Abemaciclib: The Newest CDK4/6 Inhibitor for the Treatment of Breast Cancer
Alison Palumbo, Gary Lau and Megan Saraceni
1 Oregon Health and Science University, Portland, OR, USA
Abstract
Objective: To review the pharmacology, efficacy, and safety of the cyclin-dependent kinase (CDK) inhibitor, abemaciclib, in the treatment of advanced or metastatic breast cancer (MBC). Data Sources: Relevant information was identified through a MEDLINE/PubMed (January 2000 to June 2018) literature search. The new drug application, prescribing information, and abstracts and posters from scientific meetings were also reviewed. Study Selection/Data Extraction: The literature search was limited to human studies published in the English language. Phase 1, 2, and 3 studies evaluating the pharmacology, efficacy, or safety of abemaciclib for breast cancer were included. Data Synthesis: Abemaciclib is an oral, potent, small molecule inhibitor of CDK4 and CDK6 activity, which blocks retinoblastoma tumor suppressor protein phosphorylation and thereby prevents progression through the cell cycle. Three major clinical trials, MONARCH 1, 2, and 3, established the efficacy and safety of abemaciclib for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or MBC. In these trials, response rates were promising, ranging from 19.7% to 59%, and median progression-free survival was significantly prolonged over the control arm in 2 of the trials. Common adverse effects included diarrhea, neutropenia, nausea, abdominal pain, infections, and fatigue. Relevance to Patient Care and Clinical Practice: Although no head-to-head studies have been completed between the CDK4/6 inhibitors, abemaciclib may be an attractive option because of its continuous dosing and ability to be used as monotherapy. Conclusions: Abemaciclib is an effective and well-tolerated treatment for HR-positive, HER2-negative advanced or metastatic breast cancer.
Introduction
Breast cancer is the most common cancer in women worldwide and the second most common cause of cancer- related death in women in the United States. It is estimated that there will be 266 120 new cases of invasive breast cancer diagnosed in women in the United States in 2018.1 Prognosis and treatment of breast cancer is, in part, deter- mined by tumor histology. Patients may have estrogen receptor–, progestin receptor–, and/or human epidermal growth factor receptor 2 (HER2)–expressing tumors or may not express any receptors (ie, triple-negative breast cancer). A variety of treatment modalities exist to treat breast cancer, including chemotherapy (doxorubicin, the third and newest CDK inhibitor, abemaciclib, was approved by the US Food and Drug Administration (FDA) and introduced to the market.3 This review will cover the pharmacology, pharmacokinetic properties, safety, clinical efficacy, and administration of abemaciclib.
Data Selection
A MEDLINE/PubMed literature search was conducted using the terms abemaciclib, LY2835219, CDK inhibitor, and breast cancer to find clinical trials in the English lan- guage from January 2000 to June 2018. Additional data were obtained from the literature acquired through review of the reference lists of identified articles. Finally, the abemaciclib cyclophosphamide, etc), radiation therapy, surgery, and hormonal therapy (tamoxifen, anastrozole, etc). In recent years, cyclin-dependent kinase (CDK) inhibitors have been introduced for the treatment of patients with hor- mone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC).2 In September of 2017, new drug application and prescribing information were bioavailability; however, the C meetings, governmental sources, ongoing clinical trial data, and cancer treatment guidelines.
