Elsevier

The Lancet

Volume 400, Issue 10364, 12 November 2022, Pages 1704-1711
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(22)01977-8Get rights and content

Summary

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.

Introduction

Current guidelines recommend that women with hormone receptor positive breast cancer are treated with oral adjuvant endocrine therapy, most commonly as tamoxifen or an aromatase inhibitor, for 5 to 10 years to maximise their disease-free survival.1 However, 30–50% of patients discontinue oral adjuvant endocrine therapy prematurely.2, 3 Oestrogen deficiency symptoms, notably vasomotor symptoms experienced by more than two thirds of women with breast cancer,4 are a leading cause of treatment discontinuation.5 Furthermore, women with hormone receptor positive breast cancer tend to have more severe vasomotor symptoms than age-matched women without breast cancer, even after discontinuation of oral adjuvant endocrine therapy.6

Menopausal hormone therapy, the most effective treatment for vasomotor symptoms, is contraindicated for women with hormone receptor positive breast cancer, which accounts for more than 75% of breast cancer diagnoses,7 because of the potential for triggering disease recurrence.8 The non-hormonal therapies prescribed, mostly off-label, to alleviate vasomotor symptoms in women after breast cancer have modest and variable efficacy, and side-effects might lead to their discontinuation.9 An effective and safe therapy for women with hormone receptor positive breast cancer with bothersome vasomotor symptoms, notably those taking oral adjuvant endocrine therapy, is needed.

Research in context

Evidence before this study

Vasomotor symptoms, which are highly prevalent in patients who have had breast cancer, negatively affect physical and psychological wellbeing and overall quality of life. Furthermore, vasomotor symptoms might be exacerbated by oral adjuvant endocrine therapy, including tamoxifen and aromatase inhibitors, which is recommended for women with hormone receptor positive disease to improve disease-free and overall survival. Oestrogen therapy is generally contraindicated after breast cancer and non-hormonal treatment options for vasomotor symptoms are limited. Consequently, the negative effect of vasomotor symptoms is a common cause of non-adherence to, and discontinuation of, oral adjuvant endocrine therapy. A PubMed search through to June 30, 2022, using the keywords “breast cancer”, “oral adjuvant endocrine therapy”, “vasomotor symptoms”, “hot flash”, and “hot flushes” without restrictions on language or publication date was conducted to identify articles that investigated non-hormonal treatments of adverse symptoms, including vasomotor symptoms, associated with oral adjuvant endocrine therapy. The identified studies of non-hormonal pharmacological, non-pharmacological, and complementary and alternative medicines for vasomotor symptoms report varying efficacy and tolerability. Our search found that the availability of safe and efficacious treatments of vasomotor symptoms for women taking oral adjuvant endocrine therapy for breast cancer remains a substantial unmet medical need.

Added value of this study

This is the first randomised, double-blind, placebo-controlled clinical trial of the efficacy and safety of oral Q-122 for the alleviation of moderate and severe vasomotor symptoms in women taking oral adjuvant endocrine therapy after breast cancer. Oral Q-122 significantly reduced the frequency and severity of moderate and severe vasomotor symptoms, with associated improvement in quality of life. Thus, Q-122 shows promise as a differentiated and novel non-hormonal treatment of vasomotor symptoms.

Implications of all the available evidence

The results of our study support the conduct of larger and longer studies of Q-122, with potential use extending to postmenopausal women who require an alternative to oestrogen therapy for vasomotor symptoms.

Increasing evidence shows the role of oestrogen-responsive neurons found in the infundibular (or arcuate) nucleus of the hypothalamus that co-express kisspeptin, neurokinin B, and dynorphin (KNDy neurons) in the aetiology of vasomotor symptoms.10 KNDy neurons projecting onto the thermoregulatory region in the median preoptic area of the brain11 play an important role in regulating the gonadotropin-releasing hormone pulse generator that controls reproductive hormone secretion.12 Q-122 is a novel, orally bioavailable, non-hormonal, small molecule that appears to reduce the frequency of KNDy neuron activation by a mechanism other than neurokinin 3 receptor antagonism (unpublished data).

As the efficacy of oestrogen in relieving vasomotor symptoms is not immediate, the traditional approach has been to assess initial therapeutic efficacy with respect to vasomotor symptoms at week 4 only.13, 14 However, women anticipate immediate benefits of treatment, especially women with breast cancer who might have tried multiple therapies. In this study, we took a real-world approach by cumulatively assessing Q-122 efficacy over 28 days as a purposeful primary endpoint to capture the impact of treatment. We report the efficacy of Q-122 as a non-hormonal alternative for the treatment of vasomotor symptoms in women with breast cancer taking oral adjuvant endocrine therapy.

Section snippets

Study design

This was a multicentre, randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 study conducted to assess the efficacy and safety of Q-122 versus placebo in women taking tamoxifen or an aromatase inhibitor after breast cancer. The study was conducted across 18 hospitals and clinical research sites in Australia, New Zealand, and the USA. The study was approved by independent human research ethics committees and institutional review boards for each participating centre. An

Results

Between Oct 24, 2018, and Sept 9, 2020, 243 women were screened for eligibility, 131 of whom were randomly assigned and received treatment (figure 1). COVID-19 necessitated implementation of a risk management plan to overcome the effect of COVID-19 on participant safety. Consequently, the study was halted between March 24 and May 18, 2020, and, as a result, eight (6%) participants who were on study were discontinued from treatment immediately, which was the main reason for early treatment

Discussion

In this phase 2 study, Q-122 showed a greater reduction in the frequency of moderate and severe vasomotor symptoms, with associated improvement in quality of life, evidenced by reduced vasomotor symptom daily life interference, compared with placebo, in women taking oral adjuvant endocrine therapy after breast cancer. The safety profile of Q-122 was favourable and the treatment was well tolerated.

The efficacy of Q-122 is similar to historical data for other non-hormonal compounds commonly used

Data sharing

Data sharing requests for anonymised trial data or supporting material that underlie the results reported in this Article will be considered by the sponsor on a case-by-case basis. Researchers who provide scientifically and methodologically sound proposals will be considered and the use of shared trial data or supporting material will be limited to the specific aims in the approved proposal, as determined by the sponsor, up to 36 months after publication. The final decision to share data will

Declaration of interests

AV is an employee of QUE Oncology. AL was an employee of QUE Oncology. RJB reports receiving honoraria for serving on medical advisory boards for Pfizer, Besins, Viatris, Theramex, and Mayne Health and for delivering lectures at educational meetings sponsored by Pfizer, Abbott, Viatris, and Besins. RJB has received institutional grant funding from Pfizer, Novogen, QUE Oncology, and Madorra. BGAS reports receiving honoraria for lectures from Besins and has received institutional grant funding

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