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.

Funding

QUE Oncology.

中文翻译：

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Q-122 作为一种新型非激素口服疗法，用于治疗乳腺癌后服用他莫昔芬或芳香酶抑制剂的女性的血管舒缩症状：一项 2 期、随机、双盲、安慰剂对照试验

 背景

超过三分之二接受口服辅助内分泌治疗的乳腺癌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 是一种新型非激素化合物，已显示出通过调节下丘脑中雌激素反应性神经元来减轻血管舒缩症状的前景。我们的目的是评估 Q-122 对接受口服辅助内分泌治疗并出现血管舒缩症状的乳腺癌女性的疗效和安全性。

 方法

我们在澳大利亚、新西兰和美国的 18 个地点进行了多中心、随机、双盲、安慰剂对照、概念验证的 2 期试验。符合资格的参与者是年龄 18-70 岁的女性，她们在乳腺癌后服用稳定剂量的他莫昔芬或芳香酶抑制剂，并且每周至少经历 50 次自我报告的中度至重度血管舒缩症状。使用交互式网络响应系统将参与者随机分配 (1:1)，口服 Q-122 100 mg 或相同的安慰剂，每天两次，持续 28 天。随机化根据BMI（≤30 kg/m ²或>30 kg/m ² ）和选择性血清素再摄取抑制剂、选择性去甲肾上腺素再摄取抑制剂、加巴喷丁或普加巴林中的任何一种的使用进行分层。 Q-122 和安慰剂胶囊外观相同，容器标签也相同。在双盲治疗和分析阶段，参与者、研究人员、临床研究组织工作人员和申办者都不知道治疗分配。主要结局是治疗 28 天后，Q-122 和安慰剂之间中度和重度潮热和盗汗的血管舒缩症状严重程度评分 (msVMS-SS) 相对于基线的平均百分比变化的差异。主要分析是通过修改后的意向治疗进行的，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。本研究已在 ClinicalTrials.gov 注册，NCT03518138。

 发现

2018年10月24日至2020年9月9日期间，对243名患者进行了筛查，其中131名患者被随机分配并接受治疗（Q-122 n = 65和安慰剂n = 66）。与安慰剂相比，Q-122 在治疗 28 天期间导致 msVMS-SS 相对于基线的平均百分比变化显着更大（最小二乘平均值：Q-122 –39% [95% CI –46 至 –31]与安慰剂 –26 % [–33 至 –18]；p=0·018)。治疗引起的不良事件一般为轻度至中度，且两组之间相似（Q-122 组 65 名患者中有 11 名 [17%] 出现与治疗相关的不良事件，而 Q-122 组 66 名患者中有9 名 [14%] 出现与治疗相关的不良事件。安慰剂组）； Q-122 组中的零名患者和安慰剂组中的两名 (3%) 患者出现严重不良事件。

 解释

Q-122 是一种有效且耐受性良好的非激素口服治疗药物，用于治疗乳腺癌后接受口服辅助内分泌治疗的女性的血管舒缩症状。我们的结果支持对 Q-122 进行更大规模、更长期的研究，其潜在用途扩展到需要替代绝经激素治疗的绝经后妇女。

 资金

 QUE 肿瘤学。