Merck Serono, a division of Merck KGaA, Darmstadt, Germany, announced that Erbitux (cetuximab) can now be used in Japan in combination with chemotherapy in the 1st-line treatment for patients with epidermal growth factor receptor (EGFR)-expressing, curatively unresectable (inoperable), advanced or recurrent colorectal cancer (mCRC) carrying the KRAS wildtype gene. This development is due to a change in the Japanese product information for Erbitux.

“The use of Erbitux as a 1st-line treatment for colorectal cancer is an important step in increasing the availability of treatment options for Japanese patients in this setting,” said Dr Wolfgang Wein, executive vice president, oncology, Merck Serono.

The approval of this extended usage for Erbitux was granted following submission of data from the phase III CRYSTALa trial to Japan’s Pharmaceutical and Medical Devices Agency (PMDA).

Updated data of CRYSTAL were presented at the American Society of Clinical Oncology’s 2010 Gastrointestinal Cancers Symposium (ASCO-GI) supporting the value of Erbitux in the 1st-line therapy of mCRC patients with KRAS wild-type tumours. They demonstrated a significant overall survival advantage for patients who were treated with Erbitux in combination with FOLFIRI compared to those who received chemotherapy alone. In addition, the updated analysis showed that the combination of Erbitux and FOLFIRI also significantly reduced the risk of disease progression by 30% (HR 0.696; p=0.0012) and increased the tumour response rate (RR 57.3% vs. 39.7%; p<0.0001) compared to chemotherapy alone.

“The striking improvement in response rates seen in patients treated with Erbitux added to chemotherapy is of vital importance in Japan. High response rates mean significant tumour shrinkage, and studies show that this leads to increased opportunities for complete removal of the tumor and a higher potential for the disease to be cured,” said Wayne Paterson, managing director of Merck Serono Co., Ltd, Japan. “This is of particular value in a country where cure rather than palliation is a primary treatment objective.”

In Japan, Merck Serono began marketing Erbitux as a treatment of curatively unresectable, advanced/recurrent colorectal cancer on September 19, 2008. The development of Erbitux in Japan was based on a collaborative effort between Merck KGaA, ImClone LLC (a wholly-owned subsidiary of Eli Lilly & Co.), Bristol-Myers Squibb Company, Merck Serono Co., Ltd. Japan and Bristol-Myers K.K. Merck receives 50% of the profit or loss from sales in Japan whereas ImClone and Bristol-Myers Squibb each receive 25% of the profit or loss from sales in Japan.

The incidence of colorectal cancer in Japan has increased nearly five-fold in the last 25 years, mainly due to westernization of the diet.[iii] With more than 95,000 new cases reported in Japan in 2002, it has become the most common cancer among women and the second most common among men, after stomach cancer.

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.

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 79 countries. It has been approved for the treatment of colorectal cancer in 79countries and for the treatment of squamous cell carcinoma of the head and neck (SCCHN) in 76 countries.

Merck licensed the right to market Erbitux outside the US and Canada from ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, in 1998. In Japan, ImClone, Bristol-Myers Squibb Company and Merck jointly develop and 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 and breast cancer. The vaccine was granted fast-track status in September 2004 by the FDA. Merck obtained the exclusive worldwide licensing rights from Oncothyreon Inc., Seattle, Washington, USA.

In addition, Merck is developing cilengitide, which is the first in a new class of investigational anti-cancer therapies called integrin inhibitors to reach phase III of development; it is currently being investigated for the treatment of glioblastoma, SCCHN and NSCLC. Integrin inhibitors are thought to work by targeting the tumor and its vasculature.

Merck Serono is the division for innovative prescription pharmaceuticals of Merck KGaA, Darmstadt, Germany, a global pharmaceutical and chemical company.