• Erbitux shows a 77% response rate in patients with KRAS wild-type tumors with metastases confined to the liver in CRYSTAL, a Phase III study
• Erbitux shows a 79% response rate in patients with KRAS wild-type tumors with initially unresectable metastases, leading to resection of liver metastases in 43%, with 34% being R0 resections in CELIM, a randomized Phase II study
Stockholm; Darmstadt, Sweden | September 16, 2008 | Data presented at the 33rd European Society for Medical Oncology (ESMO) Congress in Stockholm this week further reinforce the value of Merck’s Erbitux(R) (cetuximab) as a new standard in the first-line treatment of metastatic colorectal cancer (mCRC).
Enhanced efficacy in KRAS wild-type tumors
After previously reported response rates of up to 60%, an update of data from the CRYSTALa study was presented this week showing a response rate of 77% for patients with KRAS wild-type tumors and metastases limited to the liver.1 The CRYSTAL and OPUSb studies formed the basis for the recently granted approval of Erbitux in Europe for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type mCRC. The results of these studies showed that patients with KRAS wild-type tumors treated with Erbitux experienced substantially higher efficacy than those patients receiving chemotherapy alone.2-5 Given that approximately 65% of all mCRC patients have KRAS wild-type tumors,1,2,4 this enhanced efficacy is highly clinically relevant.
In both studies, the addition of Erbitux to standard chemotherapy resulted in remarkably high response rates of about 60%, clearly exceeding the response rates seen with chemotherapy alone (CRYSTAL: 59% vs. 43%; OPUS: 61% vs. 37%) and a distinct reduction in the risk of further disease progression (CRYSTAL: -32%, hazard ratio 0.68; OPUS: -43%, hazard ratio 0.57).1,5
“Tumor response, namely the reduction of tumor mass, is an important clinical achievement in the first-line treatment of mCRC,” 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. “Shrinking the tumor is of utmost importance, especially for those patients with very painful, rapidly growing or acutely life-threatening tumors or metastases, and for those patients in whom effective tumor shrinkage might allow complete surgical resection of metastases and therefore a potential cure. With KRAS testing we are now able to identify those patients who are most likely to respond to treatment with Erbitux.”
Increased potential for cure for patients with metastases limited to the liver
The outcomes of the randomized CELIMc trial further endorse the data presented from the CRYSTAL study, showing that the addition of Erbitux leads to an increase in response rate and the possibility of curative resection.6
The CELIM study investigated the efficacy of Erbitux in combination with two different standard chemotherapy regimens (FOLFIRI or FOLFOX) in patients with unresectable liver metastases. The efficacy analysis of the CELIM trial showed that 79% of patients with KRAS wild-type tumors experienced distinct tumor shrinkage, allowing resection in 43% of these patients and complete surgical removal of the tumor in 34%.6
“This study confirms that the high response rates observed in metastatic colorectal cancer patients treated with a combination of Erbitux and standard chemotherapy results in a high resection rate, importantly even in previously unresectable patients,” said Dr. Gunnar Folprecht, lead investigator of the CELIM study and Senior Consultant at the Department of Medical Oncology, University Hospital, Dresden, Germany. “Being able to achieve complete resection rates as high as 34% in these patients is remarkable and offers them a real chance of cure.”
“CELIM opens new therapeutic options, showing that almost every second patient in this randomized trial could undergo resection of liver metastases. The data from the CRYSTAL, OPUS and CELIM studies impressively demonstrate the superior activity achieved by the addition of Erbitux to standard chemotherapies with high response rates of up to 80% across the board,” concluded Dr. Wolfgang Wein, Executive Vice President, Oncology, Merck Serono, Darmstadt, Germany. “This is a major step forward for patients who depend on effective treatments for tumor shrinkage and who may now even have a chance for cure.”
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.7 Approximately 25% of patients present with metastatic disease.8 Five-year survival rates for patients with mCRC are as low as 5%.9
a CRYSTAL: Cetuximab combined with iRinotecan in first line therapY for metaSTatic colorectAL cancer
b OPUS: OxaliPlatin and cetUximab in firSt-line treatment of mCRC
c CELIM: Randomized multicenter study of CEtuximab plus FOLFOX or FOLFIRI in neoadjuvant treatment of non-resectable colorectal LIver Metastases
References
1. Van Cutsem E, et al. ESMO 2008; Abstract No: 710.
2. Van Cutsem E, et al. ASCO 2008; Abstract No: 2.
3. Bokemeyer C, et al. ASCO 2008; Abstract No: 4000.
4. Van Cutsem E, et al. WCGIC 2008; Abstract No: 471.
5. Schuch G, et al. WCGIC 2008; Abstract No: 385.
6. Folprecht G, et al. ESMO 2008; Abstract No: 510.
7. Parkin DM, et al. CA Cancer J Clin 2005;55:72–108.
8. Cunningham D and Findley M. Eur J Cancer 1993;29A(15):2077–2079.
9. Macdonald JS. CA Cancer J Clin 1999;49(4):202–219.
For more information on Erbitux in colorectal, head & neck and non-small cell lung cancer, please visit: www.globalcancernews.com.
