Based on current incidence rates, 12.4% of women born in the United States today will develop breast cancer at some time during their life.1 At the time of diagnosis, breast cancer is generally considered local, but eventually approximately 20% of patients will experience either locoregional or distant disease recurrence.2
When breast cancer recurs or is diagnosed at an advanced stage, treatment is complicated by the diverse nature of the disease, with several molecular subgroups with distinct tumor biology responding differently to different therapies.3 The biologic heterogeneity of the disease and development of resistance are regarded as major obstacles for developing more effective treatment approaches.2 Currently, hormonal status is a key tumor attribute upon which oncologists rely when determining therapy. The tumor’s estrogen receptor (ER) and progesterone receptor status, as well as the amplification and overexpression of HER2, directs treatment planning.2 More than 70% of breast cancers express ER and rely on ER signaling to grow and survive, suggesting that endocrine therapy (ET) represents the primary intervention for early- and advanced-stage ER+ breast cancer.3 However, some patients do not respond to ET (de novo resistance), and some patients who initially respond have disease that progresses during therapy (acquired resistance).3
Understanding the pathways responsible for resistance in the advanced or metastatic setting may provide important clues to the mechanisms of resistance to adjuvant ET. Multiple mechanisms for endocrine resistance have been hypothesized, including the disruption of the ER pathway components and cell signaling, as well as the activation of escape pathways to facilitate cancer-cell survival.3 Among these resistance mechanisms, the dysregulation of the cyclin D–cyclin-dependent kinase (CDK)4/6–INK4–retinoblastoma (Rb) pathway has been shown to correlate with poor response to ET.4 The cyclin D–CDK4/6–INK4–Rb pathway regulates the progression of the cell cycle from the G1 phase (pre-DNA synthesis) to the S phase (DNA synthesis).3,4 Because alterations in the CDK4/6 pathway are frequent in ER+ breast cancer, the suppression of cyclin D–supported CDK4/6 activity is a viable therapeutic option for women with breast cancer whose disease does not respond to hormone-based therapies.3-5
CDK4/6 Inhibitors in Breast Cancer
First-generation CDK inhibitors were less specific pan-CDK inhibitors that targeted other CDKs in a broad fashion and were associated with modest efficacy and chemotherapy-like toxicities, leading to unacceptable safety profiles, including intractable diarrhea and a proinflammatory syndrome associated with hypotension.2,6 More recently, a new generation of specific CDK4/6 inhibitors has been developed.
Currently, 3 CDK4/6 inhibitors have been tested in breast cancer clinical trials and approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor–positive (HR+)/HER2− advanced breast cancer (ABC) or metastatic breast cancer (MBC): palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio™). Palbociclib is approved by the FDA for the treatment of HR+/HER2− ABC or MBC in 2 clinical settings: (1) in combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or (2) in combination with fulvestrant (Faslodex®) at disease progression after ET.7 Ribociclib is approved by the FDA in combination with an aromatase inhibitor such as letrozole as initial endocrine-based therapy for the treatment of postmenopausal women with HR+/HER2− ABC or MBC.8
The safety and preliminary antitumor activity of the CDK4/6 inhibitors palbociclib and ribociclib as single agents have been investigated in several clinical trials. These studies have shown the following results.
