Abemaciclib (Verzenio) for Breast Cancer Treatment
Indications and Patient Selection
Abemaciclib is FDA-approved for three distinct clinical scenarios in HR-positive, HER2-negative breast cancer: adjuvant treatment of high-risk early breast cancer for 2 years, first-line metastatic disease in combination with an aromatase inhibitor, and later-line metastatic disease either with fulvestrant or as monotherapy. 1
Early Breast Cancer (Adjuvant Setting)
- Abemaciclib 150 mg twice daily for 2 years in combination with endocrine therapy is recommended for high-risk, node-positive early breast cancer (NCCN Category 1, preferred option) 2
- High-risk criteria include: ≥4 positive lymph nodes, OR 1-3 positive lymph nodes with at least one of: tumor ≥5 cm, grade 3, or Ki-67 ≥20% 2
- This regimen provides a 7.6% absolute benefit in invasive disease-free survival at 5 years (HR 0.680; 95% CI, 0.599-0.772) and 6.7% absolute benefit in distant recurrence-free survival 2
- Treatment continues for 2 years or until disease recurrence or unacceptable toxicity 1
Advanced/Metastatic Breast Cancer
First-line therapy:
- Abemaciclib 150 mg twice daily plus aromatase inhibitor (anastrozole or letrozole) is a Category 1 preferred option for postmenopausal women 3
- The MONARCH 3 trial demonstrated median PFS not reached versus 14.7 months with AI alone (HR 0.54; 95% CI, 0.41-0.72) 3, 4
- Objective response rate was 59% versus 44% with AI monotherapy 3, 4
- Pre/perimenopausal women must receive concurrent gonadotropin-releasing hormone agonist 1
Second-line therapy:
- Abemaciclib 150 mg twice daily plus fulvestrant is a Category 1 preferred option after progression on aromatase inhibitors 3
- This combination is appropriate for patients with prior endocrine therapy exposure and up to one line of chemotherapy 3
Later-line monotherapy:
- Abemaciclib 200 mg twice daily as monotherapy is reserved for heavily pretreated patients with progression on prior endocrine therapy AND prior chemotherapy in the metastatic setting 3
- The MONARCH 1 trial showed 19.7% objective response rate and median PFS of 6 months in patients with average of 3 prior systemic regimens 3
- Median overall survival was 22.3 months in this refractory population 3
- This is listed as "useful in certain circumstances" rather than preferred 3
Dosing Regimens
Standard Dosing
Combination therapy: 150 mg orally twice daily continuously 1
- Used with aromatase inhibitors, fulvestrant, or tamoxifen 1
Monotherapy: 200 mg orally twice daily continuously 1
- Higher dose appropriate only when used as single agent 1
Administration Details
- Take at approximately the same times each day, with or without food 1
- Swallow tablets whole; do not chew, crush, or split 1
- If dose is missed or vomiting occurs, take next dose at scheduled time (do not double dose) 1
- Do not ingest broken, cracked, or otherwise damaged tablets 1
Dose Modifications for Toxicity
Dose Reduction Schedule
For combination therapy (starting at 150 mg twice daily): 1
- First reduction: 100 mg twice daily
- Second reduction: 50 mg twice daily
- Discontinue if unable to tolerate 50 mg twice daily
For monotherapy (starting at 200 mg twice daily): 1
- First reduction: 150 mg twice daily
- Second reduction: 100 mg twice daily
- Third reduction: 50 mg twice daily
- Discontinue if unable to tolerate 50 mg twice daily
Hematologic Toxicity Management
Grade 3 neutropenia: Suspend dose until resolves to ≤Grade 2; dose reduction not required 1
Grade 3 recurrent or Grade 4 neutropenia: Suspend until resolves to ≤Grade 2, then resume at next lower dose 1
- Monitor complete blood counts prior to starting therapy, every 2 weeks for first 2 months, monthly for next 2 months, then as clinically indicated 1
- If growth factors required, suspend abemaciclib for at least 48 hours after last growth factor dose and until toxicity resolves to ≤Grade 2 1
Diarrhea Management
At first sign of loose stools: Start antidiarrheal agents immediately and increase oral fluid intake 1
