Analyses from an ongoing phase 3 study have illustrated the safety and tolerability of abemaciclib (Verzenio; Eli Lilly) in combination with standard adjuvant endocrine therapy in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) high-risk early breast cancer.
In one analysis, researchers concluded that patient-reported outcomes were comparable between patients who did and did not receive abemaciclib, an inhibitor of cyclin-dependent kinases 4 & 6. In the other, investigators said most adverse events associated with abemaciclib use started early and were manageable with dose adjustments and co-medications.
Both analyses – presented at the 17th St. Gallen International Breast Cancer Conference 2021 – were products of the monarchE trial, a randomized, open-label, multi-center investigation. As part of the study, participants were randomized to receive either 150 mg of twice-daily abemaciclib plus standard adjuvant endocrine therapy or standard adjuvant endocrine therapy alone. All patients were treated for a two-year treatment period, or until they met criteria for discontinuation.
Patients’ quality of life and perceptions of side effects were presented in abstract P008 by Sara M. Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, Massachusetts. The researchers assessed a series of patient-reported outcomes – including health-related quality-of-life, endocrine therapy symptoms, fatigue, and symptom burden – in the safety population of 5,591 patients (2800 endocrine therapy alone; 2791 abemaciclib + endocrine therapy). These measurements were made at randomization, as well as three, six, 12, and 24 months on treatment.
The investigators also performed a series of exploratory analyses on items reflecting common adverse events such as diarrhea, fatigue, arthralgia, and hot flashes. They also assessed the frequency of scores for answers to the two statements: ‘I have diarrhea’ and ‘I am bothered by side effects of treatment’. Mixed model repeated measures (MMRM) were used to compare mean summary and item scores by treatment arm.
It was found that overall patient compliance was high, and exceeded 90% of expected patients per visit. What’s more, MMRM scores reflecting fatigue, arthralgia, and hot flashes were numerically comparable between trial arms at randomization and the several post-randomization assessments.
On the other hand, MMRM mean scores for diarrhea were ≤1.37 for patients receiving abemaciclib and ≤0.21 for endocrine therapy alone. The frequency of scores for abemaciclib patients found that most patients with diarrhea reported having ‘a little bit’ (23.6% at 18 months) or ‘somewhat’ (18.0% at 18 months). Similarly, most patients in both arms reported being bothered ‘a little’ or ‘not at all’ by the side effects of treatment.
The researchers concluded that there were no notable differences in overall health-related quality of life between patients who did and did not receive abemaciclib.
“The patient-reported outcomes analysis represents another step forward in our understanding of the impact for patients who receive abemaciclib in the early breast cancer setting,” Tolaney said in a statement. “These important data demonstrate actual patient-reported outcomes, which are the first to be reported for a CDK4 & 6 inhibitor in the early breast cancer setting.”
In the second analysis (abstract P013), researchers presented safety data regarding abemaciclib plus endocrine therapy in the same safety population. The analyses included the incidence, management, and outcomes of common and clinically relevant adverse events.
According to lead author Hope Rigo, MD, of the University of California San Francisco Comprehensive Cancer Center, grade ≥3 adverse events and serious adverse events were observed in 47% and 14% of patients, respectively, who received combination therapy. This was markedly more than the 13.3% and 7.8%, respectively, who underwent endocrine therapy alone.
In addition, 59.5% of patients taking abemaciclib had dose holds due to adverse events, while 42.5% had dose reductions due to adverse events. These were primarily for diarrhea, neutropenia, and fatigue; most occurred in the first six months.
A total of 481 patients (17.2%) discontinued abemaciclib due to adverse events, 172 of whom (6.2%) also discontinued endocrine therapy. Interestingly, more than half of all abemaciclib discontinuations (53%) occurred without prior dose reduction, though 105 patients discontinued after two dose reductions. Only 16% of the 481 discontinuations occurred in the first month of treatment; the majority of these were due to grade ≤2 adverse events.
Diarrhea of any grade was observed in 82.6% of abemaciclib patients, with a median onset time of eight days; incidence and severity decreased over time. Increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) of at least grade 3 were uncommon, and generally reversible with dose adjustments. Finally, interstitial lung disease/pneumonitis and venous thromboembolism of any grade were both more common in the abemaciclib arm.
Given these results, the investigators concluded that the overall safety profile of abemaciclib in monarchE was consistent with the drug’s established profile, with no new safety concerns.
“Few patients discontinued abemaciclib after two dose reductions,” the author wrote, “supporting its tolerability in combination with endocrine therapy in this population.”
The monarchE trial is ongoing and patients will continue to be followed to assess safety, patient-reported outcomes, and other endpoints.
