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DRUG RECORD

 

PANITUMUMAB

OVERVIEW
Panitumumab

 

Introduction

Panitumumab is a human monoclonal antibody to the epidermal growth factor (EGF) receptor, which is used in the treatment of refractory metastatic colorectal cancer.  Panitumumab has been linked to minor serum enzyme elevations during therapy, but has not been implicated in cases of clinically apparent liver injury.

 

Background

Panitumumab (pan” i toom’ ue mab) is a human monoclonal IgG2 antibody to the epidermal growth factor receptor (EGFR, HER1), which is used to treat EGFR-expressing metastatic colorectal cancer.  Panitumumab has been shown to induce objective responses in metastatic colorectal cancer and to improve progression free survival.  Effects appear to be greater in patients with the wild type as opposed to mutant KRAS status.  Panitumumab was approved for use in the United States in 2006 and was the second monoclonal antibody to EGFR approved for use in metastatic colorectal cancer, the other agent being cetuximab (a chimeric mouse-human monoclonal IgG1 antibody) which has a similar profile of efficacy and safety.  Panitumumab is available in liquid solution of 100, 200 and 400 mg in single dose vials (20 mg/mL) under the brand name Vectibix.  The recommended regimen is 6 mg/kg intravenously every 14 days until disease progression or unacceptable toxicity.  Skin toxicity is the most common side effect, occurring in 90% of patients and being severe in 16% to 19%.  Other side effects include fatigue, abdominal pain, nausea, anorexia, diarrhea, electrolyte disturbance, leukopenia and infections.  Less common, but potentially severe side effects include infusion reactions, hypersensitivity reactions, severe skin toxicity, severe diarrhea and dehydration, pulmonary embolism and ocular toxicities.

 

Hepatotoxicity

The rate of serum aminotransferase elevations during panitumumab therapy has not been reported, but nor has the absence of such elevations.  If present, they must be self-limited and resolve even with continuing cyclic therapy.  No individual case reports of clinically apparent, acute liver injury with symptoms or jaundice attributed to panitumumab have been published and the product label does not discuss hepatotoxicity.

 

Mechanism of Injury

The cause of the transient enzyme elevations during monoclonal antibody therapies is generally unknown, but may relate to direct effects of the antibody reactivity to cell surface markers that may be over-expressed on cancer cells, but are also present in lower density on normal epithelial cells.

 

Drug Class:  Antineoplastic Agents, Monoclonal Antibodies

 

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REPRESENTATIVE TRADE NAMES
Panitumumab – Vectibix®

 

DRUG CLASS
Antineoplastic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO. MOLECULAR FORMULA STRUCTURE
Panitumumab 339177-26-3 Monoclonal Antibody Not Available

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References updated: 18 June 2015

  1. Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.  (Review of hepatotoxicity of immunosuppressive agents mentions rituximab and problems of reactivation of hepatitis B, but also states that "the biological immunosuppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists").

  2. Chabner BA, Barnes J, Neal J, Olson E, Mujagiv H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-53.  (Textbook of pharmacology and therapeutics).

  3. Rowinsky EK, Schwartz GH, Gollob JA, Thompson JA, Vogelzang NJ, Figlin R, Bukowski R, et al. Safety, pharmacokinetics, and activity of ABX-EGF, a fully human anti-epidermal growth factor receptor monoclonal antibody in patients with metastatic renal cell cancer. J Clin Oncol 2004; 22: 3003-15 PubMed Citation  (Among 88 patients with resistant, metastatic renal cancer treated with one of 4 doses of panitumumab intravenously once weekly, there was scant evidence of benefit and side effects were common, 68-100% of patients developing an acneiform rash, but ALT elevations and hepatotoxicity were not mentioned).

  4. Van Cutsem E, Peeters M, Siena S, Humblet Y, Hendlisz A, Neyns B, Canon JL, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007; 25: 1658-64. PubMed Citation  (Among 463 patients with metastatic, refractory colorectal cancer treated with panitumumab every two weeks or best supportive care, progression free survival was prolonged from a median of 7.3 to 8.0 weeks in the monoclonal antibody treated subjects, but overall survival was unchanged; side effects included skin toxicity in almost all patients; no mention of ALT elevations or hepatotoxicity).

  5. Panitumumab (Vectibix) for metastatic colorectal cancer. Med Lett Drugs Ther 2007; 49 (1259): 35-6. PubMed Citation  (Concise review of the efficacy and safety of panitumumab shortly after its approval for use in the US for metastatic colorectal cancer, mentions the frequency of skin related toxicities, but does not mention ALT elevations or hepatotoxicity).