Palbociclib. Early clinical trials have investigated the safety and clinical activity of palbociclib as a single agent. The most common adverse event (AE) associated with palbociclib is neutropenia; however, it is distinct from that observed with cytotoxic agents in that it is rapidly reversible, reflecting a cytostatic effect on neutrophil precursors in the bone marrow.9 Nonhematologic AEs related to treatment with palbociclib include nausea, fatigue, diarrhea, stomatitis, and asthenia.7,10,11 In a phase 1 first-in-human dose-escalation study, patients with advanced solid tumors received oral palbociclib once daily for 21 of 28 days. Neutropenia was the major toxicity observed and was also dose-limiting. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) were declared as 125 mg given once daily on a 3-weeks-on/1-week-off schedule every 28 days. Of 37 evaluable patients, 10 (27%) achieved stable disease (SD) for ≥4 cycles, 6 of whom derived prolonged benefit (>10 cycles).10
Ribociclib. As with palbociclib, hematologic AEs, including neutropenia, are common with ribociclib, and therefore a 1-week resting period is incorporated into dosing regimens in most trials.9 In a phase 1 first-in-human study, patients with advanced solid tumors or lymphomas received escalating doses of single-agent ribociclib, either as part of a 3-weeks-on/1-week-off schedule or as part of a continuous 28-day schedule. The MTD and RP2D were declared as 900 mg/day and 600 mg/day, respectively, on a 3-weeks-on/1-week-off dosing schedule. Of 110 evaluable patients, 3 had partial responses (PRs), and SD for ≥4 and ≥6 cycles was observed in 24% and 15% of patients, respectively.12
Studies have also evaluated combination approaches with ET. Preclinical studies have shown enhanced clinical activity of CDK4/6 inhibitors in combination with letrozole, an orally administered nonsteroidal aromatase inhibitor (NSAI).13 The combination of ribociclib and letrozole has also demonstrated sustained tumor control in a PIK3CA wild-type, ER+ breast cancer model.14
Palbociclib + letrozole. Perhaps the most significant clinical validation to date of the CDK4/6 pathway as an important therapeutic target was provided by the results of the PALOMA-1/TRIO-18 trial, an open-label, randomized phase 2 trial in patients with advanced ER+/HER2− breast cancer. Patients treated with palbociclib plus letrozole in the first-line setting had a median progression-free survival (PFS) of 20.2 months versus 10.2 months with letrozole only (one-sided P = .0004).15 Additional subanalyses from PALOMA-1/TRIO-18 indicated that the PFS benefit for palbociclib plus letrozole also occurred in patients aged ≥65 years and in those who had not received systemic therapy.16 Study results also showed clinically meaningful delays in progression in the bone,14 and long-term safety analyses (≥24 months) suggested that the palbociclib plus letrozole combination is not associated with cumulative or late-onset toxicities.17 In a phase 3 confirmatory study (PALOMA-2), 666 postmenopausal women with ER+/HER2− breast cancer received either palbociclib plus letrozole or placebo plus letrozole.18 Women in the palbociclib plus letrozole arm had a significantly longer PFS than those who received placebo plus letrozole; the median PFS was 24.8 months (95% confidence interval [CI], 22.1-not estimable) versus 14.5 months (95% CI, 12.9-17.1), respectively (hazard ratio, 0.58; 95% CI, 0.46-0.72; P <.001). The confirmed objective response rate (ORR) in patients with measurable disease was 55% versus 44%, respectively.18 Although the rates of myelosuppression were higher with palbociclib plus letrozole than with letrozole monotherapy, thus far the effects have been managed successfully with dose reductions and supportive care.18
Ribociclib + letrozole. A phase 1b/2 study of ribociclib in combination with letrozole observed an acceptable safety profile and preliminary clinical activity in postmenopausal women with ER+/HER2− ABC. The RP2D of ribociclib was declared as 600 mg/day (3 weeks on/1 week off) in combination with continuous letrozole 2.5 mg/day.19 The phase 3 MONALEESA-2 study is currently ongoing, with 334 patients assigned to receive ribociclib plus letrozole (ribociclib arm) and 334 patients assigned to receive placebo plus letrozole (placebo arm).20 Overall, 34% of patients had newly diagnosed ABC or MBC. Visceral disease was present in 59% of women, whereas 22% had bone-only disease. At the data cutoff date in January 2016, treatment was still being administered to 195 patients in the ribociclib arm and to 154 patients in the placebo arm. The median duration of treatment exposure from the first to the last dose of ribociclib or placebo was 13.0 months and 12.4 months, respectively. The median relative dose intensity was 100% for letrozole in both groups, 100% for placebo, and 87.5% for ribociclib. Ribociclib was interrupted in 76.9% of patients, and letrozole was interrupted in 39.5% of patients in the ribociclib arm. The most common AE leading to a dose reduction of ribociclib was neutropenia (31.1%). Treatment discontinuation in the ribociclib arm versus the placebo arm was most frequently attributed to progressive disease (PD; 26% vs 43.7%, respectively), decision by patient or physician (6.6% vs 7.8%, respectively), or AEs (7.5% vs 2.1%, respectively).20
Fulvestrant is an intramuscularly administered, selective ER antagonist approved for the treatment of HR+ MBC in postmenopausal women whose disease has progressed following antiestrogen therapy.21 Researchers are evaluating the safety and efficacy of fulvestrant in combination with palbociclib and ribociclib in ABC.
