Table 1.
A summary of efficacy, toxicity, and tissue analysis in clinical studies with small molecule kinase inhibitors in adult patients with newly diagnosed and progressive glioblastoma.
| Kinase target | First author | Year | Reference(s) | Total no. of patients in the study | No. of patients in evaluated population |
Study design | Therapy | CR (%) | PR (%) | OR (%) | mPFS | PFS6 (%) | mOS | OS12 (%) | Toxicity as no. of grade 3, 4, or 5 events in no. of evaluable patients | Tissue analysis to predict responsee | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Newly diagnosed |
Progressive |
||||||||||||||||||
| GB | AG | GB | AG | ||||||||||||||||
| Baseline studies | |||||||||||||||||||
| Stupp | 2005 | 7 | 573 | 286 | III | rth | — | — | — | 5 | 9 | 12.1 | 51 | — | NA | ||||
| Stupp | 2005 | 7 | 573 | 287 | III | rth + tmz | — | — | — | 6.9 | 27 | 14.6 | 61 | 75 in 284 | NA | ||||
| Athanassiou | 2005 | 60 | 130 | 57 | r II | rth | — | — | — | 5.2 | 45 | 7.7 | 16 | — | NA | ||||
| Athanassiou | 2005 | 60 | 130 | 53 | r II | rth + tmz | — | — | — | 10.8 | 67 | 13.4 | 56 | 6 in 110 | NA | ||||
| Brada | 2001 | 61 | 138 | 138 | II | tmz | 2 | 6 | 8 | 2.1 | 18 | 5.4 | 15 | 60 in 138 | NA | ||||
| Yung | 2000 | 62 | 225 | 112 | r II | tmz | 0 | 5 | 5 | 3 | 21 | 7.1 | 22 | 26 in 110 | NA | ||||
| Yung | 2000 | 62 | 225 | 113 | r II | Procarbazine | 0 | 5 | 5 | 2.1 | 8 | 5.6 | 18 | 26 in 110 | NA | ||||
| Wong | 1999 | 63 | 375 | 225 | d | Various salvage treatments without tmz, without kinase inhibitors | — | — | 6 | 2.3 | 15 | 6.3 | 21 | — | NA | ||||
| Single target small molecule inhibitors | |||||||||||||||||||
| EGFR | |||||||||||||||||||
| Van den Bent | 2009 | 45,64,65 | 54 | 54 | r II | Erlotinib 150–500 mg pod vs tmz or carmustine | 0 | 4 | 4 | 1.8 | 11 | 7.7 | 22 | 13 in 54 | ihc: EGFR EGFRvIII* PTEN pAKT; fish: EGFR; mut: EGFR | ||||
| Preusser | 2008 | 44 | 21 | 14 | 7 | RObs | Erlotinib 100–150 mg pod or Gefitinib 250 mg pod | 0 | 14 | 14 | 3.1 | 19 | 5.1 | 5 | 1 in 21 | ihc: EGFR EGFRvIII PTEN pAKT | |||
| Franceschi | 2007 | 42 | 16 | 16 | II | Gefitinib 250 mg pod | 0 | 0 | 0 | 2.1 | 13 | 6.2 | 14 | 5 in 28 | ihc: EGFR pAKT; fish: EGFR | ||||
| Buie | 2007 | 66 | 6 | 6 | I | Erlotinib 450–900 mg every 3 days | 0 | 17 | 17 | — | — | — | — | 0 in 6 | None | ||||
| Mellinghoff | 2006 | 46 | 49 | 49 | II | Erlotinib 150–500 mg pod or Gefitinib 250–1000 mg pod | 0 | 18a | 18 | — | — | — | — | — | ihc: EGFRvIII* PTEN*; fish: EGFR; mut: EGFR, HER2, PTEN; pcr: EGFR EGFRvIII | ||||
