The evidence supporting this protocol is provided by a phase III randomised trial (CO 17) involving 572 patients comparing cetuximab monotherapy with best supportive care in patients with metastatic colorectal cancer previously treated with or contraindicated to receive a fluoropyrimidine-based treatment.r
Between December 2003 and August 2005, 287 patients were randomised to receive weekly cetuximab 250 mg/m2 (loading dose 400 mg/m2) and 285 patients were randomised to best supportive care alone.r
The primary end point was overall survival and secondary end points were progression-free survival, response rates, quality of life and toxicity.r
A retrospective analysis conducted in patients with known KRAS status (n=394) showed that only patients with wild type K-RAS tumours had benefit from cetuximab therapy.r
Results of the ASPECCT trial (n=999) has shown that single agent panitumumab was non inferior to cetuximab in extending overall survival (OS) in patients with chemorefractory KRAS wild-type metastatic colorectal cancer. However, for patients who progress on cetuximab, there is currently no data to support switching to panitumumab.r
Monoclonal antibodies (mABs) targeting the epidermal growth factor receptor (EGFR) prolong survival in patients with metastatic colorectal cancer (mCRC) harbouring KRAS exon 2 wild type tumours. Recent evidence suggest that other RAS mutations (exon 3 and 4 of KRAS and exons 2, 3, 4 of NRAS) may also be predictive of resistancer,r and many studies suggest that anti-EGFR mAB treatment may have a detrimental effect on PFS and OS in patients with NRAS mutations.r As such, cetuximab should not be used in patients with any RAS mutations.
Efficacy
In the ITT population, cetuximab monotherapy improved the progression free survival (median 1.9 vs. 1.8 months, HR=0.68; 95% CI: 0.57-0.80; p<0.0001) and overall survival (median 6.1 vs. 4.6 months, HR=0.77; 95% CI: 0.64-0.92; p=0.0046) compared with best supportive care.r
In patients with wild-type K-RAS tumours, treatment with cetuximab improved progression free survival (median 3.7 vs. 1.9 months, HR=0.40; 95%CI: 0.30-0.54; p<0.0001) and overall survival (median 9.5 vs. 4.8 months, HR=0.55; 95% CI: 0.41-0.74; p<0.0001) compared to best supportive care. Patients with K-RAS mutant tumours derived no benefit from cetuximab.r
Kaplan-Meier curves for overall survival in patients with mutated (A) and wild-type (B) K-rasr
© New England Journal of Medicine 2008
Toxicity
There were no statistically significant differences between the cetuximab group and the supportive-care group in the incidence of grade 3 or higher adverse events, with the exception of rash (11.8% for cetuximab vs. 0.4% for supportive care, P<0.001), infection without neutropenia (12.8% vs. 5.5%, P=0.003), confusion (5.6% vs. 2.2%, P=0.05), and pain defined as "other" according to the NCI-CTC (14.9% vs. 7.3%, P=0.005).r
Haematological adverse events were uncommon, and there were no significant differences between the groups in grade 3 or higher serum chemical values or other laboratory measurements, with the exception of hypomagnesaemia, which was more common in the cetuximab group than in the group receiving supportive care alone (5.8% vs. 0.0%, P<0.001). Grade 3 or 4 infusion reactions (hypersensitivity) occurred in 4.5% of patients assigned to cetuximab.r
Toxicity of cetuximab plus best supportive care vs best supportive care aloner
© New England Journal of Medicine 2007