Cetuximab, a chimeric IgG1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor EGFR , is active in metastatic colorectal cancer mCRC. As an IgG1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. More recent studies show promising activity in second-line treatment after oxaliplatin-based therapy failure, and with first-line chemotherapy, where increased response rates seen with adding cetuximab to first-line therapy for mCRC may increase chances for curative surgery in a population for whom the therapy goal would otherwise be palliative. Cetuximab is generally well tolerated; common toxicities are acne-form rash and hypomagnesemia.
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Cetuximab, a chimeric IgG1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor EGFR , is active in metastatic colorectal cancer mCRC. As an IgG1 antibody, cetuximab may exert its antitumor efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. More recent studies show promising activity in second-line treatment after oxaliplatin-based therapy failure, and with first-line chemotherapy, where increased response rates seen with adding cetuximab to first-line therapy for mCRC may increase chances for curative surgery in a population for whom the therapy goal would otherwise be palliative.
Cetuximab is generally well tolerated; common toxicities are acne-form rash and hypomagnesemia. Rash intensity is associated with clinical efficacy, and in the future, may be used as a marker for optimal drug exposure. Cetuximab activity in mCRC is not correlated with EGFR expression, and consequently other markers will be needed to identify the most likely responders.
Cetuximab has clinically emerged as a core agent, along with 5-fluorouracil, irinotecan, oxaliplatin, and bevacizumab, for overall mCRC management to optimize survival.
Ongoing studies are exploring best combinations of cetuximab with these other agents to maximize patient outcome. LLC, Bridgewater, NJ , and biologics over the last decade has yielded incremental improvements in survival of patients with metastatic colorectal cancer mCRC. Both irinotecan and oxaliplatin improved efficacy when added to 5-fluoruracil 5-FU in first-line therapy Douillard et al ; Saltz et al and in pretreated patients Cunningham et al ; Rougier et al ; de Gramont et al These findings form the basis for the current paradigm in mCRC management: 5-FU, irinotecan, and oxaliplatin should be administered at some point during the course of treatment, typically starting with either oxaliplatin or irinotecan in combination with 5-FU.
Clinical outcome has been further improved by incorporating biologics into this treatment paradigm. The value of adding bevacizumab to irinotecan following FOLFOX failure, or continuing bevacizumab therapy after failure of a bevacizumab-containing regimen is not fully established. The recent report from the retrospective Bevacizumab Regimens Investigation of Treatment Effects and Safety BRiTE study suggests that continued use of bevacizumab may provide a meaningful clinical advantage in terms of long-term survival Grothey et al ; however, this approach is currently under investigation in the prospective SWOG and BOND 2.
Bevacizumab has very little activity when used alone or in combination with 5-FU in refractory disease Chen et al ; Giantonio et al The EGFR mediates cell proliferation, differentiation, migration, and adhesion, and enhances processes critical to tumor growth and progression, including angiogenesis, apoptosis inhibition, tumor invasiveness, and metastatic spread Lenz EGFR is overexpressed in many colorectal tumors; although some studies have shown inconsistent findings, the levels of EGFR expression are related to prognosis, with higher expression levels correlating with shorter survival times and greater metastatic potential Nicholson et al ; Spano et al This article focuses on the clinical efficacy and tolerability of cetuximab, and discusses its role in the management of mCRC.
It consists of a ligand-binding extracellular domain, a lipophilic transmembrane region, and an intracellular tyrosine kinase domain. The nature of the EGFR ligand as well as the coreceptor involved in dimerization determines which signaling pathways are activated and the final cellular response Yarden and Sliwkowski Cetuximab binds specifically to the extracellular domain of EGFR as a competitive antagonist of the endogenous ligands Harding and Burtness Together, these effects block EGFR-mediated signaling leading to cell cycle arrest in G1, and pro-apoptotic processes Huang et al ; Kiyota et al ; Harding and Burtness EGFR-dependent transcriptional programs are also affected by cetuximab, which reduces angiogenesis, tumor invasiveness, and metastatic spread Harding and Burtness Preclinical studies showed that cetuximab acts synergistically with various cytotoxic agents to augment tumor growth inhibition Huang et al ; Overholser et al Notably, the cetuximab-irinotecan combination also produced growth inhibition of irinotecan-refractory DLD-1 and HT xenografts, whereas tumor growth was not controlled by either agent alone.
On histological examination, the combination of cetuximab and irinotecan led to extensive tumor necrosis, reduced tumor cell proliferation, increased tumor cell apoptosis, and decreased tumor vasculature.
Cetuximab also enhances radiosensitivity Huang et al However, in the presence of cetuximab, EGFR nuclear import and subsequent activation of DNA repair mechanisms after radiation exposure were inhibited, and radiosensitivity was enhanced Dittmann et al Taken together, these preclinical studies illustrate that cetuximab restores chemosensitivity to cytotoxic agents and also enhances sensitivity to radiation therapy.