Palbociclib + fulvestrant. A phase 3 trial (PALOMA-3) explored the combination of palbociclib plus fulvestrant in patients whose disease has progressed after prior ET.22 After a preplanned interim analysis, PALOMA-3 was stopped based on an efficacy assessment by an independent data-monitoring committee. Addition of palbociclib to fulvestrant significantly prolonged median investigator-assessed PFS compared with fulvestrant alone (9.2 vs 3.8 months; P <.001). Interestingly, the palbociclib and fulvestrant combination demonstrated a PFS benefit across all prespecified patient subgroups, including menopausal status, site of metastatic disease (visceral or nonvisceral), and sensitivity to prior hormonal therapy.22
Ribociclib + fulvestrant. The ongoing phase 3, randomized, double-blind, placebo-controlled MONALEESA-3 study is evaluating the combination of ribociclib plus fulvestrant in men and postmenopausal women with HR+/HER2− ABC who have had ≤1 prior lines of ET.23
Clinical Development of Abemaciclib for Advanced Breast Cancer
Abemaciclib is indicated in combination with fulvestrant for the treatment of women with HR+/HER2− ABC or MBC with disease progression following ET, and as monotherapy for the treatment of adult patients with HR+/HER2− ABC or MBC with disease progression following ET and prior chemotherapy in the metastatic setting.24 Abemaciclib is structurally distinct from the other dual inhibitors (palbociclib and ribociclib) and notably exhibits greater selectivity for CDK4 than for CDK6.25 Moreover, as will be shown below, abemaciclib represents the first selective inhibitor of CDK4 and CDK6, with a safety profile allowing continuous dosing to achieve sustained target inhibition.
Abemaciclib is a small molecule that inhibits CDK4 and CDK6 with low nanomolar potency.26 A mechanistic exploration of the effects of abemaciclib on breast cancer cells demonstrated that abemaciclib inhibits Rb phosphorylation and arrests cells in G1 in both in vitro and murine models bearing human ER+ breast cancer xenografts. Moreover, prolonged and continuous exposure to abemaciclib is accompanied by a substantial increase in markers of senescence and apoptosis as well as alterations in cellular metabolism in ER+ breast cancer.27 Abemaciclib is 14 times more potent against cyclin D1/CDK4 and cyclin D3/CDK6 in enzymatic assays than palbociclib and ribociclib.28 This greater selectivity and potency has become apparent in phase 1, 2, and 3 studies, as follows.
In a phase 1 clinical study, abemaciclib as a single agent had a safety profile that enabled dosing on a continuous schedule, and responses were observed in previously treated patients with HR+ MBC, non–small cell lung cancer, and melanoma.25
A phase 1 first-in-human study demonstrated the effectiveness of abemaciclib taken orally every 12 or 24 hours in patients with advanced cancer in 5 tumor types, including breast cancer.29 In the expansion cohort, patients with HR+ breast cancer were administered abemaciclib continuously at 150 mg to 200 mg orally every 12 hours on days 1 to 28 of a 28-day cycle; 9 of 36 patients with HR+ disease had confirmed PRs with an overall response rate of 25%, and 20 (56%) achieved SD.30
On the strength of these phase 1 data, 3 pivotal clinical studies (MONARCH 1, 2, and 3) were launched to evaluate abemaciclib in patients with HR+/HER2− ABC or MBC. The study results are detailed below.
MONARCH 1: A Phase 2 Study of Single-Agent Abemaciclib in Refractory HR+/HER2− Metastatic Breast Cancer
On the basis of the single-agent activity described above, the phase 2 MONARCH 1 study was launched. This was a multicenter, single-arm, open-label study designed to evaluate the single-agent activity of abemaciclib and further characterize the AE profile in patients with HR+/HER2− MBC who had previously received cytotoxic chemotherapy for the disease.28 This is a population for whom ET would no longer be considered suitable.
