Abemaciclib Dose Reductions Lead to Prolonged Treatment in HR+/HER2- Breast Cancer

Hope Rugo, MD, FASCO

Abemaciclib (Verzenio) produced a clinically manageable safety profile in patients with hormone receptor–positive, HER2-negative, early breast cancer (EBC) or advanced breast cancer (ABC), and dose reductions were found to effectively mitigate discontinuation, according to an analysis of adverse event (AE) data from the monarchE (NCT03155997), MONARCH 1 (NCT02102490), MONARCH 2 (NCT02107703), and MONARCH 3 (NCT02246621) trials.

The profile analysis was recently presented during the 2022 ASCO Quality Care Symposium. The findings showed that most AEs associated with abemaciclib were grade 1 or 2 and occurred early during treatment.

Abemaciclib, a selective CDK4/6 inhibitor is approved to treat hormone receptor–positive and HER2-negative ABC in combination with fulvestrant or an aromatase inhibitor. It is also approved in combination with endocrine therapy as adjuvant therapy for patients with hormone receptor–positive, HER2-negative, node-positive, and high-risk EBC.

According to lead author Hope S. Rugo, MD, FASCO, abemaciclib has demonstrated efficacy and an overall tolerable safety profile. Despite this, some patients discontinue treatment without first attempting a dose modification—underscoring the need for improved symptom management.

“The objective behind this AE analysis was to provide guidance on AE management for patients with hormone receptor–positive, HER2-negative EBC or ABC who were receiving abemaciclib,” wrote Rugo, who is a professor of medicine, and director of the Breast Oncology Clinical Trials Program, at University of California San Francisco Helen Diller Comprehensive Cancer Center.

Original dosing was abemaciclib at 150 mg plus endocrine therapy for the monarchE group, 200 mg for MONARCH 1, 150 mg plus fulvestrant 500 mg or placebo plus fulvestrant 500 mg for MONARCH 2, and 150 mg plus nonsteroidal anti-inflammatory (NSAI) agents or placebo plus NSAI for MONARCH 3. Prescribing information was included in the analysis as well and end points of any-grade AEs, dose modifications, and discontinuations.

Men or women with high-risk EBC were enrolled in monarchE (n = 5637), MONARCH 1 (n = 132) enrolled women with ABC with disease progression following prior hormonal therapy and chemotherapy, MONARCH 2 (n = 669) enrolled women with ABC who progressed on/after prior endocrine therapy and MONARCH 3 (n = 493) enrolled postmenopausal women with ABC who had not received prior systemic therapy for ABC.

A patient monitoring plan assessed complete blood count and liver profile, interstitial lung disease/pneumonitis, and venous thromboembolism. The dose-reduction schedule varied for patients receiving abemaciclib as a monotherapy vs in combination with endocrine therapy.

For patients receiving abemaclicib as monotherapy, the starting dose was 200 mg twice daily, the first recommended dose reduction was 150 mg twice daily, the second recommended dose reduction was 100 mg twice daily, and the third recommended dose reduction was 100 mg twice daily. For patients receiving abemaciclib in combination with endocrine therapy, the starting dose was 150 mg twice daily, the first recommended dose reduction was 100 mg twice daily, the second recommended dose reduction was 50 mg twice daily. If 50 mg twice daily was intolerable for patients, then discontinuing treatment was advised.

The most common AEs were diarrhea, fatigue, nausea, and neutropenia; in the groups of EBC (monarchE) and ABC (MONARCH 1, 2, and 3) these AEs were responsible for both reductions and discontinuations.

For diarrhea, no dose reduction is required if the AE is grade 1 or if is grade 2 and resolves within 24 hours. In the case of persistent or recurrent grade 2 diarrhea, treatment should be initiated at a lower dose. If the diarrhea develops into grade 3, abemaciclib should be suspended until resolved to a grade 1, and then reinitiated at the next lower dose.

For fatigue or nausea, no dose reduction is required for grade 1 or 2. If there is persistent or recurrent grade 2 toxicity with maximal support, or if the grade does not resolve within 7 days, the dose should be suspended until it resolves to a grade 1, and treatment should be resumed at the next lower dose.

As with the other common AEs, no dose reduction is required for grade 1 neutropenia. No reduction is required for grade 2 neutropenia either, however, if the neutropenia becomes grade (< 1.0 to 0.5 × 109/L), abemaciclib should be suspended until toxicity resolved to grade 2—no dose reduction is required in this instance. However, if recurrent grade 3 occurs, or a grade 4 neutropenia develops, dose should be suspended until toxicity resolved to grade 2, and the dose should be reduced.

Ultimately, in the monarchE trial, dose reductions were highest in the first 6 months post-treatment, and stabilized thereafter. Following dose reduction, 9% of patients discontinued treatment. However, investigators noted that 52% of patients with EBC who discontinued abemaciclib did so without first reducing their dosage; 88% of whom discontinued in their first month of treatment.

Among those with EBC (n = 2791) who required a treatment change, 17% required a reduction because of diarrhea and 5% needed to discontinue because of diarrhea. Fatigue resulted in a dose reduction in 5% of these patients and discontinuation in 2%; nausea was associated with a 1% reduction rate and less than 1% discontinuation rate; and neutropenia made 8% reduce their dose and 1% discontinue treatment.

Among patients with ABC (n = 900), diarrhea accounted for 14% to 21% of required dose reductions but resulted in a 1% discontinuation rate. Fatigue resulted in reduction in 2% to 10% of these patients but made discontinuation necessary in less than 1%; 1% to 3% of patients needed to dose reduce because of nausea, but less than 1% discontinued treatment; and 11% to 15% reduced their dose because of neutropenia, yet the discontinuation rate associated with neutropenia was 0% to 1%.

Moreover, the analysis found that patients with ABC maintained a progression-free survival benefit regardless of whether they had a dose reduction or not— further supporting a dose reduction strategy for patients experiencing toxicities with abemaciclib.

Abemaciclib has a clinically manageable safety profile in EBC and ABC as most of the AEs occurred early in treatment and majority were grade 1 or 2, study authors concluded.

Although discontinuations did occur, reducing doses was effective in reducing the rate of them. To further prevent discontinuations patient counseling, monitoring of AEs and implementing symptom management strategies such as dose reductions should be utilized.

Reference

Rugo HS, Vitko AS, Thoele K. An overview of adverse event management for patients receiving abemaciclib. J Clin Oncol. 2022;40(suppl 28):239. doi:10.1200/JCO.2022.40.28_suppl.239