OPTIONS & TOOLS
- Cyclin-Dependent Kinase 4/6 Inhibitors in the Treatment of Breast Cancer: More Breakthroughs and an Embarrassment of Riches. June 03, 2017
- Blocking the Cycle: Cyclin-Dependent Kinase 4/6 Inhibitors in Metastatic, Hormone Receptor–Positive Breast Cancer. June 03, 2017
- Cell-Cycle Therapeutics Come of Age. June 03, 2017
DOI: 10.1200/JCO.2017.73.7585 Journal of Clinical Oncology - published online before print June 3, 2017
MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2− Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy
MONARCH 2 (ClinicalTrials.gov identifier: NCT02107703) compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, plus fulvestrant with fulvestrant alone in patients with advanced breast cancer (ABC).
MONARCH 2 was a global, double-blind, phase III study of women with hormone receptor-positive and human epidermal growth factor receptor 2-negative ABC who had progressed while receiving neoadjuvant or adjuvant endocrine therapy (ET), ≤ 12 months from the end of adjuvant ET, or while receiving first-line ET for metastatic disease. Patients were randomly assigned 2:1 to receive abemaciclib or placebo (150 mg twice daily) on a continuous schedule and fulvestrant (500 mg, per label). The primary end point was investigator-assessed progression-free survival (PFS), and key secondary end points included overall survival, objective response rate (ORR), duration of response, clinical benefit rate, quality of life, and safety.
Between August 2014 and December 2015, 669 patients were randomly assigned to receive abemaciclib plus fulvestrant (n = 446) or placebo plus fulvestrant (n = 223). Abemaciclib plus fulvestrant significantly extended PFS versus fulvestrant alone (median, 16.4 v 9.3 months; hazard ratio, 0.553; 95% CI, 0.449 to 0.681; P < .001). In patients with measurable disease, abemaciclib plus fulvestrant achieved an ORR of 48.1% (95% CI, 42.6% to 53.6%) compared with 21.3% (95% CI, 15.1% to 27.6%) in the control arm. The most common adverse events in the abemaciclib versus placebo arms were diarrhea (86.4% v 24.7%), neutropenia (46.0% v 4.0%), nausea (45.1% v 22.9%), and fatigue (39.9% v 26.9%).
More than 70% of patients with metastatic breast cancer (mBC) present with hormone receptor-positive (HR+) disease and are candidates for endocrine therapy (ET), with benefit diminishing as resistance develops.1-3 To improve the outcomes of patients whose disease progressed while receiving ET, it is necessary to understand and overcome mechanisms of ET resistance. Cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibition is proving to be an effective strategy.4-6
The molecular mechanisms governing ET resistance and oncogenic growth converge at the cell cycle. Preclinical data have revealed that estrogen receptor (ER)-induced proliferation requires cyclin D,7,8 which is highly expressed in > 50% of patients with breast cancer.9 Cyclin D is the catalyst for CDK 4 and 6, and overactivation of CDK 4 and 6 may attenuate senescence and promote cell cycle progression.10-14 Direct inhibition of CDK 4 and 6 disrupts this pathway and diminishes breast cancer cell growth. Preclinically, short-term inhibition of CDK 4 and 6 induces a temporary G1 arrest that rebounds upon withdrawal15; however, continuous inhibition of CDK 4 and 6 has demonstrated sustained growth arrest with initiation of apoptosis or senescence.16
Abemaciclib is an orally administered, potent, and selective small-molecule inhibitor of CDK 4 and 6 administered on a twice daily continuous schedule.4,10,15 Abemaciclib is structurally distinct from other CDK 4 and 6 inhibitors (such as ribociclib and palbociclib) and is 14 times more potent against cyclin D1/CDK 4 and cyclin D3/CDK 6 in enzymatic assays.10,15-18 Abemaciclib prevents CDK 4 and 6 phosphorylation of the retinoblastoma tumor suppressor protein, thereby inducing G1 arrest and abrogating cell growth.15 Preclinical evaluation demonstrated the antitumor activity of abemaciclib in an ER+/human epidermal growth factor receptor 2-negative (HER2−) breast cancer xenograft model.10 In the phase I setting, abemaciclib demonstrated activity in HR+ mBC as monotherapy and in combination with fulvestrant.10 These data prompted MONARCH 1, a phase II study of abemaciclib as a single agent (200 mg given twice daily on a continuous schedule) in patients with hormone refractory HR+/HER2− mBC, in which the investigator-assessed overall response rate was 19.7%, the median duration of response was 8.6 months, and the clinical benefit rate (CBR; complete response [CR] plus partial response [PR] plus stable disease ≥ 6 months) was 42.4%.4
Here, we report the results of MONARCH 2 (ClinicalTrials.gov identifier: NCT02107703), a phase III trial comparing the safety and efficacy of abemaciclib plus fulvestrant versus placebo plus fulvestrant in women with HR+/HER2− advanced breast cancer (ABC; ie, inoperable locally advanced or mBC) who progressed while receiving ET.