  6. Giusti RM, Shastri K, Pilaro AM, Fuchs C, Cordoba-Rodriguez R, Koti K, Rothmann M, et al. U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. Clin Cancer Res 2008; 14: 1296-302. PubMed Citation  (Analysis of efficacy and safety results that provided the basis for the FDA decision to approve panitumumab for use in metastatic colorectal cancer; combined safety analysis in 1467 patients mentions skin toxicity in 90% [severe in 16%], diarrhea in 21% [severe in 2%], infusion reactions in 4% [severe in 1%], pulmonary fibrosis in 1%; among 117 deaths in panitumumab treated patients, 1 was listed as due to hepatic failure, but no details given and rates of ALT elevations not mentioned).

  7. Wu M, Rivkin A, Pham T. Panitumumab: human monoclonal antibody against epidermal growth factor receptors for the treatment of metastatic colorectal cancer. Clin Ther 2008; 30: 14-30. PubMed Citation  (Review of efficacy and safety of panitumumab for metastatic colorectal cancer mentions side effects of skin toxicity, infusion reactions, electrolyte disturbances, pulmonary complications and nail and hair changes, but does not mention ALT elevations or hepatotoxicity).

  8. Stephenson JJ, Gregory C, Burris H, Larson T, Verma U, Cohn A, Crawford J, et al. An open-label clinical trial evaluating safety and pharmacokinetics of two dosing schedules of panitumumab in patients with solid tumors. Clin Colorectal Cancer 2009; 8: 29-37. PubMed Citation  (Among 86 patients with advanced solid tumors treated with 6 or 9 mg/kg of panitumumab every 2 weeks, all patients had at least one adverse event and therapy was stopped early in 27% of patients, the most frequent side effects being skin rash and gastrointestinal symptoms; no mention of hepatotoxicity).

  9. Nie F, Shen J, Tong JL, Xu XT, Zhu MM, Ran ZH. Meta-analysis: the efficacy and safety of monoclonal antibody targeted to epidermal growth factor receptor in the treatment of patients with metastatic colorectal cancer. J Dig Dis 2009; 10: 247-57 PubMed Citation  (Systematic review of efficacy and safety of monoclonal antibodies to EGFR in metastatic colorectal cancer summarized 7 randomized trials with 4186 patients using cetuximab or panitumumab, reported similar rates of response and adverse events with the two agents; no mention of ALT elevations or hepatotoxicity).

  10. Fakih M, Vincent M. Adverse events associated with anti-EGFR therapies for the treatment of metastatic colorectal cancer. Curr Oncol 2010; 17 Suppl 1: S18-30. PubMed Citation  (Review of frequency, nature and management of adverse effects of monoclonal anti-EGFR [cetuximab and panitumumab] therapy of metastatic colorectal cancer including skin, nail, hair, ocular toxicities, hypomagnesemia, diarrhea, and infusion reactions, but no mention of hepatotoxicity).

  11. Baumgaertner I, Ratziu V, Vaillant JC, Hannoun L, Poynard T, André T. [Hepatotoxicity of metastatic colorectal cancer chemotherapy: systematic review]. Bull Cancer 2010; 97 (5): 559-69. PubMed Citation  (Review of the hepatotoxicity of agents used for metastatic colorectal cancer mentions that the anti-EGFR monoclonal antibodies have not been reported to cause liver injury).

  12. Stremitzer S, Sebio A, Stintzing S, Lenz HJ. Panitumumab safety for treating colorectal cancer. Expert Opin Drug Saf 2014; 13: 843-51. PubMed Citation  (Review of mechanism of action and safety of panitumumab therapy of metastatic colorectal cancer discusses skin toxicity, hypomagnesemia, diarrhea and infusion reactions [which are less with panitumumab than cetuximab], but not hepatotoxicity or ALT elevations).

  13. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, et al. Final results from PRIME: randomized phase 3 study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25: 1346-55. PubMed Citation  (Among 1183 patients with previously untreated metastatic colorectal cancer given panitumumab and FOLFOX4 or FOLFOX4 alone, severe side effects more frequent in the panitumumab exposed patients included skin toxicity [27% vs 2%], diarrhea, hypokalemia, hypomagnesemia, fatigue and mucositis; no mention of hepatotoxicity or ALT elevations).

  14. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, et al. Final results from a randomized phase 3 study of FOLFIRI {+/-} panitumumab for second-line treatment of metastatic colorectal cancer. Ann Oncol 2014; 25: 107-16. PubMed Citation  (Among 1186 patients with previously treated metastatic colorectal cancer given panitumumab and FOLFIRI or FOLFIRI alone, adverse events that were more frequent with panitumumab therapy included site toxicity, hypokalemia and hypomagnesemia; no mention of ALT elevations or hepatotoxicity).

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OTHER REFERENCE LINKS
Panitumumab
  1. PubMed logoRecent References on Panitumumab

  2. Clinical Trials logoTrials on Panitumumab

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