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.
To evaluate the efficacy and harms of anti‐EGFR therapies for glioblastoma in adults.
We searched CENTRAL, MEDLINE, Embase, EBM Reviews databases, with supplementary handsearches to identify all available and relevant studies to 20 April 2020.
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.
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).
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.
Plain language summary
Drugs that target abnormal growth protein in high‐grade, aggressive brain tumours
Glioblastomas are highly aggressive brain tumours. They often appear quickly with devastating effects depending on the part of the brain they are located. They often affect previously well and high functioning individuals without any ‘warning signs’. There are no known risk factors. The impact on people with glioblastomas, their family, friends, and society is highly problematic. Standard therapy involves resection of the tumour, then combined chemotherapy and radiation therapy followed by an additional six months of chemotherapy. This strategy aims only to control and contain the disease and delay its return because at present there is no cure.
Researchers have investigated and found multiple gene changes in glioblastoma tissue samples, leading to clinical trials testing new drug therapies. The protein epidermal growth factor receptor (EGFR), which normally controls cell growth, is abnormal in glioblastomas in about 30% to 60% of cases. This abnormality can lead to unrestrained cell growth, replication, and an increase in the cancer’s aggressive potential. It is currently recognised that people with glioblastomas with an abnormal EGFR may have shorter survivals.
Some clinical trials with drugs targeting this protein have been conducted. This review aimed to collect all available evidence and investigate the risks and benefits for this type of therapy in glioblastomas, and in particular whether anti‐EGFR drugs can improve survival whilst remaining a tolerable therapy without side effects.
We searched medical databases for randomised controlled trials (a type of study in which participants are assigned to one of two or more treatment groups using a random method) that used anti‐EGFR therapies in people with glioblastoma up to April 2020.
Overall, no benefits were seen in improving overall survival with the use of anti‐EGFR therapy in newly diagnosed people with glioblastoma or in the recurrent setting. The use of anti‐EGFR therapies was not associated with increased side effects such as low white cells or platelet counts. There were some expected side effects including skin rashes and diarrhoea, but these were not severe and did not seem to impact participant quality of life. Anti‐EGFR therapy did not delay disease worsening in newly diagnosed people with glioblastomas but there was an improvement seen amongst those with recurrent disease.
At present, there is insufficient evidence to support the use of anti‐EGFR therapy in newly diagnosed or recurrent glioblastoma. Whilst the therapy is in general expected as with other anti‐EGFR therapies, significant eye side effects can arise with ABT‐414. Overall, anti‐EGFR therapies did not appear to affect quality of life. The future use of anti‐EGFR therapy in the management of glioblastoma requires more investigation. Future research should be promoted and tailored towards people with glioblastoma with known abnormal EGFR receptors.