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.
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.
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.
Methods
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 independent safety review committee monitored the safety and progress of the study.
Participants
Women, aged 18–70 years, taking a stable dose of tamoxifen or an aromatase inhibitor after breast cancer (for a minimum of 30 days), and experiencing at least 50 self-reported moderate to severe hot flushes and sweats (hereafter referred to together as vasomotor symptoms) per week were eligible to participate. Eligible participants were not pregnant or at risk of pregnancy and not lactating during the study period. Premenopausal women could participate if they had had a hysterectomy, tubal ligation, fallopian inserts, or were taking an aromatase inhibitor in combination with a gonadotropin-releasing hormone agonist. Postmenopausal status was defined as more than 12 months of amenorrhoea and an elevated follicle-stimulating hormone or history of bilateral oophorectomy. Confirmation of menopause for women on tamoxifen was determined by the primary investigator and medical monitor on a case-by-case basis when follicle-stimulating hormone concentrations were indeterminate. Women were excluded if they were taking treatment specifically for vasomotor symptoms. Selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, gabapentin, and pregabalin were permitted if not prescribed for vasomotor symptoms and the dose had been stable for at least 1 month before screening. All participants provided written informed consent at the screening visit.
Randomisation and masking
Participants were randomly assigned (1:1) using an interactive web response system to Q-122 or identical placebo, 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, except for a designated biostatistician who generated the randomisation list and kit list.
Procedures
Women who met initial screening assessments recorded their vasomotor symptoms in an electronic diary (eDiary), once in the morning before midday, and once in the evening before midnight, for a minimum 2-week and maximum 3-week screening period to provide baseline frequency and severity of symptoms. This was followed by a run-in phase during which participants were treated with masked placebo capsules twice daily for 1 week and continued to record vasomotor symptom events. Any participant with more than a 60% reduction in the frequency of moderate to severe vasomotor symptoms, or inability to correctly record their vasomotor symptoms or drug dosing in the eDiary during this period, was excluded from the study. Participants who qualified for study entry were randomly allocated to take oral Q-122 100 mg twice daily or oral placebo twice daily, post-prandial, starting on day 1 and finishing on day 28. Participants continued to complete their vasomotor symptom diaries for an additional 2 weeks after the end of treatment for the safety follow-up period before their final visit.
Participants were asked to rate the severity of each vasomotor symptom as: 1, mild (sensation of heat without sweating); 2, moderate (sensation of heat with sweating, able to continue activity); or 3, severe (sensation of heat with sweating, causing cessation of activity). The mean weekly Vasomotor Symptom Severity Score (VMS-SS) and vasomotor symptom frequency were calculated for the 2–3-week screening period (baseline score), for the entire 4 weeks on treatment, each treatment week, and for the 2-week follow-up period. The moderate and severe VMS-SS (msVMS-SS) was calculated as (2 × number of moderate vasomotor symptoms) + (3 × number of severe vasomotor symptoms), and the total VMS-SS (tVMS-SS) was calculated as (l × number of mild vasomotor symptoms) + (2 × number of moderate vasomotor symptoms) + (3 × number of severe vasomotor symptoms).15
The effect of vasomotor symptoms on work, social activities, leisure activities, sleep, mood, concentration, relations with others, sexuality, and enjoyment of life was assessed using the ten item Hot Flash Related Daily Interference Scale (HFRDIS),16 completed by participants using the eDiary. Scores ranged from 0 to 10 and higher scores indicate greater interference of vasomotor symptoms on overall quality of life and daily activities.
Outcomes
The primary outcome measure compared mean percentage change from baseline in the msVMS-SS between Q-122 and placebo over the 28-day treatment period. The secondary efficacy outcome measures compared mean percentage change from baseline in the tVMS-SS, the frequency of vasomotor symptoms between Q-122 and placebo over the 28-day treatment period, the effect on hot flash interference with daily activities as assessed using the total HFRDIS score, and the proportion of responders at week 4. The exploratory analysis replicated the primary and secondary analyses using the completers population.
Post-hoc analyses were done after unmasking to explore the mean change in frequency of vasomotor symptoms from baseline at week 4, the association between baseline vasomotor symptom frequency and treatment response, and the mean percentage change in each of the ten subdomains of HFRDIS from baseline at week 4. For the association between baseline vasomotor symptom frequency and treatment response, two post-hoc hypotheses were tested: the main effect of response versus baseline vasomotor symptoms, and the interaction effect of response versus treatment × baseline vasomotor symptoms.