Patients were enrolled at 35 sites in 4 countries (Belgium, France, Spain, and the United States). The primary end point was to evaluate the ORR (complete response [CR] + PR) based on investigator-assessed tumor response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, with the primary efficacy analysis performed at 12 months after the last patient enrolled in the study. A secondary analysis using independently reviewed tumor response was also performed. Key secondary end points were safety and tolerability, overall survival (OS), duration of response (DoR) for patients with a confirmed CR or PR (confirmed by a second assessment ≥28 days from first evidence of response), PFS, disease control rate (DCR; CR + PR + SD), and clinical benefit rate (CBR; CR + PR + SD ≥6 months). Patients were followed until death or overall study completion at 18 months after the last patient was enrolled. Patients on study therapy who continued to experience clinical benefit after study completion could continue to receive study therapy until one of the criteria for discontinuation was met.28
Key inclusion criteria for the study included women ≥18 years of age with documented HR+/HER2− MBC with adequate organ function, measurable disease according to RECIST 1.1, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1. Patients must have progressed during or after prior ET and had prior treatment with at least 2 chemotherapy regimens, at least 1 but no more than 2 of which had been administered in the metastatic setting; 1 regimen must have included a taxane either in the adjuvant or metastatic disease setting.
Key exclusion criteria included prior treatment with CDK4 and CDK6 inhibitors; major surgery within 14 days; treatment with an investigational agent within 14 or 21 days of initial dose of study drug for nonmyelosuppressive or myelosuppressive agents, respectively; evidence or history of central nervous system metastases (screening for brain metastasis was required); and history of any other cancer (except nonmelanoma skin cancer or carcinoma in situ of the cervix), unless in complete remission with no therapy for ≥3 years.28
Patients received abemaciclib 200 mg administered orally on a continuous schedule every 12 hours on days 1 to 28 of a 28-day cycle, until disease progression and/or unacceptable toxicity. Up to 3 dose reductions in 50-mg decrements and dose delays for AEs were permitted. A total of 132 patients with HR+/HER2− MBC were enrolled from June 10, 2014, through April 30, 2015, and were treated with abemaciclib. All patients had measurable disease at study entry per RECIST 1.1. The majority (90.2%) had visceral disease, and 50.8% had 3 or more metastatic sites, the most common being liver and bone. In the metastatic setting, patients had received a median of 3 (range, 1-8) prior lines of systemic therapy, including a median of 1 (1-3) line of chemotherapy and 2 (1-6) lines of ET.28
As shown in Table 1, abemaciclib demonstrated single-agent activity, with 26 of 132 patients achieving a confirmed PR, for an ORR of 19.7% (95% CI, 13.3-27.5); there were no observed CRs. Of the 26 patients with PRs, 12 (46.2%) had received ≥2 prior chemotherapies in the metastatic setting, 24 (92.3%) had visceral disease, and 12 (46.2%) had 3 metastatic sites. The median time to response was 3.7 months, with a median DoR of 8.6 months (95% CI, 5.8-10.2); the probability of a response lasting ≥6 months and ≥12 months was 70.4% and 28.2%, respectively. Patient characteristics, including baseline demographics and prior therapies received, did not distinguish patients who rapidly progressed on therapy from those who did not.28 The DCR was 67.4% (63 patients [47.7%] had SD), and the CBR was 42.4% (Table 1).28
As of April 30, 2016, 97 patients had experienced disease progression, and median PFS was 6.0 months (95% CI, 4.2-7.5); median OS was 17.7 months (95% CI, 16.0-not reached), with 47 predefined events (35.6%) occurring. A final analysis at 18 months of follow-up was conducted, showing a median OS of 22.3 months (95% CI, 17.7-not reached) with 62 events (47.0%) occurring; data for the other clinical end points were consistent with the 12-month analysis.28
In MONARCH 1, the most common treatment-emergent AEs of any grade were diarrhea, fatigue, nausea, and decreased appetite (Table 2).28 Of the 132 study patients, 119 (90.2%) experienced diarrhea, typically grade 1 (n = 55; 41.7%) or grade 2 (n = 38; 28.8%) and, less frequently, grade 3 (n = 26; 19.7%). Diarrhea tended to occur early after initiation of therapy (median time to onset, 7.0 days) and was generally limited in duration (median duration of diarrhea: grade 2, 7.5 days; grade 3, 4.5 days; grade 4, no events).
