The Evolution of Abemaciclib Clinical Trial Data for the Treatment of HR-Positive/HER2-Negative Metastatic Breast Cancer

Sponsored by 

With commentaries by

Virginia F. Borges, MD, MMSc
Professor of Medicine
University of Colorado,
Anschutz Medical Campus
Denver, CO

Overview of Abemaciclib

Abemaciclib is a CDK4/6 inhibitor currently approved for the treatment of HR-positive/HER2-negative breast cancer. CDK4 and CDK6 are kinases important in the cell cycle and are activated when they bind with the corresponding D-cyclin protein.⁵ In typical pathophysiological circumstances, such as in breast cancer, cyclin D1 and CDK4/6 promote phosphorylation of the retinoblastoma protein, cell-cycle progression, and cell proliferation.⁵ Continuous exposure to abemaciclib inhibits retinoblastoma protein phosphorylation and blocks progression from the G1 phase into the S phase of the cell cycle, resulting in cell death.⁵ Abemaciclib is 14 times more potent against CDK4 than it is against CDK6.⁶ Abemaciclib is administered orally and dosed twice daily with either 200 mg for monotherapy or 150 mg in combination with another agent.⁵

Clinical Data: MONARCH 3

MONARCH 3 is a phase 3 study of abemaciclib in combination with a nonsteroidal aromatase inhibitor (NSAI; anastrozole or letrozole) versus placebo with an NSAI in postmenopausal women with HR-positive/HER2-negative advanced breast cancer without prior systemic therapy in the advanced setting.⁷ The trial involved 493 postmenopausal women with locally tested HR-positive/HER2-negative breast cancer (Figure 1).⁷ Patients with locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or patients with metastatic disease were eligible for the trial.⁷ Postmenopausal women were randomized in a 2:1 ratio to receive either abemaciclib 150 mg twice daily (n=328) or placebo (n=165) in combination with either anastrozole 1 mg or letrozole 2.5 mg daily.⁷ Baseline and disease characteristics between the groups were well balanced.⁷ Among the patients enrolled, 79.1% of patients utilized letrozole as their NSAI, and 60.2% of patients had locoregional or metastatic recurrent breast cancer.⁷ The primary endpoint was progression-free survival (PFS), defined as the time from randomization until progressive disease or death.⁷ The key secondary endpoint of this trial was overall survival (OS), and exploratory endpoints included chemotherapy-free survival.⁷ Safety was also explored in this trial.⁷

Efficacy

With a median follow-up time of 8.1 years, median PFS was greater with the addition of abemaciclib to an NSAI (abemaciclib + NSAI vs placebo + NSAI, 29.0 months vs 14.8 months).⁷ These results were statistically significant and demonstrated a greater progression-free benefit of abemaciclib versus control (hazard ratio, 0.535; 95% confidence interval [CI], 0.429-0.668; P<.0001).⁷ Across the study population, with the same median follow-up time, 314 OS events had occurred (abemaciclib arm, 60.4%; placebo arm, 70.3%; P=.0664) (Figure 2).⁷ Although not statistically significant, median OS was greater for the abemaciclib arm compared with the placebo arm (abemaciclib + NSAI vs placebo + NSAI, 66.8 months vs 53.7 months).⁷ Five- and 6-year OS rates also followed a similar trend, resulting in 54.5% versus 42.1% and 45.7% versus 35.2% for the abemaciclib and placebo groups, respectively. In a subgroup analysis of visceral disease (sVD), median OS was 63.7 months in the abemaciclib arm and 48.8 months in the placebo arm, a numerical difference of 14.9 months in the sVD, not statistically signifcant. Consistent OS differences were observed across prespecified subgroups.⁷

Commentary From Virginia F. Borges, MD, MMSc: The overall survival and progression benefit, which is the gold standard by which we should be choosing a patient’s first-line therapy, in the MONARCH 3 study is what draws me to utilize abemaciclib in my patients.

The overall survival is the most impactful data coming out of the MONARCH trials. Anything we can do to prolong our patients’ lives and maximize their quality of life is superior to options we’ve had in the past. It’s a chance for patients to regain normalcy in their lives.