The safety population included all participants who received at least one dose of active drug or placebo. Safety assessments included physical examination, haematology and biochemistry, electrocardiograms, and reporting of adverse events. A treatment-emergent adverse event was defined as any adverse event commencing on or after random assignment to study medication. Adverse events and out-of-range values were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events scale (version 4.03).
Statistical analysis
The sample size was estimated using an expected mean percentage change in msVMS-SS in the placebo group of 25%, a mean percentage change in the Q-122 group of 50%, and a common within-group SD of 39%, based on the results of the previous phase 1b study in patients with breast cancer (NCT04080297). The desired power was 0.9, α was 0.05, and the difference in means was tested using a two-sided two-sample t-test. The α and p values were two-sided. Under these assumptions, a sample size of 53 participants per group, 106 in total, gives power of 0.9 to detect a difference of 50–25=25% between the Q-122 and placebo groups. To allow for exploratory analysis of the primary and secondary outcomes using participants who completed at least 26 days of both study drug use and efficacy measurements, defined as the completers population, a sample size of approximately 130 participants was required.
The weekly mean VMS-SS was calculated by adding the daily VMS-SS calculated that week divided by the number of days scores were recorded. The primary and secondary analyses included all randomly assigned participants who received at least one dose of study drug and had at least one efficacy measurement after the run-in period, defined as the modified intention-to-treat population. The proportion of responders was calculated on msVMS-SS and frequency of moderate and severe vasomotor symptoms. A responder was defined as having more than 50% reduction from baseline in the msVMS-SS or frequency of moderate and severe vasomotor symptoms.
Analysis of covariance, including the two stratification variables, was done for each outcome. Model residuals for each quantitative endpoint were tested for normality using the Anderson-Darling test. For the analyses presented here, the residuals did not differ significantly from normality by the Anderson-Darling test; therefore, the original values were used in the analyses.
The Benjamin-Hochberg false discovery rate (BH-FDR) estimates the expected proportion of erroneously rejected null hypotheses among the rejected ones.17 For the ten HFRDIS subdomain post-hoc p values, if the null hypothesis is rejected for the three subdomains with p less than 0.05, the BH-FDR is 0.1 or 10%.
Distribution of residuals was tested for normality through a proc univariate procedure and all analyses and summaries were performed using SAS version 9.4 or higher. This study is registered at ClinicalTrials.gov, NCT03518138.
Role of the funding source
The funder of the study had a role in study design, data interpretation, and writing of the report; however, no role in data collection or data analysis.
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 discontinuation (figure 1). The modified intention-to-treat analysis and safety populations included 65 participants in the Q-122 group and 66 participants in the placebo group. A total of 118 participants completed the study. However, the completers population, defined as all participants who had at least 26 days of both study drug use and efficacy measurements, comprised 113 participants.
Figure 1:
Trial profile
Participant demographics and baseline characteristics for the modified intention-to-treat population are summarised in table 1. The median age of the participants was 54.9 years (IQR 50.7–59.3), the mean BMI was 29.3 kg/m2 (SD 5.5), and the majority (118 [90%]) were White. The use of oral adjuvant endocrine therapy was similar for both treatment groups (table 1).
Table 1:
Baseline characteristics of the safety population
| Q-122 group (n=65) | Placebo group (n=66) | |
|---|---|---|
| Age, years | 56.2 (51.2–59.5) | 53.8 (49.1–57.2) |
| Race | ||
| White | 60 (92%) | 58 (88%) |
| Black or African American | 1 (2%) | 3 (5%) |
| Asian | 1 (2%) | 0 |
| Other | 3 (5%) | 5 (8%) |
| BMI, kg/m2 | 28.8 (5.6) | 29.7 (5.5) |
| Oral adjuvant endocrine therapy | ||
| Tamoxifen | 37 (57%) | 39 (59%) |
| Aromatase inhibitor | 27 (42%) | 27 (41%) |
| Toremifene | 1 (2%) | 0 |
| Baseline moderate and severe vasomotor symptoms | ||
| msVMS-SS per week | ||
| Mean (SD) | 219.9 (97.6) | 214.6 (88.7) |
| Median (IQR) | 192.6 (160.7–254.8) | 196.9 (142.8–263.1) |
| Moderate and severe vasomotor symptom frequency per week | ||
| Mean (SD) | 90.6 (37.5) | 88.8 (35.3) |
| Median (IQR) | 80.4 (67.3–106.9) | 77.4 (62.0–106.6) |
| Baseline total HFRDIS score | 6.48 (2.09) | 4.56 (1.54) |
Data are median (IQR), n (%), or mean (SD). HFRDIS=Hot Flash Related Daily Interference Scale. msVMS-SS=moderate and severe vasomotor symptom severity score.
