DARMSTADT, Germany, September 25 /PRNewswire/ --

- Abstracts: 3000, 3001, 3003, 3025, 3055, 3040, 3017, 5501, 0522

- Location: 14th European Congress of Clinical Oncology (ECCO) 2007, Barcelona, Spain

A wealth of promising Erbitux(R) (cetuximab) data was presented this week at the 14th European Congress of Clinical Oncology (ECCO). The studies presented across numerous cancer types demonstrate new evidence on the safety of Erbitux in combination therapy. In addition, a current summary of consistent efficacy of Erbitux in both first-line and subsequent treatment of metastatic colorectal cancer (mCRC) and an update on the efficacy of Erbitux in squamous cell carcinoma of the head and neck (SCCHN) was provided.

First-line metastatic colorectal cancer (mCRC)

The CAIRO (2) trial, a randomized Phase III trial in more than 700 patients confirmed the safety of the addition of Erbitux to a combination of capecitabine, oxaliplatin and bevacizumab in previously untreated patients with mCRC. These findings are very encouraging in light of a recently presented study investigating another EGFR monoclonal antibody in a similar setting in first-line mCRC, which was stopped prematurely due to safety concerns based on increased toxicity, without improving efficacy.(1)

Professor C. J. A. Punt, Radboud University Nijmegen Medical Center, the Netherlands, commented on the new findings: "These Erbitux data are important because safety and combinability are prerequisites for the successful development of anti-EGFR therapies in first-line mCRC."

The CRYSTAL(a) trial, a Phase III, randomized, controlled international trial studied over 1,000 patients and demonstrated a statistically significant increase of progression-free survival (PFS) in the Erbitux/FOLFIRI group compared with the FOLFIRI group. More importantly, there was an overall 15% reduction in the risk of mCRC growing or spreading. The study also showed that using Erbitux significantly increased response rate (tumor shrinkage by 50% or more) (47% in the Erbitux plus FOLFIRI group compared to 39% in the FOLFIRI alone group). In addition, the number of complete resections was three times higher in the Erbitux plus FOLFIRI arm compared with FOLFIRI alone.

The CRYSTAL study is the pivotal study for the application to the European Medicines Agency (EMEA) by Merck Serono (NYSE:SRA) to extend the use of Erbitux as a first-line therapy for the treatment of mCRC.

"These encouraging results are great news for patients as they indicate that we have a potential new first-line treatment option for metastatic colorectal cancer," said Eric Van Cutsem, MD, PhD, a professor at University Hospital Gasthuisberg in Leuven, Belgium, and lead author of the study. "Based on these findings, this combination of Erbitux plus FOLFIRI may offer real hope of cure for patients by shrinking the tumor sufficiently to enable complete resection."

Pre-treated mCRC

Relevant data to further enhance the benefit of targeted therapies were presented on the identification of biomarkers to determine the most effective therapy for individual patients. At ASCO, earlier this year, data presented on Erbitux treated patients demonstrated the potential importance of KRAS as a predictive biomarker. Retrospective analyses of KRAS mutation data demonstrated that in patients without KRAS mutation (KRAS wild type), the combination of Erbitux and irinotecan as third-line treatment of patients with mCRC resulted in a progression-free survival of 34 weeks vs. 12 weeks in patients with KRAS mutation.(2) Clearly, further investigations are required to better understand the role of the various biomarkers in defining CRC therapy.

Additional data confirming the consistent efficacy of Erbitux in CRC have been generated in previously treated patients. Data from the Phase III EPIC(b) study, which compared Erbitux plus irinotecan-based therapy with irinotecan-based therapy alone in mCRC patients who had failed first-line treatment with oxaliplatin-based chemotherapy, have demonstrated that the addition of Erbitux resulted in significantly better response rates and a significant reduction in the risk of tumor progression. With better tumor control, health-related quality of life was significantly improved in the Erbitux arm. Using a validated Quality of Life assessment tool, a statistically significant difference in favor of the Erbitux arm was seen in 10 of the 15 symptom scales, including pain (p<0.0001), nausea (p<0.0001) and global health status (p=0.047).

"The first set of data from the EPIC trial demonstrated that progression-free survival and tumor shrinkage increased significantly when Erbitux was administered to this patient population. It is therefore very encouraging to see from this data a significant clinical advantage with Erbitux according to subjective as well as objective parameters," said lead investigator Professor Alberto Sobrero, Hospedale San Martino, Genova, Italy. "For patients with metastatic colorectal cancer, feeling better while reaping the efficacy benefits of targeted therapy is clearly of great importance."

Data presented from the European MABEL(c) study suggest that the type of pre-medication given to mCRC patients might impact on the occurrence of infusion-related reactions (IRRs) associated with Erbitux plus irinotecan therapy. The data shows that the addition of corticosteroids to antihistamines may reduce IRRs to 1% and, importantly, this is achieved without altering anti-tumor efficacy.

The Latin American LABEL(d) study confirmed the therapeutic potential of Erbitux in a heavily pre-treated patient population, 24% of which had received three or more prior therapies for mCRC. In this single arm study, Erbitux plus irinotecan achieved an overall response rate of 27%, a median progression-free survival duration of more than 4 months, and an overall median survival of 9.7 months, confirming the consistent activity of Erbitux seen in previous studies.

