澳大利亚QUE Oncology公司Amanda Vrselja团队研究了Q-122作为一种新型非激素，口服治疗乳腺癌后服用他莫西芬或芳香化酶抑制剂女性血管舒缩症状的疗效与安全性。2022年11月12日，《柳叶刀》杂志发表了这一成果。

在接受口服辅助内分泌治疗的乳腺癌患者中，超过三分之二的女性会出现血管舒缩症状（潮热和盗汗）。缺乏安全有效的治疗方法。Q-122是一种新型的非激素化合物，通过调节下丘脑雌激素反应神经元，有望减少血管舒缩症状。该研究旨在评估Q-122在接受口服辅助内分泌治疗并出现血管舒缩症状的乳腺癌患者中的疗效和安全性。

研究组在澳大利亚、新西兰和美国的18个地点进行了一项多中心、随机、双盲、安慰剂对照、概念验证的2期临床试验。符合条件的参与者是18–70岁的女性，在乳腺癌后服用稳定剂量的他莫昔芬或芳香化酶抑制剂，每周至少出现50次自述的中度至重度血管舒缩症状。参与者使用交互式网络响应系统随机分配（1:1）口服Q-122 100 mg或相同剂量的安慰剂，每天两次，共28天。

随机分组按BMI（≤30 kg/m²或>30 kg/m²）和使用选择性5-羟色胺再摄取抑制剂、选择性去甲肾上腺素再摄取抑制剂、加巴喷丁或普瑞巴林中的任何一种进行分层。Q-122和安慰剂胶囊外观相同，容器标签相同。在双盲治疗和分析阶段，参与者、研究人员、临床研究机构工作人员和申办者被掩盖了治疗分配。

主要结局是Q-122和安慰剂治疗28天后，中度和重度潮热和盗汗（msVMS-SS）的血管运动症状严重程度评分与基线的平均百分比变化差异。主要分析通过改良治疗意向进行，并对接受至少一剂研究药物的所有参与者进行安全性评估。

2018年10月24日至2020年9月9日，研究组共筛选了243名患者，其中131名被随机分配并接受治疗（Q-122组65例，安慰剂组66例）。与安慰剂组相比，Q-122组在治疗28天内导致msVMS-SS与基线的平均百分比变化明显更大（最小二乘平均值：Q-122组–39%，安慰剂组–26%，组间差异显著）。

治疗引发的不良事件一般为轻度至中度，两组之间发生率相似（Q-122组65名患者中有11名[17%]，安慰剂组66名患者中有9名[14%]）；Q-122组中0名患者和安慰剂组中2名（3%）患者出现严重不良事件。

研究结果表明，Q-122是一种有效且耐受性良好的非激素口服疗法，可治疗乳腺癌后服用口服辅助内分泌疗法女性的血管舒缩症状。该结果支持对Q-122进行更大规模和更长时间的研究，其潜在应用范围扩大到绝经后妇女，她们需要替代绝经激素治疗。

附：英文原文

Title: Q-122 as a novel, non-hormonal, oral treatment for vasomotor symptoms in women taking tamoxifen or an aromatase inhibitor after breast cancer: a phase 2, randomised, double-blind, placebo-controlled trial

Author: Amanda Vrselja, Ardian Latifi, Rodney J Baber, Bronwyn G A Stuckey, Michael G Walker, Vered Stearns, Martha Hickey, Susan R Davis

Issue&Volume: 2022/11/12

Abstract:

Background

Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy and safety of Q-122 in women with breast cancer taking oral adjuvant endocrine therapy and experiencing vasomotor symptoms.

Methods

We conducted a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial at 18 sites in Australia, New Zealand, and the USA. Eligible participants were women, aged 18–70 years, taking a stable dose of tamoxifen or an aromatase inhibitor following breast cancer and experiencing at least 50 self-reported moderate to severe vasomotor symptoms per week. Participants were randomly assigned (1:1) using an interactive web response system to oral Q-122 100 mg or identical placebo, twice daily for 28 days. Randomisation was stratified by BMI (≤30 kg/m2 or >30 kg/m2) and use of any of a selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin. Q-122 and placebo capsules were identical in appearance and containers identically labelled. During the double-blind treatment and analysis phases, the participants, investigators, clinical research organisation staff, and sponsor were masked to treatment allocation. The primary outcome was the difference in the mean percentage change from baseline in the Vasomotor Symptom Severity Score of moderate and severe hot flushes and night sweats (msVMS-SS) between Q-122 and placebo after 28 days of treatment. Primary analysis was by modified intention-to-treat and safety was assessed in all participants receiving at least one dose of study drug. This study is registered at ClinicalTrials.gov, NCT03518138.

Findings

Between Oct 24, 2018, and Sept 9, 2020, 243 patients were screened, 131 of whom were randomly assigned and received treatment (Q-122 n=65 and placebo n=66). Q-122 resulted in a significantly greater mean percentage change in msVMS-SS from baseline over 28 days of treatment compared with placebo (least squares mean: Q-122 –39% [95% CI –46 to –31] vs placebo –26% [–33 to –18]; p=0·018). Treatment-emergent adverse events were generally mild to moderate and similar between the two groups (treatment-related treatment-emergent adverse events in 11 [17%] of 65 patients in the Q-122 group vs nine [14%] of 66 in the placebo group); zero patients in the Q-122 group and two (3%) patients in the placebo group had serious adverse events.

Interpretation

Q-122 is an effective and well tolerated non-hormonal oral treatment for vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Our results support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to menopausal hormone therapy.

DOI: 10.1016/S0140-6736(22)01977-8

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)01977-8/fulltext