Chemistry and Pharmacology
Continual proliferative capacity is a hallmark of cancer pathophysiology. In mammalian cells, the cell cycle con- trols proliferation. Within the cell cycle, CDKs regulate on the results of this study, it was determined that food does not have a clinically relevant impact on the pharmacokinet- ics of abemaciclib. This is consistent with prescribing infor- mation recommendations, which state to take the drug without regard to food.3
S phase in the cell cycle of a mammalian cell. These kinases phosphorylate the retinoblastoma gene product (Rb), the downstream effects of which allow the cycle to progress to the S phase. In HR-positive breast cancer, activation of the CDK4/6 pathway is associated with resistance to endocrine therapy (ET), allowing cell cycle progression despite inhi- bition of the estrogen receptor.4
Abemaciclib is a selective small molecule inhibitor of CDK4/6. Abemaciclib produces 5 metabolites, but only abemaciclib and 3 of the metabolites—hydroxyabemaciclib (M20), N-desethylabemaciclib (M2), and hydroxy-N-des- ethylabemaciclib (M18)—constitute the majority of plasma exposure.3 Abemaciclib selectively inhibits CDK4/6 with a Ki (inhibitor constant) value of 0.6 nM for cyclin D1/CDK4 and 8.2 nM for cyclin D3/CDK6.5 The IC50 values for inhi- bition of CDK4 and CDK6 for metabolites M2, M18, and M20 were between 1 and 3 nm, which were equivalent in potency to abemaciclib.4 In vitro and in vivo, abemaciclib has demonstrated potent activity against Rb phosphoryla- tion and subsequent cell cycle arrest in the G1 phase. In tumor xenograft growth models of varying histologies, including breast cancer, abemaciclib was able to inhibit cancer cell growth through competitively inhibiting ATP binding by interacting with CDKs within catalytic ATP sites.6 In a similar manner, metabolites M2, M20, and M18 also inhibit cell growth and cell cycle progression in a con- centration-dependent manner, with M2 and M20 demon- strating a potency similar to that of abemaciclib and M18 demonstrating a potency 3- to 20-fold lower than that of abemaciclib. These results encouraged the study of this medication in clinical trials, not only in breast cancer, but also in non–small-cell lung cancer.
Pharmacokinetics and Pharmacodynamics
Abemaciclib is manufactured as an oral tablet. The absolute bioavailability of abemaciclib following a 200-mg oral dose in healthy individuals was found to be 45% based on an abstract from the 2016 American Association for Cancer 200 mg by mouth twice daily and 1120 L in patients taking 150 mg by mouth twice daily.9 Conversely, the prescribing information for abemaciclib reports that the geometric mean systemic volume of distribution is approximately 690.3 L.3 Of note, abemaciclib distributes across the blood-brain barrier based on an intracranial glioblastoma xenograft model.10 According to the prescribing informa- tion, in patients with advanced cancer, concentrations of abemaciclib and its active metabolites are comparable in cerebrospinal fluid and plasma.3 Abemaciclib and its active metabolites are also highly protein bound, with bound fractions exceeding 90%.3
Abemaciclib appears to be cleared primarily via hepatic metabolism with less than 10% of parent drug recovered unchanged in the feces. Abemaciclib is metabolized primar- ily by cytochrome P450 (CYP) 3A.3 After administering a single 200-mg dose of abemaciclib, the relative adjusted unbound area under the curve (AUC) of abemaciclib and its active metabolites increased 1.2-fold in those with mild hepatic impairment (Child-Pugh A), 1.1-fold in those with moderate hepatic impairment (Child-Pugh B), and 2.4-fold in those with severe hepatic impairment (Child-Pugh C). In patients with severe hepatic impairment, elimination half- life of abemaciclib increased to 55 hours compared with 24 hours in those with normal hepatic function. Similarly, a population pharmacokinetic analysis of patients with mild and moderate renal impairment showed that exposure to abemaciclib and its active metabolites are not affected by mild or moderate renal impairment.
In an abstract published by Kulanthaivel et al,11 phar- macokinetic drug interactions with abemaciclib were elu- cidated. Pharmacokinetic data with and without concomitant use of a second drug were collected. The 2 drugs that were observed were rifampin, a strong CYP3A inducer, and clarithromycin, a strong CYP3A inhibitor. For patients who did not receive concomitant CYP3A inhibitor/inducers, the mean half-life for abemaciclib par- ent drug was 29 hours. Concomitant use of rifampin with abemaciclib reduced the AUC and C by 95% and 92%, max respectively, whereas use of clarithromycin with prolonged to 63.6 hours with use of clarithromycin.11 Based on these data, dose adjustments are recommended for abemaciclib when used concomitantly with certain medications, the specifics of which are discussed further in the section Dosage and Administration below.
