Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

Reardon, David A.; Nabors, L. Burt; Mason, Warren P.; Perry, James; Shapiro, William R.; Kavan, Petr; Mathieu, David; Phuphanich, Surasak; Cseh, A.; Fu, Yichun; Cong, Julie; Wind, Sven; Eisenstat, David D.

doi:10.1093/neuonc/nou160

Cited by 131 publications

(133 citation statements)

References 42 publications

Supporting

Mentioning

129

Contrasting

Unclassified

Order By: Relevance

“…Beyond the randomized trial leading to the approval of TMZ mentioned above, two other randomized trials with TMZ monotherapy as one of the treatment arms have been published, a direct comparison with the combination of procarbazine, lomustine and vincristine (PCV) before TMZ became first-line standard [69] and a negative trial for the epidermal growth factor recetor (EGFR) tyrosine kinase inhibitor afatinib [70] ( Table 2 and The anti-vascular endothelial growth factor (VEGF) antibody bevacizumab [72][73][74][75], interferon-α2b [76], the multikinase inhibitor sorafenib [77], O6-benzylguanine [78], irinotecan [79], cisplatin [80,81], liposomal doxorubicine [82] and ABT-414, an EGFR-targeted antibody-drug conjugate conjugated to monomethylauristatin F [83].…”

Section: Temozolomide Monotherapy and Combination Regimensmentioning

confidence: 99%

“…Several EGFR-targeting agents have been developed, such as gefitinib, erlotinib or afatinib, a strategy effective in EGFR-mutated non-small-cell lung cancer, however, so far with disappointing results in glioblastoma [57,70,108,115].…”

Section: Targeted Therapymentioning

confidence: 99%

“…The phase II trial evaluating afatinib, an irreversible ErbB family blocker, showed that in the biomarker cohort (70 patients, 59%) the median PFS in those patients treated with afatinib monotherapy with EFGRvIII-positive tumors vs -negative tumors was 3.4 vs 1.0 months pointing towards efficacy in subgroups (over-)expressing the target [70]. The efficacy of ABT-414 might be further improved in a target-selected cohort since all patients of an unselected phase I cohort with confirmed response had EGFR amplification [83].…”

Section: Targeted Therapymentioning

confidence: 99%

See 2 more Smart Citations

Therapeutic options in recurrent glioblastoma—An update

Seystahl

Wick

Weller

2016

Critical Reviews in Oncology/Hematology

177

134

View full text Add to dashboard Cite

show abstract

Section: Temozolomide Monotherapy and Combination Regimensmentioning

confidence: 99%

Section: Targeted Therapymentioning

confidence: 99%

Section: Targeted Therapymentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic options in recurrent glioblastoma—An update

Seystahl

Wick

Weller

2016

Critical Reviews in Oncology/Hematology

177

134

View full text Add to dashboard Cite

show abstract

“…Four randomized phase II clinical trials were conducted using single-agent TMZ (127,159,166,167). A randomized trial comparing sdTMZ with procarbazine, in TMZ-naive patients, revealed a PFS6 of 21% versus 8%, with a median OS 1.5 months longer in the TMZ arm (127).…”

Section: Temozolomide Monotherapy and Combination Regimensmentioning

confidence: 99%

Current Standards of Care in Glioblastoma Therapy

et al. 2017

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Regardless of ideal multidisciplinary treatment, including maximal surgical resection, followed by radiotherapy plus concomitant and maintenance temozolomide (TMZ), almost all patients experience tumor progression with nearly universal mortality and a median survival of less than 15 months. The addition of bevacizumab to standard treatment with TMZ revealed no increase in overall survival (OS) but improved progression-free survival (PFS). In newly diagnosed GBM, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been shown to predict response to alkylating agents, as well asgnosis. Therefore, MGMT promoter status may have a crucial role in the choice of single modality treatment in fragile elderly population. No standard of care is established in recurrent or progressive GBM. Treatment alternatives may include supportive care, surgery, re-irradiation, systemic therapies, and combined modality therapy. Despite numerous clinical trials, the identification of effective therapies is complex because of the lack of appropriate control arms, selection bias, small sample sizes, and disease heterogeneity. Tumor-treating fields plus TMZ represent a major advance in the field of GBM therapy, and should be Standards of Care in Glioblastoma Therapy 198 considered for patients with newly diagnosed GBM with no contraindications. As a disease with such a poor prognosis, treatment of GBM should go beyond improving survival and aim at preserving and even improving the quality of life of both the patient and the caregiver.

show abstract

“…However, these trials were not conducted in biomarker-selected populations overexpressing the target. Recently, in a phase II trial in recurrent glioblastoma evaluating the ErbB family blocker afatinib, a small efficacy signal in EGFRvIII-positive tumors versus -negative tumors was seen (median PFS 3.4 versus 1.0 months) [61]. Currently tested in phase IIb/III is ABT-414, an antibody-drug conjugate targeting EGFR in its active conformation.…”

Section: Other Targeted Therapiesmentioning

confidence: 99%

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

Seystahl

Gramatzki

Roth

2016

Expert Opinion on Pharmacotherapy

View full text Add to dashboard Cite

INTRODUCTION Glioblastoma, the most common malignant brain tumor, exhibits a poor prognosis with little therapeutic progress in the last decade. Novel treatment strategies beyond the established standard of care with temozolomide-based radiotherapy are urgently needed. AREAS COV-ERED We reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015. EXPERT OPINION In the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease. Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering 'tumor-treating fields' in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma. Areas coveredWe reviewed the literature on glioblastoma with a focus on phase III trials for pharmacotherapies and/or innovative concepts until December 2015. Expert opinionIn the last decade, phase III trials on novel compounds largely failed to introduce efficacious pharmacotherapies beyond temozolomide in glioblastoma. So far, inhibition of angiogenesis by compounds such as bevacizumab, cediranib, enzastaurin or cilengitide as well as alternative dosing schedules of temozolomide did not prolong survival, neither at primary diagnosis nor at recurrent disease.Promising strategies of pharmacotherapy currently under evaluation represent targeting epidermal growth factor receptor (EGFR) with biomarker-stratified patient populations and immunotherapeutic concepts including checkpoint inhibition and vaccination. The clinical role of the medical device delivering "tumor-treating fields" in newly diagnosed glioblastoma which prolonged overall survival in a phase III study has remained controversial. After failure of several phase III trials with previously promising agents, improvement of concepts and novel compounds are urgently needed to expand the still limited therapeutic options for the treatment of glioblastoma. 3 Article highlights• For patients with newly diagnosed glioblastoma, the standard of care remains temozolomide-based radiochemotherapy.• Phase III data on bevacizumab, cilengitide, and alternative dosing schedules for temozolomide did not show a survival benefit in newly diagnosed glioblastoma• For elderly patients ...

show abstract

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma

Abstract: Afatinib has a manageable safety profile but limited single-agent activity in unselected recurrent GBM patients.

Cited by 131 publications

References 42 publications

Therapeutic options in recurrent glioblastoma—An update

Therapeutic options in recurrent glioblastoma—An update

Current Standards of Care in Glioblastoma Therapy

Pharmacotherapies for the treatment of glioblastoma – current evidence and perspectives

Contact Info

Product

Resources

About