| Haas-Kogan | 2005 | 43 | 52 | 29 | I | Erlotinib dosage unavailable | 0 | 17 | 17 | — | — | — | — | — | ihc: EGFR* EGFRvIII pAKT*; fish: EGFR*; mut: EGFR PTEN | ||||
| Cloughesy | 2005 | 67,68 | 48 | 48 | II | Erlotinib 150–300 mg pod | 2 | 6 | 8 | — | 17 | — | — | — | ihc: EGFR EGFRvIII PTEN; fish: EGFR | ||||
| Rich | 2004 | 31,69 | 57 | 57 | II | Gefitinib 500–1000 mg pod | 0 | 0 | 0 | 2 | 13 | 9.9 | 36 | 27 in 55 | ihc: EGFR EHGRvIII; pcr: EGFR | ||||
| Uhm | 2004 | 70 | 96 | 96 | II | Gefitinib 500–1000 mg pod | — | — | — | 6.8 | 62 | 12.8 | 54 | 21 in 63 | ihc: EGFR EGFRvIII; fish: EGFR | ||||
| Raizer | 2004 | 71 | 45 | 31 | II | Erlotinib 150 mg pod | 0 | 0 | 0 | 2.3 | 0 | — | — | — | None | ||||
| Lieberman | 2004 | 72 | 65 | 38 | I/II | Gefitinib 250–1000 mg pod | 0 | 13 | 13 | 2 | 9 | — | — | — | None | ||||
| Vogelbaum | 2004 | 18,73,74 | 31 | 16 | II | Erlotinib 150 mg pod | 0 | 25 | 25 | 5.2 | — | — | — | — | fish: EGFR | ||||
| Peery | 2003 | 75 | 57 | 52 | II | Gefitinib 500–1000 mg pod | 0 | 2 | 2 | — | — | — | — | 10 in 52 | ihc: EGFR EGFRvIII; pcr: EGFR | ||||
| mTOR | |||||||||||||||||||
| Cloughesy | 2008 | 39 | 15 | 15 | I | Rapamycin 2–10 mg pod | 0 | 7 | 7 | 3.6 | — | — | — | 7 in 15 | ihc: pS6K pAKT pPRAS40* | ||||
| Galanis | 2005 | 27 | 65 | 65 | II | Temsirolimus 250 mg ivw | 0 | 0 | 0 | 2.3 | 8 | 4.4 | — | 40 in 65 | ihc: PTEN S6K pS6K* AKT pAKT; fish: EGFR PTEN; act: S6K | ||||
| Chang | 2005 | 26,76 | 43 | 43 | II | Temsirolimus 170–250 mg ivw | 0 | 5 | 5 | 2.3 | 2 | — | — | 49 in 43 | None | ||||
| Chang | 2004 | 77 | 12 | 9 | I | Temsirolimus 250–330 mg ivw | 0 | 0 | 0 | — | — | — | — | 4 in 12 | None | ||||
| VEGFR | |||||||||||||||||||
| FLT1/KDR | Batchelor | 2007 | 17 | 16 | 16 | II | Cediranib 45 mg pod | 0 | 56 | 56 | 4 | 30 | 7.5 | — | 9 in 16 | ihc: VEGFR1 VEGFR2 VEGFR3 PDGFRα PDGFRβ; plasma: VEGF PIGF* sVEGFR2* bFGF* SDF1α* | |||
| KDR | Conrad | 2004 | 28,78–80 | 55 | 55 | I/II | Vatalanib 150–2000 mg pod | 0 | 4 | 4 | 2.5 | 25 | — | — | 10 in 45 | None | |||
| PKCβ | |||||||||||||||||||
| Kreisl | 2009 | 81 | 26 | 17 | 9 | I | Enzastaurine 500–1000 mg pod | 4 | 4 | 8 | 1.4 | — | 5.7 | — | 9 in 22 | Plasma: Pgsk3β | |||
| Fine | 2008 | 34,82–84 | 266 | 174 | III | Enzastaurine 500 mg pod vs lomustine | 0 | 3 | 3 | 1.5 | 11 | 6.6 | 15 | 14 in 167 | None | ||||
| Fine | 2005 | 85,86 | 85 | 57 | II | Enzastaurine 500 mg pod | 0 | 18 | 18 | — | — | — | — | 3 in 85 | None | ||||
