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Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN).
Annals of Oncology ( IF 50.5 ) Pub Date : 2018-04-01 , DOI: 10.1093/annonc/mdy013
J-P Machiels 1 , P Bossi 2 , J Menis 3 , M Lia 3 , C Fortpied 3 , Y Liu 3 , R Lhommel 4 , M Lemort 5 , S Schmitz 1 , S Canevari 6 , L De Cecco 6 , M Guzzo 7 , R Bianchi 7 , P Quattrone 8 , F Crippa 9 , T Duprez 10 , Y Lalami 11 , M Quiriny 12 , N de Saint Aubain 13 , P M Clement 14 , R Coropciuc 15 , E Hauben 16 , L F Licitra 2
Affiliation  

Background To investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methods This study was an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14 days (day -15 until day -1) before surgery (day 0) or no treatment. Tumor biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR). Results Thirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11 days for grade 3 diarrhea with subsequent renal failure and 24 days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type. Conclusion Afatinib given for 2 weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity. Clinical trial registration ClinicalTrials.gov: NCT01538381.

中文翻译:

阿法替尼在头颈部鳞状细胞癌(SCCHN)患者术前EORTC窗口研究中的活性和安全性。

背景研究阿法替尼在术前治疗头颈部鳞状细胞癌(SCCHN)中的活性和安全性。患者和方法本研究是机会试验的开放标签,随机,多中心,II期窗口。选择接受初次根治性手术的未治疗过的SCCHN患者(比例为5:1),在手术前(第0天)的14天(第-15天至第-1天)接受阿法替尼治疗或不接受治疗。在诊断时和手术前就进行了肿瘤活检,2- [氟-18]-氟-2-脱氧-d-葡萄糖正电子发射断层扫描(FDG-PET)和磁共振成像(MRI)。主要终点是代谢性FDG-PET反应(根据EORTC指南)。其他终点包括根据实体瘤反应评估标准(RECIST)v1.1进行的反应评估,动态对比增强(DCE)-MRI,扩散加权(DW)-MRI,安全性和转化研究(TR)。结果30例患者被随机分组​​:阿法替尼25例,对照组5例。在随机分配给阿法替尼的23名合格患者中,有16名(70%; 95%CI:47%至87%)患者出现部分代谢性FDG-PET反应(PMR)。五名患者(22%; 95%CI:8%至44%)显示出RECISTv1.1的部分缓解。通过DCE-MRI和DWI-MRI评估的反应并未显示与PMR或RECIST密切相关。一名患者在11天后因3级腹泻而停药阿法替尼,随后出现肾功能衰竭,手术时间延迟了24天。没有与阿法替尼相关的4级毒性或手术合并症的报道。TR结果表明,PMR在具有高Cluster3低氧评分表达和TP53野生型的肿瘤中更为常见。结论根据RECISTv1.1,对刚诊断为SCCHN的患者给予阿法替尼2周可诱导较高的FDG-PET部分代谢反应和部分反应率。阿法替尼可以在手术前安全地给药。尽管是探索性的,但缺氧基因标记需要进一步研究,作为阿法替尼活性的预测生物标记。临床试验注册ClinicalTrials.gov:NCT01538381。
更新日期:2018-01-15
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