Cetuximab dosing regime in question for colorectal cancer


By Siobhan Calafiore

10 Sep 2023

Up to two-thirds of patients with advanced colorectal cancer receiving standard cetuximab dosing are not achieving optimal concentrations, resulting in under-exposure and compromised overall survival, Australian researchers say.

They are calling for investigation into alternative dosing strategies and therapeutic monitoring, given the potential benefits for more individualised dosing regimens.

The Australasian Gastro-Intestinal Trials Group in collaboration with the Canadian Cancer Trials Group conducted the multicentre, double-blinded phase 3 study called CO. 20, which randomised patients with RAS wild-type (WT) metastatic colorectal cancer to receive the chimeric IgG monoclonal antibody or placebo.

They followed the most common dosing regime: cetuximab 400 mg/m2 loading dose intravenously over 120 minutes followed by weekly maintenance infusions of 250 mg/m2 given over 60 minutes, plus brivanib 800 mg orally daily.

With this regimen, studies had shown inter-patient variations could be as high as 39% in area under the curve and up to 2.5 folds in trough levels, they noted.

Venous blood samples were collected at baseline and after four weeks of cetuximab treatments, prior to the scheduled week 5 cetuximab administration.

Patients were then grouped into tertiles based on plasma concentrations.

Of the 750 patients enrolled, week 5 plasma cetuximab concentrations were available in 591 (78.8%) patients. The median follow-up time was 18.7 months.

Week 5 plasma cetuximab concentrations ranged from 5.1 to 970 μg/ml, with a mean of 93 ± 66 μg/ml, showed findings in Clinical Colorectal Cancer [link here].

On univariable analysis, cetuximab concentration tertile, age, performance status, BMI, number of metastatic sites, tumour sidedness, lactate dehydrogenase and histological grade were all significantly associated with overall survival.

The median overall survival was 11.4 months for patients in the highest tertile (T3) versus only 7.8 months for those in the lowest tertile (T1), the researchers said.

On multivariable analysis, plasma cetuximab concentration was associated with overall survival (HR 0.66, T3 vs T1), and a trend towards progression-free survival for patients in the highest tertile (5.3 months in T3 vs 3.9 months in T1, HR: 0.83).

“This is not surprising since this patient population has a poor survival, with a median progression-free survival of 3.4 months for cetuximab only and 5.0 months for cetuximab and brivanib respectively. A much higher number of patients will be required to demonstrate this small benefit,” the researchers said.

There was no strong association between cetuximab concentration and skin toxicity or diarrhoea. The incidence of grade 3/4 diarrhoea was 3.2%, 5.3% and 10.8% for T1, T2 and T3 patients respectively.

The researchers argued for more pharmacokinetic-guided cetuximab dosing.

“Therapeutic drug monitoring is an accepted and routine practice for monitoring toxicity and efficacy for a number of classes of drugs including antibiotics, immunosuppressants, antiepileptics, and HIV therapy,” they said.

“In oncology, routine therapeutic drug monitoring is limited to high-dose methotrexate in a variety of diseases and mitotane for adrenocortical carcinoma, where drug levels are monitored to prevent excessive toxicity.

“Our findings and those of other investigators show a high inter-patient variability in plasma cetuximab concentrations using the standard body surface area-based dosing. Up to two out of three patients (tertiles 1 and 2) may have sub-therapeutic cetuximab concentrations with the standard dosing regimen.

“The 3.6 month difference in overall survival between the highest and lower tertiles is striking and surpasses survival benefits reported in trials of FDA-approved drugs in advanced colorectal cancer.” 

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