| Multitarget small molecule inhibitors | |||||||||||||||||||
| PDGFR/KIT/ABL | |||||||||||||||||||
| Raymond | 2008 | 87–89 | 112 | 51 | II | Imatinib 600–1000 mg pod | 0 | 6 | 6 | 1.8 | 16 | 5.9 | — | 34 in 112 | mut: KIT PDGFRα PDGFRβ ABCG2 | ||||
| Razis | 2007 | 90 | 20 | 19 | 1 | PD | Imatinib 800 mg pod | 0 | 0 | 0 | — | — | 6.2 | — | — | ihc: AKT MAPK p27 EGFR PDGFR | |||
| Viola | 2007 | 21 | 20 | 18 | 2 | II | Imatinib 800 mg pod | 0 | 0 | 0 | 7.8 | 52 | — | — | 0 in 20 | ihc: PDGFRα PDGFRβ | |||
| Wen | 2006 | 41,91,92 | 55 | 34 | I/II | Imatinib 800 mg pod | 0 | 6 | 6 | — | 3 | — | — | 35 in 55 | pcr: EGFR EGFRvIII; mut: PTEN PDGFRα PDGFRβ | ||||
| Marosi | 2006 | 20 | 34 | 23 | 11 | II | Imatinib 400 mg pod | 0 | 18 | 18 | 9.5 | 33 | 12.3 | 45 | 0 in 34 | ihc: PDGFRα PDGFRβ KIT ABL | |||
| Franceschi | 2005 | 93 | 28 | 16 | II | Imatinib 250 mg pod | 0 | 0 | 0 | 2 | 13 | 6.1 | 14 | 5 in 28 | None | ||||
| KIT/PDGFR/KDR/FLT3/RET | |||||||||||||||||||
| Chaskis | 2008 | 94 | 12 | 7 | 5b | II | Sunitinib 37.5 mg pod | 0 | 8 | 8 | — | — | — | — | 5 in 12 | None | |||
| EGFR/VEGFR | |||||||||||||||||||
| Kreisl | 2008 | 95 | 32 | 32 | II | Vandetanib 300 mg pod | 0 | 16 | 16 | — | — | — | — | 11 in 32 | None | ||||
| KDR/FLT1/PDGFR/FLT3/RET/KIT | |||||||||||||||||||
| Reardon | 2008 | 96 | 16 | 16 | II | Sorafenib 400 mg pod + tmz | 0 | 0 | 0 | — | — | — | — | 7 in 16 | None | ||||
| Combination therapy | |||||||||||||||||||
| EGFR + mTOR | |||||||||||||||||||
| Kreisl | 2009 | 36 | 22 | 22 | I/II | Gefitinib 250 mg pod + everolimus 70 mg ivw | 0 | 14 | 14 | 2.6 | 5 | — | — | 21 in 22 | ihc: EGFR PTEN pAKT pS6K EGFRvIII | ||||
| Friedman | 2008 | 97 | 27 | 27 | II | Erlotinib 150–500 mg pod + Rapamycin 5–10 mg pod | 0 | 0 | 0 | — | — | — | — | 6 in 27 | None | ||||
| Phuphanich | 2008 | 19 | 18 | 18 | I | Gefitinib 250–1000 mg pod + rapamycin 2–6 mg pod | 0 | 0 | 0 | 5 | — | 9.4 | — | 6 in 18 | None | ||||
| Reardon | 2006 | 24 | 34 | 29 | 5 | I | Gefitinib 500–750 mg pod + rapamycin 5–10 mg pod | 0 | 6 | 6 | 2.1 | 24 | — | — | 36 in 32 | ihc: pMAPK pS6K pAKT PTEN EGFR; fish: EGFR PTEN | |||
| Doherty | 2006 | 23 | 28 | 22 | RObs | Gefitinib 500 mg pod + rapamycin 4 mg pod | 0 | 18 | 18 | 3 | 25 | — | — | 3 in 28 | None | ||||
| Badruddoja | 2006 | 98 | 21 | 18 | I/II | Gefitinib 500–1500 mg pod + rapamycin 2 mg pod | 0 | 0 | 0 | 3 | 17 | — | — | 8 in 18 | None | ||||
