Phase 1b study of combined selinexor and eribulin for the treatment of advanced solid tumors and triple-negative breast cancer

被引:4
|
作者
Nelson, Blessie Elizabeth [1 ]
Saleem, Sadia [2 ]
Damodaran, Senthil [2 ]
Somaiah, Neeta [3 ]
Piha-Paul, Sarina [1 ]
Moore, Julia Ann [1 ]
Yilmaz, Bulent [1 ]
Ogbonna, Deby [1 ]
Karp, Daniel D. [1 ]
Ileana Dumbrava, Ecaterina [1 ]
Tsimberidou, Apostolia M. [1 ]
Hong, David S. [1 ]
Rodon Ahnert, Jordi [1 ]
Milton, Denai R. [4 ]
Zheng, Xiaofeng [2 ]
Booser, Daniel J. [3 ]
Ibrahim, Nuhad K. [3 ]
Conley, Anthony P. [5 ]
Bhosale, Priya [6 ]
Hernandez, Cristhiam M. Rojas M. [7 ]
Tripathy, Debasish [3 ]
Naing, Aung [1 ,8 ]
Meric-Bernstam, Funda [1 ,8 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX USA
[5] Univ Texas MD Anderson Canc Ctr, Dept Sarcoma Med Oncol, Houston, TX USA
[6] Univ Texas MD Anderson Canc Ctr, Dept Diagnost Radiol, Houston, TX USA
[7] Univ Texas MD Anderson Canc Ctr, Dept Pulm Med, Houston, TX USA
[8] Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, 1515 Holcombe Blvd,Unit 455, Houston, TX 77030 USA
关键词
advanced solid tumors; eribulin; sarcoma; selective inhibitor of nuclear export; selinexor; triple-negative breast cancer; NUCLEAR EXPORT; OPEN-LABEL; INHIBITOR; XPO1;
D O I
10.1002/cncr.34773
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundSelinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination. MethodsThe authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort. ResultsPatients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m(2) eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose-escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose-expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing). ConclusionsSelinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients. Plain Language Summary Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need.Exportin 1 is associated with the transport of cancer-related proteins.Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin.In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma.The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support.The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer.This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.
引用
收藏
页码:2201 / 2213
页数:13
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