As an IgG1 monoclonal antibody, cetuximab also has the potential to kill tumor cells through antibody-dependent cell-mediated cytotoxicity ADCC. The specificity of cetuximab for the EGFR is determined by its antigen-binding region, whereas its Fc region is characteristic of other IgG1 immunoglobulins. Studies based on the clinical effect of the genetic polymorphisms identified in both receptor isoforms have helped provide proof of principle of the clinical relevance of ADCC van Sorge et al These receptor polymorphisms have different affinities for their target Fc domains, which would be expected to translate into different levels of ADCC activity, and ultimately impact clinical response.
Whether ADCC actually contributes to the clinical efficacy of cetuximab, however, remains to be determined. This raises the possibility that solid tumors respond differently than hematological malignancies to ADCC, particularly when comparing late-stage solid tumors with first-line treatment of lymphoma.
Additional studies are needed to better define the clinical significance of ADCC to the efficacy of cetuximab. FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuzimab.
J Clin Oncol , — As knowledge about the role of EGFR in tumor growth and progression continues to advance, it will provide a better understanding about which mechanisms of cetuximab are important in conveying clinical benefit in mCRC as well as in other solid malignancies. Following the pattern of activity observed in xenograft models, cetuximab was initially investigated in combination with cytotoxic agents, particularly irinotecan.
To date, that combination remains the most effective cetuximab-based therapy for patients with mCRC disease who have received prior therapy. Numerous single-arm and randomized studies recently completed or nearing completion are generating a more complete profile of cetuximab as part of non-irinotecan-based combinations, as well as in untreated patients with mCRC. In parallel, and beyond the scope of this review, cetuximab has also been proven effective in head and neck cancers and non-small cell lung cancers Rosell et al ; Bonner et al ; Kelly et al ; Vermorken et al The initial clinical evaluation of cetuximab in mCRC was performed in patients who had been previously treated with irinotecan Table 1.
Although these studies were not comparative, they provided an important framework for the clinical development of this agent, and warranted its regulatory approval both in North America and the EU.
This regimen has remained the standard whether cetuximab is given in monotherapy or in combination with other agents. Saltz and colleagues Saltz et al evaluated single-agent cetuximab in 57 patients with EGFR-positive mCRC who had failed previous irinotecan-based therapy.
The median time to tumor progression was 1. More recently, Lenz and co-workers Lenz et al administered single-agent cetuximab to patients with EGFR-positive mCRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The median survival was 6.
These studies demonstrated the activity of cetuximab as a single agent. The most efficacious modality of cetuximab therapy in refractory mCRC, however, is the combination with irinotecan. Cunningham and colleagues Cunningham et al randomly assigned patients with EGFR-expressing mCRC who had failed a previous irinotecan-based regimen in a ratio to treatment with cetuximab plus irinotecan or cetuximab alone.
Irinotecan was given at the same dose and schedule as in the regimen that the patient had previously failed. Median survival, however, did not differ significantly between treatment groups, although it was numerically longer for those receiving cetuximab and irinotecan 8. Consistent results with cetuximab-based combinations have been reported by single-arm studies. First, the cetuximab-irinotecan combination is among the most active regimens in pretreated patients.
Second, the greater activity of this combination relative to single-agent cetuximab, even in patients refractory never responsive to irinotecan, suggests that chemosensitivity to irinotecan may be restored when it is administered in combination with cetuximab.
Third, cetuximab exhibited comparable activity in patients who had received irinotecan as in those treated with both irinotecan and oxaliplatin, suggesting that it maintains its efficacy in mCRC across later lines of therapy. Finally, in these studies, the degree of EGFR expression — whether defined by the percentage of EGFR-expressing cells or by the maximal staining intensity per cell — did not correlate with the clinical activity of cetuximab Cunningham et al ; Lenz et al Moreover, Chung and co-workers Chung et al retrospectively identified 16 irinotecan-refractory mCRC patients with EGFR-negative tumors who received cetuximab within the first 3 months of its commercial availability.
Fourteen patients were treated with cetuximab in combination with irinotecan, and the other 2 patients with cetuximab alone. These findings indicate that EGFR expression is not a valid criterion for selecting patients for cetuximab therapy, and underscore the need for selective biomarkers that can predict which patients are most likely to respond to cetuximab. As a confirmation of the role of single-agent cetuximab as standard salvage therapy after multiple treatments, a recently reported phase III has demonstrated the survival benefit associated with cetuximab treatment, over best supportive care BSC , in multi-refractory patients.
