A germline variant of FCGR2A has been identified as a biomarker to indicate which patients with metastatic colorectal cancer (mCRC) will benefit from treatment with cetuximab, a monoclonal antibody that targets epidermal growth factor receptor (EGFR).1 The findings supplement previous studies that identified polymorphisms of the BRAF and KRAS genes as tumor-based predictive biomarkers of cetuximab efficacy.2
Patients with mCRC carrying H alleles of FCGR2A who were treated with cetuximab had substantially improved overall and progression-free survival, in contrast with patients carrying R alleles (H/R or R/R) who were treated with the drug.
“Patients with colorectal cancer now have a number of existing choices of new drugs and a wide variety of clinical trials of novel agents to choose from,” said lead author Geoffrey Liu, MD, of Princess Margaret Cancer Centre in Toronto, Canada, in an interview with Cancer Therapy Advisor.
“Patients carrying the R/R genotype can avoid cetuximab, a drug that is not very effective for controlling their tumors, and these patients can be redirected quickly to try other drugs. In time, the hope is that other biomarkers can be used to direct such patients toward or away from alternative drug choices.”
Researchers used DNA samples from a phase 3 clinical trial of cetuximab monotherapy versus best supportive care alone, the final analysis for which was performed in 2006.3 They analyzed DNA extracted from normal and tumor tissue samples for the FCGR2A alleles, and compared the incidence of polymorphisms to the patients’ overall and progression-free survival. Thirty-one percent of all patients carried the H/H genotype. These patients had a hazard ratio of 0.37, compared to 0.87 for patients with the H/R genotype and 1.07 for those with the R/R genotype.
“Our ability to identify such markers will move the field of personalized oncology forward,” said Dr Liu. “We anticipate that, over time, additional refinements in how we select drugs for our patients will be found, such that community oncologists may use a panel of tests to best identify which drug or drugs should be used on which patients, and possibly in which sequence.”
“There must be caution, however: our findings are promising, but more research must be performed…to make sure that our findings apply broadly to large segments of patients with colorectal cancer, and that biomarker results from a single trial must be validated in other colorectal cancer populations. Other groups have found that these markers may not be as useful when evaluating the use of cetuximab in conjunction with other drugs. Our trial was specific to those patients who received cetuximab as a single agent.”
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Dr Liu’s research group is currently evaluating another large clinical trial that found improved PFS, but not improved OS, in CRC patients treated with cetuximab plus brivanib.4
“We hope to identify a subgroup of patients who may benefit from both drugs [in both] progression and overall survival,” he concluded.
- Liu G, Tu D, Lewis M, Cheng D, Sullivan LA, Chen Z, et al. FC-gamma-receptor polymorphisms, cetuximab therapy, and survival in the NCIC CTG CO.17 trial of colorectal cancer [published online ahead of print May 13, 2016]. Clin Cancer Res.doi: 10.1158/1078-0432.CCR-15-0414.
- Qiu LX, Mao C, Zhang J, Zhu XD, Liao RY, Xue K, et al. Predictive and prognostic value of KRAS mutations in metastatic colorectal cancer patients treated with cetuximab: a meta-analysis of 22 studies [published online ahead of print June 25, 2010]. Eur J Cancer. doi: 10.1016/j.ejca.2010.05.022.
- Jonker D, O’Callaghan C, Karapetis C, Zalcberg JR, Tu D, Au HJ, et al. Cetuximab for the Treatment of Colorectal Cancer. N Engl J Med. doi: 10.1056/NEJMoa071834