Panitumumab

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

CAS number: 339177-26-3

Definition
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Panitumumab is a monoclonal, human antibody from the group of immunoglobulins of the IgG2 type, which due to its structural composition (purely human - not humanized - genesis) has only a low immunogenicity. Panitumumab binds to a particular epitope of the HER2 receptor, which is different from the epitope to which trastuzumab binds. Panitumumab prevents the ligand-dependent dimerization of the HER2 receptor with other HER receptors (EGFR, HER3, HER4) on the surface of the cells. This prevents HER2 from being activated (see figure). The downstream signalling pathways are blocked, resulting in growth inhibition and apoptosis of the cell (Lo L et al. 2015). Furthermore, panitumumab is a mediator for antibody-dependent cell-mediated cytotoxicity.(ADCC, antibody dependent cellular cytotoxicity).

Pharmacodynamics (Effect)
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ErbB receptors, a family of transmembrane receptor tyrosine kinases and in particular HER2, have been identified as an important target in the fight against various diseases. carcinomas (e.g. also breast carcinoma) have been identified as important targets. ErbB receptors mediate their proliferative signals via a major cytoprotective signal transduction pathway involving adaptor proteins such as GRB2 and SHC, GTP exchange factors such as SOS, phospholipase Cγ (PLCγ), Ras, protein kinase C (PKC), Raf, MAPK, and PI-3 kinase-dependent signaling pathways. This signal transduction pathway directly or indirectly influences cell cycle control and transcriptional regulation, which is the trigger for the biosynthetic machinery and cell proliferation.

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Indication
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Panitumumab is approved as a monotherapy for the treatment of metastatic EGFR-expressing colorectal cancer with non-mutated (wild-type) KRAS gene in patients who have failed fluoropyrimidine, oxaliplatin and irinotecan-containing chemotherapy regimens (Vectibix® Fact Sheet).

Undesirable effects
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The most common adverse effects were reported:

skin reactions

gastrointestinal disorders such as abdominal pain, diarrhoea, nausea, vomiting and constipation

Tiredness, metabolic and nutritional disorders.

Hypomagnesemias were reported by panitumumab (Sato J et al. 2019).

Severe side effects such as keratitis occurred in rare cases.

Inflammatory diseases of the skin are frequent. It is important to know that EGF receptors are also expressed on keratinocytes of the basal epidermis and the outer hair root sheath. Here the receptor protein performs important functions for the epidermal barrier, antimicrobial defense and the regulation of epidermal homeostasis. Therefore, the use of EGF receptor inhibitors leads in almost 90% of cases to a follicular (acne-like) papulo-pustular exanthema in the seborrheic zones (face, scalp, neck, chest, upper back). Comedones are always absent (typical phenomenon of drug-induced acne, also known as steroid acne)! In the further course of the disease, confluent pustules, teleangiketasia and crusts may develop. The cause is a cytokine-dependent perifollicular inflammation. However, the severity of the papulo-pustular exanthema does not always seem to be related to the therapeutic response (Koukakis R et al. ). Furthermore, a xerosis of the skin and mucous membranes occurs. This also explains irritative conjunctivitis. After 4-6 weeks, painful paronychia occurs in 10% of the patients, and hair growth disorders with thin or brittle, sometimes wavy hair can also occur. Trichomegaly is particularly conspicuous and can affect eyelashes and eyebrows.

Remarkable is the observation that under therapy with cetuximab and panitumumab psoriasis dramatically improved within a week (Okamoto K et al. 2015).

Preparations
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Vectibix®

Note(s)
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For the first time, the influence of the KRAS gene (mutant versus non-mutant) on the therapeutic effect of EGFR antibodies was demonstrated in the panitumumab pivotal study. It is of essential importance that only those patients (approx. 60%) benefited from panitumumab therapy whose tumor parenchyma has a non-mutated KRAS gene (wild type) (McGregor M et al. 2018). The KRAS protein is part of the EGFR signalling cascade (see figure). If the KRAS gene is mutated, this mutation leads to a functionally altered, constitutively active protein. In this context, "constitutively active" means that the signal transmission remains in a constant state of activity, even if the receptor itself has been blocked by the monoclonal antibody. Tumors with mutated KRAS gene therefore do not respond to anti-EGFR therapy with panitumumab.

Literature
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  1. Annunziata MC et al (2019) Current Recommendations and Novel Strategies for the Management of Skin Toxicities Related to Anti-EGFR Therapies in Patients with Metastatic Colorectal Cancer. Clin Drug Investig 39:825-834.
  2. Technical information Vectibix June 2012 (PDF; 209 kB), accessed 6.9. 2020.
  3. Jaka A et al (2015) Predictors of Tumor Response to Cetuximab and Panitumumab in 116 Patients and a Review of Approaches to Managing Skin Toxicity. Actas Dermosifiliogr 106:483-492.
  4. Koukakis R et al (2016) Skin toxicity and quality of life during treatment with panitumumab for RAS wild-type metastatic colorectal carcinoma: results from three randomised clinical trials. Qual Life Res. 25:2645-2656. https://pubmed.ncbi.nlm.nih.gov/27083443/
  5. Lo L et al (2015) Pharmacokinetic and pharmacodynamic evaluation of panitumumab in the treatment of colorectal cancer. Expert Opinion Drug Metab Toxicol 11:1907-1924.
  6. McGregor M et al (2018) Panitumumab in the treatment of metastatic colorectal cancer, including wild-type RAS, KRAS and NRAS mCRC. Future Oncol 14:2437-2459.
  7. Okamoto K et al (2015) Cetuximab and panitumumab in a patient with colon cancer and concomitant chronic skin disease: a potential beneficial effect on psoriasis vulgaris. World JGastroenterol 21:3746-3749.
  8. Petrelli F et al (2013) The predictive role of skin rash with cetuximab and panitumumab in colorectal cancer patients: a systematic review and meta-analysis of published trials. Target Oncol 8:173-181.
  9. Petrelli F et al (2018) Different Toxicity of Cetuximab and Panitumumab in Metastatic Colorectal Cancer Treatment: A Systematic Review and Meta-Analysis of published trials. Oncology 94:191-199.
  10. Sato J et al (2019) Influence of oral magnesium-containing supplement and antacid administration on hypomagnesemia induced by panitumumab. Cancer chemother Pharmacol 83:673-679.
  11. Yang XD et al (2001) Development of ABX-EGF, a fully human anti-EGF receptor monoclonal antibody, for cancer therapy. Critical Reviews in Oncology Hematology 38: 17-23.

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Last updated on: 29.10.2020