Clinical Data: MONARCH 2

MONARCH 2 was a phase 3 study evaluating the efficacy of abemaciclib in the endocrine-resistant first- and second-line metastatic breast cancer setting. However, this study evaluated women of any menopausal state (pre- or perimenopausal with ovarian suppression or postmenopausal) who received a gonadotropin-releasing hormone agonist and were diagnosed with HR-positive/ERBB2-negative advanced breast cancer.⁸ Patients must have progressed on neoadjuvant or adjuvant endocrine therapy (ET) within 12 months from the end of adjuvant ET, or while receiving first-line ET for advanced breast cancer.⁸ Patients were randomized in a 2:1 ratio to receive either abemaciclib 150 mg twice daily (n=446) or placebo (n=223) in combination with fulvestrant 500 mg.⁸ Randomization was stratified based on the site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary).⁸ Baseline characteristics between the 2 arms were balanced, and patients were a median age of 59 years.⁸ The primary endpoint of this study was PFS, and the key secondary endpoint was OS.⁸ Exploratory endpoints included time to second disease progression, time to chemotherapy, and chemotherapy-free survival.⁸ Safety measures were also assessed in all patients who received at least 1 dose of the study drug.⁸

Efficacy

PFS was significantly improved with the combination of abemaciclib plus fulvestrant of 16.9 months compared with 9.3 months with fulvestrant (hazard ratio, 0.536; 95% CI, 0.445-0.645).⁸ Similarly, after a median follow-up time of 47.7 months, the combination of abemaciclib plus fulvestrant showed a statistically significant increase in OS of 47.3 months compared with 37.3 months in the fulvestrant group, an improvement of 9.4 months (hazard ratio, 0.757; 95% CI, 0.606-0.945; P=.01) (Figure 3).⁸ Exploratory endpoints such as time to second disease progression (hazard ratio, 0.675; 95% CI, 0.558-0.816), time to chemotherapy (hazard ratio, 0.625; 95% CI, 0.501-0.779), and chemotherapy-free survival (hazard ratio, 0.638; 95% CI, 0.527-0.773) were statistically significantly favored in the abemaciclib group compared with fulvestrant.⁸

Commentary From Virginia F. Borges, MD, MMSc: When someone is relapsing from the adjuvant setting or progressing with metastatic disease after first-line treatment with an aromatase inhibitor or other endocrine regimen, you’ll want to switch the ER blocker to a SERD such as fulvestrant and add in the CDK4/6 inhibitor. Monarch 2 confirmed a significant progression-free and overall survival benefit for abemaciclib in this setting, which is reassuring for our patients who progress early on their adjuvant therapy. With these excellent data, we do not need to reach for chemotherapy in this setting as we might have in the past.

Clinical Data: postMONARCH

postMONARCH, the first phase 3 trial to evaluate a CDK post-CDK progression examined the efficacy of abemaciclib (n=182) or placebo (n=186) in combination with fulvestrant.⁹ In this trial, patients were only eligible if they had disease progression on a CDK4/6 inhibitor plus AI as initial therapy for advanced breast cancer or relapse on or after a CDK4/6 inhibitor plus ET as adjuvant therapy for early breast cancer.⁹ No other previous treatments for advanced breast cancer were permitted.⁹ The primary endpoint of this study was investigator-assessed PFS, and secondary endpoints included PFS by blinded independent central review (BICR), OS, objective response rate (ORR), and safety.⁹ Patients included in this study primarily enrolled directly after administration of a CDK4/6 inhibitor plus ET as an initial therapy. Prior CDK4/6 inhibitor use in this population included palbociclib (59%), ribociclib (33%), and abemaciclib (8%).⁹

