ic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC08
Mechanism of action
Panitumumab is a recombinant, fully human IgG2 monoclonal antibody that binds with high affinity and specificity to the human EGFR. EGFR is a transmembrane glycoprotein that is a member of a subfamily of type I receptor tyrosine kinases including EGFR (HER1/c-ErbB-1), HER2, HER3, and HER4. EGFR promotes cell growth in normal epithelial tissues, including the skin and hair follicle, and is expressed on a variety of tumour cells.
Panitumumab binds to the ligand binding domain of EGFR and inhibits receptor autophosphorylation induced by all known EGFR ligands. Binding of panitumumab to EGFR results in internalisation of the receptor, inhibition of cell growth, induction of apoptosis, and decreased interleukin 8 and vascular endothelial growth factor production.
The KRAS (Kirsten rat sarcoma 2 viral oncogene homologue) gene encodes a small, GTP-binding protein involved in signal transduction. A variety of stimuli, including that from the EGFR activates KRAS which in turn stimulates other intracellular proteins to promote cell proliferation, cell survival and angiogenesis.
Activating mutations in the KRAS gene occur frequently in a variety human tumours and have been implicated in both oncogenesis and tumour progression.
Pharmacodynamic effects
In vitro assays and in vivo animal studies have shown that panitumumab inhibits the growth and survival of tumour cells expressing EGFR. No anti-tumour effects of panitumumab were observed in human tumour xenografts lacking EGFR expression. The addition of panitumumab to radiation, chemotherapy or other targeted therapeutic agents, in animal studies resulted in an increase in anti-tumour effects compared to radiation, chemotherapy or targeted therapeutic agents alone.
Dermatological reactions (including nail effects), observed in patients treated with Vectibix or other EGFR inhibitors, are known to be associated with the pharmacologic effects of therapy (with cross-reference to sections 4.2 and 4.8). The severity of dermatological reactions often correlates with the clinical efficacy of the EGFR inhibitor. For patients who have not developed skin toxicity after 2-4 cycles of therapy, a reassessment of the treatment effect is recommended.
Immunogenicity
As with all therapeutic proteins, there is potential for immunogenicity. Data on the development of anti-panitumumab antibodies has been eva luated using two different screening immunoassays for the detection of binding anti-panitumumab antibodies (an ELISA which detects high-affinity antibodies, and a Biosensor Immunoassay which detects both high and low-affinity antibodies). For patients whose sera tested positive in either screening immunoassay, an in vitro biological assay was performed to detect neutralising antibodies.
As monotherapy:
• The incidence of binding antibodies (excluding predose and transient positive patients) was < 1% as detected by the acid-dissociation ELISA and 3.8% as detected by the Biacore assay;
• The incidence of neutralising antibodies (excluding predose and transient positive patients) was < 1%;
• Compared with patients who did not develop antibodies, no relationship between the presence of anti-panitumumab antibodies and pharmacokinetics, efficacy and safety has been observed.
In combination with irinotecan- or oxaliplatin-based chemotherapy:
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