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: I(2) = 76%; overall survival: I(2) = 40%; and response rate: I(2) = 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 (I(2) = 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 (I(2) = 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.
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.