Amgen has 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 (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 website and will be in the April 2008 print edition.
These findings are the first published results from a phase III randomized, controlled clinical trial to affirm the link between non-mutated (wild-type) KRAS in tumours, 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 tumours. The effect of Vectibix on PFS and response rate appeared to be confined exclusively to the patients whose tumours harbour 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, 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 tumour sections.
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 tumours harbouring 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 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 US, 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 III 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 tumour types.