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The human epidermal growth factor receptor (EGFR) is a subfamily of type I receptor tyrosine kinases of the ErbB family1,2 including EGFR (HER1, c-ERbB-1), HER2/neu, HER3, and HER4. EGFR is a transmembrane glycoprotein that is constitutively expressed in many normal epithelial tissues, including the skin and hair follicle.1,2
Overexpression of EGFR is also detected in many human cancers, including those of the colon and rectum. Interaction of EGFR with its normal ligands (eg, EGF, transforming growth factor-alpha) leads to phosphorylation and activation of a series of intracellular tyrosine kinases, which in turn regulate transcription of molecules involved with cellular growth and survival, motility, proliferation, and transformation.2,3
In a number of different types of cancer, upregulation of EGFR is associated with a poor prognosis. In fact, when EGFR is overproduced in colon cancer, it is associated with poor response to treatment, greater disease progression, and poor rates of survival.3 EGFR is, therefore, an attractive target for the development of anticancer therapy.2
Vectibix® binds to the ligand-binding domain of EGFR with high affinity and inhibits the growth and survival of selected tumor cells expressing EGFR in both in vitro assays and in vivo animal studies.
In nonclinical studies, the binding of Vectibix® to EGFR on both normal and tumor cells:
• Competitively inhibits the binding of ligands to EGFR
• Prevents ligand-induced receptor autophosphorylation and activation of receptor-associated kinases
• Inhibits cell growth, induces apoptosis, decreases proinflammatory cytokine and vascular endothelial growth factor production, and internalizes EGFR1
Binding of Vectibix® to the EGFR disrupts inappropriate
intracellular signalling, which may prevent tumor cell growth and
spread.1
References
1. Vectibix® (panitumumab) package insert. Amgen; 2007.
2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127-137.
3. Coutinho AK, Rocha Lima CMS. Metastatic colorectal cancer: systemic treatments in the new millennium. Cancer Control. 2003;10:224-238.
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Vectibix® is indicated as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma (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 are available that demonstrate an improvement in disease related symptoms or increased survival with Vectibix®.
Important Safety Information
Safety data are available from 15 clinical trials in which 1,467 patients received Vectibix®; of these, 1,293 received Vectibix® monotherapy and 174 received Vectibix® in combination with chemotherapy.
WARNING Infusion Reactions: Severe infusion reactions occurred with the administration of Vectibix® in approximately 1% of patients. Severe infusion reactions were identified by reports of anaphylactic reaction, bronchospasm, fever, chills, and hypotension. Although fatal infusion reactions have not been reported with Vectibix®, fatalities have occurred with other monoclonal antibody products. Stop infusion if a severe infusion reaction occurs. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix®.
Dermatologic Toxicity:Dermatologic toxicities, related to Vectibix® blockade of EGF binding and subsequent inhibition of EGFR-mediated signaling pathways, were reported in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix® monotherapy. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Severe dermatologic toxicities were complicated by infection including sepsis, septic death, and abscesses requiring incisions and drainage. Withhold or discontinue Vectibix® and monitor for inflammatory or infectious sequelae in patients with severe dermatologic toxicities.
Vectibix® is not indicated for use in combination with chemotherapy with or without bevacizumab. In an interim analysis of a randomized (1:1) clinical trial of patients with previously untreated metastatic colorectal cancer, the addition of Vectibix® to the combination of bevacizumab and chemotherapy resulted in decreased progression-free survival (n=947) and increased incidence of NCI-CTC grade 3-5 (87% vs. 72%) adverse reactions (n=926).
In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.
Pulmonary fibrosis occurred in less than 1% (2/1,467) of patients in clinical trials of Vectibix®. Following the initial fatality, patients with a history of interstitial pneumonitis, pulmonary fibrosis, and evidence of interstitial pneumonitis were excluded from clinical studies. Therefore, the estimated risk in such patients is uncertain. Permanently discontinue Vectibix® therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.
In the randomized, controlled clinical trial, median magnesium levels decreased by 0.1 mmol/L in the Vectibix® arm. Additionally, hypomagnesemia (NCI-CTC grade 3 or 4) requiring electrolyte repletion occurred in 2% of patients 6 weeks or longer after the initiation of Vectibix®. In some patients, hypomagnesemia was associated with hypocalcemia. Patients should be periodically monitored, and treated appropriately, for hypomagnesemia and hypocalcemia during and for 8 weeks after the completion of Vectibix® therapy.
It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving Vectibix®, since sunlight can exacerbate any skin reactions that may occur.
In women of childbearing potential, appropriate contraceptive measures must be used during, and for 6 months after, treatment with Vectibix®.
The most common adverse events observed in clinical studies of Vectibix® (n = 1,467) were skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration. The most serious adverse events observed were pulmonary fibrosis, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation.
