Commentary (Grem)-Cetuximab-Associated Infusion Reactions: Pathology and Management

Drs. Patel and Goldberg summarize the clinical toxicities associated with cetuximab (Erbitux), a chimeric monoclonal antibody directed against the transmembrane epidermal growth factor receptor (EGFR). The variable region of cetuximab is of murine origin and comprises about one-third of the antibody; the remainder consists of human immunoglobin G.

Cetuximab is currently approved by the US Food and Drug Administration (1) in combination with irinotecan (Camptosar) for EGFR-expressing colorectal cancer that has progressed on prior irinotecan-containing therapy or as monotherapy if irinotecan is not tolerated, and (2) in combination with radiation therapy for initial therapy of advanced head and neck cancer or as monotherapy for locally recurrent head and neck cancer or metastatic disease after initial treatment has failed.

Antihistamine Prophylaxis

From its initial clinical development, cetuximab has been linked with concern about possible infusion reactions. Therefore, clinical investigators used antihistamines prophylactically in colorectal cancer trials for at least the first dose; all subjects received a test dose of cetuximab, 20 mg IV given over 10 minutes, before a 2-hour infusion of the 400-mg/m² loading dose. Unfortunately, the test dose did not reliably predict whether an infusion reaction would occur and is no longer recommended.

With recommended use of antihistamine prophylaxis, grade 1 or 2 infusion reactions occurred in about one of five cetuximab-treated patients; these reactions typically were characterized by fever, chills, and dyspnea. Severe reactions, which included symptoms of airway compromise, urticaria, and/or hypotension, have been reported in up to 5% of patients. Fatalities have occurred rarely. The vast majority of severe reactions occur with the first dose. Unfortunately, there are limited data concerning the possible mechanism(s) underlying the infusion reactions.

Discontinuation and Rechallenge

The package insert for cetuximab states that the monoclonal antibody should be discontinued immediately in patients experiencing a severe infusion-related reaction, and that such patients should not be rechallenged. According to the National Cancer Institute Common Terminology Criteria for Adverse Events Criteria versions 2.0 and 3.0, grade 3 allergic reactions are considered to be severe and are described as "symptomatic bronchospasm, requiring parenteral medication(s), with or without urticaria; allergy-related edema/angioedema, and hypotension."[1] However, Drs. Patel and Goldberg state that individual patients with "severe" infusion reactions have been managed with antihistamines and slower infusion rates, which introduces some uncertainty as to whether the prohibition against rechallenge in such patients is appropriate.

The authors suggest that if rechallenge following a severe infusion-related reaction is considered to be in the best interests of the patient, it is essential that a clinical immunologist become involved to implement a desensitization protocol or a graded rechallenge process in an appropriately monitored environment. Toward this end, publication of any such successful protocols or processes would be welcome.

Severe Reactions

Severe cetuximab-associated infusion reactions should be managed according to practice guidelines issued by the Joint Council of Allergy, Asthma and Immunology.[2] Assessing airway patency and oxygen saturation, supporting blood pressure, and monitoring cardiac status are essential. Epinephrine 0.2-0.5 mg IM or SC is a mainstay of treatment, although other medications and modalities also are used as clinically indicated.

The package insert for cetuximab indicates that a histamine H1 antagonist should be administered prior to each dose of monoclonal antibody. Given the low cost of using an agent such as diphenhydramine for prophylaxis relative to the cost of the biologic agent itself and the risk of causing an infusion reaction, this recommendation is reasonable. For patients who become sedated by diphenhydramine, antihistamines that feature minimal sedating properties may be considered.

Timoney and colleagues recently reported that in a retrospective analysis, 115 patients received one or more doses of cetuximab (746 doses total) without the benefit of diphenhydramine premedication.[3] Instead, they received diphenhydramine, 50 mg, before their first dose of cetuximab and 25 mg of the antihistamine prior to the second dose. These patients experienced no severe or life-threatening infusion reactions. However, the abstract for this study does not detail whether these patients had grade 1/2 infusion-related symptoms during their first two exposures to cetuximab or with subsequent exposures without diphenhydramine premedication.

A recent safety analysis of 800 patients treated with irinotecan and cetuximab in a randomized phase III trial conducted in Europe, Australia, and the United States indicated that the overall incidence of infusion reactions was 4%, with only 0.5% considered to be of grade 3 or 4 severity.[4] It is uncertain whether this seemingly lower incidence of infusion reactions is due to possible differences in incidence based on geographic regions or to varying definitions of what constitutes an infusion reaction.

Panitumumab Findings

Peeters et al[5] recently reported the results of a randomized trial of best supportive care given with or without panitumumab (Vectibix), a fully human antibody against EGFR, to colorectal cancer patients having at least 1% tumor cell membrane staining for EGFR by immunohistochemistry; these patients had progressed during therapy with fluoropyrimidines, oxaliplatin (Eloxatin), and irinotecan. Panitumumab at 6 mg/kg given every 2 weeks produced objective responses in 8% of patients and stable disease in 28%; progression-free survival improved as well. The subjects in this trial had not received prior cetuximab.

Interestingly, these patients were not given antihistamine prophylaxis, yet the incidence of panitumumab infusion-associated reactions occurred in fewer than 5% of subjects, with no life-threatening or fatal reactions reported. It remains to be determined whether panitumumab can be used safely in patients who have previously experienced severe or life-threatening cetuximab infusion-related reactions.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. National Cancer Institute-Cancer Therapy Evaluation Program: Common Terminology Criteria for Adverse Events v2.0 and v3.0. Available at http://ctep.info.gov. Accessed September 13, 2006.

2. Lieberman P, Kemp SF, Oppenheimer J: The diagnosis and management of anaphylaxis: An updated practice primer. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. J Allergy Clin Immunol 115:S483-S523, 2005.

3. Timoney J, Chung KY, Park V, et al: Cetuximab use without chronic antihistamine premedication (abstract 13521). J Clin Oncol 24(18S):617s, 2006.

4. Abubakr Y, Eng C, Pautret V, et al: Cetuximab plus irinotecan for metastatic colorectal cancer: Safety analysis of 800 patients in a randomized phase III trial (EPIC). J Clin Oncol 24:3556, 2006.

5. Peeters M, Van Cutsem E, Siena S, et al: A Phase 3, multicenter, randomized controlled trial of panitumumab plus best supportive care (BSC) vs. BSC alone in patients with metastatic colorectal cancer (abstract CP-1). Proc Am Assoc Cancer Res, 2006.