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|KRAS Biomarker Analysis from Pivotal Vectibix(TM) Trial Published|
|Manuscript Data Delineate Potential Role of KRAS Oncogene in Patient Selection for Vectibix Treatment|
THOUSAND OAKS, Calif., Mar 04, 2008 (BUSINESS WIRE) -- Amgen (NASDAQ: AMGN) today announced that the results from a biomarker analysis of the pivotal "408" trial were published in the Journal of Clinical Oncology (JCO). The analysis showed that KRAS mutations could be used to identify patients who may not respond to treatment with Vectibix(TM) (panitumumab) monotherapy, the first fully human anti-epidermal growth factor receptor (EGFr) monoclonal antibody. These data were previously reported at the European Cancer Conference in 2007 and the Gastrointestinal Cancer Symposium in January 2008. The paper was made available early online on the JCO Web site and will be in the April 2008 print edition.
These findings are the first published results from a Phase 3 randomized, controlled clinical trial to affirm the link between non-mutated (wild-type) KRAS in tumors, and the efficacy of treatment with anti-EGFr in patients with metastatic colorectal cancer (mCRC). The analysis met primary and secondary endpoints by demonstrating that the effect of Vectibix on progression-free survival (PFS) was different in patients according to the mutational status of the KRAS gene in their tumors. The effect of Vectibix on PFS and response rate appeared to be confined exclusively to the patients whose tumors harbor normal, non-mutated KRAS.
"These results validate the importance of the KRAS oncogene in identifying appropriate patients for treatment with Vectibix monotherapy in the advanced colorectal cancer setting," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "We have developed the first prospective clinical trials with KRAS in earlier lines of mCRC to enhance our understanding of this biomarker and its potential application. We also are continuing to investigate the role of other markers to further refine patient selection."
These analyses were derived from the pivotal "408" trial, which had shown that Vectibix monotherapy was significantly more effective than best supportive care in treating mCRC patients in the chemorefractory setting. Activating KRAS mutations were detected using real-time polymerase chain reaction (PCR) on DNA derived mostly from fixed, archived tumor sections.
Results from studies performed over the last twenty-five years indicate that KRAS plays an important role in cell growth regulation. In mCRC, the EGFr transmits signals through a set of intracellular proteins. Upon reaching the nucleus, these signals instruct the cancer cell to reproduce and metastasize, leading to cancer progression. Anti-EGFr therapies work by blocking the activation of EGFr, thereby inhibiting downstream events that lead to malignant signaling. However, it is hypothesized that in patients with tumors harboring a mutated KRAS gene, the KRAS protein is always turned "on," regardless of whether the EGFr has been activated or therapeutically inhibited.
Vectibix was approved in the United States (U.S.) in September 2006 as a single agent for the treatment of patients with EGFr expressing mCRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing mCRC is based on PFS. Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. In the U.S., Vectibix is not approved for use based on KRAS status. In December 2007, the European Medicines Agency (EMEA) granted a conditional marketing authorization for Vectibix as monotherapy for the treatment of patients with EGFr expressing mCRC with non-mutated KRAS genes after failure of standard chemotherapy regimens. Regulatory applications in the rest of the world are still pending.
There are currently ongoing Phase 3 trials examining Vectibix in combination with chemotherapy in the first- and second-line of mCRC. KRAS and other biomarker analyses have and will continue to be integrated into the ongoing clinical program studying Vectibix in earlier lines of mCRC therapy in combination with chemotherapy, as well as in other tumor types.
Important Product Safety Information - U.S.
Dermatologic toxicities, related to Vectibix blockade of EGF binding and subsequent inhibition of EGF receptor-mediated signaling pathways, included but were not limited to dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Dermatologic toxicities were reported in 89 percent of patients treated with Vectibix and were severe in 12 percent of patients. Severe dermatologic toxicities were complicated by infection, including sepsis, septic death, and abscesses requiring incisions and drainage. Vectibix may need to be withheld or discontinued for severe dermatologic toxicities.
Severe infusion reactions occurred with Vectibix in approximately 1 percent of patients. Severe infusion reactions were identified as anaphylactic reactions, bronchospasm, fever, chills, and hypotension. Although fatal infusion reactions have not been reported with Vectibix, they have occurred with other monoclonal antibody products. Severe infusion reactions require stopping the infusion and possibly permanently discontinuing Vectibix, depending on the severity and/or persistence of the reaction.
Important Product Safety Information - European Union
Dermatologic related reactions, a pharmacologic effect observed with EGFr inhibitors, are experienced with nearly all patients (approximately 90 percent) treated with Vectibix. The majority of dermatological reactions are mild to moderate in nature. In clinical studies, subsequent to the development of severe dermatological reactions (including stomatitis), infectious complications including sepsis, in rare cases leading to death, and local abscesses requiring incisions and drainage were reported. Patients who have severe dermatologic reactions or who develop worsening reactions whilst receiving Vectibix should be monitored for the development of inflammatory or infectious sequelae, and appropriate treatment promptly initiated.
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