MONARCH 3 gets wings: CDK4/6 inhibition continues to improve the frontline setting of HR+ / HER2- advanced breast cancer treatment

by Stephanie Hawthorne | Sep 12, 2017

Co-Authored by Liseth Parra, Ph.D. 

Results from the Phase III MONARCH 3 trial (NCT02246621) evaluating abemaciclib (Eli Lilly), a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, were presented in the Madrid auditorium on Sunday’s Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress of 2017.

The trial results were well received, as they validate the clinical activity previously seen with selective targeting of CDK4/6 pathways combined with endocrine therapy for the treatment of hormone receptor (HR)+/HER2- breast cancer patients, which constitutes approximately 80% of breast cancer patients.1 CDK4/6 pathways are key drivers of cellular growth in breast cancer oncogenesis and studies continue to show substantial gain in progressive-free survival (PFS) in selected patients treated with standard endocrine therapy in combination with CDK4/6 inhibitors compared to the standard endocrine treatment alone.2,3

In the MONARCH 3 trial, 493 post-menopausal HR+/HER2 women with metastatic or recurrent advanced breast cancer were randomized to treatment with a non-steroidal aromatase inhibitor [nsAI; either anastrozole (1 mg PO, QD) or letrozole (2.5 mg PO, QD), per physician’s choice] with or without abemaciclib (150 mg PO BID). Patients were enrolled from November 2014 to November 2015 at 155 clinical centers and in 22 countries globally.  The majority of enrolled patients had not received any adjuvant or neoadjuvant chemotherapies or endocrine therapy prior trial enrollment (62% and 64%, respectively).  Common sites of metastasis were of visceral (53%) or bone only origin (23%).

The primary endpoint of PFS was met at the time of interim analysis. Median PFS was not reached in the abemaciclib + nsAI arm compared to 14.7 months in the nsAI alone arm, representing a 45% reduction in the risk of disease progression or death (HR 0.543, p= 0.000021); blinded independent central review confirmed this level of benefit (p= 0.000102).1

The secondary endpoint of objective response rate (ORR) was also significantly improved with the addition of abemaciclib [48.2% in patients treated with abemaciclib plus nsAI versus 34.5% in patients treated with nsAI alone (p=0.0002)]. Notably, sub analysis of patients with measurable disease at baseline showed an increased in the response rate when treated with the combination regimen (60%; n=267) compared to patients treated with nsAI alone (44%; n=130).  Determining overall survival (OS) was not possible at the time of this interim analysis as the data had not yet reached maturity.  However, this trial (like many other trials conducted in the first-line HR+/HER2- setting) is unlikely to show an OS benefit due to the confounding nature of the  multiple lines of therapy these patients will eventually receive over the course of their disease and study designs that are underpowered for OS.    The discussant of this abstract, Dr. Nicholas Turner from the UK’s Institute of Cancer Research (ICR), suggested that meta-analysis of this and other recently completed studies in this setting may be able to provide insight on the ultimate impact on OS by adding CDK4/6 inhibitors to endocrine therapy.

Preplanned subgroup analyses sought to explore the benefit among various subgroup of patients, particularly to distinguish clinical profiles of patients with good or poor prognosis to determine which patient types might be most appropriate for treatment with abemaciclib. In the exploratory PFS phase analysis of this trial, There was a meaningful difference in PFS in both patients with bone-only disease (n=106; HR 0.58) and patients without bone-only disease (n=384; HR 0.51), although in bone-only patients the benefit favoring the abemaciclib arm emerged later than in the patients without bone-only disease and the significance of this comparison may be limited by the small sample size.   Additionally, patients both with and without liver metastases derived a benefit from the addition of abemaciclib (HR 0.47 and HR 0.57, respectively). 

These findings suggest that patients with more advanced disease (e.g., presenting liver metastasis) are likely to gain more benefit from treatment regimens that consist of endocrine therapy paired with CDK4/6 inhibition, than patients with less advanced disease.  Another factor which demonstrated a differential benefit between the two arms is treatment-free interval (TFI).  Patients who had received prior adjuvant endocrine therapy were evaluated in two groups: those with a TFI <36 months (i.e., those patients whose disease recurred while on or within 3 years of completing adjuvant endocrine therapy) and those with a TTI ≥36 months (i.e., those with a very durable response to adjuvant endocrine therapy).  Analysis of PFS outcomes in MONARCH-3 found that patients who had a short (<36 months) TFI derived a significant PFS benefit with the addition of abemaciclib (HR 0.48), whereas patients with a long TFI derived very little PFS benefit with the combination regimen (HR 0.83). 

The safety profile of abemaciclib in this trial was similar to what has been observed in the Phase III MONARCH 2 trial (NCT02107703) that evaluated abemaciclib in combination with Faslodex® (fulvestrant, AstraZeneca) as either first or second line treatment options for women with advanced HR+/HER2- breast cancer. 4 The most common Grade 3/4 adverse events (AEs) observed with abemaciclib therapy in the MONARCH 3 trial were neutropenia (22%) and diarrhea (10%). Notably, these AEs were not observed with endocrine monotherapy (0.6% and 1.2%, respectively). Due to these AEs, 20% of patients treated with abemaciclib discontinued treatment compared to only 2.5% of patients in the control arm, and dose reductions were also more common in the abemaciclib arm (43% versus 6%).  However, the authors emphasized that diarrhea occurred early and was successfully managed with loperamide as in previous studies.

