Panitumumab

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Compound Name:PanitumumabMolecular Target:human EGFR (Epidermal Growth Factor Receptor)Molecular Structure:recombinant human IgG2? monoclonal antibodyLicensed Indication:treatment of EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan- containing chemotherapy regimensManufacturer and/or Distributor:AmgenInitial FDA Approval:2006Summary:Panitumumab (Vectibix®) is a fully humanized IgG2k monoclonal antibody that binds to the extracellular domain of the human epidermal growth factor receptor (EGFR; also known as ErbB-1 and Her1). EGFR is present on normal epithelial tissues, and it is overexpressed in colorectal cancers. Panitumumab was approved in 2006 by the US FDA for the treatment of metastatic carcinomas of the colon and rectum. Panitumumab competitively inhibits the binding of ligands (such as EGF, TGFa, amphiregulin and others) to EGFR, and thereby blocks its signaling cascade. This leads to inhibition of cell growth, induction of apoptosis, and decreased pro-inflammatory cytokine and vascular growth factor production. The K-Ras gene is downstream of EGFR in the signaling cascade. Patients with a mutated K-Ras gene therefore do not respond to panitumumab. Panitumumab is administered intravenously every two weeks. Panitumumab is indicated for metastatic colorectal cancer with wild-type KRAS (see next) as either first-line therapy in combination with FOLFOX (FOLinic acid/leucovorin, Fluorouracil, OXaliplatin) or as monotherapy for the treatment of EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan- containing chemotherapy regimens. It is not recommended for patients who have mutations in the 12th or 13th codons of the K-Ras gene, so that the status of the K-Ras gene in the tumor needs to be determined before initiating therapy. Its approval was based on demonstration of improved disease progression-free survival. Significant adverse events include the following: (1) Skin: Because of the presence of EGFR on normal epithelium, dermatological toxicities to panitumumab are very common (90% of patients) and include: papulo-pustular rash (acneiform eruption); erythema; dry skin; skin fissures; paronychia; and bullous mucocutaneous disease with blisters, erosions and skin sloughing. They may be severe, and in fact their severity correlates with the tumor response. It is recommended that patients wear sunscreen and hats and limit sun exposure while receiving panitumumab, since sunlight can exacerbate any skin reactions that may occur. (2) Infections, including necrotizing fasciitis, abscesses and sepsis. Possibly increased risk of febrile neutropenia. (3) Electrolyte disturbances (e.g. low Mg+2, low K+); (4) Diarrhea with dehydration; (5) Interstitial lung disease (1%) and pulmonary fibrosis; (6) Keratitis and ulcerative keratitisReferences

Package Insert: http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf

1. Siena S, Peeters M, Van Cutsem E, Humblet Y, Conte P, Bajetta E, et al. Association of progression-free survival with patient-reported outcomes and survival: results from a randomised phase 3 trial of panitumumab. Br J Cancer. 2007 Dec 3;97(11):1469-1474. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18040272

2. Lin AY, Buckley NS, Lu AT, Kouzminova NB, Salpeter SR. Effect of KRAS mutational status in advanced colorectal cancer on the outcomes of anti-epidermal growth factor receptor monoclonal antibody therapy: a systematic review and meta-analysis. Clin Colorectal Cancer. 2011 Mar 1;10(1):63-69. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21609938

3. Yarom N, Jonker DJ. The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med. 2011 Feb;11(57):95-105. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21356164

4. Gibson TB, Ranganathan A, Grothey A. Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clin Colorectal Cancer. 2006 May;6(1):29-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16796788

5. Dahabreh IJ, Terasawa T, Castaldi PJ, Trikalinos TA. Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 2011 Jan 4;154(1):37-49. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21200037

6. Ibrahim EM, Abouelkhair KM. Clinical outcome of panitumumab for metastatic colorectal cancer with wild-type KRAS status: a meta-analysis of randomized clinical trials. Med Oncol. 2011 Dec;28 Suppl 1:S310-317. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=21221853

7. Funakoshi T, Suzuki M, Tamura K. Infectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: A systematic review and meta-analysis. Cancer Treat Rev. 2014 Sep 19. pii: S0305-7372(14)00149-2. doi: 10.1016/j.ctrv.2014.09.002

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