Seront Emmanuel, Schmitz Sandra, Papier Matthias, van Maanen Aline, Henry Stéphanie, Lonchay Christophe, Rottey Sylvie, van Caloen Gabrielle, Machiels Jean-Pascal
Department of Medical Oncology, Centre Hospitalier de Jolimont, La Louvière, Belgium.
Departments of Medical Oncology and Head and Neck Surgery, Institut Roi Albert II, Institut de Recherche Clinique et Expérimentale (Pole MIRO), Cliniques Universitaires Saint-Luc, Catholic University of Louvain, Woluwe-Saint-Lambert, Belgium.
Front Oncol. 2019 Mar 19;9:155. doi: 10.3389/fonc.2019.00155. eCollection 2019.
The majority of human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) present upregulation of the epidermal growth factor receptor (EGFR) and frequent alterations in the cyclin D1-cyclin dependent kinase (CDK) 4/6 (CDK 4/6)-retinoblastoma protein (pRb) pathway, resulting in cell cycle progression and tumor proliferation. This study investigated the combination of ribociclib, an orally highly selective inhibitor of CDK 4/6, and cetuximab in recurrent and/or metastatic (R/M) SCCHN. A phase I trial using a 3 + 3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of ribociclib with standard dose of weekly cetuximab in HPV-negative patients with R/M SCCHN. Ribociclib was administered orally (3 weeks on/1 week off) at dose level 1 of 400 mg daily and dose level 2 of 600 mg daily. The MTD of ribocilib was then further evaluated in an expansion cohort. 10 patients were enrolled in the escalation trial. No DLTs were observed at dose level 1 ( = 3); at dose level 2, one patient was replaced due to rapid disease progression, and one patient out of six evaluable patients experienced a DLT (grade 4 thrombocytopenia >7 days). Ribociclib 600 mg daily was thus determined to be the MTD. Eleven additional patients were enrolled in the expansion cohort. Diarrhea (52%), rash (52%), fatigue (43%), nausea (33%), and mucositis (28%) were the most frequent grade 1-2 adverse events (AE). Neutropenia was the most frequent grade 3-4 AE (20%). Median progression-free survival (PFS) was 3.5 months (range 0.4-17.3 months) and median overall survival (OS) was 8.3 months (range 0.4-24.1 months). Among the 19 radiologically evaluable patients, two (10.5%) achieved a partial response and 11 (58%) had stable disease. The MTD of ribociclib is 600 mg daily when administered in combination with standard dose cetuximab for 3 weeks on and 1 week off. This combination was safe and showed efficacy. Further clinical trials should be conducted to evaluate the antitumor effects of this combination. ClinicalTrials.gov: NCT02429089; Eudract number 2014-005371-83.
大多数人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（SCCHN）表现出表皮生长因子受体（EGFR）上调，且细胞周期蛋白D1 - 细胞周期蛋白依赖性激酶（CDK）4/6（CDK 4/6）-视网膜母细胞瘤蛋白（pRb）通路频繁改变，从而导致细胞周期进展和肿瘤增殖。本研究调查了口服高选择性CDK 4/6抑制剂瑞博西尼与西妥昔单抗联合用于复发和/或转移性（R/M）SCCHN的情况。采用3 + 3设计进行了一项I期试验，以确定瑞博西尼与标准剂量每周一次西妥昔单抗联合用于HPV阴性的R/M SCCHN患者的剂量限制毒性（DLT）和最大耐受剂量（MTD）。瑞博西尼以每日400 mg的剂量水平1和每日600 mg的剂量水平2口服给药（3周用药/1周停药）。然后在一个扩大队列中进一步评估瑞博西尼的MTD。10名患者参加了剂量递增试验。在剂量水平1（n = 3）未观察到DLT；在剂量水平2，一名患者因疾病快速进展被替换，6名可评估患者中有一名经历了DLT（4级血小板减少>7天）。因此确定瑞博西尼的MTD为每日600 mg。另外11名患者参加了扩大队列。腹泻（52%）、皮疹（52%）、疲劳（43%）、恶心（33%）和黏膜炎（28%）是最常见的1 - 2级不良事件（AE）。中性粒细胞减少是最常见的3 - 4级AE（20%）。中位无进展生存期（PFS）为3.5个月（范围0.4 - 17.3个月），中位总生存期（OS）为8.3个月（范围0.4 - 24.1个月）。在19名可进行影像学评估的患者中，两名（10.5%）达到部分缓解，11名（58%）病情稳定。瑞博西尼与标准剂量西妥昔单抗联合给药，3周用药/1周停药时，MTD为每日600 mg。该联合用药安全且显示出疗效。应开展进一步的临床试验以评估该联合用药的抗肿瘤效果。ClinicalTrials.gov：NCT02429089；Eudract编号2014 - 005371 - 83。