The NCCN v2.2017 guidelines for invasive breast cancer state that CDK4/6 inhibitors in combination with letrozole may be considered as treatment option for post-menopausal breast cancer patients with HR+/HER2- disease.5   ESMO’s guidelines for the treatment of HR+ breast cancer disease currently state that the most important advance in the management of advanced breast cancer over the last two years has undoubtedly been the introduction of CDK4/6 inhibitors, in combination with an endocrine agent and is therefore one of the preferred treatment options in this setting, where available, although OS results are still awaited.6    The use of CDK4/6 inhibitors in combination of endocrine therapy has already become the new standard of care for women with HR+ metastatic disease, a trend that has been growing since the February 2015 approval of Ibrance® (palbociclib, Pfizer) and the March 2017 FDA approval of Kisqali® (ribociclib, Novartis) – both are approved for use in combination with an aromatase inhibitor in first-line metastatic patients, and Ibrance has an additional FDA indication for use in combination with Faslodex® (fulvestrant, AstraZeneca) in endocrine therapy-pretreated breast cancer; in Europe, Ibrance gained the same label in November 2016 but Kisqali is not yet approved for use (although the CHMP has issued a positive opinion, so EMA  approval is expected shortly). 

If successful, abemaciclib will be the third marketed CDK4/6 agent to enter the HR+ / HER2- breast cancer space, and as such it will face significant competition from the already well-adopted Ibrance. A comparison of efficacy across the multiple pivotal trials that have been completed suggests that a similar magnitude of benefit is offered by each of these three CDK4/6 inhibitors in comparison with nsAI alone (HR 0.58 for Ibrance in PALOMA-2 trial2; HR 0.58 for Kisqali in MONALEESA-2 trial3; HR 0.54 for abemaciclib in MONARCH 31).  It is important to note, however, that there are different toxicity profiles among the different CDK4/6 inhibitors available; in particular Ibrance and Kisqali have higher rates of neutropenia than abemaciclib whereas abemaciclib has higher rates of diarrhea.  Their unique profiles seem to be dependent on the biochemical affinity they each have for cyclin dependent kinases. With these toxicity profiles, identifying the patient subgroups that clearly benefit from endocrine therapy alone versus endocrine therapy plus CDK4/6 inhibitor is critical in order to identify patients who would benefit the most from these combination regimens. 

Of note, there is no data available as yet that supports the use of additional lines of therapies with CDK4/6 inhibitors if there is disease progression while on a CDK4/6 inhibition plus letrozole, indicating that data is still needed to decide whether these different inhibitors could show promising activity if used sequentially after disease progression on CDK4/6 inhibition.  Therefore, increased understanding of the biology of cyclin kinase pathways and the underlying mechanisms of resistance to cyclin dependent inhibition developed by tumor cells is crucial in improving the future management of HR+/HER2- metastatic breast cancer.  Future areas of investigation include identification of CDK4/6 inhibition resistant mechanisms and exploration of immune therapy treatments in combination with CDK4/6 inhibition; for the latter, preclinical studies have shown that inhibition of cyclin dependent kinases can enhance the immune system.  Together, these agents could synergistically alter the current clinical outcome of women suffering from HR+/HER2-  breast cancer progression.

For patients with HR+/HER2- metastatic breast cancer, delaying the time to cytotoxic chemotherapy is a highly desirable goal of treatment.  For this reason, the introduction of targeted agents that can extend the time to progression in patients receiving endocrine therapy is a fundamental advance in therapy.  The MONARCH 3 results offer a new option for these patients to achieve such a goal.  Although this is a setting which has met with other recent advances, it’s still relevant to provide unique treatment options for patients who might not respond to or be able to receive one of the other approved agents.  Abemaciclib will enter a crowded and highly competitive market, but nuanced differences in mechanism of action, safety profile, and even dosing differences could help abemaciclib spread its wings and find its niche in the treatment paradigm, either in first-line or in later lines (it has already filed with the FDA for approval in relapsed / refractory disease based on results of the MONARCH-1 and -2 trials). 



  1. Di Leo A, et al. MONARCH 3: Abemaciclib as initial therapy for patients with HR+/HER2- advanced breast cancer. Ann Oncol: abstract 236O-PR, 2017.
  2. Finn RS, et al. Palbociclib and letrozole in advanced breast cancer. N Engl J Med, 375 (20): 1925- 1936, 2016.
  3. Hortobagyi et al.  Updated results from MONALEESA-2, a phase 3 trial of first-line ribociclib + letrozole in honormone-receptor-positive (HR+), HER2-negative (HER2-), advanced breast cancer (ABC). J Clin Oncol 25, 2017 (suppl; abstr 1038).
  4. Sledge GW, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in patients with HR+/ HER2- advanced breast cancer who progressed on endocrine therapy. J Clin Oncol. 35: Abstract 1000, 2017.
  5. The NCCN Clinical Practice Guidelines in Oncology, Breast Cancer, National Comprehensive Cancer Network, version 2.2017.
  6. Cardoso F, et al. 3rd ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3), 2006.

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