Clinical Trials
Phase II Trials
MONARCH 1. MONARCH 1 was a phase II single-arm open-label study conducted in women with refractory HR- positive, HER2-negative MBC. To be eligible for inclusion, patients must have progressed on or after prior ET and had prior treatment with at least 2 chemotherapy regimens. At least 1, but no more than 2, of the chemotherapy regimens must have been administered in the metastatic setting and 1 regimen must have included a taxane. Women were excluded if they had received prior treatment with a CDK4/6 inhibitor or if they had evidence of central nervous system (CNS) metastases. Patients (n = 132) received abemaciclib 200 mg by mouth every 12 hours continuously until disease progression or unacceptable toxicity.12
At the 12-month final analysis, abemaciclib achieved an overall response rate (ORR) of 19.7% (95% CI = 13.3- 27.5), with no observed complete responses (CRs). The clinical benefit rate (defined as CR + partial response + stable disease ⩾6 months) was 42.4%. The median time to response was 3.7 months, with a median duration of response (DoR) of 8.6 months (95% CI = 5.8-10.2). Median progression-free survival (PFS) at the time of data analysis was 6 months (95% CI = 4.2-7.5), and median overall survival (OS) was 17.7 months (95% CI = 16 to Not reached). Of note, these patients had a median of 3 (range, 1-8) lines of prior systemic therapy in the meta- static setting; 90.2% had visceral disease (defined as hav- ing liver and/or lung metastases), and 50.8% had greater than or equal to 3 metastatic sites neoMONARCH. Abemaciclib has also been studied in the neoadjuvant setting. In the neoMONARCH trial, post- menopausal women with HR-positive, HER2-negative breast cancer who were deemed appropriate for neoadju- vant therapy were eligible for enrollment. Patients (n = 223) were randomized to 1 of 3 arms: abemaciclib 150 mg by mouth every 12 hours plus anastrozole for 16 weeks; abemaciclib alone for 2 weeks, followed by the combination of abemaciclib plus anastrozole for an addi- tional 14 weeks; or anastrozole alone for 2 weeks, fol- lowed by the combination of abemaciclib plus anastrozole for an additional 14 weeks. Of note, loperamide was given as prophylaxis for 4 weeks and then at physician discretion. The primary end point was change from base- line to week 2 of treatment in Ki67 expression, a cellular marker for proliferation. Abemaciclib, either alone or in combination, appeared to reduce the Ki67 more greatly than anastrozole alone. The pathological CR and ORR were 3.33% and 57.14%, respectively, in the combination arm.13 These results demonstrate the feasibility of abe- maciclib in the neoadjuvant setting; however, clinical practice guidelines do not currently recommend use for this indication.2
Phase III Trials
MONARCH 2. MONARCH 2 was a phase III randomized, double-blind, placebo-controlled trial comparing abemaci- clib plus fulvestrant to fulvestrant alone in patients with HR-positive, HER2-negative advanced breast cancer (ABC). Patients were enrolled regardless of menopausal status and had to have measurable disease by RECIST cri- teria or nonmeasurable bone-only disease. Patients must have progressed on neoadjuvant or adjuvant ET, within 12 months after receiving adjuvant ET, or while receiving ET for ABC. Patients were excluded if they previously received fulvestrant, everolimus, or another CDK4/6 inhibitor or if CNS metastases were present. Patients (n = 669) were ran- domized 2:1 to receive either abemaciclib 150 mg or pla- cebo by mouth twice daily on a continuous schedule plus fulvestrant 500 mg per the labeled schedule.14