| Nguyen | 2006 | 99 | 19 | 19 | I/II | Gefitinib 250 mg pod + everolimus 30–70 mg ivw | 0 | 11 | 11 | 2.6 | 5 | 6.5 | — | — | None | ||||
| EGFR + conventional therapy | |||||||||||||||||||
| Prados | 2009 | 32,100 | 65 | 65 | II | Erlotinib 100–300 mg pod + tmz | — | — | — | 8.2 | 72 | 19.3 | 68 | 48 in 65 | ihc: EGFR EGFRvIII PTEN*; fish: EGFR; pcr: MGMT* | ||||
| Schwer | 2009 | 25 | 15 | 11 | 4 | I | Gefitinib 250 mg pod + radiosurgery | — | — | — | — | 53 | 10 | — | — | None | |||
| Brown | 2008 | 101 | 97 | 97 | II | Erlotinib 150 mg pod+ tmz + rth | — | — | — | 7.2 | — | 15.3 | 61 | — | ihc: EGFR EGFRvIII PTEN p53; fish: EGFR | ||||
| De Groot | 2008 | 37,102 | 44 | 43 | II | Erlotinib 150–200 mg pod + carboplatin | 0 | 2 | 2 | 2 | 13 | 7.5 | — | 82 in 43 | ihc: EGFR EGFRvIII pAKT PTEN | ||||
| Chakravarti | 2006 | 103–106 | 178 | 178 | I/II | Gefitinib 500 mg pod + rth | — | — | — | 5.1 | — | 11 | — | — | ihc: EGFRvIII PTEN | ||||
| Prados | 2006 | 107,108 | 83 | 60 | I | Erlotinib 100–500 mg pod + tmz | 0 | 8 | 8 | 2 | 7 | — | — | 36 in 83 | None | ||||
| Krishnan | 2006 | 109 | 19 | 19 | I | Erlotinib 100–200 mg pod + rth | 0 | 0 | 0 | 6 | — | 13.8 | — | 5 in 20 | None | ||||
| Brewer | 2006 | 33,38,110 | 28 | 28 | II | Erlotinib 50–150 mg pod + tmz + rth | 0 | 0 | 0 | 3.6 | — | — | — | 40 in 27 | Fish: EGFR | ||||
| PDGFR/KIT/ABL + hydroxyurea | |||||||||||||||||||
| Shah | 2007 | 33 | 16 | 11 | 5 | RObs | Imatinib 400–500 mg pod + hydroxyurea | 0 | 21 | 21 | — | — | 10 | — | 8 in 16 | None | |||
| Dresemann | 2008 | 111,112 | 240 | 120 | III | Imatinib 600 mg pod + hydroxyurea vs hydroxyurea | 0 | 2 | 2 | 1.6 | 5 | — | — | — | None | ||||
| Dresemann | 2008 | 35,113 | 30 | 30 | II | Imatinib 600 mg pod + hydroxyurea | 0 | 13 | 13 | — | 60 | — | 67 | 4 in 30 | None | ||||
| Dresemann | 2006 | 29 | 30 | 30 | RObs | Imatinib 400–600 mg pod + hydroxyurea | 3 | 17 | 20 | 2.5 | 32 | 4.8 | 25 | 0 in 30 | None | ||||
| Reardon | 2005 | 22,114–116 | 33 | 33 | II | Imatinib 400–500 mg pod + hydroxyurea | 3 | 6 | 9 | 3.6 | 27 | 12.2 | — | 14 in 33 | None | ||||
| Others | |||||||||||||||||||
| KDR + PDGFR/KIT/ABL | Kirkpatrick | 2008 | 30 | 37 | 34 | 3 | I | Vatalanib 2000 mg pod + imatinib 'standard dose' + hydroxyurea | 0 | 22 | 22 | — | 27 | — | — | — | None | ||
| EGFR + VEGF | Sathornsumetee | 2008 | 16,117,118 | 25 | 25 | II | Erlotinib 200–650 mg pod + bevacizumab | — | — | 48 | — | 24 | — | — | — | None | |||
