一项关于泛 class I PI3K 抑制剂 buparlisib 联合 cetuximab 治疗复发性或转移性头颈部癌患者的初步研究。
A pilot study of the pan-class I PI3K inhibitor buparlisib in combination with cetuximab in patients with recurrent or metastatic head and neck cancer.
机构信息
Oakland University William Beaumont School of Medicine, Rochester, Michigan.
Department of Medicine, The University of Chicago Medicine, Chicago, Illinois.
出版信息
Head Neck. 2019 Nov;41(11):3842-3849. doi: 10.1002/hed.25910. Epub 2019 Sep 4.
Abstract
BACKGROUND
This study assessed the maximum tolerated dose (MTD) of the PI3K inhibitor buparlisib given concurrently with cetuximab in recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
METHODS
Twelve patients with R/M HNSCC were enrolled. Patients were given oral buparlisib starting day 7 and daily thereafter. The dose of buparlisib was escalated in a 3 + 3 design followed by a dose expansion cohort of 6 patients. The MTD of buparlisib per protocol was 100 mg daily with cetuximab given intravenously every 14 days starting day 0.
RESULTS
Ten patients had ≥2 previous treatment regimens (11 with prior cetuximab). There were no dose limiting toxicities observed during dose escalation. One patient achieved a partial response and 4 achieved stable disease.
CONCLUSION
Based on this pilot study, buparlisib at 100 mg daily plus cetuximab proved to be well-tolerated. Patients previously treated with cetuximab monotherapy showed benefit from this combination.
摘要
背景
本研究评估了在复发性和转移性（R/M）头颈部鳞状细胞癌（HNSCC）患者中，与西妥昔单抗联合应用时，PI3K 抑制剂 Buparlisib 的最大耐受剂量（MTD）。
方法
共纳入 12 例 R/M HNSCC 患者。患者从第 7 天开始口服 Buparlisib，每天一次。Buparlisib 剂量采用 3+3 设计递增，随后进行了 6 例患者的扩展队列研究。方案规定的 Buparlisib 的 MTD 为每日 100mg，西妥昔单抗于第 0 天开始每 14 天静脉滴注一次。
结果
10 例患者有≥2 种既往治疗方案（11 例有既往西妥昔单抗治疗）。在剂量递增期间未观察到剂量限制毒性。1 例患者部分缓解，4 例患者疾病稳定。
结论
基于这项初步研究，每日 100mg 的 Buparlisib 联合西妥昔单抗显示出良好的耐受性。既往接受西妥昔单抗单药治疗的患者从该联合治疗中获益。
相似文献
1
A pilot study of the pan-class I PI3K inhibitor buparlisib in combination with cetuximab in patients with recurrent or metastatic head and neck cancer.一项关于泛 class I PI3K 抑制剂 buparlisib 联合 cetuximab 治疗复发性或转移性头颈部癌患者的初步研究。
Head Neck. 2019 Nov;41(11):3842-3849. doi: 10.1002/hed.25910. Epub 2019 Sep 4.
2
Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial.布帕利昔单抗联合紫杉醇治疗铂类预处理后复发或转移性头颈部鳞状细胞癌患者（BERIL-1）：一项随机、双盲、安慰剂对照的 2 期临床试验。
Lancet Oncol. 2017 Mar;18(3):323-335. doi: 10.1016/S1470-2045(17)30064-5. Epub 2017 Jan 26.
3
Mouse-human co-clinical trials demonstrate superior anti-tumour effects of buparlisib (BKM120) and cetuximab combination in squamous cell carcinoma of head and neck.鼠人联合临床试验表明，比帕利斯布（BKM120）和西妥昔单抗联合治疗头颈部鳞状细胞癌具有更好的抗肿瘤效果。
Br J Cancer. 2020 Dec;123(12):1720-1729. doi: 10.1038/s41416-020-01074-2. Epub 2020 Sep 23.
4
Pazopanib plus cetuximab in recurrent or metastatic head and neck squamous cell carcinoma: an open-label, phase 1b and expansion study.帕唑帕尼联合西妥昔单抗治疗复发性或转移性头颈部鳞状细胞癌：一项开放标签、1b 期和扩展研究。
Lancet Oncol. 2018 Aug;19(8):1082-1093. doi: 10.1016/S1470-2045(18)30350-4. Epub 2018 Jul 11.
