Plasma Cetuximab Concentrations Correlate With Survival in Patients With Advanced KRAS Wild Type Colorectal Cancer,Clinical Colorectal Cancer

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Plasma Cetuximab Concentrations Correlate With Survival in Patients With Advanced KRAS Wild Type Colorectal Cancer
Clinical Colorectal Cancer ( IF 3.4 ) Pub Date : 2023-08-23 , DOI: 10.1016/j.clcc.2023.08.006
Di Maria Jiang ₁ , Shruti Parshad ₁ , Luna Zhan ₁ , Hao-Wen Sim ₂ , Lillian L Siu ₁ , Geoffrey Liu ₁ , Jeremy D Shapiro ₃ , Timothy J Price ₄ , Derek J Jonker ₅ , Christos S Karapetis ₆ , Andrew H Strickland ₇ , Wenjiang Zhang ₁ , Mark Jeffery ₈ , Dongsheng Tu ₉ , Siobhan Ng ₁₀ , Sabe Sabesan ₁₁ , Jenny Shannon ₁₂ , Amanda Townsend ₄ , Chris J O'Callaghan ₉ , Eric X Chen ₁

Affiliation

Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto ON.
School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, and NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Ausutralia.
Department of Medical Oncology, Cabrini Hospital, Cabrini Monash University, Melbourne, Australia.
Department of Hematology and Oncology, Queen Elizabeth Hospital, CALHN, Adelaide, South Australia.
Ottawa Hospital Research Institute, University of Ottawa, Ottawa ON.
Flinders Medical Center, Flinders University, Adelaide, South Australia.
Monash Cancer Centre, Monash University, Clayton, Australia.
Canterbury Regional Cancer and Hematology Service Centre, Christchurch Hospital, Christchurch, New Zealand.
Canadian Cancer Trials Group, Queen's University, Kingston, ON.
Sir Charles Gairdner Hospital, Nedlands, Australia.
Townsville Hospital, Townsville, Australia.
Nepean Cancer Care Centre, Kingswood, Australia.

Background

Cetuximab is a standard of care therapy for patients with RAS wild-type (WT) advanced colorectal cancer. Limited data suggest a wide variation in cetuximab plasma concentrations after standard dosing regimens. We correlated cetuximab plasma concentrations with survival and toxicity.

Methods

The CO. 20 study randomized patients with RAS WT advanced colorectal cancer in a 1:1 ratio to cetuximab 400 mg/m² intravenously followed by weekly maintenance of 250 mg/m², plus brivanib 800 mg orally daily or placebo. Blood samples obtained at week 5 precetuximab treatment were analyzed by ELISA. Patients were grouped into tertiles based on plasma cetuximab concentrations. Cetuximab concentration tertiles were correlated with survival outcomes and toxicity. Patient demographic and biochemical parameters were evaluated as co-variables.

Results

Week 5 plasma cetuximab concentrations were available for 591 patients (78.8%). The median overall survival (OS) was 11.4 months and 7.8 months for patients in the highest (T3) and lowest tertiles (T1) respectively. On multivariable analysis, plasma cetuximab concentration was associated with OS (HR 0.66, 95% confidence interval [CI]: 0.53-0.83, P < .001, T3 vs. T1), and a trend towards progression-free survival (HR 0.82, 95% CI: 0.66-1.02, P = .07, T3 vs. T1). There was no association between cetuximab concentration and skin toxicity or diarrhea.

Conclusion

The standard cetuximab dosing regimen may not be optimal for all patients. Further pharmacokinetic studies are needed to optimize cetuximab dosing given the potential improvement in OS.

中文翻译：

血浆西妥昔单抗浓度与晚期 KRAS 野生型结直肠癌患者的生存相关

背景

西妥昔单抗是 RAS 野生型 (WT) 晚期结直肠癌患者的标准护理疗法。有限的数据表明标准给药方案后西妥昔单抗血浆浓度存在很大差异。我们将西妥昔单抗血浆浓度与生存率和毒性相关联。

方法

CO. 20 研究将 RAS WT 晚期结直肠癌患者以 1:1 的比例随机分配给西妥昔单抗 400 mg/m ²静脉注射，然后每周维持 250 mg/m ²，加上每日口服 800 mg 布立尼布或安慰剂。通过 ELISA 分析 precetuximab 治疗第 5 周获得的血样。根据血浆西妥昔单抗浓度将患者分为三分位数。西妥昔单抗浓度三分位数与生存结果和毒性相关。患者人口统计和生化参数作为协变量进行评估。

结果

591 名患者 (78.8%) 可获得第 5 周血浆西妥昔单抗浓度。最高三分位数 (T3) 和最低三分位数 (T1) 患者的中位总生存期 (OS) 分别为 11.4 个月和 7.8 个月。在多变量分析中，血浆西妥昔单抗浓度与 OS 相关（HR 0.66，95% 置信区间 [CI]：0.53-0.83，P < .001，T3 与 T1）以及无进展生存趋势（HR 0.82， 95% CI：0.66-1.02，P = 0.07，T3 与 T1）。西妥昔单抗浓度与皮肤毒性或腹泻之间没有关联。