| EGFR + SRC | Reardon | 2008 | 119 | 15 | 13 | 2 | I | Erlotinib 150–450 mg pod + dasatinib 100 mg pod | 0 | 0 | 0 | — | — | — | — | 1 in 15 | None | ||
| KIT/PDGFR/KDR/FLT/RET | Wuthrick | 2008 | 120 | 10 | 10 | I | Sunitinib 37.5 mg pod + rth | 0 | 10 | 10 | — | — | — | — | 1 in 10 | None | |||
| KDR + PDGFR/KIT/ABL | Sathornsumetee | 2007 | 121 | 35 | 35 | I | Vatalanib 500–1000 mg pod + imatinib 400–500 mg pod + hydroxyurea | 0 | 29 | 29 | — | — | — | — | 4 in 35 | None | |||
| KDR/FLT1/PDGFR + EGFR/HER2 | Reardon | 2007 | 122 | 32 | 32 | II | Pazopanib 400 mg pod + lapatinib 1000 mg pod | 0 | 0 | 0 | — | — | — | — | 10 in 75 | ihc: PTEN EGFRvIII | |||
| PDGFR/KIT/ABL | Sathornsumetee | 2006 | 123 | 56 | 46 | 10c | I | Imatinib unavailable dose + tmz | 0 | 7 | 7 | — | — | — | — | 5 in 56 | None | ||
| PDGFR/KIT/ABL + mTOR | Desjardins | 2006 | 124 | 28 | 28 | I | Imatinib 400 mg pod + hydroxyurea + everolimus 2.5 mg ivd | 0 | 4 | 4 | — | — | — | — | 1 in 5 | None | |||
| KDR | Reardon | 2004 | 125,126 | 60 | 60 | I/II | Vatalanib 500–1500 mg pod + tmz or lomustine | 0 | 7 | 7 | 3.5 | 15 | — | — | 3 in 60 | None | |||
Abbreviations: rII, randomized phase II study; Robs, retrospective observational study; PD:, pharmacodynamic study; tmz, temozolomide 150–200 mg/m2 po 5 days/28 days; rth, radiotherapy; pod, per os daily; ivw, intravenous weekly; ivd, intravenous daily; CR, complete response; PR, partial response; mPFS, median progression-free survival; PFS6: progression-free survival at 6 months; mOS, median overall survival; OS12, overall survival at 12 months; ihc, immunohistochemistry to determine protein expression; fish, fluorescence in situ hybridization to determine gene amplification; mut, sequencing analysis to determine gene mutation; pcr, PCR to determine gene copy number or gene expression; act, kinase activity assay to determine protein activity; plasma, plasma protein concentration analysis; na, not applicable. For comparison, baseline studies with conventional therapies are listed. Studies are categorized by single-target inhibitors, multitarget inhibitors, and combination therapies; subcategorized by kinase drug target; and sorted by year of publication and number of patients.
aPartial response defined as > 25% decrease of bidirectional area.
bIncluding 4 progressive low-grade gliomas.
cIncluding 1 pleiomorph xanthoastrocytoma.
dPrognosis study with data from 8 phase II trials.
eTissue analysis results that are significantly correlated with efficacy are marked with an asterisk.