About KRAS
KRAS is a gene that codes for a protein involved in the EGFR pathway. In tumors with the wild-type (non-mutated) KRAS gene, the KRAS protein is tightly regulated and only activated by certain stimuli such as EGFR signaling. This allows the EGFR targeted antibody Erbitux to effectively block the downstream signaling. 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.
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 75 countries. It has been approved for the treatment of colorectal cancer in 74 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, Japan, Kazakhstan, Kuwait, Lebanon, Liechtenstein, Malaysia, Mexico, Moldavia, 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, Japan, Lebanon, Mexico, Moldavia, New Zealand, Nicaragua, Panama, Peru, the Philippines, Russia, Singapore, Thailand, the US, and Venezuela. In the European Union, the license was updated in July 2008 for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type mCRC (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.
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 68 countries: Argentina, Australia, Belarus, Brazil, Chile, Colombia, Costa Rica, Croatia, El Salvador, the European Union, Guatemala, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Kuwait, Lebanon, Liechtenstein, Malaysia, Mexico, Moldavia, New Zealand, Nicaragua, Norway, Oman, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Africa, South Korea, Switzerland, Taiwan, Ukraine, Uruguay, the US, and Venezuela. In Argentina, Chile, Costa Rica, El Salvador, Guatemala, Hong Kong, Israel, Lebanon, Mexico, Moldavia, 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(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 Oncothyreon Inc., Bellevue, Washington, USA.
About Merck
All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to http://www.subscribe.merck.de to register online, change your selection or discontinue this service.
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 31,946 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.
SOURCE: Merck
Post Views: 154
• Erbitux shows a 77% response rate in patients with KRAS wild-type tumors with metastases confined to the liver in CRYSTAL, a Phase III study
• Erbitux shows a 79% response rate in patients with KRAS wild-type tumors with initially unresectable metastases, leading to resection of liver metastases in 43%, with 34% being R0 resections in CELIM, a randomized Phase II study
Stockholm; Darmstadt, Sweden | September 16, 2008 | Data presented at the 33rd European Society for Medical Oncology (ESMO) Congress in Stockholm this week further reinforce the value of Merck’s Erbitux(R) (cetuximab) as a new standard in the first-line treatment of metastatic colorectal cancer (mCRC).
Enhanced efficacy in KRAS wild-type tumors
After previously reported response rates of up to 60%, an update of data from the CRYSTALa study was presented this week showing a response rate of 77% for patients with KRAS wild-type tumors and metastases limited to the liver.1 The CRYSTAL and OPUSb studies formed the basis for the recently granted approval of Erbitux in Europe for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type mCRC. The results of these studies showed that patients with KRAS wild-type tumors treated with Erbitux experienced substantially higher efficacy than those patients receiving chemotherapy alone.2-5 Given that approximately 65% of all mCRC patients have KRAS wild-type tumors,1,2,4 this enhanced efficacy is highly clinically relevant.
In both studies, the addition of Erbitux to standard chemotherapy resulted in remarkably high response rates of about 60%, clearly exceeding the response rates seen with chemotherapy alone (CRYSTAL: 59% vs. 43%; OPUS: 61% vs. 37%) and a distinct reduction in the risk of further disease progression (CRYSTAL: -32%, hazard ratio 0.68; OPUS: -43%, hazard ratio 0.57).1,5
“Tumor response, namely the reduction of tumor mass, is an important clinical achievement in the first-line treatment of mCRC,” 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. “Shrinking the tumor is of utmost importance, especially for those patients with very painful, rapidly growing or acutely life-threatening tumors or metastases, and for those patients in whom effective tumor shrinkage might allow complete surgical resection of metastases and therefore a potential cure. With KRAS testing we are now able to identify those patients who are most likely to respond to treatment with Erbitux.”