MONARCH 2 was a phase III, randomized, double-blind, placebo-controlled study of fulvestrant with or without abemaciclib in women with HR+/HER2− ABC whose disease had progressed while receiving prior ET. The study was conducted in 142 centers in 19 countries.
Eligible women were ≥ 18 years old with any menopausal status (pre- or perimenopausal women received a gonadotropin-releasing hormone agonist) and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Disease had to be measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.119 or nonmeasurable bone-only disease (ie, blastic, lytic, or mixed). Patients were required to have disease that progressed while receiving neoadjuvant or adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for ABC. Patients must not have received more than one ET or any prior chemotherapy for ABC. Exclusion criteria included prior treatment with fulvestrant, everolimus, or CDK 4 and 6 inhibitors; presence of visceral crisis; or evidence or history of CNS metastasis.
All patients provided informed consent before joining the study. Before the start of the trial, the protocol received ethical and institutional review board approvals. This study was performed in compliance with the Declaration of Helsinki. A steering committee oversaw the conduct of the trial. An independent data monitoring committee reviewed the safety data quarterly.
Using an interactive, web-based randomization scheme, patients were assigned to receive abemaciclib plus fulvestrant or placebo plus fulvestrant in a 2:1 ratio. Randomized assignment was stratified according to metastatic site (visceral, bone only, or other) and ET resistance (primary or secondary). Primary ET resistance, as defined by European Society for Medical Oncology guidelines, includes patients whose disease relapsed while receiving the first 2 years of neoadjuvant or adjuvant ET or progressed while receiving the first 6 months of ET for ABC.20,21 Patients who were not considered to have primary ET resistance were defined as having secondary resistance.
Patients received 500 mg fulvestrant 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 were receiving 200 mg underwent a mandatory dose reduction to 150 mg. Treatment continued until progressive disease (PD), death, or patient withdrawal.
Dose interruptions and reductions of abemaciclib or placebo were permitted according to prespecified dose-adjustment procedures for patients who exhibited treatment-related toxicities. Fulvestrant dose reductions were permitted per US label as determined by the investigator. Patients were not permitted to switch treatment groups. If either abemaciclib or placebo was discontinued, patients were permitted to continue receiving fulvestrant; if fulvestrant required discontinuation, patients were permitted to continue receiving abemaciclib or placebo.
Tumors were measured by computed tomography or magnetic resonance imaging according to RECIST version 1.1 within 28 days before random assignment (baseline) and then every 8 weeks the first year, every 12 weeks thereafter, and within 2 weeks of clinical progression. Patients underwent bone scintigraphy at baseline, and then again every sixth cycle starting with cycle 7. Hematologic and blood chemistry laboratory tests were performed centrally on days 1 and 15 of the first cycle and day 1 of all remaining cycles.
Adverse events (AEs) were recorded and graded according to the National Cancer Institute Common Terminology Criteria, version 4.0, and were evaluated at every patient visit from baseline until follow-up. All AEs were characterized by severity and whether they were related to the study drug.
The primary end point, investigator-assessed PFS, was analyzed from the time of random assignment until objective PD or death for any reason. Key secondary end points included objective response rate (ORR; ie, proportion of patients with CR or PR), duration of response (time from CR or PR until PD or death), CBR, and safety and tolerability. Other secondary end points not reported in this analysis are overall survival (OS), quality of life measures, and pharmacokinetics.
The study was designed to compare the PFS for abemaciclib plus fulvestrant to that for placebo plus fulvestrant. The study initially planned to enroll 450 patients into the intent-to-treat (ITT) population. However, after a change in the starting dose of the blinded-study drug from 200 mg to 150 mg, the sample size was increased to 630 patients to ensure at least 450 patients were enrolled at the 150-mg dose. The primary statistical analyses for investigator-assessed PFS were performed on the ITT population, which included all patients regardless of starting dose. Sensitivity analyses were planned that (1) included only patients enrolled after the change in starting dose and that (2) determined progression on the basis of a blinded, independent central review.