5
Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.Buparlisib（BKM120），一种口服全类 I PI3K 抑制剂，在日本晚期实体瘤患者中的 I 期剂量递增研究。
Cancer Sci. 2014 Mar;105(3):347-53. doi: 10.1111/cas.12350. Epub 2014 Feb 13.
6
Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.适应 EXTREME 方案一线治疗适合的、年龄较大的复发性或转移性头颈部鳞状细胞癌（ELAN-FIT）患者：一项多中心、单臂、2 期试验。
Lancet Healthy Longev. 2024 Jun;5(6):e392-e405. doi: 10.1016/S2666-7568(24)00048-5. Epub 2024 May 14.
7
A phase 1 study of concurrent cabozantinib and cetuximab in recurrent or metastatic head and neck squamous cell cancer.卡博替尼与西妥昔单抗联合治疗复发性或转移性头颈部鳞状细胞癌的 1 期研究。
Oral Oncol. 2024 Jul;154:106861. doi: 10.1016/j.oraloncology.2024.106861. Epub 2024 May 24.
8
A randomized phase 2 network trial of tivantinib plus cetuximab versus cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.一项替沃扎尼联合西妥昔单抗对比西妥昔单抗治疗复发/转移性头颈部鳞状细胞癌的随机 2 期网络试验。
Cancer. 2020 May 15;126(10):2146-2152. doi: 10.1002/cncr.32762. Epub 2020 Feb 19.
9
An evaluation of buparlisib for the treatment of head and neck squamous cell carcinoma.评估布帕利昔单抗治疗头颈部鳞状细胞癌。
Expert Opin Pharmacother. 2021 Feb;22(2):135-144. doi: 10.1080/14656566.2020.1825684. Epub 2020 Oct 30.
10
Treatment sequence of cetuximab and immune checkpoint inhibitor in head and neck squamous cell carcinoma differentially affects outcomes.头颈部鳞状细胞癌中西妥昔单抗和免疫检查点抑制剂的治疗顺序对结局有不同影响。
Oral Oncol. 2020 Dec;111:105024. doi: 10.1016/j.oraloncology.2020.105024. Epub 2020 Oct 13.
引用本文的文献
1
Multimodal profiling of oral squamous cell carcinoma identifies genomic alterations and expression programs associated with betel quid chewing.口腔鳞状细胞癌的多模态分析确定了与嚼槟榔相关的基因组改变和表达程序。
Neoplasia. 2025 Aug 9;68:101218. doi: 10.1016/j.neo.2025.101218.
2
PI3K/AKT/mTOR Axis in Cancer: From Pathogenesis to Treatment.癌症中的PI3K/AKT/mTOR轴：从发病机制到治疗
MedComm (2020). 2025 Jul 30;6(8):e70295. doi: 10.1002/mco2.70295. eCollection 2025 Aug.
3
Metabolic targeting of regulatory T cells in oral squamous cell carcinoma: new horizons in immunotherapy.口腔鳞状细胞癌中调节性T细胞的代谢靶向：免疫治疗的新视野
Mol Cancer. 2024 Dec 19;23(1):273. doi: 10.1186/s12943-024-02193-7.
4
Future investigative directions for novel therapeutic targets in head and neck cancer.头颈部癌症新型治疗靶点的未来研究方向。
Expert Rev Anticancer Ther. 2024 Nov;24(11):1067-1084. doi: 10.1080/14737140.2024.2417038. Epub 2024 Oct 16.
5
EGFR and PI3K Signalling Pathways as Promising Targets on Circulating Tumour Cells from Patients with Metastatic Gastric Adenocarcinoma.表皮生长因子受体和 PI3K 信号通路作为转移性胃腺癌患者循环肿瘤细胞的有前途的靶点。
Int J Mol Sci. 2024 May 20;25(10):5565. doi: 10.3390/ijms25105565.
6
Clinical and genomic characterization of chemoradiation-resistant HPV-positive oropharyngeal squamous cell carcinoma.抗放化疗的人乳头瘤病毒阳性口咽鳞状细胞癌的临床与基因组特征
Front Oncol. 2024 Mar 5;14:1336577. doi: 10.3389/fonc.2024.1336577. eCollection 2024.
7
Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers.各种癌症中的磷酸肌醇-3-蛋白激酶（PI3K）途径的分子靶向治疗。
Int J Mol Sci. 2024 Feb 6;25(4):1973. doi: 10.3390/ijms25041973.
