide that allowed the distinction between prognostic and predictive markers for outcome. It has been suggested that the association between increased progression free survival and EGFR molecular characteristics may simply reflect the prognostic, and not the predictive relevance of the mutations [
49]. The low molecular weights of these inhibitors should enable them to cross the blood brain barrier, however they do so in insufficient concentrations and this may be a further source of variation in the studies [
50,
51]. Both gefitinib and erlotinib are metabolised by CYP3A4 enzymes and drug levels determined by pharmacokinetic measures drop significantly in patients taking enzyme-inducing anti-epileptics (EIAEDs). Although the low toxicity observed suggests that greater doses may be tolerated, it may be difficult to standardise the amounts of active drug in these patients Surrogate markers of systemic anti-EGFR activity such as development of rash or diarrhoea do not define activity in the tumour, but may represent a minimal level of activity and have been correlated with treatment response in some trials [
34,
52,
53]. However, the lack of availability of tumour tissue post treatment for validation of target inhibition results in uncertainties regarding the sufficient inhibition of the EGFR signalling.
Table 1
Summary of clinical trials targeting survival and apoptosis pathways in GBM
EGFR
| Erlotinib | Randomised, controlled, phase II #26032 | 110 Recurrent GBM | 6-month PFS: 11.4% vs 24% control, Low akt borderline significance | |
| Erlotinib (+RT+TMZ) | Phase I/II cf historical controls #N0177 | 97 newly diagnosed GBM | Median survival 15.3 months, no benefit at OS | |
| Erlotinib (+RT +TMZ) | Phase II cf historical controls | 65 newly diagnosed GBM/gliosarcoma | Median survival 19.3 months vs 14.1 controls, positive correlation MGMT methylation with survival and MGMT methylation + PTEN positivity with improved survival | |
| Erlotinib (+RT +TMZ) | Phase II | 27 newly diagnosed GBM | OS 8.6 months median PFS 2.8 months | |
| Erlotinib (+RT+TMZ) | Phase II #NCT00187486 | Newly diagnosed GBM/gliosarcoma | | |
| Erlotinib single-agent | Phase II open-label, multicenter #NCT00337883 | First Relapse GBM | | |
| Gefitinib | Phase II | 53 Recurrent GBM | 31 patients had radiographic progressive disease within the first 2 months, 51 progressed eventually median EFS: 8.1 weeks | |
| Erlotinib +RT+TMZ) | Phase II #NCT00274833 | Newly diagnosed GBM | | |
Akt
| Perifosine | Phase II #NCT00590954 | Recurrent/progressive Malignant Gliomas | | |
| Perifosine and Temsirolimus | Phase I/II #NCT01051557 | Recurrent/progressive Malignant Glioma | | |
| Nelfinavir (+TMZ +RT) | Phase I/II #NCT00694837 | Newly diagnosed GBM | | |
PI3K/mTOR
| XL765 +TMZ | Phase I #NCT00704080 | Adults Malignant Gliomas | | |
mTOR
| Temsirolimus (CCI-779) | Phase II | 65 Recurrent GBM | 6-month PFS: 7.8% median OS 4.4 months, high levels phospho p70s6K appear to predict benefit of treatment | |
| Temsirolimus | Phase II | 43 Recurrent GBM | No evidence of efficacy, 1 patient PF at 6-month: 2 PR, 20 SD, median time to progression 9 weeks | |
| Temsirolimus (+TMZ+RT) | Phase I #NCT00316849 | newly diagnosed GBM | | |
| Temsirolimus (+ Erlotinib+ Tipifarnib) | Phase I/II #NCT00335764 | recurrent GBM/gliosarcoma. | | |
| Everolimus + gefitinib | Phase I/II #NCT00085566 | Progressive GBM | | |
| Everolimus | Phase I/II Pilot, Multicenter #NCT00515086 | Recurrent GBM | Completed, Decemeber 2009 | |
| Everolimus +AEE788 | Phase IB/II multicenter, two-Arm, dose-escalation | Recurrent GBM | | |
Bcl-2
| Gossypol | Phase II #NCT00540722 | Recurrent GBM | | |
| Gossypol (AT-101) +RT +TMZ vs AT-101 +Adjuvant TMZ | Phase I non-randomised #NCT00390403 | Newly diagnosed GBM | Completed, June 2009 | |