Press Release

Barcelona/Darmstadt, June 30, 2008 – 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 tumors. 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 tumors 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, tumors experienced significantly increased response rates and significantly decreased risk of progression compared to the patients with a KRAS mutation in their tumors.1,2 These data were recently presented at this year’s American Society of Clinical Oncology (ASCO) congress.3,4

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 2007.5,6 Since then, several smaller studies have indicated that the KRAS status of a patient’s tumor has an impact on the therapeutic benefit of Erbitux in the treatment of mCRC patients.7-9 The data presented now confirm the increased efficacy of Erbitux in combination with standard chemotherapy in patients with KRAS wild-type tumors in 1st-line treatment. This increased efficacy was reflected in the remarkably high response rates, which led to improved outcomes for these patients.1,2 The data were based on current, state-of-the-art standard chemotherapies FOLFIRI and FOLFOX, rather than the outdated regimen IFL, which is no longer considered a standard of care and rarely used in treatment practice.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 tumors 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 tumors receiving Erbitux, their chance of being alive after one year without tumor 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 tumors led to:1
• 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 tumors experienced an increased benefit from Erbitux. In this case the addition of Erbitux led to:2
• 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 tumors, so a huge patient population will benefit from the improved response rate, tumor shrinkage and decreased risk of tumor 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 tumors with wild-type KRAS, the KRAS protein is tightly regulated and only activated in response to certain stimuli such as EGFR signaling allowing an effective blockade of the downstream signaling 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 tumors 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 tumor may continue to grow, proliferate and spread.

More than 370,000 people develop colorectal cancer in Europe every year, accounting for 13% of the total cancer burden and around 200,000 deaths.10 Approximately 25% of patients present with metastatic disease.11 Five-year survival rates for patients with mCRC are as low as 5%.12

References
1. Van Cutsem E, et al. WCGIC 2008; Abstract No: 471
2. Schuch G, et al. WCGIC 2008; Abstract No: 385
3. Van Cutsem E, et al. ASCO 2008; Abstract No: 2
4. Bokemeyer C, et al. ASCO 2008; Abstract No: 4000
5. Van Cutsem E, et al. ASCO 2007; Abstract No: 4000
6. Bokemeyer C, et al. ASCO 2007; Abstract No: 4035
7. De Roock W, et al. Ann Oncol 2007;Nov 12 Epub.
8. Lievre A, et al. J Clin Onc 2008;26(3):374-379.
9. Tabernero J, et al. ASCO GI 2008;Abstract No: 435
10. Parkin DM et al. CA Cancer J Clin 2005; 55: 72-108.
11. Cunningham D and Findley M. Eur J Cancer 1993;29A(15);2077–2079
12. Macdonald JS. CA Cancer J Clin 1999;49(4),202-219.

For more information:
http://www.merck.de