Efficacy

In postMONARCH, at the time of the primary analysis, abemaciclib in combination with fulvestrant demonstrated significantly improved investigator-assessed PFS compared with placebo (hazard ratio, 0.73; 95% CI, 0.57-0.95).⁹ With a median PFS of 6.0 and 5.3 months for the abemaciclib and placebo groups, respectively, PFS rates at 6 months favored abemaciclib (abemaciclib plus fulvestrant vs fulvestrant, 50% vs 37%).⁹ ORR was improved in the abemaciclib group (abemaciclib vs fulvestrant, 17% vs 7%), as well as PFS by BICR (hazard ratio, 0.55; 95% CI, 0.39-0.77).⁹ OS remains immature at a 20.9% event rate.⁹

Clinical Data: EMBER 3

At the 2024 San Antonio Breast Cancer Symposium, EMBER 3 data regarding the combination of imlunestrant and abemaciclib in the treatment of estrogen receptor (ER)-positive/HER2-negative, advanced breast cancer was presented.¹⁰ Imlunestrant is a next-generation, brain-penetrant, oral selective estrogen receptor degrader or SERD. In the combination arm, 213 patients were treated, with the primary endpoint being investigator-assessed PFS of the combination therapy versus imlunestrant alone.¹⁰ Secondary endpoints included ORR and safety. At the conclusion of the study, the combination of imlunestrant and abemaciclib (median PFS, 9.4; 95% CI, 7.5-11.9 months) demonstrated a 43% reduction in the risk of progression or death over imlunestrant alone (median PFS, 5.5; 95% CI, 3.8-5.6 months) (hazard ratio, 0.57; 95% CI, 0.44-0.73).¹⁰ Imlunestrant monotherapy significantly improved PFS versus standard-of-care (SOC) ET in patients with ESR1m (hazard ratio, 0.62; 95% CI, 0.46-0.82) but did not reach statistical significance in the overall population (hazard ratio, 0.87; 95% CI, 0.72-1.04).¹⁰ The PFS benefit was consistent regardless of ESR1 mutational status, prior treatment with a CDK4/6 inhibitor, and presence of a PI3K pathway mutation.¹⁰ ORR was also greater for the combination arm compared with both imlunestrant alone and SOC ET.¹⁰

Commentary From Virginia F. Borges, MD, MMSc: We do have data to show that we can repurpose and sequence CDK4/6 inhibitors and still continue to get benefit when the second CDK4/6 inhibitor is abemaciclib. In the case of the postMONARCH clinical trial, the ER-blocking partner was fulvestrant, but we’re also getting some new data for the newer SERDs [selective estrogen receptor degraders].

In my clinic, if somebody has experienced a durable benefit out of their first CDK4/6 regimen, I would think they’re a great candidate for continuing on with the CDK4/6 sequencing option.

Clinical Data: MONARCH 1

While MONARCH 2 and MONARCH 3 focused on abemaciclib in combination with either fulvestrant or an NSAI, respectively, MONARCH 1 was the first trial within the program and examined the effectiveness of abemaciclib as monotherapy.¹¹ MONARCH 1 was a phase 2, single-arm, open-label trial that enrolled 132 women with HR-positive/HER2-negative metastatic breast cancer who had progressed on or after prior ET and had 1 or 2 chemotherapy regimens in the metastatic setting.¹¹ Patients were administered abemaciclib 200 mg orally every 12 hours for a 28-day cycle until disease progression or unacceptable toxicity.¹¹ Of the patients enrolled into the study, patients had received a median of 3 prior lines of systemic therapy in the metastatic setting, 90.2% had visceral disease, and 50.8% had ≥3 metastatic sites.¹¹ The primary endpoint of this study was ORR, and secondary endpoints included PFS, OS, duration of response (DOR), disease control rate (DCR), and clinical benefit rate (CBR).¹¹

Efficacy

At the time of the 12-month final analysis, ORR was 19.7% (95% CI, 13.3-27.5).¹¹ Of note, there were no observed complete responses, and of the 26 partial responses, 12 (46.2%) patients had received at least 2 prior chemotherapies in the metastatic setting, 24 (92.3%) had visceral disease, and 12 (46.2%) had ≥3 metastatic sites.¹¹ Median PFS was 6.0 months and median OS was 17.7 months for abemaciclib monotherapy.¹¹ Median DOR was 8.6 months (95% CI, 5.8-10.2), and the chance of a response lasting either 6 or 12 months was 70.4% and 28.2%, respectively. DCR was 67.4% and CBR was 42.4%.¹¹