Grade 2 diarrhea: If does not resolve within 24 hours to ≤Grade 1, suspend dose until resolution; no dose reduction required 1
Grade 2 persistent/recurrent despite maximal supportive measures: Suspend until resolves to ≤Grade 1, resume at next lower dose 1
Grade 3-4 diarrhea or requiring hospitalization: Suspend until resolves to ≤Grade 1, resume at next lower dose 1
Hepatotoxicity Management
- Monitor ALT, AST, and bilirubin prior to starting, every 2 weeks for first 2 months, monthly for next 2 months, then as clinically indicated 1
Persistent/recurrent Grade 2 or Grade 3 ALT/AST elevation (without bilirubin >2x ULN): Suspend until resolves to baseline or Grade 1 1
Safety Profile and Common Adverse Events
Adjuvant Setting
Grade ≥3 adverse events occurred in 50% of patients receiving abemaciclib plus endocrine therapy versus 16% with endocrine therapy alone 2
Common adverse events: 2
- Diarrhea: 83.5% (any grade)
- Neutropenia: 45.8%
- Fatigue: 40.6%
- Thromboembolic events: 3%
- Interstitial lung disease: 3%
- Fatal adverse events: 0.8%
Metastatic Setting (First-line with AI)
Most frequent Grade 3-4 adverse events in MONARCH 3: 3
- Neutropenia: 21.1-23.9% (versus 1.2% with AI alone)
- Diarrhea: 9.5% (versus 1.2% with AI alone)
- Leukopenia: 7.6-8.6% (versus 0.6% with AI alone)
- Fatigue: 2% (versus 0% with AI alone)
Diarrhea of any grade occurred in 81.3% but was predominantly Grade 1 (44.6%) 3, 4
- Effectively managed in 83.8% of cases with dose modifications and antidiarrheal medications 3
Monotherapy in Heavily Pretreated Patients
MONARCH 1 adverse events: 3
- Diarrhea: 90.2% (any grade)
- Fatigue: 65.2%
- Nausea: 64.4%
- Decreased appetite: 45.5%
- Grade 3-4 neutropenia: 26.9%
Key Clinical Considerations
Distinguishing Features from Other CDK4/6 Inhibitors
Abemaciclib differs from palbociclib and ribociclib in several important ways: 3
- Administered continuously (not 21 days on/7 days off) 3
- Diarrhea occurs more frequently than neutropenia as the dose-limiting toxicity 3
- Has demonstrated single-agent activity, leading to FDA approval as monotherapy 3
Combination with Endocrine Therapy Partners
Aromatase inhibitors: Abemaciclib has been studied with letrozole and anastrozole; any AI can be substituted based on individual tolerance 3
Tamoxifen combination: The nextMONARCH trial showed that adding tamoxifen to abemaciclib did not significantly improve PFS (9.1 months) compared with abemaciclib 200 mg monotherapy (7.4 months) in heavily pretreated patients 5
Fulvestrant combination: Appropriate for second-line therapy after AI progression 3
Quality of Life Considerations
In MONARCH 3, there were no clinically meaningful differences in functioning or symptoms between treatment arms except for diarrhea 3
- Diarrhea showed both statistically significant and clinically meaningful difference (18.68 ± 1.80 points; P < .001) 3
- Time to deterioration was shorter for diarrhea in abemaciclib arm (HR 1.74; 95% CI, 1.25-2) 3
- All other quality of life measures remained stable 3
Sequential Therapy Considerations
Abemaciclib and olaparib should not be combined due to overlapping toxicities but may be considered sequentially with olaparib first 3
If progression occurs on everolimus-containing regimen, there are no data supporting additional everolimus therapy 3
Common Pitfalls to Avoid
Do not use 200 mg twice daily dosing when combining with endocrine therapy - the combination dose is 150 mg twice daily 1
Do not delay antidiarrheal treatment - start at first sign of loose stools, not after diarrhea becomes severe 1
Do not forget GnRH agonist in pre/perimenopausal women when combining with aromatase inhibitors or fulvestrant 1
Do not overlook the need for frequent monitoring - CBC every 2 weeks for 2 months, then monthly for 2 months; same schedule for liver function tests 1
Do not use abemaciclib monotherapy as first-line therapy - it is reserved for heavily pretreated patients who have progressed on both endocrine therapy and chemotherapy 3
Do not continue growth factors without suspending abemaciclib - hold abemaciclib for at least 48 hours after last growth factor dose 1