medwireNews: The oral nonhormonal agent Q-122 appears to be an efficacious and well tolerated option for the control of vasomotor symptoms in women with breast cancer receiving adjuvant endocrine therapy, suggest phase 2 trial data.
Q-122 treatment was also associated with an improvement in quality of life (QoL) relative to placebo, “which exceeded the minimally important change that is perceived as beneficial for women with vasomotor symptoms,” say the researchers in The Lancet.
This “might reduce discontinuation of oral adjuvant endocrine therapy and thus have far reaching benefit beyond the relief of vasomotor symptoms,” they continue.
Outlining the rationale for the study, the authors explain that “[m]enopausal 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, because of the potential for triggering disease recurrence.”
And the currently prescribed nonhormonal therapies, mostly off-label, “have modest and variable efficacy, and side-effects [that] might lead to their discontinuation,” they add.
The team therefore investigated Q-122, “a novel, orally bioavailable, non-hormonal, small molecule” that targets the activation of kisspeptin, neurokinin B, and dynorphin neurons – known to play a role in the etiology of vasomotor symptoms – by a mechanism other than neurokinin 3 receptor antagonism.
The double-blind trial included 131 women (median age 54.9 years) who were on a stable dose of adjuvant tamoxifen or an aromatase inhibitor and reported at least 50 moderate to severe vasomotor symptoms – hot flashes or night sweats – per week. They were randomly assigned to receive Q-122 100 mg twice daily or placebo, after food, for 28 days.
The primary outcome was the mean percentage change from baseline in the moderate and severe Vasomotor Symptom Severity Score (VMS-SS) over the 28-day treatment period, and Q-122 was associated with a significantly greater reduction than placebo, at least squares means of 39% and 26%, respectively.
Treatment with Q-122 also resulted in a significantly greater reduction over the treatment period in the total VMS-SS from baseline versus placebo (least squares means of 35% and 25%, respectively) and in the frequency of moderate and severe vasomotor symptoms (least squares mean treatment difference of –13%).
But there was no significant difference between groups in terms of the proportion of patients who reported a decrease of at least 50% in the moderate and severe VMS-SS over 28 days of treatment, at 37% in the Q-122 group and 23% in the placebo group.
Study participants also reported the effects of vasomotor symptoms on their QoL using the 10-item Hot Flash Related Daily Interference Scale. The least-squares mean percentage change from baseline at day 28 significantly favored Q-122 over placebo with regard to the total score (–36 vs –21%), as well as for the social activities (–34 vs –11%), leisure activities (–37 vs –4%), and sleep (–36 vs –20%) subdomains.
Finally, the safety analysis showed that “[t]reatment with Q-122 was well tolerated, and the majority of adverse events were mild or moderate in severity,” say Amanda Vrselja, from QUE Oncology in Melbourne, Victoria, Australia, and co-investigators.
Treatment-emergent adverse events (TEAEs) of any grade occurred in 55% of participants given Q-122 and 65% of those given placebo, most commonly hot flashes (8 vs 2%) and urinary tract infections (6 vs 2%), and led to discontinuation in a respective 3% and 0%.
Seventeen percent of patients in the Q-122 group experienced any-grade TEAEs considered related to the study drug, as did 14% of those in the placebo group.
“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,” note Vrselja and colleagues.
And they conclude: “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.”
The authors of a related commentary highlight a few key limitations, such as the relatively short follow-up period, which “limits evaluation of longer-term benefit or toxicity,” and the potential challenge for clinicians to translate the primary outcome into daily practice.
Focussing on the secondary outcome of the change in the frequency of moderate and severe vasomotor symptoms, Carolyn Crandall and Patricia Ganz (both from the David Geffen School of Medicine at UCLA, Los Angeles, California, USA) point out that the reduction with Q-122 versus placebo “translated to an average of only two fewer moderate or severe vasomotor symptom episodes per day.”
They continue: “For context, menopausal oestrogen therapy decreases vasomotor symptom frequency by approximately 75% compared with placebo.”
The commentators therefore conclude: “[O]ne must view this study as preliminary, with future evaluation necessary before adoption in the clinic.
“In the meantime, the use of venlafaxine or other selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors is likely to remain the first-line pharmacological option to treat vasomotor symptoms in women with breast cancer.”
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