The results of MABEL and LABEL studies confirm the findings of the pivotal BOND study, on which Erbitux's current license is based.(3)

Dose escalation or alternative dosing studies in mCRC

The 045 study presented reviewed the safety and efficacy of Erbitux given every second week. Results showed that Erbitux can be safely administered every two weeks at dose of 500 mg/m2.

Data from the EVEREST(e) study indicate that individual dose adjustments guided by the degree of skin reaction may result in higher response rates. The EVEREST study examined the effect of Erbitux dose escalation on mCRC patients who experienced no or mild skin reaction when treated with the standard dose of Erbitux (250 mg/m2) for 3 weeks. The study showed that increasing the dose of Erbitux incrementally up to 500 mg/m2/week can lead to a tumor response in patients who may not respond to the standard dose.

"The wealth of data from these studies in metastatic colorectal cancer also includes patients with a less good performance status than 0 and 1, which makes the data representative of the daily practice of physicians treating cancer," said Dr. Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono - a division of Merck KGaA, Darmstadt, Germany. "We are delighted with this promising Erbitux data shown across numerous cancer types. The results contribute towards our overall strategy in oncology of developing innovative targeted therapies to advance treatment options for patients with 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)

First-line squamous cell carcinoma of the head and neck (SCCHN)

Erbitux combined with platinum-based chemotherapy as a first-line treatment has also proven effective in increasing overall survival for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN), which is notoriously difficult to treat. A Phase III randomized controlled European trial, EXTREME(f), studied more than 400 patients treated with Erbitux in combination with either cisplatin- or carboplatin-based therapy compared with patients treated with platinum-based therapy alone. Patients receiving Erbitux had a significantly higher response rate, an almost doubling of the time to tumor progression and a significantly longer survival. The trial represents a significant breakthrough and the first time in 25 years that a survival benefit has been demonstrated in this group of patients in a randomized Phase III trial.

Lead investigator for the EXTREME trial, Professor J. Vermorken, Department of Oncology, University Hospital, Antwerp, commented "These results provide great hope for patients who for so many years have been faced with little optimism. For the first time in 25 years, we can offer patients a therapy that has proven effective in increasing overall survival without compromising quality of life. Erbitux really is a breakthrough in treatment for this type of cancer."

Head and neck cancer may occur in the epithelial cells of any tissue or organ in the head and neck region excluding the eyes, brain, ears, thyroid or esophagus. Most head and neck cancers occur in the oral cavity (43%) followed by the pharynx (33%) and the larynx (24%).(7) The estimated incidence of head and neck cancers in Europe is around 140,000 annually, with over 65,000 deaths per year.(8) Currently, median survival for patients with recurrent or metastatic disease is only about six months.(9)

(a) CRYSTAL: Cetuximab combined with iRinotecan in first line therapY for metaSTatic colorectAL cancer

(b) EPIC: European Prospective Investigation of Cancer

(c) MABEL: Monoclonal Antibody ErBitux in a European Pre-License Study

(d) LABEL: Latin American ErBitux prE-License study

(e) EVEREST: Evaluation of Various ErBitux REgimens by means of Skin and Tumour biopsies

(f) EXTREME: ErbituX in first line Treatment of REcurrent or MEtastatic head & neck cancer

Notes for Editors

About ERBITUX

ERBITUX(R) 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 68 countries. It has been approved for the treatment of colorectal cancer in 67 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, Montenegro, New Zealand, Nicaragua, Norway, Panama, Peru, the Philippines, Russia, Serbia, Singapore, South Korea, Switzerland, Taiwan, Thailand, Ukraine, 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 60 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, Montenegro, Nicaragua, Norway, Panama, Peru, the Philippines, Russia, Serbia, Singapore, Switzerland, Taiwan, Ukraine, 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, Merck KGaA has co-exclusive marketing rights with ImClone Systems. 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(R) (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(R) (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 Biomira Inc. of Edmonton, Alberta, Canada.

About KRAS

KRAS plays an important role in tumor development. It is a specific marker of downstream pathways.

References:

(1) Amgen Press Release, March 22, 2007.

(2) De Roock W et al. J Clin Oncol 2007;25(18S):Abstract 4132.

(3) Cunningham D, et al. Bowel Oncology with cetuximab antibody (BOND) study. Proc Am Soc Clin Oncol 2003; 22.

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

(5) GLOBOCAN. http://www-dep.iarc.fr/

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

(7) Parkin DM et al. CA Cancer J Clin 2005; 55; 72-108.

(8) GLOBOCAN. http://www-dep.iarc.fr/

(9) Argiris A et al. Cancer 2004; 101: 2222-2229.

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(R)), multiple sclerosis (Rebif(R)), infertility (Gonal-f(R)), metabolic and cardiometabolic disorders (Glucophage(R), Concor(R), Saizen(R), Serostim(R)), as well as psoriasis (Raptiva(R)). With an annual R&D investment of EUR 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.

For more information, please visit http://www.merckserono.net or http://www.merck.de

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 35,214 employees in 63 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.

Contact: Dr. Raphaela Farrenkopf, Phone: +49-6151-72-2274