Panitumumab

Panitumumab, sold under the brand name Vectibix, is a fully human monoclonal antibody specific to the epidermal growth factor receptor (also known as EGF receptor, EGFR, ErbB-1 and HER1 in humans).[1][2]

Panitumumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetEpidermal growth factor receptor (EGFR)
Clinical data
Trade namesVectibix
Other namesABX-EGF
AHFS/Drugs.comMonograph
MedlinePlusa607066
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life~9.4 days (range: 4-11 days)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC6398H9878N1694O2016S48
Molar mass144324.12 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Panitumumab is manufactured by Amgen and was originally developed by Abgenix Inc.

In 2014, Amgen and Illumina entered into an agreement to develop a companion diagnostic to accompany panitumumab.[3]

Medical uses

Panitumumab was approved by the U.S. Food and Drug Administration (FDA) for the first time in September 2006, for "the treatment of EGFR-expressing metastatic colorectal cancer with disease progression" despite prior treatment.[4] Panitumumab was approved by the European Medicines Agency (EMEA) in 2007, and by Health Canada in 2008, for "the treatment of refractory EGFR-expressing metastatic colorectal cancer in patients with non-mutated (wild-type) KRAS".

Panitumumab was the first monoclonal antibody to demonstrate the use of KRAS as a predictive biomarker.

Contraindications

Panitumumab does not work in patients who have KRAS or NRAS mutations.[5]

Adverse effects

Panitumumab has been associated with skin rash, fatigue, nausea, diarrhea, fever, and decreased magnesium levels. Often, skin rash is noted in the sun exposed parts of the body, such as the face or chest. Oral antibiotics may be needed for worsening skin rash, such as one accompanied with blisters and ulcers. Otherwise, topical steroid creams like hydrocortisone may help.[6]

Ocular toxicity or keratitis was observed in 16% of patients on panitumumab, usually necessitating the discontinuance of therapy.[7]

In clinical trials, 90% of patients had dermatological toxicities and 15% of those were severe. Because of this, panitumumab has a boxed warning cautioning patients. Skin toxicities were typically apparent two weeks after beginning treatment. More severe skin toxicities were associated with improved progression free survival and overall survival.[7]

Pulmonary fibrosis and interstitial lung disease were observed in clinical trials.[7]

Pharmacology

Mechanism of action
Main article: Epidermal growth factor receptor

EGFR is a transmembrane protein. Panitumumab works by binding to the extracellular domain of the EGFR preventing its activation. This results in halting of the cascade of intracellular signals dependent on this receptor.[8]

Pharmacokinetics

The pharmacokinetics (PK) of panitumumab shows the so-called target-mediated disposition behavior.[9] However, the pharmacokinetics is approximately linear at clinical doses, and the terminal half-life for a typical male patient of 80 kg and 60 years of age with colorectal cancer is about 9.4 days.

History

Panitumumab was generated using Abgenix's XenoMouse platform technology, in which engineered mice were utilized to produce human antibodies. Abgenix partnered with Immunex Corporation to develop the antibody, and Amgen acquired Immunex in 2003. In 2006, Amgen acquired Abgenix as well. In 2013, Amgen formed an agreement with Zhejiang Beta Pharma to form Amgen Beta Pharmaceuticals and market panitumumab in China. Amgen and Takeda have an agreement under which Takeda will develop and commercialise panitumumab in Japan.[10] Panitumumab is licensed to Dr Reddys Laboratories in India and GlaxoSmithKline in the UK.

FDA approval

Panitumumab was initially approved on September 27, 2006, for EGFR-expressing, metastatic CRC with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing regimens, based on the results of a study which showed clinical benefit in metastatic colorectal cancer patients.[11] In July 2009, the FDA updated the labels of two anti-EGFR monoclonal antibody drugs (panitumumab and cetuximab) indicated for the treatment of metastatic colorectal cancer to include information about KRAS mutations.[12] This was the result of a study, which demonstrated lack of benefit with Panitumumab in patients who carried NRAS mutations.[5]

It is also approved as a first-line agent in combination with FOLFOX.[7]

Research

Panitumumab is being studied in numerous phase II and III clinical trials. Phase III clinical trials include treatment of esophageal cancer,[13] urothelial carcinoma,[14] metastatic head and neck cancer,[15] and liver metastasis in colorectal cancer.[16] Early trials showed limited efficacy in patients with malignant melanoma, bladder cancer, prostate cancer, and renal cell carcinoma.[10]

