Amgen today announced the publication of a biomarker analysis of Vectibix® (panitumumab) in combination with FOLFOX, a type of oxaliplatin-based chemotherapy, for the first-line treatment of patients with metastatic colorectal cancer (mCRC). Published in the New England Journal of Medicine, the analysis found that RAS mutations, beyond the known KRAS exon 2 mutations, predict lack of response to Vectibix in combination with FOLFOX. RAS mutations are mutations occurring in exons 2, 3 and 4 of KRAS and NRAS.
“In recent years, we have made important progress in treating colorectal cancer with anti-EGFR (epidermal growth factor receptor) antibody therapies. Patients with KRAS exon 2 mutations, however, do not benefit from this treatment. Our latest findings now show that patients with mutations in other regions of KRAS — exons 3 and 4 — as well as those with mutations occurring in exons 3 and 4 of NRAS, do not benefit from treatment with panitumumab”, said Dr. Josep Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron University Hospital, Director of the Vall d´Hebron Institute of Oncology (VHIO), and co-author of the study. “This represents an important step in furthering our understanding of molecular cancer biology and more effectively tailoring anti-colorectal cancer therapies to individual patients”.
This predefined retrospective subset analysis of the PRIME (‘203) study assessed the safety and efficacy of Vectibix plus FOLFOX, compared to FOLFOX alone based on RAS or BRAF mutation status. By more precisely narrowing the pool of patients treated with Vectibix plus FOLFOX to those with wild-type RAS, greater improvements in overall survival (OS) and progression-free survival (PFS) were observed. Specifically, previous data found that OS was improved by 4.4 months in patients with wild-type KRAS. By further narrowing to patients with wild-type RAS, an improvement in OS of 5.8 months was observed.
In patients with wild-type RAS, OS was 26.0 months and 20.2 months (HR = 0.78; 95 percent CI, 0.62 – 0.99) and PFS was 10.1 months and 7.9 months (HR = 0.72, 95 percent CI, 0.58 – 0.90) in the Vectibix plus FOLFOX arm compared to the FOLFOX alone arm, respectively. BRAF mutations were not observed to have predictive value.
Conversely, in the patients with RAS mutations, inferior OS (HR = 1.25, 95 percent CI, 1.02-1.55) and PFS (HR = 1.34, 95 percent CI, 1.07-1.60) were observed in the Vectibix plus FOLFOX arm compared to the FOLFOX alone arm. Amgen has informed investigators and physicians of this important new safety information, and is working with regulatory agencies regarding appropriate communication of the outcomes of the analysis.
“Amgen is proud of our continuing work to identify and establish predictive biomarkers, like RAS, that will help better inform therapeutic decisions,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “As a result of this information, the European Commission has refined the prescribing information for Vectibix to the treatment of adult patients with wild-type RAS metastatic colorectal cancer.”
No new safety signals were identified in this analysis.
PRIME (‘203) Study Design
The PRIME (Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy) (‘203) trial is a global, multicenter, randomized Phase 3 study designed to evaluate Vectibix (6.0 mg/kg every two weeks) plus FOLFOX versus FOLFOX alone in patients with wild-type KRAS exon 2 mCRC. The primary endpoint is PFS.
The primary objective of this predefined retrospective subset analysis was to determine the effect of Vectibix plus FOLFOX versus FOLFOX alone on OS and PFS in patients with mCRC based on RAS or BRAF mutation status. The analysis included 512 patients who were identified with wild-type RAS tumors.
About KRAS and RAS
Results from studies performed over the last 30 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.1 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 percent of mCRC patients.2,3 Additional RAS mutations occurred in approximately 17 percent of patients with wild-type KRAS exon 2 tumors.
About Colorectal Cancer
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.4,5 Approximately 1.2 million cases of colorectal cancer are expected to occur globally. The highest incidence rates are found in Japan, North America, parts of Europe, New Zealand and Australia, and rates are low in Africa and Southeast Asia.6
1 Malumbres, M. and Barbacid, M. RAS oncogenes: the first 30 years. Nature Reviews Cancer. 3:459-65, 2003.
2 Karapentis C, S. Snell, L, E. The Laboratory Assessment of KRAS Mutation Status in Colorectal Cancer. Asia Pacific Journal of Oncology and Hematology. 2010.
3 Friday BB and Adjei AA. K-ras as a target for cancer therapy. Biochim. Biophys. Acta 1756: 127-144, 2005.
4 Cancer Facts and Figures 2013. American Cancer Society website. http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/a cspc-036845.pdf. Accessed March 25, 2013.
5 Colorectal Cancer Prevention (PDQ®). National Cancer Institute. Accessed March 25, 2013. http://www.cancer.gov/cancertopics/pdq/prevention/colorectal/HealthProfessional/page3.
6 Jemal. Global Cancer Statistics. CA Cancer J Clin. 2011;61:69-90.
7 Vectibix (panitumumab) Prescribing Information. Thousand Oaks, Calif: Amgen; 2011.