Infusion reactions to the chimeric EGFR inhibitor cetuximab—change to the fully human anti-EGFR monoclonal antibody panitumumab is safe
Authors: G. Resch, R. Schaberl-Moser, P. Kier, G. Kopetzky, W. Scheithauer, T. Sliwa, R. Greil, T. Nösslinger, B. Mayrbäurl, J. Thaler
Journal: Annals of Oncology (2011)

In recent years, clinical investigators have focused upon monoclonal antibodies (mAbs) that inhibit cancer progression such as mAbs against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor. Targeted therapies have rapidly gained attraction in the treatment of advanced colorectal cancer and are under active investigation. But infusion reactions (IRs) are serious complications in this modern antibody therapy of otherwise well-tolerated mAbs. In order to reduce the incidence and severity of such reactions, the newer generations of mAbs are fully human. However, there is limited clinical experience of administering a fully human mAb, such as panitumumab, to patients (pts) who have experienced IRs to a chimeric anti-EGFR mAb, such as cetuximab [1.Nielsen D.L. Pfeiffer P. Jensen B.V. Six cases of treatment with panitumumab in patients with severe hypersensitivity reactions to Cetuximab.Ann Oncol. 2009; 20: 798Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 2.Helbling D. Borner M. Successful challenge with the fully human EGFR antibody panitumumab following an infusion reaction with the chimeric EGFR antibody Cetuximab.Ann Oncol. 2007; 18: 963-964Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]). We now report about the Austrian Compassionate Use programme, in which pts received panitumumab monotherapy after IRs to cetuximab.Eligible chemotherapy refractory pts (n = 20) with metastatic colorectal cancer (mCRC) who experienced an IR after treatment with cetuximab received panitumumab monotherapy (6 mg/kg every 2 weeks) were recruited in 10 Austrian institutions. At the time of initiation, the predictive value of KRAS status on response to anti-EGFR therapy was not known and thus, was not an inclusion criterion for this programme. Patients included in this programme were heavily pretreated, with the majority having received at least 4 prior lines of chemotherapy (range 1–7). Median number of panitumumab cycles received was 6 (range 1–32). During the whole application period no panitumumab-related IRs were reported. Response data [3.Resch G. Schaberl-Moser R. Kier P. et al.Analysis of the Austrian compassionate use program of panitumumab in patients with metastatic colorectal cancer.ASCO GI. 2009; (Abstract 428)Google Scholar] were similar to previously published data.The first generation of mAbs was murine-derived and highly immunogenic in humans. To overcome this issue, chimeric mAbs, such as cetuximab, were constructed by combining the antigen-binding regions of the mouse antibody with human immunoglobulin G-constant domains. Chimeric mAbs still consist of approximately 34% of mouse protein—which results in various immunogenic responses, including infusion-related reactions. Cetuximab has been associated with IRs of any grade in 15%–21% of pts, grade 3 to 4 IRs occurred to 2%–5% of pts (e.g. bronchospasm, stridor, urticaria, hypotension and cardiac arrest) [4.ImClone Systems Incorporated, Bristol-Myers Squibb. Erbitux (Cetuximab) package insert. 2006Google Scholar, 5.Saltz L.B. Meropol N.J. Loehrer Sr, P.J. et al.Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.J Clin Oncol. 2004; 22: 1201-1208Crossref PubMed Scopus (1616) Google Scholar, 6.Peeters M. Cutsem V. Berlin J. et al.Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor, in patients with metastatic colorectal cancer across clinical trials.J Clin Oncol. 2007; 25: 413Crossref Google Scholar]. The clinical and economic impacts of these IRs are substantial, as they often require inpatient treatment and cause disruption of infusion or discontinuation of therapy [7.Foley K.A. Wang P.F. Barber B.L. et al.Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with Cetuximab.Ann Oncol. 2010; 21: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar].Panitumumab is the first fully human mAb to EGFR and is approved as monotherapy for EGFR-expressing mCRC with nonmutated KRAS after failure of standard chemotherapy [8.Van Cutsem E. Siena S. Humblet Y. et al.An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy.Ann Oncol. 2008; 19: 92-98Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar]. Clinical trials have reported <2% of infusion-related reactions of which approximately 1% were severe, which is most likely due to the drug's nonchimeric structure [9.VectibixTM (panitumumab) [package insert]Minervum, the NetherlandsAmgen Europe B.VGoogle Scholar, 10.Peeters M. Cutsem V. Berlin J. et al.Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor, in patients with metastatic colorectal cancer across clinical trials.J Clin Oncol. 