Abemaciclib Safety

Overall, safety events were consistent across all studies with abemaciclib.^7-11 The most common nonhematological AE across all the MONARCH trials was diarrhea. While diarrhea tended to occur early after initiation of therapy with a median time to onset of 6 to 8 days, the duration was generally limited.¹¹ Other common AEs included neutropenia, leukopenia, and anemia.⁷ Dose reductions due to AEs occurred in approximately 43% to 49% of patients across the 3 MONARCH trials. Importantly, in MONARCH 3, when reducing the dose of abemaciclib, there was no difference in PFS when reducing from 150 mg to 100 mg (hazard ratio, 0.76; 95% CI, 0.47-1.25) or from 150 mg to 50 mg (hazard ratio, 0.99; 95% CI, 0.51-1.90).¹² There is also data from MONARCH 2 to support that efficacy is maintained following dose reductions.¹² Permanent treatment discontinuation due to AEs ranged from 8% to 13% in all the MONARCH trials. Additionally, the safety profile in EMBER 3 was comparable and consistent with the well-established safety profile of abemaciclib.¹⁰ Because of the marked and clinically meaningful OS and PFS benefit seen with abemaciclib use, maintaining adherence through proactive AE management is crucial.

Commentary From Virginia F. Borges, MD, MMSc: We can feel quite reassured that going from 150 mg to 100 mg does not impact the benefit that we see in terms of efficacy. Some patients may need to reduce to below 100 mg in order to tolerate the medication. I make sure to teach my patients at the time of starting the medication to potentially expect a dose reduction, and that it’s not a problem; it’s just their body telling us that this is how it handles this medication.

I think there is an opportunity to increase awareness regarding the dose-reduction data and side-effect mitigation to ensure patients are being offered the regimens with the best evidence for benefit. I find abemaciclib can be given as safely and as manageably as any of the other CDK4/6 inhibitors.

I think it’s all the more important that the dose-reduction message gets out there because we have all these new combinations that are showing fantastic results, and we need to be offering our patients these novel therapies as they become the standard of care.

Administering Abemaciclib

As abemaciclib is an oral medication, dosing considerations are minimal. Generally, abemaciclib has no meal requirements, should be swallowed whole, and taken at approximately the same time every day.¹³ If a patient vomits or misses a dose of abemaciclib, it is recommended that they take the next dose at its scheduled time.⁵ Patients with metastatic breast cancer may receive abemaciclib as a twice-daily, 150-mg dose in combination with an NSAI or fulvestrant, or as a single 200-mg dose.⁵ In either case, the medication is continued until disease progression or unacceptable toxicity.⁵ When administering abemaciclib to a patient, avoid concomitant use of strong or moderate CYP3A inducers, as the combination may decrease plasma concentrations of abemaciclib and lead to reduced antitumor activity.⁵ Dose modification may be necessary based on the individual patient’s tolerability of abemaciclib.⁵ Dosing reductions are recommended to be done in 50-mg intervals.⁵ For patients with severe hepatic impairment (Child-Pugh class C), the recommendation is to decrease the dosing frequency to once daily.⁵

Commentary From Virginia F. Borges, MD, MMSc: We rarely get grade 3 diarrhea when we premedicate, but sometimes we do, or we get grade 2 or bothersome grade 1. In those situations, we look for an opportunity to reduce the dose, and that often makes treatment far more tolerable for patients.

