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Studies Demonstrate Increased Efficacy of Erbitux in Metastatic Colorectal Cancer Patients with KRAS Wild-Type Tumors

DARMSTADT,  Germany, Jan. 28, 2008 – Findings from three studies demonstrate the increased efficacy of Erbitux® (cetuximab) in patients with metastatic colorectal cancer (mCRC) who have a wild-type KRAS tumor, highlighting the potential role of KRAS as a predictive biomarker in the treatment of this common cancer.1-3

Data presented at the American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium in Orlando, FL, showed that response rate (RR) for Erbitux plus FOLFIRI was higher for the patient population with wild-type KRAS than for those patients with mutated KRAS. The wild-type KRAS patients showed a RR of 55% versus 32% for those with mutated KRAS. The relative risk of progression in the KRAS wild-type group was reduced by 53% compared to the KRAS mutant group.

Two other retrospectively analyzed studies recently published in the Journal of Clinical Oncology and Annals of Oncology confirm this clinically important correlation.

“Biomarkers are proving to be an interesting area of investigation. Not only do the results demonstrate that Erbitux is highly effective in patients with KRAS wild-type tumors but they also add to the pool of evidence that supports the use of predictive factors in the future of oncology treatment,” commented study principal investigator, Professor Josep Tabernero, Vall D’Hebron University Hospital, Barcelona, Spain. "These data give the first evidence of the importance of KRAS as a biomarker in the first-line setting as well as in pretreated patients. Using biomarkers to predict which patients are likely to respond best to targeted therapies allows us to stratify their treatment appropriately and thus improve outcomes. This is of particular importance in the first-line setting as it enables us to select the best treatment strategy for the patient with metastatic disease from day one."

The wild-type or non-mutant KRAS gene is found in up to 65% of colorectal cancer patients and it may prove to be an important biomarker for predicting patient response to targeted treatments such as Erbitux that inhibit the epidermal growth factor receptor (EGFR) pathway.

The two retrospective analyses investigating the impact of KRAS mutations on the efficacy of Erbitux demonstrated that patients with mCRC who have the wild-type KRAS tumor realize a greater benefit from Erbitux in combination with irinotecan-based chemotherapy than those patients with a KRAS mutation.1,2

* The study recently published in the Journal of Clinical Oncology found that pretreated mCRC patients with KRAS wild-type tumors had improved survival over patients with a mutated KRAS tumor [median PFS: 31 weeks vs 10 weeks, p=0.0001].2

* The second study published in Annals of Oncology also demonstrated an improved survival in pretreated mCRC patients with KRAS wild-type tumors vs. tumors with the mutated gene [median overall survival (OS): 43 weeks vs. 27 weeks respectively, p=0.020]. In addition, the results found that patients with the wild-type tumor experienced more significant decreases in tumor size than patients with a mutated tumor, and these patients experienced significantly better OS compared to those without decreases in tumor size [median OS: 75 weeks vs 31 weeks, p=0.00000012].1

“The treatment outcome with Erbitux in combination with irinotecan for metastatic CRC patients with KRAS wild-type tumors reported in these analyses is outstanding for a population of pretreated patients. Progression free survival clearly exceeds earlier findings in non-selected patients,” said Professor Pierre Laurent-Puig from the Université Paris-Descartes and Assistance Publique-Hôpitaux de Paris, France.

"These studies demonstrate – in both first-line and pretreated settings – the consistent, clinically relevant efficacy of Erbitux in metastatic CRC patients with KRAS wild-type tumors, further exceeding the benefit provided by Erbitux plus irinotecan in non-selected patients," added Professor Sabine Tejpar, University Hospital Gasthuisberg in Leuven, Belgium.

Merck Serono is committed to improving the lives of people with cancer and is pioneering research into the use of biomarkers to identify patients who will most benefit from treatment with targeted therapies such as Erbitux. The ongoing analyses of the large randomized first-line studies of Erbitux in combination with chemotherapy will further help to understand the potential role of KRAS in the treatment of metastatic colorectal cancer.

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.4 Approximately 25% of patients present with metastatic disease.5 Five-year survival rates for patients with mCRC are as low as 5%.6

About KRAS

Mutations in the KRAS gene can turn it into an oncogene that plays an important role in the EGFR signaling pathway and activates other proteins associated with cancer proliferation.7 It is a specific marker of downstream pathways.


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 tumor cells and the spread of tumors to new sites. It is also believed to inhibit the ability of tumor cells to repair the damage caused by chemotherapy and radiotherapy and to inhibit the formation of new blood vessels inside tumors, which appears to lead to an overall suppression of tumor growth.