After a median follow-up of 19.5 months, in the intent- to-treat population, abemaciclib demonstrated a superior PFS of 16.4 months compared with 9.3 months in the con- trol arm (hazard ratio = 0.553; 95% CI = 0.449-0.681; P < 0.001). This improvement in PFS was seen across all sub- groups. The ORR was 35.2% (95% CI = 30.8-39.6%) in the abemaciclib arm and 16.1% (95% CI = 11.3-21.0%) in the control arm (P < 0.001). This included 14 CRs (3.1%) in the abemaciclib arm compared with 1 CR (0.4%) in the control arm. The median DoR had not been reached at the time of study analysis. OS data were not yet mature at the time of publication.14
MONARCH 3. MONARCH 3 sought to justify use of abemaciclib in the front-line setting for ABC. In this double-blind, randomized, phase III study, women who were postmenopausal and had HR-positive, HER2-nega- tive disease that was locoregionally recurrent were enrolled. Patients could not have received previous sys- temic therapy; however, prior ET was permitted if the patient had a disease-free interval of at least 12 months following completion of ET. Patients (n = 493) were randomized 2:1 to receive abemaciclib 150 mg or pla- cebo by mouth twice daily continuously plus either anas- trozole or letrozole daily.15
After a median follow-up of 17.8 months, the median PFS for patients treated with abemaciclib was signifi- cantly prolonged compared with placebo (hazard ratio = 0.54; 95% CI = 0.41-0.72; P = 0.000021). The ORR was 48.2% (95% CI = 42.8%-53.6%) in the abemaciclib arm and 34.5% (95% CI = 27.3%-41.8%) in the placebo arm (P = 0.002). Median DoR was not reached in the abe- maciclib arm and was 14.1 months in the placebo arm. Survival data were not mature at the time of publication.15 The results of this study led to the approval of abemaci- clib by the FDA in February 2018 in the front-line setting for patients with ABC or MBC.16 A summary of all clini- cal trials is outlined in Table 1.
Safety and Tolerability
In all the phase II/III studies, diarrhea was the most com- mon adverse effect (AE) reported, with the greatest fre- quency of diarrhea seen in patients who received the higher dose of abemaciclib 200 mg by mouth twice daily.12-15,17 The onset to first episode of diarrhea was typically around a week from starting therapy, and the duration of diarrhea was also about a week. In all studies, diarrhea was largely low grade with no cases of grade 4 diarrhea reported.12-15,17 A majority of patients who expe- rienced diarrhea did not undergo any treatment modifica- tions but were managed with antidiarrheal therapy. In MONARCH 1, 2, and 3, patients were advised to use antidiarrheal medication at the first onset of diarrhea, and the incidence of diarrhea ranged from 61.4% to 90.2%. However, in neoMONARCH, patients were given loper- amide 2 mg by mouth every 12 hours for the first 4 weeks of study treatment. This resulted in an incidence of diar- rhea of 40.54% in the combination arm (abemaciclib plus anastrozole) during the first 2 weeks of treatment and an incidence of 38.79% among all patients during the subse- quent 14 weeks of combination treatment. Prophylactic use of loperamide also resulted in constipation: 32.43% in the combination arm during the first 2 weeks of treatment and 19.16% among all patients during the subsequent 14 weeks of combination treatment.
