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Little Apparent Activity of Cetuximab in Refractory Metastatic Colorectal Cancer With KRAS G13D Mutation

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Key Points

  • Six-month progression-free survival was 10% in the cetuximab group vs 23% in the cetuximab/irinotecan group.
  • Response rates were 0% vs 9%.

Cetuximab (Erbitux) exhibited little apparent activity in refractory metastatic colorectal cancer harboring the KRAS G13D mutation, according to the findings of the phase II Australasian Gastro-Intestinal Trials Group ICECREAM study, which were reported by Segelov et al in the Journal of Clinical Oncology. Although RAS mutations have been shown to predict lack of response to epidermal growth factor receptor (EGFR) inhibitors in metastatic colorectal cancer, preclinical and retrospective data have suggested a benefit of cetuximab in patients with tumors harboring the KRAS G13D mutation.

Study Details

In the ICECREAM study, 50 evaluable patients from 14 sites in Australia and 1 site each in Spain, Italy, and England who had chemotherapy-refractory disease and had shown disease progression within 6 months of irinotecan therapy were randomized between November 2012 and December 2014 to receive cetuximab at a 400-mg/m2 loading dose and then 250 mg/m2 once per week (n = 25) or cetuximab plus irinotecan at 180 mg/m2 once every 2 weeks. The primary endpoint was 6-month progression-free survival.

Outcomes

The 6-month progression-free survival rate was 10% (95% confidence interval [CI] = 2%–26%) in the cetuximab group vs 23% (95% CI = 9%–40%) in the cetuximab/irinotecan group (hazard ratio [HR] = 0.74, 95% CI = 0.42–1.32). Response rates were 0% vs 9%, and stable disease rates were 58% vs 70%, respectively. The 6-month overall survival rate was 56% vs 42% (HR = 0.95, 95% CI = 0.53–1.68).

Toxicity was more common with combination treatment, with grade ≥ 3 adverse events occurring in 44% vs 59% and serious adverse events occurring in 20% vs 37%.

The investigators concluded: “In patients with G13D-mutated chemotherapy-refractory metastatic colorectal cancer, there was no statistically significant improvement in disease control at 6 months with either cetuximab monotherapy or cetuximab plus irinotecan. No responses were seen with single-agent cetuximab. The responses observed with the combination of cetuximab and irinotecan may reflect true drug synergy or persistent irinotecan sensitivity. The ICECREAM … study demonstrates the need to prospectively evaluate hypotheses that were previously supported by retrospective analyses and exemplifies the value of international collaboration in trials of rare molecular subtypes.”

The study was supported by Merck Serono Australia.

Eva Segelov, MD, of the University of New South Wales, is the corresponding author of the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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