Regorafenib Metastatic CRC Benefits Found Across Mutation Subgroups

Regorafenib provides survival gains in metastatic colorectal cancer across patient mutation subgroups

medwireNews: Analysis of plasma samples from CORRECT trial participants with metastatic colorectal cancer suggests that the multikinase inhibitor regorafenib is beneficial for patients with and without key oncogenic mutations.

Josep Tabernero, from Universitat Autonoma de Barcelona in Spain, and co-workers report correlative analyses for the CORRECT trial in which 503 patients were assigned to receive regorafenib or placebo.

Regorafenib offered significant progression-free survival (PFS) benefits over placebo for both patients with and without a KRAS mutation, with hazard ratios (HRs) of 0.51 and 0.52, respectively.

Likewise, patients with and without a PIK3CA mutation derived PFS benefit from the multikinase inhibitor, with HRs of 0.54 and 0.50, respectively.

In addition, circulating DNA concentration was significantly associated with PFS, with a HR of 0.53 in favour of regorafenib treatment for patients with low DNA concentrations and a HR of 0.52 for those with high circulating concentrations.

“[A]nalysis of circulating DNA has some potential shortcomings, including the possibility that not all tumours release a sufficient quantity of DNA into circulation to enable detection, and the inability to assign a specific genotype to each particular tumour in patients with multiple metastases”, the researchers concede.

“Nonetheless, analysis of circulating DNA on a commercial scale could be an invaluable tool in clinical practice”, they believe.

The researchers used BEAMing (beads, emulsions, amplification and magnetics) technology to examine for mutations in plasma DNA of the 503 trial participants. BEAMing technology was also used to examine tumour tissue DNA in 239 patients.

Plasma DNA analysis revealed KRAS mutations in 69% of patients, PIK3CA mutations in 17% and BRAF mutations in 3%, with hot-spot mutations making up a large proportion of the KRAS and PIK3CA variants identified.

Moreover, 48% of the 86 patients who had previously been given treatment targeting the epidermal growth factor receptor and had archived tumour tissue with wild-type KRAS were found to have KRAS mutations in their plasma DNA in the later BEAMing analysis.

“Tumour genotyping using circulating plasma-derived DNA offers potential advantages over archival tumour DNA testing, including convenience, non-invasive sample collection, and more accurate representation of a tumour's current mutational status”, the authors explain in The Lancet Oncology.

“Such a method of monitoring tumour genotype could be useful to establish a patient's suitability for a particular treatment. For example, the emergence of RAS mutations during treatment could provide the rationale for a switch to an alternative drug that has been shown to be active against colorectal cancer tumours with such gene alterations.”


Tabernero J, Lenz H-J, Siena S, et al. Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial. Lancet Oncol; Advance online publication 13 July 2015. DOI:

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