The primary end point, investigator-assessed PFS, was evaluated using a log-rank test stratified by metastatic site and ET resistance. The final analysis was planned at 378 PFS events, which would provide approximately 90% power assuming a hazard ratio (HR) of 0.703 at a one-sided α of 0.025, which corresponds to a 2.75-month improvement over the true median PFS for the control arm of 6.5 months.22 One efficacy interim analysis was planned to be at 70% of the final PFS events. The α control for the secondary end point of OS was maintained using a hierarchical testing approach.
The odds ratio estimator and the stratified Cochran-Mantel-Haenszel test were used to compare the rates of binary end points. Two-sided P values were used to compare efficacy between treatment groups and for interaction tests associated with the subgroup factors. An exploratory mixed-model analysis was used to compare change in tumor size over time. Unless otherwise noted, all hypothesis tests were performed at the two-sided .05 level, and all confidence intervals used a 95% confidence level. Safety was assessed in all patients who received at least one dose of study drug (ie, the safety population). SAS (version 9.2 or later; SAS Institute, Cary, NC) was used for statistical analyses.
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; Fig 1). The data cut off occurred February 14, 2017. Patients had well-balanced baseline characteristics (Table 1). 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 (20.9%) patients were progesterone receptor-negative. Most patients entered the study after progressing while receiving prior ET (8.8% of patients progressed within 12 months after completing adjuvant therapy).
At the data cut off, 170 patients (38.1%) in the abemaciclib arm versus 45 (20.2%) in the placebo arm were continuing to receive the study drug. Patients in the abemaciclib arm received a median of 15 cycles compared with nine cycles in the control arm. Patients who received 200 mg of abemaciclib before the mandatory dose-reduction amendment (n = 121; 27.4%) received a median of 34 days of drug before dose reduction or discontinuation. Dose intensities were 273.1 mg/d in the abemaciclib arm compared with 298.2 mg/d in the placebo arm.
Abemaciclib was discontinued for AEs in 70 patients (15.9%) versus seven patients (3.1%) in the placebo arm. The abemaciclib dose was reduced because of AEs in 189 patients (42.9%) compared with three (1.3%) receiving placebo. Abemaciclib was interrupted because of AEs in 229 patients (51.9%) and in 26 patients (11.7%) in the placebo arm.
In the ITT population, 379 PFS events (documented progression or death without documented progression) occurred (n = 222 [49.8%] in the abemaciclib plus fulvestrant arm and n = 157 [70.4%] in the control arm). The median length of follow-up was 19.5 months. The abemaciclib plus fulvestrant arm achieved a median PFS of 16.4 months compared with 9.3 months in the control arm (HR, 0.553; 95% CI, 0.449 to 0.681; P < .001; Fig 2A). A blinded central analysis demonstrated consistent PFS results (HR, 0.460; 95% CI, 0.363 to 0.584; P < .001; Fig 2B). A sensitivity analysis including only those patients enrolled after the change in starting dose was consistent with the ITT analysis (HR, 0.588; 95% CI, 0.458 to 0.754). The addition of abemaciclib to fulvestrant improved PFS across all patient subgroups (Fig 3).
The ORR in the ITT population was 35.2% (95% CI, 30.8% to 39.6%) in the abemaciclib arm and 16.1% (95% CI, 11.3% to 21.0%) in the control arm (P < .001; Table 2). This included 14 CRs (3.1%) in the abemaciclib arm compared with one CR (0.4%) in the control arm. Responses in both arms were durable, with 12-month duration of response rates of 67.8% in the abemaciclib arm and 66.9% in the placebo arm. The median duration of response 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% to 53.6%) in the abemaciclib arm and 21.3% (95% CI, 15.1% to 27.6%) in the control arm (P < .001).
In addition, an exploratory analysis of change in tumor size over time was conducted. After 12 cycles of treatment, the mean change in tumor size for the abemaciclib arm was −62.5%, compared with −32.8% for the placebo arm (Fig 4). The CBR was 72.2% (95% CI, 68.0% to 76.4%) in the abemaciclib arm and 56.1% (95% CI, 49.5% to 62.6%; P < .001) in the placebo arm. Best response of PD was lower in the abemaciclib arm than the placebo arm (9.0% v 20.2%). At the time of the data cut off, 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 adverse events of any grade were diarrhea, neutropenia, nausea, fatigue, and abdominal pain (Table 3). These occurred at predominately grade 1 or 2 severity. Febrile neutropenia was reported in six patients in the abemaciclib arm. Of these cases, one patient had grade 2 afebrile neutropenia miscoded as febrile neutropenia, and one patient had febrile neutropenia 53 days after discontinuing abemaciclib and had received poststudy paclitaxel before the event. The four remaining cases of febrile neutropenia were not associated with severe infection (grade ≥ 3). Granulocyte colony-stimulating factor use was low in both arms (Appendix Table A1, online only). There was a higher incidence of infections in the abemaciclib arm (42.6%) than in the placebo arm (24.7%) regardless of relatedness; however, these infections were predominately of grade 1 to 2 severity (6.6% in the abemaciclib arm v 3.6% in the placebo arm were grade ≥ 3).
