Merck KGaA: Erbitux - Enhanced Efficacy Demonstrated in Patients With KRAS Wild-Type Tumors

Merck KGaA: Erbitux - Enhanced Efficacy Demonstrated in Patients With KRAS Wild-Type Tumors in First-Line Metastatic Colorectal Cancer

Data from two new analyses establish Erbitux as a future standard treatment in 1st-line mCRC patients with KRAS wild-type tumors

Chicago/Darmstadt, June 1, 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 so-called tumors with wild-type KRAS. These results were presented today 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 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)

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.(3,4) 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.(5,6,7) The data presented today 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 mirrored in the remarkably high response rates, translating to favorable outcomes for these patients.(1,2)
"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 tumors," 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 tumor 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 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=0.02], 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% and a very meaningful decrease in the risk of progression of up to 43% in patients with KRAS wild-type tumors 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 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) 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.(8) Approximately 25% of patients present with metastatic disease.(9) Five-year survival rates for patients with mCRC are as low as 5%.(10)

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


About ERBITUX
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 72 countries. It has been approved for the treatment of colorectal cancer in 71 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, Liechtenstein, Malaysia, Mexico, New Zealand, Nicaragua, Norway, Oman, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Africa, 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 65 countries: Argentina, Australia, Belarus, Brazil, Chile, Colombia, Costa Rica, Croatia, El Salvador, the European Union, Guatemala, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Lebanon, Liechtenstein, Malaysia, Mexico, New Zealand, Nicaragua, Norway, Oman, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Africa, Switzerland, Taiwan, Ukraine, Uruguay, the US, and Venezuela. In Argentina, Chile, Costa Rica, El Salvador, Guatemala, Hong Kong, Israel, Lebanon, Mexico, Nicaragua, 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 1st-line treatment of metastatic colorectal cancer.

Merck is also investigating among other cancer treatments the use of 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.

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Merck is a global pharmaceutical and chemical company with total revenues of € 7.1 billion in 2007, a history that began in 1668, and a future shaped by 31,681 employees in 60 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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