Table 1. . Targeted therapies in high-grade gliomas.

Study	Year	Setting	N	Design	Findings	Ref.
EGF inhibition
Rich et al.	2004	Recurrent glioblastoma	57	Phase II trial Gefitinib 500–1000-mg daily	ORR: 0% PFS-6: 13%	[60]
Neyns et al.	2009	Recurrent glioblastoma or anaplastic glioma	55	Phase II trial Cetuximab 250 mg/m2 weekly	ORR: 6% PFS-6: 9%	[61]
van den Bent et al.	2009	Recurrent glioblastoma	110	Phase II trial 1. Erlotinib 150–200-mg daily 2. Temozolomide 150–200 mg/m2 D1–5 q4w or carmustine 60–80 mg/m2 D1–3 q8w	ORR: 4 vs 10% PFS-6: 11 vs 24%	[62]
Li et al.	2010	Newly diagnosed glioblastoma	192	Phase II trial Temozolomide chemoradiotherapy + mAb 425	mOS: 15.7 m	[63]
Peereboom et al.	2013	Recurrent glioblastoma	56	Phase II trial Erlotinib 150 mg daily + sorafenib 400 mg twice-daily	ORR: 5% PFS-6: 14%	[64]
Reardon et al.	2015	Recurrent glioblastoma	119	Phase II trial 1. Afatinib 40 mg daily + temozolomide 75 mg/m2 D1–21 q4w 2. Afatinib 40 mg daily 3. Temozolomide 75 mg/m2 D1–21 q4w	ORR: 14 vs 14 vs 21% PFS-6: 10 vs 3 vs 23%	[65]
Westphal et al.	2015	Newly diagnosed glioblastoma	149	Phase III trial 1. Temozolomide chemoradiotherapy + nimotuzumab 2. Temozolomide chemoradiotherapy	mPFS: 7.7 vs 5.8 m mOS: 22.3 vs 19.6 m	[66]
EGF antibody drug conjugate
Gan et al. (abstract)	2014	Recurrent glioblastoma	12	Phase I trial ABT-414	ORR: 33%	[67]
Reardon et al.	2016	Newly diagnosed glioblastoma	45	Phase I trial Temozolomide chemoradiotherapy + ABT-414	mPFS: 6.1 m mOS: not reached	[68]
EGF peptide vaccine
Schuster et al.	2015	Newly diagnosed glioblastoma expressing EGFRvIII	65	Phase II trial Temozolomide chemoradiotherapy + rindopepimut	mPFS: 9.2 m mOS: 21.8 m	[54]
Reardon et al. (abstract)	2015	Recurrent glioblastoma expressing EGFRvIII	72	Phase II trial 1. Rindopepimut + bevacizumab 2. Bevacizumab	ORR: 24 vs 17% PFS-6: 27 vs 11% mOS: 12.0 vs 8.8 m	[56]
Weller et al. (abstract)	2016	Newly diagnosed glioblastoma expressing EGFRvIII	745	Phase III trial 1. Temozolomide chemoradiotherapy + rindopepimut 2. Temozolomide chemoradiotherapy	Minimal residual disease mOS: 20.1 vs 20.0 m Nonminimal residual disease mOS: 14.8 vs 14.1 m	[55]
VEGF inhibition
Batchelor et al.	2010	Recurrent glioblastoma	31	Phase II trial Cediranib 45-mg daily	ORR: 27% PFS-6: 26%	[69]
Iwamoto et al.	2010	Recurrent glioblastoma	35	Phase II trial Pazopanib 800-mg daily	ORR: 6% PFS-6: 3%	[70]
de Groot et al.	2011	Recurrent glioblastoma or anaplastic glioma	58	Phase II trial Aflibercept 4 mg/kg q2w	Glioblastoma ORR: 18% PFS-6: 8% Anaplastic glioma ORR: 44% PFS-6: 25%	[71]
Pan et al.	2012	Recurrent glioblastoma or anaplastic glioma	30	Phase II trial Sunitinib 50-mg daily D1–28 q6w	Glioblastoma ORR: 0% PFS-6: 17% Anaplastic glioma ORR: 0% PFS-6: 22%	[72]
Kreisl et al.	2012	Recurrent glioblastoma or anaplastic glioma	64	Phase II trial Vandetanib 300-mg daily	Glioblastoma ORR: 13% PFS-6: 7% Anaplastic glioma ORR: 7% PFS-6: 7%	[73]
Muhic et al.	2013	Recurrent glioblastoma	25	Phase II trial Nintedanib 200 mg twice-daily	ORR: 0% PFS-6: 4%	[74]
Reardon et al.	2013	Recurrent glioblastoma	41	Phase II trial Pazopanib 400-mg daily + lapatinib 1000-mg daily	PTEN/EGFRvIII positive PFS-6: 0% PTEN/EGFRvIII negative PFS-6: 15%	[75]
Kreisl et al.	2013	Recurrent glioblastoma	63	Phase II trial Sunitinib 37.5-mg daily	Bevacizumab naive PFS-6: 10% Bevacizumab resistant PFS-6: 0%	[76]
Batchelor et al.	2013	Recurrent glioblastoma	325	Phase III trial 1. Cediranib 20-mg daily + lomustine 110 mg/m2 q6w 2. Cediranib 30-mg daily 3. Placebo + lomustine 110 mg/m2 q6w	ORR: 17 vs 15 vs 9% PFS-6: 35 vs 25 vs 16 mPFS: 4.1 vs 3.0 vs 2.7 m mOS: 9.4 vs 8.0 vs 9.8 m	[77]