Serious adverse events (SAEs) were reported in 22.4% of patients in the abemaciclib arm and 10.8% of patients in the placebo arm. SAEs possibly related to the study drug were reported in 8.8% of patients on the abemaciclib arm and 1.3% of patients on the placebo arm, with the most frequent being diarrhea (1.4% in the abemaciclib arm v 0% in the placebo arm). Thromboembolic events were the most frequently reported SAE and occurred in nine patients (2.0%) in the abemaciclib arm and one patient (0.4%) in the placebo arm. Of the patients in the abemaciclib arm, four 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. In contrast, grade 3 diarrhea was less frequent (n = 59 [13.4%] v n = 1 [0.4%] in the abemaciclib and control arms, respectively). In the abemaciclib arm, diarrhea events typically occurred in the first treatment cycle (median onset of diarrhea was 6 days). In most cases, diarrhea was effectively managed using antidiarrheal medications and with dose adjustments. In the abemaciclib arm, 14.5% of patients who experienced an initial grade 2 diarrhea event and 1.1% of patients who experienced an initial grade 3 diarrhea event also experienced a recurrence at the same or higher grade. The majority (70.1%) of patients in the abemaciclib arm with an AE of diarrhea did not require treatment modification (ie, dose interruption, reduction, or discontinuation); however, 2.9% of patients discontinued study drug because of diarrhea.
On the basis of central laboratory analysis, the most common abnormalities were increased serum creatinine level, decreased WBC and neutrophil counts, and anemia. Approximately 25% more patients in the abemaciclib arm experienced an increase in serum creatinine level than those in the placebo arm (Appendix Table A2, online only). Abemaciclib has been shown to increase serum creatinine levels due to inhibition of renal tubular secretion of creatinine without affecting glomerular function.23
There were 14 deaths (3.2%) in the abemaciclib arm (nine due to AEs) and 10 (4.5%) in the control arm (two due to AEs) while those patients were receiving therapy or within 30 days of treatment discontinuation. Of these, three deaths (0.7%) in the abemaciclib arm were determined to be related to the study treatment; two were due to sepsis in patients in whom guidance regarding granulocyte colony-stimulating factor administration and dose reduction was not followed, and one was due to viral pneumonia in a patient receiving steroids for spinal stenosis.
The MONARCH 2 study demonstrated that abemaciclib, a potent CDK 4 and 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 2 evaluated patients whose disease progressed while they were receiving neoadjuvant or adjuvant ET, ≤ 12 months after adjuvant ET, or while receiving ET for ABC. Only 8.8% of patients progressed within 12 months after completing adjuvant therapy. Patients could not have received chemotherapy or more than one line of ET for mBC, making this a more homogeneous population than in previous studies of patients whose disease progressed while they were receiving prior ET for ABC.5,22,24-26 The MONARCH 2 population is readily identifiable in the clinical setting. To the best of our knowledge, the median PFS of 16.4 months and the 7.2-month improvement over control therapy observed in patients who received abemaciclib plus fulvestrant represents the longest reported in a population with ABC whose disease had progressed while they were receiving prior ET.5,22,24-26
It is not typical for ET-based treatments to induce substantial tumor shrinkage, especially in patients whose disease has progressed while they were receiving prior ET.27 The addition of abemaciclib to fulvestrant significantly improved ORR, which included 14 patients in the abemaciclib arm experiencing a CR. Tumor size reduction was more pronounced in the abemaciclib arm, and tumor response was durable (Fig 4). To the best of our knowledge, the ORR achieved in patients who received abemaciclib plus fulvestrant is the highest observed in a phase III study of patients whose disease had progressed while they were receiving prior ET.5,22,24,26 Fewer patients in the abemaciclib arm experienced disease progression at the first imaging assessment, despite disease in most of the study population having progressed while they were still receiving ET.
