Targeting the epidermal growth factor receptor (EGFR) has proven to be of clinical benefit in the management of metastatic colorectal cancer (mCRC). While the use of small-molecule tyrosine kinase inhibitors in this setting has not shown any significant activity and has been associated with increased gastrointestinal toxicity when combined with chemotherapy, a different picture has emerged with the use of EGFR-targeting monoclonal antibodies.[1-3]
Cetuximab (Erbitux), a chimeric immunoglobulin (Ig)G1 monoclonal antibody targeting EGFR has single-agent activity producing response rates of 6% to 12%[4,5] and results in an improvement in overall survival compared to best supportive care in patients with chemotherapy-resistant mCRC. The combination of cetuximab and irinotecan (Camptosar) in irinotecan-resistant mCRC improves the overall response rate (RR) and progression-free survival (PFS) compared to cetuximab alone. Furthermore, the integration of cetuximab in first- and second-line irinotecan-based chemotherapy has recently been shown to result in improvements in RR and PFS compared to chemotherapy alone.[6,7]
Panitumumab (Vectibix), a human IgG2 monoclonal antibody targeting the EGFR has also been investigated extensively in mCRC. Similar to cetuximab, panitumumab decreases the risk of progression in comparison to best supportive care in patients with chemotherapy-resistant mCRC. However, this agent has been associated with a significant increase in the risk of severe toxicities when combined with oxaliplatin (Eloxatin) or irinotecan-based combination chemotherapy in the first-line treatment of mCRC. Furthermore, the addition of panitumumab to oxaliplatin-based first-line combination chemotherapy resulted in a worsening in PFS and overall survival compared to chemotherapy alone.
Thus, current clinical data support the use of cetuximab alone or in combination with irinotecan-based therapy in irinotecan-resistant patients, whereas panitumumab use should be limited to single-agent administration in patients who have failed chemotherapy and who cannot tolerate irinotecan plus cetuximab after irinotecan failure. The integration of cetuximab in the first- or second-line settings in combination with irinotecan or oxaliplatin-based combinations to improve the chances of downstaging or to delay disease progression is supported by randomized clinical trials—which will likely result in the increased use of this agent in earlier settings in mCRC. This will undoubtedly result in an increase in toxicities associated with the prolonged use of cetuximab, such as hypomagnesemia.
Grade 3/4 hypomagnesemia has been consistently reported across clinical trials of cetuximab and panitumumab. The National Cancer Institute of Canada (NCIC) CO.17 study randomized patients to receive single-agent cetuximab vs best supportive care. The incidence of grade 3/4 hypomagnesemia among cetuximab-treated patients (n = 288) was 5.8% vs 0% in the best supportive care arm.
In another randomized study—the Erbitux Plus Irinotecan in CRC (EPIC) trial—of irinotecan plus cetuximab vs irinotecan after therapy with oxaliplatin and fluoropyrimidine had failed, the incidence of grade 3/4 hypomagnesemia was 3.3% for the cetuximab based combination vs 0.4% in the irinotecan arm. In the CRYSTAL study, which randomized patients to receive irinotecan, fluorouracil (5-FU), and leucovorin with or without cetuximab, the incidence of grade 3/4 hypomagnesemia was 1.8% in the cetuximab-based arm vs 0.2% in the chemotherapy-only arm. However, neither the EPIC nor CRYSTAL study mandated monitoring of magnesium levels in enrolled patients. In fact, only 20% of patients in the CRYSTAL study had a magnesium level drawn sometime during treatment. This explains the lower rate of hypomagnesemia noted in the first- and second-line studies in comparison with the NCIC study, where patients were exposed to considerably shorter durations of treatments with cetuximab.
Other data clearly point to a direct relationship between the duration of cetuximab exposure and hypomagnesemia. In a study of 114 patients at Roswell Park Cancer Institute, we have reported grade 3/4 hypomagnesemia in 5%, 23%, and 47% of patients receiving < 3 months, 3 to 6 months, and > 6 months of cetuximab, respectively. In a prospective study of 98 patients treated with EGFR-targeting monoclonal antibodies with or without chemotherapy, Tejpar reported no grade 3/4 hypomagnesemia in patients receiving < 3 months of treatment, whereas patients receiving 3 to 6 months or > 6 months experienced grade 3/4 hypomagnesemia rates of 3% and 12%, respectively.
Dr. Fakih has received honoraria from ImClone for educational activities.
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