* Data presented at ASCO confirm KRAS and first-cycle rash as markers of Erbitux efficacy
* Erbitux at forefront of ongoing research involving numerous other exploratory biomarkers such as BRAF to personalize cancer care
Orlando, FL, USA & Darmstadt, Germany | May 31, 2009 | Merck KGaA announced today that the results of numerous studies presented at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting have further extended current knowledge about the utility of biomarkers of response for Erbitux. The ability to predict which patients are most likely to benefit from targeted therapy will allow treatments to be truly personalized, minimizing the likelihood of ‘unnecessary’ side effects and optimizing overall healthcare resource utilization.
Dr Wolfgang Wein, Executive Vice President, Oncology, of Merck’s division Merck Serono said, “Merck Serono Oncology has emerged as one of the leaders in personalizing cancer care, not only by developing new targeted agents, but also by making one of the largest contributions to the expanding science of biomarkers to further personalize treatment.” He continued, “Pairing targeted treatments with predictive biomarkers not only improves the efficacy in the target group, improves the patient benefit and the efficiency of the new drugs, but also differentiates this approach from treatments still administered with the outdated paradigm of unselective use.”
Colorectal Cancer: KRAS Proven Predictive Biomarker
New data support previous findings that metastatic colorectal cancer (mCRC) patients with tumors bearing a normal or ‘wild-type’ KRAS gene – approximately 65% of the overall population – are the most likely to benefit from Erbitux® (cetuximab) therapy. From an analysis of mature overall survival data from KRAS wild-type patients in the pivotal CRYSTALa study, adding Erbitux to FOLFIRI significantly increased the odds for tumor response nearly two-fold, reduced the risk of disease progression by 32% and resulted in a median overall survival of 24.9 months.1 The importance of KRAS status in this setting is further confirmed following a post-study survival update from the CECOG/CORE1.2.001 trial. After a median follow-up of 29 months, median overall survival in patients with KRAS wild-type tumors was significantly improved compared to patients with KRAS mutant tumors (20.8 vs. 15.9 months; Hazard Ratio 1.62; p=0.0296). KRAS was also found to be a strong independent predictor for prolonged survival under Erbitux treatment (p<0.005).2 KRAS as a predictive biomarker for Erbitux efficacy was identified by ASCO as one of the top research advances of 2008.3
An analysis of the potential role of BRAF in mCRC from the CRYSTAL study concluded that BRAF does not appear to show a predictive value for the usage of Erbitux, but seems to be a prognostic marker in first-line metastatic colorectal cancer, affecting 5% percent of evaluable patients in the CRYSTAL study.1
Non-Small Cell Lung Cancer: First-Cycle Rash Early Indicator for Survival
New data from Merck Serono’s pivotal FLEX study showed that the benefit of Erbitux in first-line NSCLC is independent of KRAS status and EGFR gene copy number.4 In addition, the FLEX study did show that those patients who developed first-cycle rash had a median survival of 15 months, clearly exceeding the survival in the chemotherapy alone arm.4 These findings confirm that first-cycle rash can be considered to be an early indicator for a longer survival for patients treated with Erbitux and chemotherapy in this setting.
Head and Neck Cancer: Research Continues
No association between EGFR gene copy number and clinical outcome was found in an analysis from the EXTREME study in recurrent and/or metastatic squamous cell carcinoma of the head and neck.5
Other Biomarkers Under Investigation
Preliminary data on the association between the expression level of – or polymorphisms in – other genes related to EGFR signaling (e.g. EREG, EGFR),1,6-8 antibody-dependent cellular cytotoxicity (FCGR),9 drug metabolism (MTHFR)8 or tumorigenesis (CD133)10 and clinical outcome have yielded interesting results, suggesting that at least some of these potential biomarkers may have a role in predicting treatment response. However, the precise clinical utility of these markers remains to be proven in large-scale, randomized clinical trials.
Dr Oliver Kisker, Senior Vice-President, Global Clinical Development Unit, Merck Serono Oncology, said, “Using targeted therapies to provide good treatment for most cancer patients is only the start.” He continued, “At Merck Serono we are at the forefront of an evolution in personalizing cancer care. We are going further, providing suitable treatments to those patients who can benefit most."
a CRYSTAL: Cetuximab combined with iRinotecan in 1st-line therapY for metaSTatic colorectAL cancer
References
1. Koehne C, et al. ASCO Congress 2009; Abstract No: 4068.
2. Koza I, et al. ASCO Congress 2009; Abstract No: 4055.
3. Winer E, et al. J Clin Oncol 2009;27:812-26.
4. O’Byrne K, et al. ASCO Congress 2009; Abstract No: 8007.
5. Licitra L, et al. ASCO Congress 2009; Abstract No: 6005.
6. Winder T, et al. ASCO Congress 2009; Abstract No: 4061.
7. Jonker D, et al. ASCO Congress 2009; Abstract No: 4016.
8. Yang D, et al. ASCO Congress 2009; Abstract No: 4022.
9. Etienne-Grimaldi M, et al. ASCO Congress 2009; Abstract No: 4069.
10. Pohl A, et al. ASCO Congress 2009; Abstract No: 4062.
For more information on Erbitux in colorectal, head & neck and non-small cell lung cancer, please visit: www.globalcancernews.com.
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 76 countries. It has been approved for the treatment of colorectal cancer in 75 countries and for the treatment of squamous cell carcinoma of the head and neck (SCCHN) in 71 countries:
· December 2003 (Switzerland), February 2004 (USA), June 2004 (EU) and followed by other countries: for use in combination with irinotecan in patients with EGFR-expressing mCRC (metastatic colorectal cancer) who have failed prior irinotecan therapy. In addition, Erbitux is also approved for single-agent use in further countries.
· April 2006 (EU) and followed by other countries: for use in combination with radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN). In further countries, Erbitux is also approved as monotherapy in patients with recurrent and/or metastatic SCCHN who failed prior chemotherapy.
· July 2008 (EU): license was updated for the treatment of patients with epidermal growth factor receptor (EGFR) expressing, KRAS wild-type mCRC 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.
· July 2008 (Japan): for use in combination with irinotecan in patients with EGFR-expressing mCRC who have failed prior irinotecan therapy
· In November 2008 (EU): license was updated for the use in combination with platinum-based chemotherapy in patients with recurrent and/or metastatic SCCHN
Merck licensed the right to market Erbitux outside the US and Canada from ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, in 1998. In Japan, ImClone Systems, 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 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.