In the primary analysis, across the 28-day treatment period, Q-122 resulted in a significantly greater mean percentage change from baseline in the msVMS-SS than placebo (least-squares means: Q-122 −39% [95% CI −46 to −31] vs placebo −26% [−33 to −18]; p=0.018; figure 2). Q-122 also significantly reduced the mean percentage change from baseline in tVMS-SS compared with placebo (least-squares means: Q-122 −35% [95% CI −42 to −29] vs placebo −25% [−31 to −18]; p=0–022; appendix p 1). There was no statistically significant effect of concomitant medication (selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin) use or BMI on outcomes (data not shown).
Figure 2: Change in msVMS-SS from baseline over 28 days of treatment in the modified intention-to-treat population.
The mean weekly msVMS-SS was calculated forthe entire 2-week screening period (baseline) and over the 28-day treatment period. Analysis of covariance model used was: mean percentage change from baseline over 28 days of treatment in msVMS-SS=treatment + selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor (yes or no) + BMI up to 30 kg/m2 (yes or no). Data are represented as least-squares means with 95% CI.
msVMS-SS=moderate and severe vasomotor symptom severity score.
Q-122 treatment resulted in a greater reduction in the mean percentage change from baseline in the frequency of moderate and severe vasomotor symptoms over 28 days of treatment compared with placebo (least-squares mean treatment difference: −13% [95% CI −26 to 0]; p=0.044) and at all timepoints during the treatment period (figure 3). The mean percentage change from baseline of moderate and severe vasomotor symptoms at treatment week 4 was also greater for Q-122 compared with placebo (least-squares mean: Q-122 −38% [95% CI −47 to −30] vs placebo −25% [−34 to −16]; p=0.031; appendix p 2). Q-122 also resulted in a greater reduction (improvement) in the overall mean HFRDIS score from baseline at 4 weeks compared with placebo (table 2).
Figure 3: Frequency of moderate and severe vasomotor symptoms over time in the modified intention-to-treat population.
Weekly number of moderate and severe vasomotor symptoms at screening, on treatment (weeks 1–4) and at end of study (week 6) of the modified intention-to-treat population (Q-122 n=65 and placebo n=66).The mean weekly frequency is calculated for the entire 2-week screening period (baseline), and for each week, except week 5 and week 6, which are combined in week 6.
Table 2:
Changes in HFRDIS score from baseline at week 4 in the modified intention-to-treat population
| Least-squares mean percentage change from baseline at week 4 (95% CI) | Treatment difference, least-squares mean (95% CI) | p value | ||
|---|---|---|---|---|
| Q-122 group (n=65) | Placebo group (n=66) | |||
| Total HFRDIS score | −36% (−46 to −25) | −21% (−31 to −9) | −15% (−30 to 0) | 0.054 |
| Work | −26% (−43 to −8) | −19% (−38 to −1) | −6% (−31 to 19) | 0.62 |
| Social activities | −34% (−48 to −20) | −11% (−27 to 3) | −23% (−43 to −2) | 0.030 |
| Leisure activities | −37% (−57 to −17) | −4% (−25 to 17) | −33% (−61 to −4) | 0.025 |
| Sleep | −36% (−47 to −26) | −20% (−31 to −10) | −16% (−31 to −2) | 0.029 |
| Mood | −29% (−45 to −12) | −14% (−31 to 3) | −14% (−38 to 9) | 0.23 |
| Concentration | −32% (−46 to −17) | −19% (−35 to −4) | −12% (−33 to 9) | 0.25 |
| Relations with others | −25% (−52 to 1) | −13% (−40 to 15) | −13% (−50 to 25) | 0.51 |
| Sexuality | −31% (−57 to −6) | −3% (−29 to 23) | −28% (−64 to 8) | 0.12 |
| Enjoyment of life | −23% (−43 to −3) | −15% (−36 to 6) | −8% (−36 to 20) | 0.58 |
| Overall quality of life | −31% (−47 to −15) | −18% (−35 to −1) | −13% (−35 to 10) | 0.27 |
Analysis of covariance model used was percentage change from baseline at week 4 in measured instrument=treatment + selective serotonin reuptake inhibitor, selective norepinephrine reuptake inhibitor, gabapentin, or pregabalin (yes or no) + BMI up to 30 kg/m2 (yes or no). Two-sided p value for difference in least-squares means between treatment groups; Q-122 group compared with the placebo group. HFRDIS=Hot Flash Related Daily Interference Scale.