PDGF inhibition
Lassman et al.	2011	Recurrent glioblastoma with overexpression of dasatinib molecular targets	50	Phase II trial Dasatinib 100 mg twice-daily	ORR: 0% PFS-6: 6%	[78]
mTOR inhibition
Chang et al.	2005	Recurrent glioblastoma	43	Phase II trial Temsirolimus 250-mg intravenously weekly	ORR: 5% PFS-6: 2%	[79]
Galanis et al.	2005	Recurrent glioblastoma	65	Phase II trial Temsirolimus 250-mg intravenously weekly	ORR: 36% PFS-6: 8%	[80]
Kreisl et al.	2009	Recurrent glioblastoma	22	Phase II trial Everolimus 70-mg weekly + gefitinib 250-mg daily	ORR: 14% PFS-6: 0%	[81]
PI3K inhibition
Pitz et al.	2015	Recurrent glioblastoma	33	Phase II trial Sonolisib 8-mg daily	ORR: 3% PFS-6: 17%	[82]
PKC inhibition
Kreisl et al.	2010	Recurrent glioblastoma or anaplastic glioma	118	Phase II trial Enzastaurin 500–525-mg daily	Glioblastoma ORR: 30% PFS-6: 7% Anaplastic glioma ORR: 15% PFS-6: 16%	[83]
Wick et al.	2010	Recurrent glioblastoma	266	Phase III trial 1. Enzastaurin 500-mg daily q6w 2. Lomustine 100–130 mg/m2 q6w	ORR: 3 vs 4% PFS-6: 11 vs 19% mPFS: 1.5 vs 1.6 m mOS: 6.6 vs 7.1 m	[84]
c-Met inhibition
Wen et al. (abstract)	2010	Recurrent glioblastoma	124	Phase II trial Cabozantinib 125–175-mg daily	PFS-6: 21%	[85]
Wen et al.	2011	Recurrent glioblastoma	61	Phase II trial Rilotumumab 10–20 mg/kg q2w	ORR: 0%	[86]
Integrin inhibition
Reardon et al.	2008	Recurrent glioblastoma	81	Phase II trial 1. Cilengitide 500 mg twice-weekly 2. Cilengitide 2000 mg twice-weekly	ORR: 5 vs 13% PFS-6: 10 vs 15%	[87]
Gilbert et al.	2012	Recurrent glioblastoma undergoing surgery	30	Phase II trial Cilengitide 2000 mg twice-weekly	PFS-6: 12%	[88]
Stupp et al.	2014	Newly diagnosed glioblastoma with MGMT promoter methylation	545	Randomized Phase III trial 1. Temozolomide chemoradiotherapy + cilengitide 2000 mg twice-weekly 2. Temozolomide chemoradiotherapy	mPFS: 13.5 vs 10.7 m mOS: 26.3 vs 26.3 m	[89]
Microtubule inhibition
Stupp et al.	2011	Recurrent glioblastoma	38	Phase II trial Sagopilone 16 mg/m2 q3w	ORR: 0% PFS-6: 7%	[90]
Chamberlain et al.	2014	Recurrent glioblastoma	56	Phase II trial Verubulin 3.3 mg/m2 D1, 8, 15 q4w	Bevacizumab naive PFS-6: 14% Bevacizumab resistant PFS-6: 8%	[91]
Histone deacetylase inhibition
Galanis et al.	2009	Recurrent glioblastoma	66	Phase II trial Vorinostat 200 mg twice-daily D1–14 q3w	ORR: 3% PFS-6: 15%	[92]
Friday et al.	2012	Recurrent glioblastoma	37	Phase II trial Vorinostat 400-mg daily D1–14 q3w + bortezomib 1.3 mg/m2 D1, 4, 8, 11 q3w	ORR: 3% PFS-6: 0%	[93]
Lee et al.	2015	Recurrent glioblastoma or anaplastic glioma	39	Phase II trial Panobinostat 30 mg D1, 3, 5 q2w + bevacizumab 10 mg/kg q2w	Glioblastoma ORR: 29% PFS-6: 30% Anaplastic glioma ORR: 27% PFS-6: 47%	[94]
TGF-β inhibition
Brandes et al.	2016	Recurrent glioblastoma	158	Phase II trial 1. Galunisertib 150 mg twice-daily D1–14 q4w + lomustine 100–130 mg/m2 q6w 2. Galunisertib 150 mg twice-daily D1–14 q4w 3. Placebo + lomustine 100–130 mg/m2 q6w	ORR: 1 vs 5 vs 0% PFS-6: 6 vs 15 vs 6% mPFS: 2 vs 2 vs 2 m mOS: 6.7 vs 8.0 vs 7.5 m	[95]
XPO inhibition
Mau-Sørensen (abstract)	2016	Recurrent glioblastoma	35	Phase II trial 1. Selinexor 50 mg/m2 twice-daily ×3, then surgery 2. Selinexor 50 mg/m2 twice-daily 3. Selinexor 60 mg twice-daily 4. Selinexor 80-mg daily	Pooled results ORR: 11% PFS-6: 15%	[96]

D#: Day #; EGFRvIII: EGFR variant III; m: Month; mAb: Monoclonal antibody; MGMT: O6-methylguanine-DNA methyltransferase; mOS: Median overall survival; mPFS: Median progression-free survival; N: Number; ORR: Objective response rate; PFS-6: Progression-free survival rate at 6 months; PTEN: Phosphate and tensin homolog; q8w: Every # weeks; XPO: Exportin-1.