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Meta-Analysis
. 2020 May 12;5(5):CD013238.
doi: 10.1002/14651858.CD013238.pub2.

Anti-epidermal growth factor receptor therapy for glioblastoma in adults

Adrian Lee  1 , Malmaruha Arasaratnam  1 , David Lok Hang Chan  1 , Mustafa Khasraw  2 , Viive M Howell  1 , Helen Wheeler  1
Affiliations
Meta-Analysis

Anti-epidermal growth factor receptor therapy for glioblastoma in adults

Adrian Lee et al. Cochrane Database Syst Rev. .

Abstract

Background: Glioblastoma is an uncommon but highly aggressive type of brain tumour. Significant gains have been achieved in the molecular understanding and the pathogenesis of glioblastomas, however clinical improvements are difficult to obtain for many reasons. The current standard of care involves maximal safe surgical resection followed by chemoradiation and then adjuvant chemotherapy European Organisation for Research and Treatment of Cancer and the NCIC Clinical Trials Group (EORTC-NCIC) protocol with a median survival of 14.6 months. Successive phase III international randomised controlled studies have failed to significantly demonstrate survival advantage with newer drugs. Epidermal growth factor receptor (EGFR) is observed to be aberrant in 30% to 60% of glioblastomas. The receptor aberrancy is driven by abnormal gene amplification, receptor mutation, or both, in particular the extracellular vIII domain. EGFR abnormalities are common in solid tumours, and the advent of anti-EGFR therapies in non-small cell lung cancer and colorectal adenocarcinomas have greatly improved clinical outcomes. Anti-EGFR therapies have been investigated amongst glioblastomas, however questions remain about its ongoing role in glioblastoma management. This review aimed to report on the available evidence to date and perform a systematic analysis on the risks and benefits of use of anti-EGFR therapies in glioblastomas.

Objectives: To evaluate the efficacy and harms of anti-EGFR therapies for glioblastoma in adults.

Search methods: We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020.

Selection criteria: All randomised controlled trials (RCTs) using anti-EGFR therapies in adults with glioblastoma were eligible for inclusion. Anti-EGFR therapies included tyrosine kinase inhibitors, monoclonal antibodies, or vaccines. The comparison included investigational product added to standard of care versus standard of care or placebo, or investigational product against standard of care or placebo.

Data collection and analysis: The authorship team screened the search results and recorded the extracted data for analysis. We used standard Cochrane methodology to performed quantitative meta-analysis if two or more studies had appropriate and available data. Otherwise, we conducted a qualitative and descriptive analysis. We used the GRADE system to rate the certainty of the evidence. The analysis was performed along the two clinical settings: first-line (after surgery) and recurrent disease (after failure of first line treatment). Where information was available, we documented overall survival, progression-free survival, adverse events, and quality of life data from eligible studies.

Main results: The combined searches initially identified 912 records (after removal of duplicates), and further screening resulted in 19 records for full consideration. We identified nine eligible studies for inclusion in the review. There were three first-line studies and six recurrent studies. Five studies used tyrosine kinase inhibitors (TKIs); two studies used monoclonal antibodies; and two studies used targeted vaccines. More recent studies presented greater detail in the conduct of their studies and thus had a lower risk of bias. We observed no evidence benefit in overall survival with the use of anti-EGFR therapy in the first-line or recurrent setting (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76 to 1.04; 3 RCTs, 1000 participants, moderate-certainty evidence; and HR 0.79, 95% CI 0.51 to 1.21, 4 RCTs, 489 participants, low-certainty evidence, respectively). All the interventions were generally well tolerated with low-certainty evidence for lymphopenia (odds ratio (OR) 0.97, 95% CI 0.19 to 4.81; 4 RCTs, 1146 participants), neutropenia (OR 1.29, 95% CI 0.82 to 2.03; 4 RCTs, 1146 participants), and thrombocytopenia (OR 3.69, 95% CI 0.51 to 26.51; 4 RCTs, 1146 participants). A notable toxicity relates to ABT-414, where significant ocular issues were detected. The addition of anti-EGFR therapy showed no evidence of an increase in progression-free survival (PFS) in the first-line setting (HR 0.94, 95% CI 0.81 to 1.10; 2 RCTs, 894 participants, low-certainty evidence). In the recurrent setting, there was an increase in PFS with the use of anti-EGFR therapy (HR 0.75, 95% CI 0.58 to 0.96, 3 RCTs, 275 participants, low-certainty evidence). The available quality of life assessment data showed that anti-EGFR therapies were neither detrimental or beneficial when compared to standard care (not estimable).