The safety profile of abemaciclib with fulvestrant was broadly consistent with that reported for other CDK 4 and 6 inhibitors,5,6 with the exception of diarrhea. Most diarrhea was of low grade, occurred early in the first treatment cycle, and was managed with dose adjustment and standard antidiarrheal medication. Other frequent, nonhematological AEs in the abemaciclib arm included nausea, fatigue, and abdominal pain. Severe neutropenia has been frequently reported in phase III studies with other CDK 4 and 6 inhibitors and was a dose-limiting toxicity leading to the definition of intermittent dosing schedules.5,6,28,29 This has not been the case in MONARCH 2 and other studies of abemaciclib, in which severe neutropenia has been infrequent.4,10,30 This may be due to the greater relative potency of abemaciclib for cyclin D1/CDK4 compared with cyclin D3/CDK6 observed in cell-free enzymatic assays.16
In conclusion, MONARCH 2, an evaluation for abemaciclib given at a dosage of 150 mg twice daily on a continuous schedule in combination with fulvestrant, significantly improved PFS and ORR compared with placebo plus fulvestrant and showed a tolerable safety profile in patients with HR+/HER2− ABC whose disease had progressed while they were receiving prior ET. Abemaciclib plus fulvestrant was an effective treatment for patients with HR+/HER2− ABC whose disease progressed while they were receiving ET.
Funded by Eli Lilly.
Processed as a Rapid Communication manuscript.
Clinical trial information: NCT02107703.
See accompanying Editorial on page 2857
See accompanying Oncology Grand Rounds on page 2866
See accompanying Biology of Neoplasia on page 2949
Conception and design: George W. Sledge Jr., Masakazu Toi, Xavier Pivot, Olga Burdaeva, Eva-Maria Grischke, Martin Frenzel, Ian C. Smith, Nawel Bourayou
Provision of study materials or patients: George W. Sledge Jr., Meena Okera, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, Antonio Llombart-Cussac
Collection and assembly of data: George W. Sledge Jr., Masakazu Toi, Patrick Neven, Joohyuk Sohn, Kenichi Inoue, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Martin Frenzel, Yong Lin, Susana Barriga, Ian C. Smith, Nawel Bourayou
Data analysis and interpretation: George W. Sledge Jr., Masakazu Toi, Patrick Neven, Xavier Pivot, Norikazu Masuda, Peter A. Kaufman, Martin Frenzel, Yong Lin, Susana Barriga, Ian C. Smith, Nawel Bourayou, Antonio Llombart-Cussac
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Stock or Other Ownership: Syndax
Consulting or Advisory Role: Symphogen, Coherus Biosciences, Radius Health, Peregrine Pharmaceuticals, Taiho Pharmaceutical
Research Funding: Roche (Inst)
Travel, Accommodations, Expenses: Nektar, Radius Health, Taiho Pharmaceutical
No relationship to disclose
No relationship to disclose
Research Funding: AstraZeneca, Eli Lilly, Novartis, Genentech, Pfizer, MSD Oncology
Research Funding: Novartis (Inst), Puma Biotechnology (Inst), Eli Lilly (Inst), Chugai Pharma (Inst), Pfizer (Inst), MSD Oncology (Inst)
No relationship to disclose
No relationship to disclose
No relationship to disclose
Honoraria: Chugai Pharma, AstraZeneca
Research Funding: Chugai Pharma (Inst), AstraZeneca (Inst), Kyowa-Kirin (Inst), MSD Oncology (Inst), Novartis (Inst), Pfizer (Inst), Eli Lilly (Inst)
Consulting or Advisory Role: Galena Biopharma, Amgen
Research Funding: Eli Lilly (Inst)
No relationship to disclose
No relationship to disclose
Employment: Eli Lilly
Stock or Other Ownership: Eli Lilly
Employment: Eli Lilly
Stock or Other Ownership: Eli Lilly
Employment: Eli Lilly
Employment: Eli Lilly
Employment: Eli Lilly
Stock or Other Ownership: Eli Lilly
Honoraria: Roche, Novartis, Pfizer
Consulting or Advisory Role: Roche, AstraZeneca, Eli Lilly
Research Funding: Pfizer, Roche
Travel, Accommodations, Expenses: Roche, Celgene
We thank the MONARCH study steering committee, the patients and their caregivers for participating in this trial, and the investigators and their support staff who generously participated in this work. Writing and editorial assistance were funded by Eli Lilly. Molly Hardebeck of Eli Lilly (Indianapolis, IN) provided writing assistance, and Cynthia Bush of inVentiv Health Clinical (Indianapolis, IN) provided editorial assistance. Fulvestrant was provided by AstraZeneca for this trial.
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