Other frequent AEs reported in MONARCH 1, 2, and 3 included neutropenia (41.3%-87.7%), nausea (38.5%-64.4%), fatigue (39.9%-65.2%), abdominal pain (29.1%-38.6%), and decreased appetite (24.5%-45.5%).12-15,17 In neoMONARCH, among all patients during the 14 weeks of combination therapy, the most frequent AEs were nausea (26.64%), fatigue (23.83%), neutropenia (14.95%), and decreased appetite (12.15%). Additionally, MONARCH 1 demonstrated a high rate of increased serum creatinine with all grades reported as 98.5%.12 Uniquely, MONARCH 3 reported a high rate of infections at 39.1%.15 Overall, neu- tropenia was significant, yet grade 4 rates of neutropenia remained low with a range of 0% to 4.6%.12-15,17 Neutrophil counts typically reached nadir within a month after the start of treatment, remained depressed and stable throughout the dosing period, and increased to normal levels following treatment discontinuation. Similar to diarrhea, higher rates of neutropenia were reported in patients taking abemaciclib 200 mg by mouth twice daily.12 Of note, venous thrombo- embolism (VTE) was reported in 4.9% of patients receiving abemaciclib with an aromatase inhibitor (AI) and in 2% of patients receiving abemaciclib with fulvestrant. This inci- dence of VTE was higher in the abemaciclib arms than the control arms; however, no VTE was reported when abe- maciclib was used as monotherapy. In MONARCH 1, dose reductions and omissions caused by AEs occurred in 49.2% and 57.6% of patients, respectively, most often as a result of diarrhea or neutropenia. Discontinuations caused by AEs were infrequent. A comparison of AEs among the currently available CDK inhibitors is outlined in Table 2.3,12,14,15,18-23
Place in Therapy
In the National Comprehensive Cancer Network (NCCN) guidelines for breast cancer, abemaciclib, in combination with an AI or fulvestrant, is currently listed as a category 1 recommended agent for patients with HR-positive, HER2- negative recurrent or stage IV disease. The other available CDK4/6 inhibitors, palbociclib and ribociclib, are also listed as category 1.2 Because there are no head-to-head studies between CDK inhibitors, there is currently no pref- erence for one agent established by the guidelines. NCCN also lists abemaciclib as a treatment option in certain cir- cumstances—namely, as monotherapy after progression on prior ET and prior chemotherapy in the metastatic setting.2 At this time, there is no indication to use a CDK4/6 inhibi- tor following progression on another CDK4/6 inhibitor- containing or everolimus-containing regimen.2
Dosage and Administration
At the time of this article’s publication, abemaciclib is FDA indicated in 3 settings: (1) as initial endocrine-based ther- apy in combination with an AI for postmenopausal women with HR-positive, HER2-negative advanced or MBC, (2) in combination with fulvestrant for the treatment of HR-positive, HER2-negative ABC or MBC in women with disease progression following ET, and (3) as monotherapy for the treatment of HR-positive, HER2-negative ABC or MBC in patients with disease progression following ET and prior chemotherapy in the metastatic setting. Dosing varies depending on whether abemaciclib is used alone or in com- bination with another agent. The dose is 150 mg by mouth twice daily with combination therapy and 200 mg by mouth twice daily as monotherapy.3 Doses may be taken with or without food as stated previously based on the results of the study by Turner et al.7 Because of the dependence on CYP3A for abemaciclib metabolism, patients should be counseled to avoid grapefruit and grapefruit-containing products.3
As stated above, abemaciclib is extensively metabolized by CYP3A and, therefore, use of strong CYP3A inhibitors and inducers should be avoided if possible. Per the prescrib- ing information, ketoconazole should be completely avoided; however, concomitant use of other strong CYP3A inhibitors is permitted, provided the dose of abemaciclib is reduced. With strong CYP3A inhibitors, the initial dose should be reduced to 100 mg by mouth twice daily (if the starting dose was intended to be 200 or 150 mg twice daily). In patients who received a dose reduction to 100 mg twice daily because of toxicities, the dose may be reduced to 50 mg twice daily. Permanent discontinuation of abemaciclib treatment is recommended in patients unable to tolerate 50 mg twice daily.3
For end organ impairment, the prescribing information also offers guidance for how to adjust the dose of abemaci- clib. Patients with a creatinine clearance (CrCl) of at least 30 mL/min do not require dose adjustment; however, abe- maciclib has not been studied in patients with a CrCl of less than 30 mL/min. For hepatic impairment at treatment initia- tion, no dosage adjustment is necessary in patients with Child-Pugh class A or B; patients with Child-Pugh class C require the abemaciclib dosing frequency to be reduced to once daily. There are separate dose adjustment recommen- dations for patients who experience hepatotoxicity during treatment.3
Future Directions
Abemaciclib is also undergoing phase I to III clinical trials in a number of other cancer settings, including other breast cancer populations (ie, triple negative), lung cancer, glio- blastoma, liposarcoma, head and neck cancer, melanoma, and more. Two prominent trials are discussed below.