The most frequently reported laboratory abnormality was increased serum creatinine, with 97.7% of patients assessed having a grade 1/2 event (Table 2). Elevation in serum creatinine occurred during the first cycle, and levels remained elevated and stable throughout the dosing period but decreased at the short-term follow-up visit within 30 days of discontinuation of study treatment.28 Decreases in neutrophil counts occurred in 114 patients (87.7%); the majority of patients (60.8%) had a grade 1 or 2 decrease, 22.3% had a grade 3 decrease, and 4.6% had a grade 4 decrease (Table 2). Neutrophil counts typically reached nadir between 2 and 4 weeks after the start of treatment and remained depressed and stable throughout the dosing period. Less than 10% of patients received hematopoietic growth factor support.28
One patient experienced febrile neutropenia, occurring during the study follow-up period (19 days after discontinuation of abemaciclib and 8 days after the patient began cytotoxic chemotherapy [fluorouracil and vinorelbine]). Forty-one patients (31.1%) experienced an infection, most of which were low grade, with no apparent relationship between the occurrence of neutropenia and infection.
Dose reductions attributed to AEs occurred in 65 patients (49.2%); 46 patients had 1 dose reduction, 18 had 2, and 1 had 3. Most dose reductions were due to diarrhea (n = 27; 20.5%) or neutropenia (n = 14; 10.6%). Fifty (76.9%) of the 65 patients who required a dose reduction had their dose reduced within the first 3 cycles. Dose omissions attributed to AEs occurred in 76 patients (57.6%) and were most often due to diarrhea (n = 32; 24.2%) or neutropenia (n = 21; 15.9%). Dose omissions were typically short, with a median relative dose intensity of 89.2%. Discontinuations attributed to AEs were infrequent (n = 10; 7.6%). The majority of patients in MONARCH 1 went on to receive further cytotoxic chemotherapy.28
The MONARCH 1 study showed that abemaciclib as a single agent had clinical activity in a poor-prognosis, heavily pretreated patient population with refractory HR+/HER2− MBC who had received prior chemotherapy in the metastatic setting, with an ORR of 19.7%. When evaluated alongside historical data, the ORR observed in MONARCH 1 was consistent with the approximate ORR range of 10% to 20% observed with approved cytotoxic chemotherapy treatments (ie, eribulin, ixabepilone, and capecitabine) in patients with MBC who had been previously treated with taxanes.31-33
MONARCH 2: A Phase 3 Study of Abemaciclib plus Fulvestrant in Advanced Breast Cancer That Progressed on Endocrine Therapy
MONARCH 2 was a randomized, double-blind, placebo-controlled phase 3 trial comparing the safety and efficacy of abemaciclib plus fulvestrant versus placebo plus fulvestrant in women with HR+/HER2− ABC (defined as inoperable, locally advanced, or MBC) who progressed while receiving ET.34 The study was conducted in 142 centers in 19 countries.
Eligible women were aged ≥18 years with any menopausal status and had an ECOG PS 0 or 1. Patients had to have measurable disease by RECIST 1.1 or nonmeasurable bone-only disease (blastic, lytic, or mixed). Patients also were required to have disease that had progressed either while receiving neoadjuvant or adjuvant ET, ≤12 months after receiving adjuvant ET, or while receiving ET for ABC. Patients must not have received >1 ET or any prior chemotherapy for ABC. Exclusion criteria included prior treatment with fulvestrant, everolimus, or CDK4/6 inhibitors; presence of visceral crisis; or evidence or history of central nervous system metastasis.34
Using an interactive, web-based randomization scheme, patients were randomly assigned 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant and were stratified according to metastatic site (visceral, bone only, or other) and ET resistance (primary or secondary). Patients received fulvestrant 500 mg by intramuscular injection on days 1 and 15 of the first cycle and on day 1 of subsequent cycles (every 28 days). Patients received abemaciclib or placebo twice daily during each 28-day cycle. At study initiation, patients in the abemaciclib arm received 200 mg twice daily. After a review of safety data and dose-reduction rates, the protocol was amended to reduce the starting dose to 150 mg for new patients, and all patients who had been receiving 200 mg underwent a mandatory dose reduction to 150 mg. Treatment continued until PD, death, or patient withdrawal.
The primary end point was investigator-assessed PFS, analyzed from the time of random assignment until objective PD or death for any reason. Key secondary end points included ORR, DoR (time from CR or PR until PD or death), CBR, and safety and tolerability.
