New research from Europe suggests that patients with advanced or metastatic colorectal cancer who have the normal, or wild type of a gene called KRAS are likely to benefit from treatment that includes the targeted therapy drug Erbitux (cetuximab) in addition to first line treatment chemotherapy. The researchers suggested that around two thirds of colorectal cancer patients have the normal form of the gene.

Data from two radomized controlled trials, the Phase III CRYSTAL and Phase II OPUS, showed that advanced colorectal cancer patients with normal or non mutated tumours with the wild type of KRAS gene, responded significantly better and had significantly decreased progression when Erbitux was added to their standard chemotherapy, compared to patients with the mutated form of KRAS.

The research findings were presented at the 44th Annual Meeting of the American Society for Clinical Oncology (ASCO), taking place in Chicago from 30th May to 3rd June.

Dr Wolfgang Wein, Executive Vice President, Oncology, Merck KGaA, Darmstadt, Germany, the manufacturer of Erbitux, said that:

“Both studies show highly consistent response rates of 60 per cent and a very meaningful decrease in the risk of progression of up to 43 per cent in patients with KRAS wild-type tumors treated with Erbitux plus standard chemotherapy.”

Last year, results from the two trials had already reported that Erbitux was showing significant benefits to patients, and since then smaller trials have hinted at a role played by the KRAS gene in increasing the efficacy of Erbitux in the treatment of advanced metastatic colorectal cancer. This most recent trial data confirms this.

Eric Van Cutsem, Professor of Medicine and Digestive Oncology from the University Hospital Gasthuisberg in Leuven, Belgium, and lead investigator of the CRYSTAL study, said these latest findings are “extremely exciting”, and represent a “real advance” in the first line treatment of metastatic colorectal cancer because:

“They are the first biomarker data from major studies in the 1st-line setting, which clearly demonstrate the increased efficacy of Erbitux in combination with standard chemotherapy in patients who have wild-type KRAS tumors.”

“The chance that these patients would be alive after one year without tumor growth nearly doubled compared to those receiving irinotecan-based chemotherapy alone.”

CRYSTAL Results

The controlled Phase III CRYSTAL trial investigated 540 patients who were randomized either to standard chemotherapy FOLFIRI alone or with Erbitux.

The results showed that those patients who had the wild form of the KRAS gene and also received Erbitux had:

  • A signifincantly higer response rate of up to 59 per cent compared to 43 per cent for those who had FOLFIRI alone.
  • A 32 per cent lower risk of progression, which also reflected in a statistically significant higher progression free survival, compared to patients on FOLFIRI alone.

OPUS Results

The controlled Phase II OPUS trial investigated 134 patients who were randomized to receive either oxaliplatin-based standard chemotherapy regimen FOLFOX alone, or with Erbitux.

The results showed that those patients who had the wild form of the KRAS gene and also received Erbitux had:

  • A significantly higher response rate of up to 61 per cent compared to 37 per cent in patients treated with FOLFOX alone.
  • A 43 per cent lower risk of progression, which also reflected in a statistically significant higher progression free survival, compared to patients on FOLFOX alone.

Lead investigator of the OPUS study, Professor Carsten Bokemeyer, from the Universitatsklinikum Eppendorf, Hamburg, Germany, said:

“These findings are an important step forward in the development of tailored therapies.”

“Determining a patient’s KRAS status should now form part of our standard diagnostic practice as the test identifies the patients who will benefit most from Erbitux,” added Bokemeyer.

The KRAS gene codes for a protein involved in the the epidermal growth factor receptor (EGFR) pathway, which plays a role in the control of cell growth, proliferation, and differentiation, and cancer risk.

In tumours with wild type of KRAS, the protein is tightly controlled and only activated under certain conditions, which allows the monoclonal antibody Erbitux to block signals in the EGFR pathway.

In tumours with the mutant type of KRAS, the protein is permanently “switched on”, and the researchers speculate that this stops the drug from being able to block the “downstream” effects of EGFR, thus allowing the tumour to grow, proliferate, and spread.

The researchers said the wild type of KRAS is found in around 65 per cent of colorectal cancer patients.

Colorectal cancer accounts for around 13 per cent of the cancer burden in Europe, where more than 370,000 people develop it every year, and around 200,000 people die from the disease. About 25 per cent of patients present with the metastatic form of the disease, and five year survival for these patients is is as low as 5 per cent.

“KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience.”
E. Van Cutsem, I. Lang, G. D’haens, V. Moiseyenko, J. Zaluski, G. Folprecht, S. Tejpar, O. Kisker, C. Stroh, P. Rougier.
J Clin Oncol 26: 2008 (May 20 suppl; abstr 2)
Presented as Abstract No 2, at 44th Annual Meeting of American Society of Clinical Oncology (ASCO), May 30th – June 3rd, 2008, Chicago.

Click here to view Abstract (ASCO).

“KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience.”
C. Bokemeyer, I. Bondarenko, J. T. Hartmann, F. G. De Braud, C. Volovat, J. Nippgen, C. Stroh, I. Celik, P. Koralewski.
J Clin Oncol 26: 2008 (May 20 suppl; abstr 4000)
Presented as Abstract No 4000, at 44th Annual Meeting of American Society of Clinical Oncology (ASCO), May 30th – June 3rd, 2008, Chicago.

Click here to view Abstract (ASCO).

Source: ASCO Abstracts, Merck KGaA press statement.

Written by: Catharine Paddock, PhD