Panitumumab vs. cetuximab

Although they both target the EGFR, panitumumab (IgG2) and cetuximab (IgG1) differ in their isotype and they might differ in their mechanism of action. Monoclonal antibodies of the IgG1 isotype may activate the complement pathway and mediate antibody-dependent cellular cytotoxicity (ADCC).[17] It is not clear at this time, if one drug is superior to the other. In one of the studies, both these drugs were noted to be similar in activity.[18]

References
  1. "Vectibix- panitumumab solution". DailyMed. 25 August 2021. Archived from the original on 6 April 2022. Retrieved 6 July 2022.
  2. "Vectibix EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 13 August 2021. Retrieved 6 July 2022.
  3. "Illumina, Amgen to Develop CDx for Colorectal Cancer". News: Molecular Diagnostics. Gen. Eng. Biotechnol. News (paper). Vol. 34, no. 4. February 15, 2014. p. 32. Archived from the original on September 19, 2016. Retrieved December 2, 2014.
  4. "Drug Approval Package: Vectibix NDA #125147". U.S. Food and Drug Administration (FDA). 29 May 2007. Archived from the original on 31 March 2021. Retrieved 6 July 2022.
  5. Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, et al. (September 2013). "Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer". The New England Journal of Medicine. 369 (11): 1023–34. doi:10.1056/NEJMoa1305275. PMID 24024839. S2CID 14556160.
  6. Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, et al. (March 2010). "Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer". Journal of Clinical Oncology. 28 (8): 1351–7. doi:10.1200/JCO.2008.21.7828. PMID 20142600. S2CID 30651519.
  7. "UpToDate". Archived from the original on 2017-02-02. Retrieved 2017-01-27.
  8. Plunkett, Jack W. (September 30, 2005). Plunkett's Biotech & Genetics Industry Almanac 2006. Plunkett Research. ISBN 978-1-59392-033-3.
  9. Ma P, Yang BB, Wang YM, Peterson M, Narayanan A, Sutjandra L, et al. (October 2009). "Population pharmacokinetic analysis of panitumumab in patients with advanced solid tumors". Journal of Clinical Pharmacology. 49 (10): 1142–56. doi:10.1177/0091270009344989. PMID 19723673. S2CID 25766549.
  10. "Panitumumab - Amgen". AdisInsight. Archived from the original on 2017-11-03. Retrieved 2017-01-27.
  11. Gibson TB, Ranganathan A, Grothey A (May 2006). "Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer". Clinical Colorectal Cancer. 6 (1): 29–31. doi:10.3816/CCC.2006.n.01. PMID 16796788.
  12. "FDA updates Vectibix and Erbitux labels with KRAS testing info". 20 July 2009. Archived from the original on 3 March 2016. Retrieved 2 December 2014.
  13. Clinical trial number NCT01627379 for "Cisplatin and 5-FU +/- Panitumumab for Patients With Nonresectable,Advanced or Metastatic Esophageal Squamous Cell Cancer" at ClinicalTrials.gov
  14. Clinical trial number NCT00460265 NCT00460265 for "I-MVAC +/- Panitumumab as First-line Treatment of Advanced Urothelial Carcinoma Without H-Ras Nor K-Ras Mutations" at ClinicalTrials.gov
  15. Clinical trial number NCT00460265 NCT00460265 for "Study of Panitumumab Efficacy in Patients With Recurrent and/or Metastatic Head and Neck Cancer" at ClinicalTrials.gov
  16. Clinical trial number NCT02162563 for "Treatment Strategies in Colorectal Cancer Patients With Initially Unresectable Liver-only Metastases" at ClinicalTrials.gov
  17. HealthValue: IgG1 & IgG2 Archived 2019-06-05 at the Wayback Machine
  18. Price TJ, Peeters M, Kim TW, Li J, Cascinu S, Ruff P, et al. (May 2014). "Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study". The Lancet. Oncology. 15 (6): 569–79. doi:10.1016/S1470-2045(14)70118-4. hdl:2381/43402. PMID 24739896.

Further reading
  • "Panitumumab". Drug Information Portal. U.S. National Library of Medicine.
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