The primary study endpoint was overall survival. Cetuximab produced a significantly higher objective response rate than BSC alone 6. Thus, NCIC confirms the efficacy of single-agent cetuximab in multi-refractory mCRC patients, and is the first study to demonstrate a survival benefit associated with an anti-EGFR agent in this setting. As discussed above, by the time of FDA and EMEA approval of cetuximab, the combination with irinotecan had been proven to be effective after irinotecan failure; however, bona-fide comparative data documenting the additive contribution of cetuximab to this regimen were lacking.
Single-agent irinotecan was used as comparator, as it was the standard of care in this setting at the time EPIC was initiated. Adding cetuximab to irinotecan was superior to irinotecan alone, as it significantly improved PFS 4. Importantly, adding cetuximab to irinotecan did not exacerbate toxicity, except for acne-form rash. Despite the positive results for the secondary endpoints, however, the primary study point, overall survival, was not met. Median survival was comparable between treatments This lack of difference, however, is a likely consequence of the imbalances in post-trial therapy.
Beyond the interpretation of these results in terms of cetuximab efficacy, this study also highlights the ongoing challenges of clinical trial design and endpoint selection in a fast evolving area such as mCRC. While prolonging survival is unarguably the most relevant clinical goal, it is debatable whether median survival provides an accurate measure of clinical efficacy, versus PFS, for an agent given in first-line or second-line treatment of mCRC.
Depending on the therapeutic setting, the reliability of median survival as an endpoint may be confounded by significant factors beyond the control of a trial design, whereas PFS is more likely to reflect only protocol-controlled variables, and is sufficient for showing the clinical advantage of one regimen over another. Building upon the effectiveness of cetuximab in refractory mCRC, several studies have also been conducted to explore whether adding cetuximab to first-line therapy would improve patient outcome Table 2.
Of particular interest is the benefit derived by patients with liver disease only, whose rates of R0 resectability increased by 3 fold with the addition of cetuximab. These findings infer that cetuximab is active in the first-line setting, and especially valuable for patients with synchronous liver disease, but it is difficult to extrapolate them to current clinical practice in the United States, where practice patterns strongly favor FOLFOX plus bevacizumab as first-line treatment.
Furthermore, several smaller trials in which cetuximab was added to first-line FOLFOX have produced promising results. No unexpected toxicities were seen. Folprecht and colleagues Folprecht et al reported comparable results in a study of 21 patients with EGFR-expressing mCRC who received cetuximab in combination with weekly irinotecan and low-dose or high-dose infusional 5-FU. Enrollment to this study, however, could not be completed due to the fast adoption of bevacizumab as a component of first-line therapy.
The study was closed to accrual after a total of of the planned patients were enrolled. At the time of the report, the median follow-up was 16 months, still too early to tell whether adding cetuximab improved PFS Venook et al b. The ongoing OPUS study is also evaluating whether adding cetuximab to FOLFOX-4 will improve response rates, and secondarily whether it will allow more patients to undergo potentially curative surgery for metastases, and prolong the duration of response, PFS, and overall survival Bokemeyer Another promising avenue of therapeutic development for cetuximab in mCRC could bring together the activity of the 2 biologic agents effective in CRC, cetuximab and bevacizumab, based on a strong mechanistic rationale.
The EGFR pathway controls the production of VEGF and other angiogenic factors in cells, targeting both markers may therefore have a greater antitumor effect.
The feasibility of administering these 2 monoclonal antibodies in combination was addressed in the BOND-2 study, focusing on patients otherwise candidates for cetuximab therapy. In this phase II trial, 74 patients with irinotecan-refractory mCRC were randomly assigned to treatment with cetuximab, bevacizumab, and irinotecan, or to cetuximab and bevacizumab Saltz et al These patients had not been treated previously with cetuximab or bevacizumab, and were not required to have EGFR-expressing tumors.
Notably, as observed in the initial BOND study by Cunningham et al see above , the addition of irinotecan results in greater activity in these patients who had already progressed after one irinotecan-containing regimen.
The observed toxicities were consistent with those of the individual agents, with no evidence that adding bevacizumab enhanced toxicity. Pharmacogenomic analysis revealed several polymorphisms of genes involved in angiogenesis, the EGFR pathway, and DNA repair that may be potential markers for clinical outcome in mCRC patients receiving both biologics Lenz et al The BOND2.
The next step is the investigation of the cetuximab-bevacizumab doublet in untreated patients, for whom bevacizumab is already part of standard treatment. The primary endpoint in this study is overall survival, with response rate, PFS, duration of response, and time to progression as secondary endpoints. Additionally, this study will explore which regimen is most likely to allow patients to undergo potentially curative surgery of metastases following chemotherapy.
Cetuximab in the management of colorectal cancer
Generic Name: cetuximab Dosage Form: injection, solution. Medically reviewed by Drugs. Last updated on Feb 1, Infusion Reactions: Erbitux can cause serious and fatal infusion reactions [see Warnings and Precautions 5. Immediately interrupt and permanently discontinue Erbitux for serious infusion reactions [see Dosage and Administration 2.
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