Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN)
Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN)
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DOI：
10.1093/annonc/mdy013
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发表时间：
2018-04-01
影响因子：
50.5
通讯作者：
Licitra, L. F.
中科院分区：
文献类型：
--
作者：
Machiels, J. -P.;Bossi, P.;Licitra, L. F.
背景：探讨阿法替尼在头颈部鳞状细胞癌（SCCHN）术前治疗中的活性和安全性。患者和方法：该研究是一项开放标签、随机、多中心、II期机会窗口试验。选择首次治疗的SCCHN患者进行初次治愈性手术，随机（5:1比例）在手术前（第0天）14天（第15天至第1天）接受阿法替尼治疗或不接受治疗。在诊断时和手术前进行肿瘤活检、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FDG-PET反应（根据EORTC指南）。其他终点包括基于实体肿瘤反应评价标准（RECIST） v1.1，动态对比增强(DCE)-MRI，扩散加权(DW)-MRI，安全性和转化研究（TR）的反应评估。结果：30例患者随机分组：25例阿法替尼组，5例对照组。在随机分配到阿法替尼的23例符合条件的患者中，16例（70%；95% CI: 47%至87%）患者有部分代谢FDG-PET反应（PMR）。5例患者（22%；95% CI: 8%至44%）通过RECISTv1.1显示部分缓解。通过DCE-MRI和DWI-MRI评估的反应与PMR或RECIST没有很强的关联。1例患者因3级腹泻11天后停用阿法替尼，随后出现肾功能衰竭，手术延迟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结果显示，PMR在cluster3 -缺氧评分高表达和TP53野生型的肿瘤中更为常见。结论：根据RECISTv1.1标准，新诊断的SCCHN患者给予2周阿法替尼可诱导较高的FDG-PET部分代谢反应和部分缓解率。在手术前使用阿法替尼是安全的。虽然是探索性的，但缺氧基因标记作为阿法替尼活性的预测性生物标志物需要进一步研究。
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-naive 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.