Prevention and Management of AEs

As diarrhea was the most common reason for dose reduction in all of the MONARCH trials, it is important to understand how to mitigate this AE. At the first sign of loose stools, patients should initiate an antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider.⁵ For grade ≥3, grade 2 recurrent, or diarrhea that requires hospitalization, it is recommended to discontinue abemaciclib until the toxicity resolves to grade ≤1, and then restart abemaciclib at the next lower dose.⁵ Grade 1 diarrhea requires no dose modification, and for grade 2, if grade 2 diarrhea does not resolve within 24 hours to grade ≤1, dosing should be suspended until resolution.⁵

Hematologic toxicities are similarly managed. Patients initiating abemaciclib should have their complete blood count monitored before the start of abemaciclib therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and then as needed.⁵ Grade 1 or 2 hematologic toxicities require no intervention.⁵ However, toxicities of grade ≥3 require a suspension of the dose until the toxicity resolves to grade ≤2.⁵ Whether a dose modification is required depends on the grade of the hematologic toxicity; if the toxicity is grade 3, a dose reduction is not required.⁵ However, if a toxicity is a recurrent grade 3 or a grade 4, it is recommended to resume at the next lower dose.⁵

While there are recommendations for a dose reduction for hepatic toxicities, there are also situations where it is necessary to discontinue abemaciclib. Elevations in either aspartate aminotransferase or alanine aminotransferase 3 times the upper limit of normal with a total bilirubin increase of >2 times the upper limit of normal warrant a complete discontinuation of abemaciclib, as does a grade 4 toxicity signified by any value >20 times the upper limit of normal.⁵

Across all trials for abemaciclib (MONARCH 1 to EMBER 3) tolerability has been shown to improve over time as healthcare providers have learned to proactively manage AEs.

Commentary From Virginia F. Borges, MD, MMSc: Abemaciclib is fairly well known for gastrointestinal impacts, particularly diarrhea. Even grade 1 diarrhea is bothersome to the patient, and we want to be proactive about managing that.

I spend a lot of time discussing with my patients about what to expect. Through this and dedicated teaching sessions with nurses and PharmDs, it’s rare I have a patient who cannot stay on abemaciclib due to gastrointestinal impacts.

My patients are also very resourceful. They’ll figure out what foods they need to avoid and what they can eat. The patient is a big partner in figuring out the optimal care plan.

Access to Care

To access abemaciclib, Lilly has provided a variety of support services for patients. Lilly Support Services provides patients with personalized support to ensure a positive experience when taking abemaciclib, including identifying savings opportunities and assisting with insurance-related issues.¹⁴ Patients with commercial insurance can pay as little as $0 a month when utilizing a savings card for abemaciclib.¹⁴

Aside from financial assistance, patients utilizing abemaciclib may benefit from additional services provided by third-party assistance organizations and nonprofits. These can range from counseling, educational materials, and integrative therapies offered by organizations such as Unite for HER, Breastcancer.org, Living Beyond Breast Cancer, and the Cancer Support Community.¹⁴

Conclusion

Treatment for breast cancer is complex, even more so when considering different receptor expression and menopausal states. HR-positive/HER2-negative breast cancer has traditionally relied on AIs, fulvestrant, and CDK4/6 inhibitors as the backbone of therapy. Abemaciclib represents a safe and efficacious CDK4/6 inhibitor that can be used in combination with fulvestrant, NSAIs, or as monotherapy in the treatment of HR-positive/HER2-negative advanced breast cancer. In combination with fulvestrant, NSAIs, or even as monotherapy, abemaciclib has shown clinically meaningful progression and survival benefit with a predictable and manageable AE profile. Because of these qualities, the National Comprehensive Cancer Network^® (NCCN^®) recommends the use of abemaciclib in women with HR-positive/HER2-negative disease, and postmenopausal or premenopausal disease receiving ovarian ablation or suppression, marking its place in the treatment landscape of HR-positive/HER2-negative breast cancer. With optimal monitoring, care, and administration, abemaciclib may deliver the same optimal outcomes reported in clinical trials to clinical practice.¹⁵

Commentary From Virginia F. Borges, MD, MMSc: Abemaciclib, and CDK4/6 inhibitors in general, are something [we will be needing to use] in an increasing way, in part because we now have a percentage of patients who will be receiving CDK4/6 inhibitor therapy in the adjuvant setting and be developing metastatic disease despite that additional intervention. I think making sure that we are doing the best we can for our patients with having the knowledge base amongst not just oncologists, but our oncology APP partners, our PharmDs, our nurses, is necessary so that we can really be on task with curbing hesitancy toward abemaciclib treatment.

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15. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.5.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed October 24, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.