Authors' conclusions: In summary, there is no evidence of a demonstrable overall survival benefit with the addition of anti-EGFR therapy in first-line and recurrent glioblastomas. Newer drugs that are specially designed for glioblastoma targets may raise the possibility of success in this population, but data are lacking at present. Future studies should be more selective in pursuing people displaying specific EGFR targets.

PubMed Disclaimer

Conflict of interest statement

AL: has received honorarium and grants from Eisai, Mundipharma, Sanofi, and Bayer for non‐glioma conditions. MA: none known. DC: has received honoraria from Novartis and Ipsen for educational activities outside the submitted work. MK: has served on AbbVie GBM advisory boards, and his institution received research grants from AbbVie and BMS to fund clinical trials in glioblastoma. VH: none known. HW: the analysis for this Cochrane Review is based on peer‐reviewed data prepared by an independent steering trials committee. My involvement in the Australian Roche advisory board was to discuss completed trial results and how the drug may be introduced into the clinic in Australian centres. My participation on the Merck Serono‐centric steering committee was to review ongoing trial recruitment and severe adverse events. None of these activities influenced the analysis of the review data or contributed to any presented/published conclusions.

Figures

1
1
PRISMA flow diagram.
2
2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Overall survival, outcome: 1.1 First‐line.
4
4
Forest plot of comparison: 1 Overall survival, outcome: 1.2 Recurrent disease.
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Forest plot of comparison: 2 Progression‐free survival, outcome: 2.1 First‐line.
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Forest plot of comparison: 3 Progression‐free survival, outcome: 3.2 Recurrent disease.
1.1
1.1. Analysis
Comparison 1: Overall survival, Outcome 1: First‐line
1.2
1.2. Analysis
Comparison 1: Overall survival, Outcome 2: Recurrent disease
1.3
1.3. Analysis
Comparison 1: Overall survival, Outcome 3: Sensitivity analysis low risk of bias
1.4
1.4. Analysis
Comparison 1: Overall survival, Outcome 4: Sensitivity analysis for comparative and non‐comparative studies
1.5
1.5. Analysis
Comparison 1: Overall survival, Outcome 5: Sensitivity analysis (6 studies)
2.1
2.1. Analysis
Comparison 2: Toxicities of first‐line anti‐EGFR therapies ‐ grade 3 and above, Outcome 1: Lymphopenia
2.2
2.2. Analysis
Comparison 2: Toxicities of first‐line anti‐EGFR therapies ‐ grade 3 and above, Outcome 2: Neutropenia
2.3
2.3. Analysis
Comparison 2: Toxicities of first‐line anti‐EGFR therapies ‐ grade 3 and above, Outcome 3: Thrombocytopenia
2.4
2.4. Analysis
Comparison 2: Toxicities of first‐line anti‐EGFR therapies ‐ grade 3 and above, Outcome 4: Rash
2.5
2.5. Analysis
Comparison 2: Toxicities of first‐line anti‐EGFR therapies ‐ grade 3 and above, Outcome 5: Diarrhoea
2.6
2.6. Analysis
Comparison 2: Toxicities of first‐line anti‐EGFR therapies ‐ grade 3 and above, Outcome 6: Fatigue
3.1
3.1. Analysis
Comparison 3: Progression‐free survival, Outcome 1: First‐line
3.2
3.2. Analysis
Comparison 3: Progression‐free survival, Outcome 2: Recurrent disease
3.3
3.3. Analysis
Comparison 3: Progression‐free survival, Outcome 3: Sensitivity analysis low risk of bias PFS
See this image and copyright information in PMC

Update of

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