There was no between-group difference in the proportion of participants in the modified intention-to-treat population who met the definition of being a responder with at least a 50% reduction in the msVMS-SS over 28 days of treatment (24 [37%] of 65 patients in the Q-122 group vs 15 [23%] of 66 in the placebo group; p=0.12). There were more high responders with more than 80% reduction in the frequency of moderate and severe vasomotor symptoms at week 4 among patients in the Q-122 group (seven [11%] of 65) than the placebo group (one [2%] of 66).
The outcomes for the completers population were similar to, and consistent with, the results for the modified intention-to-treat population (data not shown).
Treatment with Q-122 was well tolerated, and the majority of adverse events were mild or moderate in severity. The most frequently reported treatment-emergent adverse events were hot flushes, diarrhoea, and urinary tract infection (table 3). The rates of treatment-related treatment-emergent adverse events were similar between the two treatment groups: 11 (17%) of 65 participants in the Q-122 group and nine (14%) of 66 participants in the placebo group. Two treatment-emergent adverse events led to study drug (Q-122) discontinuation: hot flushes, which were considered mild and related to the study drug and remained ongoing 2 weeks after treatment discontinuation; and pancreatitis, which was considered mild and not related to study drug and resolved during the study while off drug in the follow-up period. There were no notable trends or clinically significant changes over the course of the study or between treatment groups in laboratory parameters (appendix p 3), vital signs, or electrocardiogram results.
Table 3:
Summary of treatment-emergent adverse events in the safety population
| Q-122 group | Placebo group | |||
|---|---|---|---|---|
| Number of participants (n=65) | Number of events | Number of participants (n=66) | Number of events | |
| Any treatment-emergent adverse event | 36 (55%) | 96 | 43 (65%) | 90 |
| Any treatment-emergent adverse event of grade 3 or worse | 2 (3%) | 3 | 4 (6%) | 5 |
| Any related treatment-emergent adverse event | 11 (17%) | 16 | 9 (14%) | 16 |
| Any treatment-emergent adverse event leading to Q-122 or placebo discontinuation | 2 (3%) | 2 | 0 | 0 |
| Any serious treatment-emergent adverse event | 0 | 0 | 2 (3%) | 3 |
| Treatment-emergent adverse events occurring in ≥5% of participants in any treatment group | ||||
| Hot flushes | 5 (8%) | 6 | 1 (2%) | 2 |
| Diarrhoea | 2 (3%) | 2 | 4 (6%) | 4 |
| Urinary tract infection | 4 (6%) | 4 | 1 (2%) | 1 |
A treatment-emergent adverse event was defined as any adverse event with an onset date on or after the random assignment to one of the treatment groups in the double-blind treatment period. Any related treatment-emergent adverse events were considered by the investigator to be related to study drug. Grade 3 is a severe adverse event described as medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care activities of daily living.
In post-hoc analyses, the number of moderate and severe vasomotor symptoms at baseline significantly predicted the magnitude of change from baseline (p=0.0040; appendix p 4). However, in a model including the interaction term for treatment × baseline, the interaction was not significant (p=0.87; appendix p 4), indicating that the effect of treatment did not depend on the baseline number of vasomotor symptoms. Application of a Bonferroni correction for multiple hypothesis testing of these two post-hoc hypotheses did not change the conclusions.
Post-hoc exploratory analyses of the HFRDIS subdomains showed the greatest improvements with Q-122 compared with placebo were seen for the subdomains of sleep, social activities, and leisure activities (table 2). Among the ten HFRDIS subdomains, there were three subdomains with unadjusted p values less than 0.05. The BH-FDR results indicate that treatment is associated with improvement in these three subdomains.
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 for the treatment of vasomotor symptoms in patients with breast cancer.18–20 However, direct between-study comparisons cannot be made as the participants in the present study had a mean of more than 90 moderate to severe vasomotor symptoms per week, substantially greater than other studies of non-hormonal therapies for vasomotor symptoms.19–23 For example, Stearns and colleagues20 reported effects of paroxetine in women with 6.9–7.8 vasomotor symptoms per day at baseline, Pandya and colleagues18 reported a mean frequency of 8.5–8.8 vasomotor symptoms per day at baseline, and other studies did not include baseline reporting of the number of vasomotor symptoms per day.19,22 Importantly, the placebo-corrected reduction in moderate to severe vasomotor symptom frequency of more than 14 per week seen with Q-122 is considered by the US Food and Drug Administration to be a clinically significant reduction.24 The placebo-corrected reduction in moderate to severe vasomotor symptom frequency observed in our study is greater than that reported for paroxetine (a difference of 1.2 vasomotor symptoms per day),20 and similar to that of a 900 mg/day dose of gabapentin (a difference of 2.02 vasomotor symptoms per day).18 Furthermore, the benefit of Q-122 treatment over placebo, in terms of reduction in the msVMS-SS, was observed almost immediately within the first week, with outcomes similar across the total 28-day treatment period and at week 4.
