Abemaciclib is an oral, selective, and potent inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 & 6) dosed twice daily (BID) on a continuous schedule . Resulting from the MONARCH series of clinical trials, abemaciclib is approved as monotherapy and in combination with endocrine therapy (ET) for the treatment of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) .
MONARCH 1, a single-arm Phase 2 study of abemaciclib 200mg BID monotherapy in patients with refractory HR+, HER2- ABC, demonstrated promising clinical activity (objective response rate (ORR) of 19.7% (95% confidence interval [CI]: 13.3–27.5) .
MONARCH 2 was a randomized, double-blind, Phase 3 study of abemaciclib 150mg BID in combination with fulvestrant compared to placebo plus fulvestrant in women with HR+, HER2 − ABC who had progressed following ET therapy . This trial demonstrated significantly improved progression-free survival (PFS) (median 16.4 versus 9.3 months; hazard ratio [HR] [95% CI]: 0.553 [0.449–0.681]; p < .001) and overall survival (OS) (median 46.7 versus 37.3 months; HR [95% CI]: 0.757 [0.606–0.945]; p = .01) [1, 4].
MONARCH 3 was a randomized, double-blind Phase 3 study of abemaciclib 150mg BID in combination with a non-steroidal aromatase inhibitor (NSAI) compared to placebo plus NSAI as initial therapy in women with HR+, HER2 − ABC . Abemaciclib plus NSAI significantly improved PFS (median 28.18 versus 14.76 months; HR [95% CI]: 0.540 [0.418–0.698]; p = .000002).
Diarrhea was the most frequently reported treatment-emergent adverse event (TEAE) of any-grade in patients prescribed abemaciclib in all three pivotal studies, irrespective of whether abemaciclib was taken as a monotherapy (MONARCH 1 [200mg BID]: diarrhea = 90.2%) or in combination with ET (MONARCH 2 and MONARCH 3 [150mg BID]: diarrhea = 87.1% and 82.3% respectively) [1, 3, 5]. Grade 3 diarrhea was reported in 20% of patients in MONARCH 1, 14% in MONARCH 2 and 10% in MONARCH 3 [3–5]. In all three trials, incidence of Grade 2 and Grade 3 diarrhea was greatest during the first month of treatment and decreased over the remaining cycles of therapy (Fig. 1). The median duration of any-grade diarrhea was similar across the 3 trials ranging 6–8 days, with the median duration of Grade 2 diarrhea ranging 8–11 days and Grade 3 diarrhea, 5–8 days [1, 3, 5]. In each study, diarrhea was retrospectively assessed by the investigator at the beginning of each 28-day cycle and graded as per Common Terminology Criteria for Adverse events (CTCAE) criteria [1, 3, 5]. To our knowledge, no patient-reported daily data on abemaciclib and diarrhea have been published to date.
Standardized anti-diarrheal management plans are outlined in the product label . Patients are advised to commence over-the-counter (OTC) antidiarrheal medication such as loperamide at the first sign of loose stools, increase their fluid intake, and contact their physician. If diarrhea has not resolved within 24 hours, abemaciclib should be suspended until resolution occurs. Resolution is defined as either a reduction to baseline or Grade 1 (< 4 stools per day increase over baseline). The label also includes detailed guidance for dose modifications and reductions according to severity of diarrhea .
Consistent with management guidance, 21%, 19%, and 14% of patients in MONARCH 1, 2, and 3 respectively required dose reductions and 1%, 3%, and 2% respectively discontinued the study drug due to diarrhea [1, 3, 5]. Antidiarrheal use across the studies varied between 61% in MONARCH 1, 76% in MONARCH 2, and 61% in MONARCH 3.
In MONARCH 2 and 3, a paper version of the patient-reported outcomes (PRO) assessment was completed once at baseline, and on treatment; with more frequent collection in earlier cycles, and at the follow-up visit [6, 7]. PRO results from abemaciclib in combination with fulvestrant (MONARCH 2) or in combination with NSAI (MONARCH 3) did not show clinically significant differences in patient-reported global health, functioning, or most symptoms compared to ET alone [6, 7]. Baseline scores were similar between treatment arms in each study. In both trials, diarrhea was the only patient-reported symptom with a statistically significant and clinically meaningful difference between treatment arms. These diarrhea findings were reported in early treatment cycles, consistent with investigator assessments, decreased in later cycles and returned to near baseline levels at the post-therapy follow-up visits [6, 7].
For some drugs, coadministration with food can impact bioavailability and may have clinically significant consequences. In clinical studies, a high-fat, high-calorie meal increased the exposure (AUC) of abemaciclib analytes by 9% and increased Cmax by 25% . These changes in exposure are not clinically meaningful and abemaciclib is therefore given without regard to food. However, it is possible that taking abemaciclib with food may impact local gastrointestinal toxicity independently of systemic pharmacokinetics (PK) and thus alter drug tolerability. As an example, ingestion of food with nonsteroidal anti-inflammatory drugs (NSAIDs) is often preferred because it reduces local gastrointestinal adverse effects . In order to address this issue and at the request of the U.S. Food and Drug Administration (FDA), this randomized study (I3Y-MC-JPCP) evaluated the impact of coadministration of food on the incidence and tolerability of diarrhea in patients with HR+, HER2- ABC receiving abemaciclib monotherapy.