Table 1.

Epidermal growth factor receptor (EGFR)-targeted therapies for adult high-grade gliomas currently in investigational and/or clinical use.

Therapeutic Agent	Mechanism	Results	Reference
Afatinib (Tovok, BIBW2992)	Second-generation EGFR inhibitor	As a single agent, Afatinib proved good safety, but limited activity on GBM patients. It was promising in combination with TMZ in a case report.6 months progression-free survival (PFS) worse than TMZ: Afatinib alone 3% vs. Afatinib + TMZ 10% vs. TMZ alone 23% Ongoing clinical trials: NCT02423525	[79]
Cetuximab (Erbitux, DTXSID70142901)	Antibody targeting the L2 domain of EGFR	Cetuximab was not very effective in GBM clinical trials. 6-month PFS was 33%, and median PFS was 16 weeks Ongoing clinical trials: NCT02800486 NCT02861898	[80]
Dacomitinib (Vizimpro, PF299804)	Second-generation EGFR inhibitor	Dacomitinib proved to be promising in pre-clinical models. 6-months PFS was 10.6% with a median PFS of 2.7 months Ongoing clinical trials: NCT01112527 NCT01520870	[81]
Erlotinib (Tarceva, OSI-774)	First-generation EGFR inhibitor	Erlotinib showed poor results in GBM clinical trials. The median PFS: 1.8 months Erlotinib vs. 2.4 months TMZ/BCNU (bis-chloroethylnitrosourea) Ongoing clinical trials: NCT01257594 NCT02239952	[82]
Gefitinib (Iressa, ZD1839)	First-generation EGFR inhibitor	Gefitinib showed poor results in GBM clinical trials. The median overall survival time from treatment initiation was 39.4 weeks	[83]
Lapatinib (Tykerb, GSK 572016)	First-generation EGFR inhibitor	Lapatinib demonstrated poor results in GBM clinical trials. The studies lacked objective responses, with early progression rate of 76%. Ongoing clinical trials: NCT01591577 NCT02101905	[84]
Nimotuzumab (OSAG101)	Antibody targeting the L2 domain of EGFR	Nimotuzumab in addition to standard treatment is well tolerated and has increased survival rates in EGFR positive expression newly diagnosed GBM patients. The PFS and OS rates were 49.3% and 83.3% for 1-year and 29.0% and 51.1% for 2-year. Ongoing clinical trials: NCT03620032	[85]
Osimertinib (AZD9291)	Third-generation EGFR inhibitor	Osimertinib is in phase I/II clinical trial. Compared to other EGFR-TKIs, AZD9291 demonstrated improved ability to inhibit GBM cells proliferation.Complete response of left frontal lobe tumor after 4 weeks of osimertinib.	[86,87,88]
Panitumumab (Vectibix, ABX-EGF)	Antibody targeting the L2 domain of EGFR	Panitumumab was not very effective in GBM clinical trials.Panitumumab-IRDye800CW specificities for tumor core and margin were slightly higher than those of 5-ALA. Ongoing clinical trials: NCT03510208	[89]
Rindopepimut (CDX110)	Vaccine	When co-administrated with Bevacizumab, Rindopepimut significantly prolonged patient survival. 6 months PFS was 28% (rindopepimut), compared with 16% (control)Phase II trial (NCT00458601) was completed in 2018.	[90]
Vandetanib (Caprelsa, ZD6474)	Second-generation EGFR inhibitor	Vandetanib was a moderately tolerated drug, with no significant activity as a single agent in patients with recurrent malignant glioma. Median overall survival was 6.3 months. Ongoing clinical trials: NCT02239952	[91]
Tesevatinib (KD019)	Second-generation EGFR inhibitor	Tesevatinib is in Phase II study in patients with recurrent glioblastoma, with no results posted. Ongoing clinical trials: NCT02844439	[92]
bscEGFRvIIIxCD3	Antibody BisAbs	Fully human bispecific single chain antibody fragments bi-scFv (EGFRvIII:CD3 bi-scFv) was recently developed with the aim to redirect CD3-expressing T cells to target malignant EGFRvIII-expressing glioma.	[93]
mAB806	Antibody targeting the EGFRvIII-specific sequence	Structural extracellular mutations lead to a similar intermediate conformation, that can be synergistically targeted intra- and extracellularly by mAb806 antibody. Lapatinib co-treatment sensitized unresponsive wild type (WT)-EGFR to mAb806.	[94]
125I mAB425	Antibody toxin or radioactive isotope conjugated	Single or in combination with TMZ, 125I mAB425 prolonged patient survival (median survival of 20.4 months, compared to 14.5 months for 125I mAB425 alone), with minimal toxicity in normal tissue.	[95]
Chimeric anti-gen receptor T cell therapy (CAR-T cells)	Chimeric antigen receptor therapy (CARs) targeting EGFRvIII	Chimeric antigen receptor (CAR) T cells are in phase I clinical trials in high-grade glioma (HGG) patients. Pre-clinical models proved to be promising. Ongoing clinical trials: NCT02331693 NCT02844062 NCT02209376 NCT01454596 NCT02664363	[96,97]
Antisense oligonucleotides, siRNA, ribozymes, and miRNA-based therapy	RNA-based therapies	Feasibility of RNA-based therapies must be further evaluated using pre-clinical models.	[98,99]