Amgen, a company discovers, develops, manufactures and delivers innovative human therapeutics, has reported results from three analyses of Vectibix (panitumumab) in combination with Folfox, an oxaliplatin-based chemotherapy regimen, as a first-line treatment for metastatic colorectal cancer (mCRC). These analyses include the description of new predictive biomarkers of clinical response to Vectibix, activating mutations in KRAS (beyond exon 2) and mutations in NRAS, collectively referred to as RAS.

"Amgen helped establish KRAS gene mutation as a biomarker for lack of response to anti-EGFR treatment," said Sean E Harper, MD, executive vice president of R&D at Amgen. "The identification of new biomarkers may further help to identify appropriate patients with this incurable disease for such treatment."

The RAS biomarkers were identified in a predefined retrospective subset analysis of the PRIME trial, where RAS was defined as exons 2, 3 and 4 of KRAS and NRAS. Mutational status of tumours was determined by Sanger sequencing in parallel with WAVE-based SURVEYOR Scan Kits (CRC RAScan) from Transgenomic, Inc. (TBIO). In this exploratory analysis, patients with wild-type RAS mCRC who were administered Vectibix in combination with FOLFOX demonstrated an improvement in median overall survival (OS) of 26.0 months compared to 20.2 months for patients treated with FOLFOX alone (HR = 0.78, 95 percent CI, 0.62-0.99).

Patients with mutant RAS tumour status had inferior progression-free survival (PFS) (HR = 1.34, 95 per cent CI, 1.07-1.60) and OS (HR = 1.25, 95 per cent CI, 1.02-1.55) when administered Vectibix in combination with FOLFOX chemotherapy versus Folfox alone. These results suggest that RAS mutation status beyond KRAS may be predictive of negative outcomes in patients receiving Vectibix plus FO Folfox mCRC. Amgen is working to inform investigators and physicians of this important new safety information, as well as working with regulatory agencies regarding appropriate communication of the outcomes of this analysis.

Results of this study will be presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.

In a separate and updated exploratory analysis of longer follow-up of OS of the PRIME trial (primary endpoint of PFS), an improvement in OS was observed in patients with wild-type KRAS exon 2 mCRC treated with Vectibix in combination with Folfox. Median OS was 23.8 months compared to 19.4 months for patients treated with Folfox alone (HR = 0.83, 95 per cent CI, 0.70-0.98). In both PRIME analyses, the most commonly reported adverse events for the Vectibix treatment arms included rash, hypomagnesemia and diarrhoea. The adverse event profiles for the wild-type tumour and mutant tumour populations were similar.

In a separate predefined secondary objective subset analysis of the PEAK study, patients with wild-type RAS mCRC treated with Vectibix in combination with Folfox had a median PFS of 13.1 months compared to 9.5 months (HR = 0.63, 95 percent CI, 0.43-0.94) for patients treated with bevacizumab in combination with Folfox. Median OS was not reached in the Vectibix arm, but the OS HR favored the Vectibix arm (HR = 0.55, 95 per cent CI, 0.33-1.01). The most commonly reported adverse events for the Vectibix treatment arm included rash, hypomagnesemia and dehydration. The adverse event profiles for the wild-type tumor and mutant tumor populations were similar. No new toxicities were identified for Vectibix.

The PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy) ('203) trial is a global, multicenter, randomized phase III study designed to evaluate (primary endpoint of PFS) Vectibix (6.0 mg/kg every two weeks) plus Folfox versus Folfox alone in patients with wild-type KRAS exon 2 mCRC. The primary objective of this predefined retrospective subset analysis was to determine the effect of Vectibix plus Folfox versus Folfox alone on overall survival in patients with mCRC based on RAS or BRAF mutation status. A total of 641 patients were included in this analysis. RAS status was ascertained in 90 per cent of the patients with wild-type KRAS tumours.

The PEAK (Panitumumab Efficacy in Combination with mFOLFOX6 Against bevacizumab plus mFOLFOX6 in mCRC subjects with wild-type KRAS tumors) ('509) trial is a global, multi-centre, randomized phase II study designed to compare the efficacy (primary endpoint of PFS) of Vectibix in combination with FOLFOX to the efficacy of bevacizumab in combination with Folfox in patients with previously untreated, unresectable, wild-type KRAS exon 2 mCRC. The primary objective of this predefined retrospective subset analysis was to determine the effect of Vectibix plus Folfox versus bevacizumab plus FOLFOX o Folfox OS in patients with mCRC based on RAS mutation status.

Results from studies performed over the last 25 years indicate that KRAS plays an important role in cell growth regulation. In mCRC, 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 antibody therapies work by inhibiting the activation of EGFR, thereby inhibiting downstream events that lead to malignant signaling. However, in patients whose tumors harbor a mutated KRAS gene, the KRAS protein is always turned "on," regardless of whether the EGFR has been activated or therapeutically inhibited. Common KRAS mutations occurring in exon 2 (codons 12/13) are present in approximately 40 to 50 per cent of mCRC patients. RAS mutations are mutations occurring in exons 2, 3 and 4 of KRAS and NRAS and based on study data, appear to occur in approximately 16 per cent of patients with wild-type KRAS exon 2.

Colorectal cancer is the third most common cancer found in both men and women in the United States, and is the second leading cause of cancer deaths.

Vectibix is the first fully human anti-EGFR antibody approved by the US Food and Drug Administration (FDA) for the treatment of mCRC. Vectibix was approved in the United States in September 2006 as a single agent for the treatment of patients with EGFR-expressing mCRC with 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. More than half of patients who receive Vectibix monotherapy respond to treatment with an average six month PFS benefit. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.

Retrospective subset analyses of mCRC trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of mCRC with these mutations.