Table 8. . Summary of Phase II clinical trials utilizing EGFR inhibition for the treatment of recurrent malignant glioma and newly diagnosed glioblastoma.
| Study (year) | Regimen | Patients (n) | Results | Ref. |
|---|---|---|---|---|
| Recurrent malignant glioma studies | ||||
| Rich et al. (2004) | Gefitinib (500 mg q.d., escalated to 750–1000 mg q.d.) | 53 GB | No objective tumor response PFS6: 13%, mPFS 8.1 weeks, mOS 39.4 weeks |
[100] |
| Franceschi et al. (2007) | Gefitinib (250 mg q.d.) | 16 GB 9 AA 3 AO |
PFS: 14.3% (95% CI: 4–32.7%) for the whole cohort. EGFR expression or gene status, and p-Akt expression did not predict activity | [98] |
| Kreisl et al. (2009) | Gefitinib 250 mg q.d. Everolimus 70 mg qweek |
20 GB | 3 PR (14%), PFS6: 5% mPFS 2.6 months, mOS 5.8 months |
[99] |
| de Groot et al. (2008) | Carboplatin (AUC 6 mg x ml/min d1) q28 days Erlotinib (150 mg/day dose escalated to 200 mg/day as tolerated) |
43 GB | PFS6: 14% 1 PR 20 SD mFS 9 weeks, mOS 30 weeks |
[42] |
| van den Bent et al. (2009) | Erlotinib (150 mg/day dose escalated to 200 mg/day (no EIASD) or 300 mg/day dose escalated to 500 mg/day (EIASD) – experimental arm TMZ or Carmustine – control arm |
110 GB | PFS6: 11.4% (95% CI: 4.6–21.5%) – experimental arm 0/8 patients with EGFRvIII mutant presence and PTEN expression had 6-month PFS PFS6: 24% control arm |
[96] |
| Raizer et al. (2010) | Erlotinib (150 mg/day, no EIASD) | 53 recurrent MG | PFS6: 3%, median PFS 2 months for recurrent GB No effect on EGFR or intratumoral signaling was seen |
[95] |
| Reardon et al. (2010) | Erlotinib (150 mg q.d.) Sirolimus (5 mg q.d.) – no EIASD Erlotinib (450 mg q.d.) Sirolimus (10 mg q.d.) – EIASD |
32 GB | No CR or PR PFS6: 3.1% |
[76] |
| Yung et al. (2010) | Erlotinib (150 mg q.d.) – no EIASD Erlotinib (300 mg q.d.) – EIASD |
48 GB | 1 CR, 2 PR, mOS 9.7 months (95% CI: 5.9–11.6 months) PFS6: 20% (95% CI: 10–32.4%) Outcomes not related to EGFR amplification or EIASD status |
[97] |
| Sathornsumetee et al. (2010) | Erlotinib (200 mg/day) – no EIASD Erlotinib (500 mg/day) – EIASD Bevacizumab (10 mg/kg q2 weeks) |
25 GB 32 AG |
PFS6: 28%, mOS 42 weeks – GB PFS6: 44%, mOS 71 weeks – AG Similar PFS benefit and radiographic response as compared with historical bevacizumab-containing regimens |
[81] |
| Hegi et al. (2011) | Gefitinib 500 mg q.d. prior to surgery, then postoperative until recurrence | 22 GB | Resected tissue had high concentrations of gefitinib (median 4.1 µg/g). EGFR was efficiently dephosphorylated in treated patients compared with control No effect on 12 pathway constituents. Thus, regulation of downstream signal transducers in the EGFR pathway seems to be dominated by regulatory circuits independent of EGFR phosphorylation |
[101] |
| Newly diagnosed GB studies | ||||
| Brown et al. (2008) | Erlotinib (150 mg daily) x 1 week, then concurrently with TMZ (75 mg/m2/day) and RT (60 Gy), then concurrently with TMZ (200 mg/m2 5 days every 28 day) | 97 GB | mOS 15.3 months No benefit compared with historical TMZ controls Presence of rash, diarrhea, EGFRvIII, combination EGFR and PTEN, and EGFR amplification status were not predictive of survival |
[102] |
| Prados et al. (2009) | Erlotinib (100 mg/day during RT and 150 mg/day after RT) – non-EIASD Erlotinib (200 mg/day during RT and 300 mg/day after RT) All patients received standard RT/TMZ |
65 GB | mOS 19.3 months | [104] |
| Peereboom et al. (2010) | Erlotinib 50 mg/day, increased by 50 mg/day every 2 weeks until grade 2 rash or maximum Erlotinib 150 mg/day All received standard RT/TMZ |
27 GB | mOS 8.6 months, mPFS 2.8 months | [103] |
| Uhm et al. (2011) | Gefitinib 500 mg/day Gefitinib 1000 mg/day – EIASD or dexamethasone |
100 GB | 1-year OS 54.2% (not statistically different from historical controls) Clinical outcome was not affected by EGFR status (amplification or vIII mutation) |
[105] |
AA: Anaplastic astrocytoma; AG: Anaplastic glioma; AO: Anaplastic oligodendroglioma; CR: Complete response; EIASD: Enzyme-inducing antiseizure drug; GB: Glioblastoma; MG: Malignant glioma; mOS: Median overall survival; mPFS: Median progression-free survival; PFS6: Percentage of patients progression-free at 6 months; PR: Partial response; q2 week: Once every 2 weeks; q.d.: Daily; qweek: One per week; RT: Radiotherapy; SD: Stable disease; TMZ: Temozolomide.