Increased potential for cure for patients with metastases limited to the liver
The outcomes of the randomized CELIMc trial further endorse the data presented from the CRYSTAL study, showing that the addition of Erbitux leads to an increase in response rate and the possibility of curative resection.6
The CELIM study investigated the efficacy of Erbitux in combination with two different standard chemotherapy regimens (FOLFIRI or FOLFOX) in patients with unresectable liver metastases. The efficacy analysis of the CELIM trial showed that 79% of patients with KRAS wild-type tumors experienced distinct tumor shrinkage, allowing resection in 43% of these patients and complete surgical removal of the tumor in 34%.6
“This study confirms that the high response rates observed in metastatic colorectal cancer patients treated with a combination of Erbitux and standard chemotherapy results in a high resection rate, importantly even in previously unresectable patients,” said Dr. Gunnar Folprecht, lead investigator of the CELIM study and Senior Consultant at the Department of Medical Oncology, University Hospital, Dresden, Germany. “Being able to achieve complete resection rates as high as 34% in these patients is remarkable and offers them a real chance of cure.”
“CELIM opens new therapeutic options, showing that almost every second patient in this randomized trial could undergo resection of liver metastases. The data from the CRYSTAL, OPUS and CELIM studies impressively demonstrate the superior activity achieved by the addition of Erbitux to standard chemotherapies with high response rates of up to 80% across the board,” concluded Dr. Wolfgang Wein, Executive Vice President, Oncology, Merck Serono, Darmstadt, Germany. “This is a major step forward for patients who depend on effective treatments for tumor shrinkage and who may now even have a chance for cure.”
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.7 Approximately 25% of patients present with metastatic disease.8 Five-year survival rates for patients with mCRC are as low as 5%.9
a CRYSTAL: Cetuximab combined with iRinotecan in first line therapY for metaSTatic colorectAL cancer
b OPUS: OxaliPlatin and cetUximab in firSt-line treatment of mCRC
c CELIM: Randomized multicenter study of CEtuximab plus FOLFOX or FOLFIRI in neoadjuvant treatment of non-resectable colorectal LIver Metastases
References
1. Van Cutsem E, et al. ESMO 2008; Abstract No: 710.
2. Van Cutsem E, et al. ASCO 2008; Abstract No: 2.
3. Bokemeyer C, et al. ASCO 2008; Abstract No: 4000.
4. Van Cutsem E, et al. WCGIC 2008; Abstract No: 471.
5. Schuch G, et al. WCGIC 2008; Abstract No: 385.
6. Folprecht G, et al. ESMO 2008; Abstract No: 510.
7. Parkin DM, et al. CA Cancer J Clin 2005;55:72–108.
8. Cunningham D and Findley M. Eur J Cancer 1993;29A(15):2077–2079.
9. Macdonald JS. CA Cancer J Clin 1999;49(4):202–219.
For more information on Erbitux in colorectal, head & neck and non-small cell lung cancer, please visit: www.globalcancernews.com.
About KRAS
KRAS is a gene that codes for a protein involved in the EGFR pathway. In tumors with the wild-type (non-mutated) KRAS gene, the KRAS protein is tightly regulated and only activated by certain stimuli such as EGFR signaling. This allows the EGFR targeted antibody Erbitux to effectively block the downstream signaling. 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.
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 75 countries. It has been approved for the treatment of colorectal cancer in 74 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, Japan, Kazakhstan, Kuwait, Lebanon, Liechtenstein, Malaysia, Mexico, Moldavia, 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, Japan, Lebanon, Mexico, Moldavia, New Zealand, Nicaragua, Panama, Peru, the Philippines, Russia, Singapore, Thailand, the US, and Venezuela. In the European Union, the license was updated in July 2008 for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type mCRC (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.
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 68 countries: Argentina, Australia, Belarus, Brazil, Chile, Colombia, Costa Rica, Croatia, El Salvador, the European Union, Guatemala, Hong Kong, Iceland, India, Indonesia, Israel, Kazakhstan, Kuwait, Lebanon, Liechtenstein, Malaysia, Mexico, Moldavia, New Zealand, Nicaragua, Norway, Oman, Panama, Peru, the Philippines, Qatar, Russia, Serbia, Singapore, South Africa, South Korea, Switzerland, Taiwan, Ukraine, Uruguay, the US, and Venezuela. In Argentina, Chile, Costa Rica, El Salvador, Guatemala, Hong Kong, Israel, Lebanon, Mexico, Moldavia, 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(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 Oncothyreon Inc., Bellevue, Washington, USA.
About Merck
All Merck Press Releases are distributed by e-mail at the same time they become available on the Merck Website. Please go to http://www.subscribe.merck.de to register online, change your selection or discontinue this service.
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 31,946 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.
SOURCE: Merck
Post Views: 154