From August 7, 2014, to December 29, 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). At baseline, 373 patients (55.8%) presented with visceral disease and 180 (26.9%) with bone-only disease. A total of 169 patients (25.3%) had primary ET resistance, and 18 (2.7%) had locally advanced disease; 140 patients (20.9%) were progesterone receptor–negative. Most patients entered the study after having progressed while receiving prior ET (8.8% of patients progressed within 12 months after completing adjuvant therapy).
As shown in Figure 1A, in the intent-to-treat (ITT) population (n = 669) at a median follow-up of 19.5 months, patients in the abemaciclib plus fulvestrant arm achieved an investigator-assessed median PFS of 16.4 months versus 9.3 months in the control arm (hazard ratio, 0.553; 95% CI, 0.449-0.681; P <.001).34 A blinded central analysis demonstrated consistent PFS results (hazard ratio, 0.460; 95% CI, 0.363-0.584; P <.001; Figure 1B).34 Moreover, the addition of abemaciclib to fulvestrant improved PFS across all patient subgroups (Figure 2).34
The ORR in the ITT population 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 <.001). This included 14 CRs (3.1%) in the abemaciclib arm compared with 1 CR (0.4%) in the control arm. Responses in both arms were durable, with 12-month DoR rates of 67.8% in the abemaciclib arm and 66.9% in the placebo arm. The median DoR had not been reached in the abemaciclib arm, with 90 responders (57.3%) continuing to receive treatment at the time of the analysis. Patients with measurable disease achieved an ORR of 48.1% (95% CI, 42.6%-53.6%) in the abemaciclib arm and 21.3% (95% CI, 15.1%-27.6%) in the control arm (P <.001). After 12 cycles of treatment, the mean change in tumor size for the abemaciclib arm was −62.5% versus −32.8% for the placebo arm. The CBR was 72.2% (95% CI, 68.0%-76.4%) in the abemaciclib arm and 56.1% (95% CI, 49.5%-62.6%) in the placebo arm (P <.001). At the time of the data cutoff, OS results were not yet mature, with 85 deaths (19.1%) in the abemaciclib arm and 48 (21.5%) in the placebo arm.
In the safety population (abemaciclib, n = 441; placebo, n = 223), the most frequent AEs of any grade were diarrhea, neutropenia, nausea, fatigue, and abdominal pain, mostly of grade 1 or 2 severity. Febrile neutropenia was reported in 6 patients in the abemaciclib arm. There was a higher incidence of infections in the abemaciclib arm (42.6%) than in the placebo arm (24.7%), regardless of relatedness; however, most of these infections were of grade 1 or 2 severity, with only 6.6% versus 3.6%, respectively, of grade ≥3 severity.
Serious adverse events (SAEs) occurred in 22.4% in the abemaciclib arm and 10.8% in the placebo arm. SAEs possibly related to the study drug were reported in 8.8% in the abemaciclib arm and 1.3% in the placebo arm, with the most frequent being diarrhea (1.4% vs 0%, respectively). Thromboembolic events were the most frequently reported SAE, occurring in 9 patients (2.0%) in the abemaciclib arm and 1 (0.4%) in the placebo arm. Of the patients in the abemaciclib arm, 4 experienced an SAE of pulmonary embolism, none of which resulted in death. Grade 1 or 2 diarrhea occurred in 322 patients (73.0%) in the abemaciclib arm and 54 (24.2%) in the control arm.34
The most common laboratory abnormalities were increased serum creatinine level, decreased white blood cell and neutrophil counts, and anemia. Approximately 25% more patients in the abemaciclib arm experienced an increase in serum creatinine level than in the placebo arm.34 There were 14 deaths (3.2%) in the abemaciclib arm (9 attributed to AEs) and 10 (4.5%) in the control arm (2 attributed to AEs) while patients were receiving therapy or within 30 days of treatment discontinuation.
The MONARCH 2 study demonstrated that abemaciclib, a potent CDK4/6 inhibitor dosed on a continuous schedule, significantly extended PFS when added to fulvestrant in women with HR+/HER2− ABC whose disease had progressed while they were receiving ET. This benefit was consistent across subgroups.