Moderately and severely bothersome vasomotor symptoms independently contribute to lower psychological and general wellbeing, impair workability, and are associated with more depressive symptoms.25,26 Crucially, vasomotor symptoms are a common cause of discontinuation of oral adjuvant endocrine therapy in women after breast cancer.5 Low adherence is associated with increased all-cause mortality, and the longer a patient is non-adherent, the greater their risk of all-cause and breast-cancer-specific mortality and recurrence.27 The recommended 5–10-year treatment duration with tamoxifen or an aromatase inhibitor means vasomotor symptoms might persist, adversely affecting quality of life, such that non-adherence could become a major issue.1 Consequently, the improvement in quality of life with Q-122, evidenced by the reduction in the HFRDIS score, which exceeded the minimally important change that is perceived as beneficial for women with vasomotor symptoms,28 might reduce discontinuation of oral adjuvant endocrine therapy and thus have far reaching benefit beyond the relief of vasomotor symptoms.
The only regulator-approved non-hormonal therapy for vasomotor symptoms, paroxetine, has the potential to reduce the effectiveness of tamoxifen and is therefore contraindicated in this context.29 Other non-hormonal therapies commonly prescribed off-label for vasomotor symptoms after breast cancer, including gabapentin, venlafaxine, desvenlafaxine, escitalopram, citalopram, clonidine, and oxybutynin, have variable efficacy and frequent side-effects ranging from somnolence and fatigue18, 30 to decreased appetite, nausea and constipation,19 urinary retention, and blurred vision.21 In this phase 2 study, Q-122 was well tolerated and had an excellent safety profile. The reported adverse events were mild or moderate in severity, with no notable trends or clinically significant changes within or between the Q-122 and placebo treatment groups. The lack of any signal of even mild adverse effects that might trigger discontinuation sets Q-122 apart from other non-hormonal therapies in current use.
The strengths of this study include assessing the effect of Q-122 therapy over 28 days rather than solely at week 4 of treatment and assessing the severity and frequency of vasomotor symptoms as one measure (msVMS-SS) as the primary endpoint. Furthermore, participation was limited to women with at least 50 moderate and severe vasomotor symptoms per week. Although we did not examine oral adjuvant endocrine therapy compliance, a study requirement was to be on a stable dose of tamoxifen and aromatase inhibitor for the study duration. There was an extremely low treatment discontinuation rate, excluding the participants who were discontinued early due to the implementation of the COVID-19 risk management plan. A limitation of this study was that participants were predominantly White and had to be of non-childbearing potential, so the majority were postmenopausal. Additionally, as no pharmacokinetic data were collected, exposure-response modelling was not possible, and this should be prioritised in future studies.
In summary, Q-122 is a novel, well tolerated, non-hormonal therapy that reduces vasomotor symptoms and their associated impact on quality of life in women taking oral adjuvant endocrine therapy after breast cancer. Although this study was specifically in women after breast cancer, Q-122 holds promise for other populations with vasomotor symptoms who choose not to or cannot take menopausal hormone therapy. Further studies of longer duration with a larger and more demographically diverse population are required to confirm the promising efficacy and safety of Q-122 treatment.
Supplementary Material
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.
Acknowledgments
We thank all the women who participated in this study. We thank Julie M Cherrington, Joyce James, and Gary A Shangold for their review of this manuscript. This study was funded by QUE Oncology.
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 from QUE Oncology. MGW is a consultant for QUE Oncology. VS reports participation on an advisory board for Novartis, is the chair of the data safety monitoring board for AstraZeneca, and has received institutional grant funding from AbbVie, Biocept, Novartis, Pfizer, Puma Biotechnology, and QUE Oncology. MH reports grants from the National Health and Medical Research Council (NHMRC) Australia and has received institutional grant funding from QUE Oncology and Madorra. SRD is an NHMRC senior principal research fellow (grant number 1135843). SRD reports grants from the NHMRC Australia; personal fees for educational activities from Besins Healthcare, Abbott Chile, BioFemme, Biosyent, and Lawley Pharmaceuticals; personal advisory board or consultancy fees from Theramex, Abbott Laboratories, Astellas, Southern Star Research, Mayne Pharma, Roche Diagnostics, Lawley Pharmaceuticals, QUE Oncology, and Gedeon Richter; and has received institutional grant funding from QUE Oncology and Ovocabio research.
Footnotes
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 be made by the sponsor. Proposals should be directed to the corresponding author. To gain access, data requestors will need to sign a data access agreement.
See Online for appendix
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