2007; 25: 413Crossref Google Scholar]. No fatal reactions to panitumumab have been reported. Our data indicate that the fully human mAb panitumumab can be safely administrated to pts after IRs to cetuximab.disclosureWS had received honoraries from Amgen for consultant and advisory board meeting activities and as invited speaker. All other authors have declared no conflicts of interest. In recent years, clinical investigators have focused upon monoclonal antibodies (mAbs) that inhibit cancer progression such as mAbs against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor. Targeted therapies have rapidly gained attraction in the treatment of advanced colorectal cancer and are under active investigation. But infusion reactions (IRs) are serious complications in this modern antibody therapy of otherwise well-tolerated mAbs. In order to reduce the incidence and severity of such reactions, the newer generations of mAbs are fully human. However, there is limited clinical experience of administering a fully human mAb, such as panitumumab, to patients (pts) who have experienced IRs to a chimeric anti-EGFR mAb, such as cetuximab [1.Nielsen D.L. Pfeiffer P. Jensen B.V. Six cases of treatment with panitumumab in patients with severe hypersensitivity reactions to Cetuximab.Ann Oncol. 2009; 20: 798Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 2.Helbling D. Borner M. Successful challenge with the fully human EGFR antibody panitumumab following an infusion reaction with the chimeric EGFR antibody Cetuximab.Ann Oncol. 2007; 18: 963-964Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar]). We now report about the Austrian Compassionate Use programme, in which pts received panitumumab monotherapy after IRs to cetuximab. Eligible chemotherapy refractory pts (n = 20) with metastatic colorectal cancer (mCRC) who experienced an IR after treatment with cetuximab received panitumumab monotherapy (6 mg/kg every 2 weeks) were recruited in 10 Austrian institutions. At the time of initiation, the predictive value of KRAS status on response to anti-EGFR therapy was not known and thus, was not an inclusion criterion for this programme. Patients included in this programme were heavily pretreated, with the majority having received at least 4 prior lines of chemotherapy (range 1–7). Median number of panitumumab cycles received was 6 (range 1–32). During the whole application period no panitumumab-related IRs were reported. Response data [3.Resch G. Schaberl-Moser R. Kier P. et al.Analysis of the Austrian compassionate use program of panitumumab in patients with metastatic colorectal cancer.ASCO GI. 2009; (Abstract 428)Google Scholar] were similar to previously published data. The first generation of mAbs was murine-derived and highly immunogenic in humans. To overcome this issue, chimeric mAbs, such as cetuximab, were constructed by combining the antigen-binding regions of the mouse antibody with human immunoglobulin G-constant domains. Chimeric mAbs still consist of approximately 34% of mouse protein—which results in various immunogenic responses, including infusion-related reactions. Cetuximab has been associated with IRs of any grade in 15%–21% of pts, grade 3 to 4 IRs occurred to 2%–5% of pts (e.g. bronchospasm, stridor, urticaria, hypotension and cardiac arrest) [4.ImClone Systems Incorporated, Bristol-Myers Squibb. Erbitux (Cetuximab) package insert. 2006Google Scholar, 5.Saltz L.B. Meropol N.J. Loehrer Sr, P.J. et al.Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.J Clin Oncol. 2004; 22: 1201-1208Crossref PubMed Scopus (1616) Google Scholar, 6.Peeters M. Cutsem V. Berlin J. et al.Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor, in patients with metastatic colorectal cancer across clinical trials.J Clin Oncol. 2007; 25: 413Crossref Google Scholar]. The clinical and economic impacts of these IRs are substantial, as they often require inpatient treatment and cause disruption of infusion or discontinuation of therapy [7.Foley K.A. Wang P.F. Barber B.L. et al.Clinical and economic impact of infusion reactions in patients with colorectal cancer treated with Cetuximab.Ann Oncol. 2010; 21: 1455-1461Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Panitumumab is the first fully human mAb to EGFR and is approved as monotherapy for EGFR-expressing mCRC with nonmutated KRAS after failure of standard chemotherapy [8.Van Cutsem E. Siena S. Humblet Y. et al.An open-label, single-arm study assessing safety and efficacy of panitumumab in patients with metastatic colorectal cancer refractory to standard chemotherapy.Ann Oncol. 2008; 19: 92-98Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar]. Clinical trials have reported <2% of infusion-related reactions of which approximately 1% were severe, which is most likely due to the drug's nonchimeric structure [9.VectibixTM (panitumumab) [package insert]Minervum, the NetherlandsAmgen Europe B.VGoogle Scholar, 10.Peeters M. Cutsem V. Berlin J. et al.Safety of panitumumab, a fully human monoclonal antibody against the epidermal growth factor receptor, in patients with metastatic colorectal cancer across clinical trials.J Clin Oncol. 2007; 25: 413Crossref Google Scholar]. No fatal reactions to panitumumab have been reported. Our data indicate that the fully human mAb panitumumab can be safely administrated to pts after IRs to cetuximab. disclosureWS had received honoraries from Amgen for consultant and advisory board meeting activities and as invited speaker. All other authors have declared no conflicts of interest. WS had received honoraries from Amgen for consultant and advisory board meeting activities and as invited speaker. All other authors have declared no conflicts of interest.