MONARCH 3: A Phase 3 Study of Abemaciclib as Initial Therapy for Advanced Breast Cancer
On the strength of the MONARCH 2 data, a study was initiated to evaluate abemaciclib as initial therapy in postmenopausal women with HR+/HER2− ABC. MONARCH 3 was a randomized, double-blind phase 3 trial of abemaciclib or placebo plus an NSAI (anastrozole or letrozole per physician’s choice) conducted at 158 sites in 22 countries.35 Eligible postmenopausal women were ≥18 years of age with HR+/HER2− locoregionally recurrent breast cancer not amenable to surgical resection or radiotherapy with curative intent, or with metastatic disease. Patients must have had measurable disease or nonmeasurable bone-only disease (blastic, lytic, or mixed) as defined by RECIST 1.1 and must not have received systemic therapy for advanced disease. ET in the neoadjuvant or adjuvant setting was permitted if the patient had had a disease-free interval >12 months from the completion of ET. Patients must have had adequate organ function and an ECOG PS ≤1. Exclusion criteria included presence of visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis; inflammatory breast cancer; evidence or history of central nervous system metastases; or prior treatment with everolimus or a CDK4/6 inhibitor.35
Patients were randomly assigned 2:1 to receive abemaciclib 150 mg twice daily or matching placebo, plus an NSAI: either anastrozole 1 mg or letrozole 2.5 mg, given orally once a day during each 28-day cycle. Patients were stratified by metastatic site (visceral, bone only, or other) and prior neoadjuvant or adjuvant ET (aromatase inhibitor, no ET, or other). Treatment continued until disease progression, unacceptable toxicity, death, or patient withdrawal for any reason.
Tumors were assessed by computed tomography or magnetic resonance imaging according to RECIST 1.1 at baseline, every second cycle during cycles 2 to 18, every third cycle thereafter, and within 14 days of clinical progression. All patients underwent bone scintigraphy at baseline and every sixth cycle starting with cycle 6. AEs were graded for severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). The primary end point was investigator-assessed PFS, evaluated from random assignment until the time of objective PD or death. Secondary end points included ORR (percentage of patients with best response of CR or PR), DoR (time from CR or PR until PD or death), CBR (percentage of patients with best response of CR, PR, or SD ≥6 months), and safety and tolerability. Other end points not included in this analysis included OS, quality of life, pharmacokinetics, and biomarker analyses.35
Between November 18, 2014, and November 11, 2015, 493 patients were randomly assigned 2:1 to receive abemaciclib plus an NSAI (n = 328) or placebo plus an NSAI (n = 165). Patient baseline characteristics were well-balanced between arms. At baseline, 261 patients (52.9%) had visceral disease, 196 (39.8%) presented with de novo MBC, and 230 (46.7%) had previously received neoadjuvant or adjuvant ET, including 135 (27.4%) who had received prior NSAI therapy.35 The majority of patients (79.1%) received letrozole as their NSAI.
At a median follow-up of 17.8 months, MONARCH 3 met its primary end point, with an observed investigator-assessed PFS hazard ratio of 0.54 (95% CI, 0.41-0.72; P = .000021; Figure 3A) in the ITT population.35 The median PFS was not reached in the abemaciclib arm versus 14.7 months in the placebo arm. Consistent PFS results (hazard ratio, 0.51; 95% CI, 0.36-0.72) were observed by independent central review (Figure 3B).35
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 = .002). In patients with measurable disease, the ORR was 59.2% (95% CI, 53.3%-65.1%) in the abemaciclib arm and 43.8% (95% CI, 35.3%-52.4%) in the placebo arm (P = .004). In the ITT population, the CBR was 78.0% (95% CI, 73.6%-82.5%) in the abemaciclib arm versus 71.5% (95% CI, 64.6%-78.4%) in the placebo arm. Median DoR was not reached in the abemaciclib arm versus 14.1 months in the placebo arm.35
A PFS benefit was demonstrated across all prespecified subgroups (Figure 4).35 Although there was no interaction seen between race and treatment effect in the MONARCH 2 study, a greater PFS hazard ratio was observed in the Asian population than in the white population in MONARCH 3.34 In exploratory subgroup analyses, the hazard ratios for the abemaciclib arm versus the placebo arm were consistent across subgroups relating to prognosis and endocrine sensitivity (eg, treatment-free interval, metastatic site). Of note, patients with a short treatment-free interval or liver metastases benefited substantially from the addition of abemaciclib.