Currently, most data for albemaciclib focus on patients with HR-positive, HER2-negative breast cancer; however, one study is seeking to determine if abemaciclib may have some utility in HR-positive, HER2-positive advanced or meta- static disease as well. The monarcHER trial is a phase II,
randomized, open-label study that is currently enrolling patients into 1 of 3 arms: abemaciclib with fulvestrant and trastuzumab; abemaciclib with trastuzumab; or trastuzumab with standard of care chemotherapy. The primary outcome of this study will be PFS. The primary completion date is planned for August 2018.24
JUNIPER
The JUNIPER trial is an ongoing phase III study comparing abemaciclib 200 mg orally every 12 hours with erlotinib 150 mg orally every 24 hours in patients with stage IV non– small-cell lung cancer with a detectable KRAS mutation following progression on platinum-based chemotherapy. The rationale for use of abemaciclib is its activity against CDK4. In a KRAS-mutant lung adenocarcinoma model, ablation of CDK4 selectively induced senescence of KRAS- expressing cells, indicating that use of a CDK4 inhibitor, such as abemaciclib, may be beneficial in such patients.25 Results from this trial have yet to be published, but in a statement made by Lilly, abemaciclib did not meet its pri- mary end point of OS. However, an analysis of both PFS and ORR showed evidence of abemaciclib activity. Full data from this study will be released later in 2018.26
Relevance to Patient Care and Clinical Practice
Although no direct comparisons have been made between CDK4/6 inhibitors, abemaciclib has demonstrated a few unique characteristics compared with palbociclib and ribociclib. There is some preclinical evidence to suggest that continuous use of a CDK4/6 inhibitor may be prefer- able to intermittent use. In a study by Gelbert et al,27 colo- 205 xenograft-bearing mice were treated with either a 56-day continuous or intermittent schedule of abemaci- clib. Both schedules produced a similar inhibition of tumor growth; however, the pharmacokinetic/pharmaco- dynamic analysis concluded that continuous in vivo pRb inhibition and cell cycle arrest are required for robust effi- cacy.27 Palbociclib and ribociclib are both given on an intermittent schedule for 21 days of a 28-day cycle. Intermittent dosing is necessary with these 2 drugs given the dose-limiting toxicity of neutropenia. Because the incidence of neutropenia is lower with abemaciclib, con- tinuous dosing is allowable, and the dose-limiting toxicity is grade 3 fatigue.28
Another unique characteristic of abemaciclib compared with other CDK4/6 inhibitors is the ability to use it as mono- therapy. As demonstrated in MONARCH 1, single-agent activity of abemaciclib is appealing because patients with multiply recurrent HR-positive breast cancer typically do not develop optimal responses to traditional chemotherapy.12 ORRs with cytotoxic chemotherapy range from 10% to 20%, with median DoRs between 4 and 6 months.2,29-34 Although a direct comparison with chemotherapy in this setting has not been done, this is consistent with the ORR of 19.7% observed with single-agent abemaciclib in MONARCH 1.12 Additionally, abemaciclib may offer a more tolerable toxicity profile compared with chemotherapy, which is often associ- ated with decreased quality of life resulting from toxicities, such as alopecia, hand-foot syndrome, nausea/vomiting, cytopenias, febrile neutropenia, and peripheral neuropathy. Finally, there is a subset of patients who refuse additional ET because of the AE profile of these agents, such as hot flashes, arthralgias, myalgias, mood changes, and more. In these patients, the ability to offer abemaciclib monotherapy, with- out the need for concomitant ET, provides an advantage over other CDK inhibitors.
Summary
Abemaciclib, the newest CDK4/6 inhibitor, is an effective treatment for patients with HR-positive, HER2-negative ABC or MBC. It may be used in combination with an AI as initial endocrine-based therapy in postmenopausal women or it may be used as monotherapy or in combination with fulvestrant for progressive disease following prior ET. Abemaciclib is unique in that it is the only CDK2-IN-73 that may be given continuously and as monotherapy. The most common AE of abemaciclib is diarrhea, but this is often low grade and self-limiting, and can be managed with supportive antidiarrheal medications. It is expected that abemaciclib will also be indicated in other oncology patient populations in the near future.