"While the KRAS exon 2 biomarker is well-known and has facilitated selection of patients more likely to respond to anti-EGFR treatment, we found that there were still some patients who didn't benefit from treatment," said
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.
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 U.S., 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
Vectibix is the first fully human anti-EGFR antibody approved by the
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.7
Important U.S. Product Information
Vectibix is indicated as a single agent for the treatment of 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 progression-free survival. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.
Vectibix is not indicated for the treatment of patients with KRAS mutation-positive mCRC or for whom KRAS mCRC status is unknown. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Vectibix in combination with oxaliplatin-based chemotherapy is not indicated for the treatment of patients with RAS (KRAS or NRAS) mutation-positive mCRC or for whom RAS status is unknown.
WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS
Dermatologic Toxicity: Dermatologic toxicities occurred in 89 percent of patients and were severe (NCI-CTC grade 3 or higher) in 12 percent of patients receiving Vectibix monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions (5.1), and Adverse Reactions (6.1)].
Infusion Reactions: Severe infusion reactions occurred in approximately one percent of patients. Fatal infusion reactions occurred in postmarketing experience [See Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Reactions (6.1, 6.3)].
The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea and diarrhea, including diarrhea resulting in dehydration.
The most serious adverse reactions of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting and constipation.
This news release contains forward-looking statements that are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described. All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the
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The scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by the
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.
3 Friday BB and Adjei AA. K-ras as a target for cancer therapy. Biochim. Biophys.
4 Cancer Facts and Figures 2013.
5 Colorectal Cancer Prevention (PDQ®).
6 Jemal. Global Cancer Statistics. CA Cancer J Clin. 2011;61:69-90.
7 Vectibix (panitumumab) Prescribing Information.