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 KRAS wild-type tumours.

These results were presented by Merck Serono, a division of Merck KGaA, Darmstadt, Germany, at the 10th Meeting of the World Congress on Gastrointestinal Cancers (WCGIC). 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. These data were recently presented at this year's American Society of Clinical Oncology (ASCO) congress.

The beneficial effect of adding Erbitux to standard chemotherapy in the overall population was demonstrated in the Crystal and OPUS trials, and presented at ASCO in 2007. 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 now 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 reflected in the remarkably high response rates, which led to improved outcomes for these patients. The data were based on current, state-of-the-art standard chemotherapies FOLFIRI and FOLFOX, rather than the outdated regimen IFL, which is no longer considered a standard of care and rarely used in treatment practice.

"This is the first time that analysis of biomarker data in patients with colorectal cancer has demonstrated a clear benefit for patients with KRAS wild-type tumours treated with Erbitux in the 1st-line setting," 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. "For patients with KRAS wild-type tumours receiving Erbitux, their chance of being alive after one year without tumour growth nearly doubled compared to those receiving irinotecan-based chemotherapy alone. From my point of view, in future, KRAS-testing should be routinely conducted in all mCRC patients immediately after diagnosis."

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% compared to 43% for those receiving FOLFIRI alone [p=0.0025]; a 32% decrease in risk of progression [HR=0.68; p=0.017], 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% compared to 37% in patients treated with FOLFOX alone [p=0.011]; a 43% decreased risk of progression [HR=0.57; p=0.016], which was also reflected in a significantly higher progression free survival time (PFS) compared to patients receiving FOLFOX alone.

"These findings are the link to the development of tailored therapies in colon cancer. A simple diagnostic test can determine a patient's KRAS status and identify patients who will benefit most from Erbitux," commented Dr. Gunter Schuch, investigator of the OPUS study from the Universitatsklinikum Eppendorf, Hamburg, Germany.

"With the evidence from these studies and the recent CHMP positive opinion, we see Erbitux holding the key to the future of colorectal cancer treatment," added Dr. Wolfgang Wein, executive vice president, oncology, Merck Serono. "The majority of patients with colorectal cancer have KRAS wild-type tumours, so a huge patient population will benefit from the improved response rate, tumour shrinkage and decreased risk of tumour progression associated with Erbitux."

At the end of May, Merck was 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% of colorectal cancer patients.1,3 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.

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.