Background
Cancer of the colon or rectum that has spread to other organs (metastatic colorectal cancer) is a commonly occurring disease that usually cannot be surgically removed. The main treatment is chemotherapy, targeted therapy (such as EGFR inhibitors, the subject of this review), or both. The epidermal growth factor receptor (EGFR) is a protein found on cells that plays a vital role in promoting cell growth. Monoclonal antibodies are molecules developed to attach to a particular protein in order to enhance or decrease action at that protein site. EGFR monoclonal antibodies (EGFR MAb), such as cetuximab and panitumumab, specifically target and block EGFR, which stops cancer cell growth. Research has shown that people with mutations (gene changes) in KRAS (a gene related to EGFR) may not benefit from these drugs ('KRAS mutant'), but those without mutations ('KRAS wild type') do benefit. Recent research also suggests that people with mutations in another related gene (NRAS) may not benefit from these drugs either – that is, patients need to have no mutation in either KRAS or NRAS (otherwise known as 'extended RAS wild type').
Another type of EGFR-blocking drug known as tyrosine kinase inhibitor (EGFR TKI) (e.g. erlotinib and gefitinib) is effective in the treatment of lung cancer with EGFR mutations, but its benefit in colorectal cancer is unclear.
Objectives
To determine the benefit and harms of EGFR MAb and EGFR TKI in the treatment of metastatic colorectal cancer. Our primary aim was to look at whether these drugs prolonged the time before disease progression (growth of the disease, usually defined as growth more than 20% or development of a new metastasis), but we also evaluated whether the drugs prolonged survival, caused the tumour to shrink, or resulted in more side effects (particularly rash and diarrhoea).
Study investigation
We reviewed the evidence for EGFR inhibitors in people with metastatic colorectal cancer. We selected randomised studies that compared people receiving standard treatment with those who received standard treatment plus an EGFR inhibitor (both the more commonly used drug type (EGFR MAb) or the less commonly used drug type (EGFR TKI)). We searched for published studies up to September 2016 and identified 33 studies involving 15,025 participants, of which 27 studies looked at EGFR MAbs and 6 looked at EGFR TKIs.
Main results
Our main finding was that the addition of EGFR MAb drugs to standard treatment in people whose tumours were KRAS wild type reduces the risk of disease progression by 30%. The risk of death is reduced by 12% (i.e. patients live longer overall), and the chance of tumour shrinkage is increased from 31% to 46%. In people who are both KRAS and NRAS (extended RAS) wild type, the risk of disease progression is reduced by 40%; risk of death is reduced by 23%; and the rate of tumour shrinkage increases from 21% to 48%.
There was no evidence of any difference in outcome between the combination of EGFR MAb plus chemotherapy and the combination of bevacizumab (another targeted drug) plus chemotherapy.
There was no evidence that the use of EGFR TKI improved outcomes, although the number of studied participants (and trials) was too small for a formal analysis.
There was no evidence that adding EGFR MAb to both chemotherapy and bevacizumab improved outcomes, and in fact was found to increase toxicity.
Quality of the evidence
The evidence we identified was generally of moderate to high quality. Our main reason for not judging the evidence for all outcomes as high quality was that in some studies the treating doctors assessed their patients’ scans for tumour shrinkage or growth, and their knowledge of what treatment the patient received resulted in a higher risk of bias. Another reason for our judging of the evidence as lower quality was that there were differences between the studies grouped in the meta-analyses calculations (heterogeneity).
The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.
Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity.
To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.
The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed.
We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone.
We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type).
We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).
The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression-free survival: I2 = 76%; overall survival: I2 = 40%; and response rate: I2 = 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.
For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I2 = 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.
We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate-quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I2 = 51%), likely due to the pooling of first-line and second-line studies.
The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.
Scant information on quality of life was reported in the identified studies.