In the safety population (n = 327, abemaciclib arm; n = 161, placebo arm), the most frequent AEs reported by the investigator in the abemaciclib arm were diarrhea, neutropenia, fatigue, and nausea, and the most frequently reported laboratory abnormalities were increased serum creatinine, decreased white blood cell and neutrophil counts, and anemia.35 SAEs were reported in 27.5% of patients in the abemaciclib arm and 14.9% in the placebo arm, with lung infection being the most frequent (2.8% vs 0%, respectively).
A total of 41.3% of patients in the abemaciclib arm experienced neutropenia. Overall, once decreased, the neutrophil count typically remained stable during abemaciclib treatment and was reversible following discontinuation.35 Laboratory-based abnormalities of increased ALT were observed in 47.6% of patients treated with abemaciclib (grade 3, 6.4%; grade 4, 0.6%) versus 25.2% of those treated with placebo (grade 3, 1.9%; no grade 4). Increased AST was observed in 36.7% of patients in the abemaciclib arm (grade 3, 3.8%; no grade 4) versus 23.2% in the placebo arm (grade 3, 0.6%; no grade 4).
Infections occurred in 39.1% of patients in the abemaciclib arm and 28.6% in the placebo arm, with most being grade 1/2 (33.3% vs 25.5%, respectively). Venous thromboembolic events occurred in 16 patients (4.9%) in the abemaciclib arm versus 1 (0.6%) in the placebo arm. The majority of patients (11 of 16) treated with abemaciclib did not discontinue treatment (4 had dose interruptions at the time of the event).
Although data were not mature at the time the MONARCH 3 results were published, OS was similar between the arms, with 32 deaths (9.8%) in the abemaciclib group versus 17 (10.3%) in the placebo group (hazard ratio, 0.97). A final OS analysis will occur after 315 events.
These interim trial results demonstrated significant improvements in PFS and ORR when combining abemaciclib with an NSAI as initial therapy for patients with HR+/HER2−ABC.
On the strength of the final MONARCH 3 data, on February 26, 2018, the FDA approved abemaciclib in combination with an aromatase inhibitor as initial endocrine-based therapy for postmenopausal women with HR+, HER2– advanced or metastatic breast cancer.
Abemaciclib has demonstrated substantial antitumor activity as initial therapy for patients with metastatic disease (MONARCH 3) and in patients who have progressed on ET (MONARCH 2). In both of these studies, the addition of abemaciclib to ET provided benefits across all subgroups. However, not all patients benefited equally from endocrine monotherapy. Exploratory subgroup analyses of the MONARCH 3 study indicate that some subpopulations (prolonged treatment-free interval, bone-only disease, no liver metastases) exhibited a comparatively better prognosis with endocrine monotherapy. Conversely, subpopulations without these characteristics exhibited early progression on endocrine monotherapy and may derive greater advantage from the addition of abemaciclib.
The MONARCH 3 data suggest the potential of using clinical factors to determine patient subgroups who may derive benefit from the addition of abemaciclib in this setting. Identifying which patients may benefit the most from the addition of abemaciclib as initial treatment and which patients may be treated with abemaciclib after progression on ET remains a topic of future research to better support more personalized treatment strategies.
Moreover, in contrast to other CDK4/6 inhibitors, the most common AE associated with abemaciclib use was low-grade diarrhea, which was readily managed in most instances with conventional antidiarrheal medications and dose adjustments. In MONARCH 1, 2, and 3, the majority of patients did not experience severe neutropenia, which differentiates abemaciclib from other CDK4/6 inhibitors and allows for dosing on a continuous schedule, unlike palbociclib and ribociclib, which require dose interruption after 21 days for recovery of neutrophil counts.7,8 Another important difference between the 3 CDK4/6 inhibitors seems to be that abemaciclib has shown a more potent ability to cross the blood–brain barrier than palbociclib and ribociclib, making it a potentially more effective agent to treat brain metastases.2
Currently, there are no biomarkers predictive of treatment benefit of CDK4/6 inhibitors. Biomarkers that track cellular proliferation, including those that evaluate Rb protein and ER activity, are logical candidates. Future studies and biomarker analyses are warranted to help identify patients most likely to benefit from this class of medicines.
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