New analyses of two randomized, controlled clinical trials investigating Erbitux (cetuximab) in the treatment of 1st-line metastatic colorectal cancer (mCRC) highlight the increased efficacy of Erbitux in patients with "normal," non-mutated or so-called tumours with wild-type KRAS.

These results were presented at the plenary session of the 44th Annual Meeting of the American Society for Clinical Oncology (ASCO). The analyses from the major randomized, controlled phase III CRYSTAL and phase II OPUS trials found that patients with KRAS wild-type tumours treated with Erbitux in combination with standard chemotherapy in the 1st-line setting experienced significantly enhanced efficacy compared to those bearing a KRAS mutation. Patients with KRAS wild-type, or non-mutant, tumours experienced significantly increased response rates and significantly decreased risk of progression compared to the patients with a KRAS mutation in their tumours.

The beneficial effect of adding Erbitux to standard chemotherapy in the overall population was demonstrated in the CRYSTAL and OPUS trials, and presented at last year's ASCO meeting. Since then, several smaller studies have indicated that the KRAS status of a patient's tumour has an impact on the therapeutic benefit of Erbitux in the treatment of mCRC patients. The data presented confirm the increased efficacy of Erbitux in combination with standard chemotherapy in patients with KRAS wild-type tumours in 1st-line treatment. This increased efficacy was mirrored in the remarkably high response rates, translating to favourable outcomes for these patients.

"These results are extremely exciting. 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 tumours," commented Professor Eric Van Cutsem, lead investigator of the CRYSTAL study and Professor of Medicine and Digestive Oncology from the University Hospital Gasthuisberg in Leuven, Belgium. "The chance that these patients would be alive after one year without tumour growth nearly doubled compared to those receiving irinotecan-based chemotherapy alone. This is a real advance in 1st-line mCRC treatment."

The new analysis of the randomized, controlled phase III CRYSTAL study investigating Erbitux in combination with the standard chemotherapy regimen FOLFIRI in 540 patients found that the addition of Erbitux in patients with KRAS wild-type tumours led to: a significant increase in response rate up to 59 per cent compared to 43 per cent for those receiving FOLFIRI alone; a 32 per cent decrease in risk of progression, which was also reflected in a statistically significant higher progression-free survival time (PFS) compared to patients receiving FOLFIRI alone.

The analysis of the major randomized, controlled phase II OPUS study investigating Erbitux with the oxaliplatin-based standard chemotherapy regimen FOLFOX in 134 patients, also found that patients with KRAS wild-type tumours experienced an increased benefit from Erbitux. In this case the addition of Erbitux led to: a significant increase in response rate up to 61 per cent compared to 37 per cent in patients treated with FOLFOX alone; a 43 per cent decreased risk of progression, which was also reflected in a significantly higher progression free survival time (PFS) compared to patients receiving FOLFOX alone.

"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," commented Professor Carsten Bokemeyer, lead investigator of the OPUS study from the Universitatsklinikum Eppendorf, Hamburg, Germany.

"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 tumours treated with Erbitux plus standard chemotherapy," added Dr. Wolfgang Wein, executive vice president, Oncology, Merck KGaA, Darmstadt, Germany. "This is a further verification of the outstanding quality of Erbitux specifically and the oncology program at Merck KGaA in general".

Merck was recently granted a positive opinion by the Committee for Medicinal Products for Human Use (CHMP), the scientific committee of the European Medicines Agency (EMEA) for Erbitux for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer, in combination with chemotherapy and as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.

KRAS is a gene that codes for a protein involved in the EGFR pathway. In tumours with wild-type KRAS, the KRAS protein is tightly regulated and only activated in response to certain stimuli such as EGFR signalling allowing an effective blockade of the downstream signalling by the EGFR targeted antibody Erbitux. The wild-type or non-mutant KRAS gene is found in up to 65 per cent of colorectal cancer patients.1 In mutant KRAS tumours the KRAS protein is permanently "turned on" and therefore it has been hypothesized that the drug's inhibition of the downstream effects is less efficient and the tumour may continue to grow, proliferate and spread.

More than 370,000 people develop colorectal cancer in Europe every year, accounting for 13 per cent of the total cancer burden and around 200,000 deaths. Approximately 25 per cent of patients present with metastatic disease.

Erbitux is a first-in-class and highly active IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of action of Erbitux is distinct from standard non-selective chemotherapy treatments in that it specifically targets and binds to the EGFR. This binding inhibits the activation of the receptor and the subsequent signal-transduction pathway, which results in reducing both the invasion of normal tissues by tumour cells and the spread of tumours to new sites. It is also believed to inhibit the ability of tumour cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumours, which appears to lead to an overall suppression of tumour growth.