Abstract P1-16-02: A randomized phase II study investigating oral metronomic vinorelbine versus conventional dosage of vinorelbine in HER2-negative metastatic breast cancer previously treated with anthracycline or taxane:clinical results and biomarker analysis
Authors: Ma Fei , Liu Xinlan , Shi Yanxia , Guan Xiuwen , Li Huihui , Wang Xiaojia , Teng Yuee , Liu Qiang , Yang Jin , Li Man , Zhang Qingyuan , Zhao Weihong , Du Caiwen , Sheng Lili , Xu Binghe 
Published: March 2022

Abstract
Background: Metronomic chemotherapy, defined as frequent administration of. chemotherapeutic agents at a non-toxic dose without extended rest periods, can overcome drug resistance and achieve disease control with reduced toxicity compared to conventional chemotherapy in maximum tolerated dose by shifting the therapeutic target from tumor cells to tumor endothelial cells. Some of the previous studies of oral vinorelbine have shown good data in efficacy and safety in advanced breast cancer. Methods: The multicenter, open-label, non-inferiority, randomized phase 2 study (NCT03854617) aimed to evaluate the efficacy and safety of oral metronomic vinorelbine in 13 hospitals in China. Eligible HER2-negative breast cancer patients previously treated with anthracycline or taxane regimens were randomized (1:1) to receive metronomic dosage of oral vinorelbine (50mg/3 times a week) or conventional dosage of oral vinorelbine (60mg/m2 weekly for cycle 1 and 80mg/m2 weekly for subsequent cycles in the absence of grade 3 or 4 toxicity) for first-line/second-line chemotherapy. The primary end point was Disease Control Rate (DCR) and a non-inferiority margin of 6% was defined for DCR. Patient characteristics, progression-free survival (PFS), overall survival (OS) and safety/adverse events (AEs) were among the parameters assessed. The expression of 27 cytokines was profiled longitudinally in these patients at baseline and at regular intervals during therapy. Results: Between February 2019 and September 2020, a total of 171 patients were enrolled and randomized to metronomic dosage group (86 patients) and conventional dosage group (85 patients). 136 patients were hormone receptor(HR)positive and 117 patients (68.4%) had visceral metastases. The DCR was 59.3% (95% CI:48.17% to 69.78%) in the metronomic dosage group and 67.1% (95% CI:56.02% to 76.87%) in the conventional dosage group. Whereas, the 18-month survival rate was higher in the metronomic dosage group than that in the conventional dosage group (68.7% vs 43.0%).The median progression-free survival in the metronomic dosage group was 2.8 months (95% CI:1.40 to 3.50) compared with 4.1 months (95% CI:2.80 to 6.20) in the conventional dosage group. Grade 3 or higher adverse events were significantly less frequent in patients in the metronomic dosage group than patients in the conventional dosage group (19.8% vs 48.2%, P&lt;0.001). By comparing the variation of cytokine profiles at baseline and after 6-week treatment in 122 patients, multilevel partial least squares discriminant analysis (PLS-DA) suggested the variation of VEGF, MIP-1α, IL-1B, IL-17, MCP-1, IL-13, PDGF-BB, IL-4 and RANTES were significantly different between the metronomic dosage group and the conventional dosage group during the treatment (all VIP values &gt; 1.2). As for the patients in the metronomic dosage group, GM-CSF, MCP-1, TNF-α, IL-10, IL-13 and MIP-1α were potential biomarkers between the response patients and non-response patients (all VIP values &gt; 1.2). Conclusions: Oral metronomic vinorelbine decreased the risk of severe toxicity significantly and may be an option for older patients and for those intolerable to standard chemotherapy with proper predictive biomarkers, though this study couldn’t prove to show the non-inferiority of oral metronomic vinorelbine for first-line or second-line chemotherapy previously treated with anthracycline or taxane in HER2-negative metastatic breast cancer.
Citation Format: Fei Ma, Xinlan Liu, Yanxia Shi, Xiuwen Guan, Huihui Li, Xiaojia Wang, Yuee Teng, Qiang Liu, Jin Yang, Man Li, Qingyuan Zhang, Weihong Zhao, Caiwen Du, Lili Sheng, Binghe Xu. A randomized phase II study investigating oral metronomic vinorelbine versus conventional dosage of vinorelbine in HER2-negative metastatic breast cancer previously treated with anthracycline or taxane:clinical results and biomarker analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-02.