The most commonly reported side effect with Erbitux is an acne-like skin rash that seems to be correlated with a good response to therapy. In approximately 5% of patients, hypersensitivity reactions may occur during treatment with Erbitux; about half of these reactions are severe.

Erbitux has already obtained market authorization in 69 countries. It has been approved for the treatment of colorectal cancer in 68 countries so far: Argentina, Australia, Belarus, Canada, Chile, China, Colombia, Costa Rica, Croatia, Dominican Republic, Ecuador, El Salvador, the European Union, Guatemala, Honduras, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Lebanon, Malaysia, Mexico, New Zealand, Nicaragua, Norway, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Korea, Switzerland, Taiwan, Thailand, Ukraine, Uruguay, the US, and Venezuela for use in combination with irinotecan in patients with EGFR-expressing mCRC who have failed prior irinotecan therapy. Erbitux is also approved for single-agent use in: Argentina, Australia, Canada, Chile, Colombia, Costa Rica, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Hong Kong, Lebanon, Mexico, New Zealand, Nicaragua, Panama, Peru, the Philippines, Russia, Singapore, Thailand, the US, and Venezuela.

In addition, Erbitux in combination with radiotherapy has been approved for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) in 61 countries: Argentina, Australia, Belarus, Brazil, Chile, Colombia, Costa Rica, Croatia, El Salvador, the European Union, Guatemala, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Lebanon, Malaysia, Mexico, Nicaragua, Norway, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, Switzerland, Taiwan, Ukraine, Uruguay, the US, and Venezuela. In Argentina, Chile, Costa Rica, El Salvador, Guatemala, Hong Kong, Israel, Lebanon, Mexico, Nicaragua, Panama, Peru, the Philippines, Russia, and the US, Erbitux is also approved as monotherapy in patients with recurrent and/or metastatic SCCHN who failed prior chemotherapy.

Merck licensed the right to market Erbitux outside the US and Canada from ImClone Systems Incorporated of New York in 1998. In Japan, ImClone Systems Incorporated, Bristol-Myers Squibb Company and Merck jointly develop and, upon approval, commercialize Erbitux. Merck has an ongoing commitment to the advancement of oncology treatment and is currently investigating novel therapies in highly targeted areas, such as the use of Erbitux in colorectal cancer, squamous cell carcinoma of the head and neck and non-small cell lung cancer. Merck has also acquired the rights for the cancer treatment UFT® (tegafur-uracil) – an oral chemotherapy administered with folinic acid (FA) for the first-line treatment of metastatic colorectal cancer.

Merck is also investigating among other cancer treatments the use of Stimuvax® (formerly referred to as BLP25 Liposome Vaccine) in the treatment of non-small cell lung cancer. The vaccine was granted fast-track status in September 2004 by the FDA. Merck obtained the exclusive worldwide licensing rights from Oncothyreon Inc., Bellevue, Washington, USA.



1. De Roock W et al. Ann Oncol 2007; Nov 12 Epub.

2. Lievre, A et al. J Clin Onc 2008; 26(3): 374-379.

3. Tabernero et al. Abstract Number 435; ASCO GI 2008.

4. Parkin DM et al. CA Cancer J Clin 2005; 55: 72-108.


6. Argiris A et al. Cancer 2004; 101: 2222-2229.

7. Benvenuti, S. Cancer Res 2007; 67: 2643-2648.

About Merck Serono

Merck Serono, the new division for innovative small molecules and biopharmaceuticals of Merck, was established following the acquisition of Serono and the integration of its business with the former Merck Ethicals Division. Headquartered in Geneva, Switzerland, Merck Serono discovers, develops, produces and commercializes innovative products to help patients with diseases with unmet needs. Our North American business operates in the United States and Canada under EMD Serono.

Merck Serono has leading brands serving patients with cancer (Erbitux®), multiple sclerosis (Rebif®), infertility (Gonal-f®), metabolic and cardiometabolic disorders (Glucophage®, Concor®, Saizen®, Serostim®), as well as psoriasis (Raptiva®). With an annual R&D investment of € 1bn, we are committed to growing our business in specialist-focused therapeutic areas, such as Neurology and Oncology, as well as new therapeutic areas potentially arising out of our research and development in autoimmune and inflammatory diseases.

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About Merck KGaA

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Merck is a global pharmaceutical and chemical company with sales of EUR 6.3 billion in 2006, a history that began in 1668, and a future shaped by 30,962 employees in 61 countries. Its success is characterized by innovations from entrepreneurial employees. Merck's operating activities come under the umbrella of Merck KGaA, in which the Merck family holds an approximately 70% interest and free shareholders own the remaining approximately 30%. In 1917 the U.S. subsidiary Merck & Co. was expropriated and has been an independent company ever since.


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Posted: January 2008