8
A systematic literature review of the human papillomavirus prevalence in locally and regionally advanced and recurrent/metastatic head and neck cancers through the last decade: The "ALARM" study.一项针对过去十年局部晚期和区域性进展/转移性头颈部癌症中人乳头瘤病毒流行率的系统文献回顾：“ALARM”研究。
Cancer Med. 2024 Feb;13(3):e6916. doi: 10.1002/cam4.6916. Epub 2024 Jan 21.
9
Establishment of head and neck squamous cell carcinoma mouse models for cetuximab resistance and sensitivity.建立用于西妥昔单抗耐药和敏感的头颈鳞状细胞癌小鼠模型。
Cancer Drug Resist. 2023 Oct 17;6(4):709-728. doi: 10.20517/cdr.2023.62. eCollection 2023.
10
Targeted therapy for head and neck cancer: signaling pathways and clinical studies.头颈部癌症的靶向治疗：信号通路与临床研究。
Signal Transduct Target Ther. 2023 Jan 16;8(1):31. doi: 10.1038/s41392-022-01297-0.
本文引用的文献
1
Cancer statistics, 2018.癌症统计数据，2018 年。
CA Cancer J Clin. 2018 Jan;68(1):7-30. doi: 10.3322/caac.21442. Epub 2018 Jan 4.
2
Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial.Buparlisib 联合氟维司群治疗接受 mTOR 抑制剂治疗后进展的激素受体阳性、HER2 阴性晚期乳腺癌的绝经后妇女（BELLE-3）：一项随机、双盲、安慰剂对照的 3 期临床试验。
Lancet Oncol. 2018 Jan;19(1):87-100. doi: 10.1016/S1470-2045(17)30688-5. Epub 2017 Dec 7.
3
Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.生物标志物预测阿法替尼相较于甲氨蝶呤二线治疗复发性和/或转移性头颈部鳞癌患者可带来更好的临床结局。
Ann Oncol. 2017 Oct 1;28(10):2526-2532. doi: 10.1093/annonc/mdx344.
4
Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial.布帕利昔单抗联合紫杉醇治疗铂类预处理后复发或转移性头颈部鳞状细胞癌患者（BERIL-1）：一项随机、双盲、安慰剂对照的 2 期临床试验。
Lancet Oncol. 2017 Mar;18(3):323-335. doi: 10.1016/S1470-2045(17)30064-5. Epub 2017 Jan 26.
5
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.纳武利尤单抗用于复发性头颈部鳞状细胞癌
N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252. Epub 2016 Oct 8.
6
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial.帕博利珠单抗治疗头颈部复发或转移性鳞状细胞癌的安全性和临床活性（KEYNOTE-012）：一项开放标签、多中心、1b 期试验。
Lancet Oncol. 2016 Jul;17(7):956-965. doi: 10.1016/S1470-2045(16)30066-3. Epub 2016 May 27.
7
Genetic Landscape of Human Papillomavirus-Associated Head and Neck Cancer and Comparison to Tobacco-Related Tumors.人乳头瘤病毒相关头颈部癌的基因图谱及其与烟草相关肿瘤的比较。
J Clin Oncol. 2015 Oct 10;33(29):3227-34. doi: 10.1200/JCO.2015.62.1086. Epub 2015 Sep 8.
8
Safety and Efficacy of Buparlisib (BKM120) in Patients with PI3K Pathway-Activated Non-Small Cell Lung Cancer: Results from the Phase II BASALT-1 Study.布帕利昔布（BKM120）用于PI3K通路激活的非小细胞肺癌患者的安全性和有效性：II期BASALT-1研究结果
J Thorac Oncol. 2015 Sep;10(9):1319-1327. doi: 10.1097/JTO.0000000000000607.
9
Targeting the PI3K/AKT/mTOR pathway in squamous cell carcinoma of the head and neck.靶向头颈部鳞状细胞癌中的PI3K/AKT/mTOR信号通路。
Oral Oncol. 2015 Apr;51(4):291-8. doi: 10.1016/j.oraloncology.2014.11.012. Epub 2014 Dec 17.
10
Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.Buparlisib（BKM120），一种口服全类 I PI3K 抑制剂，在日本晚期实体瘤患者中的 I 期剂量递增研究。
Cancer Sci. 2014 Mar;105(3):347-53. doi: 10.1111/cas.12350. Epub 2014 Feb 13.
Zotero 插件