SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 310,720 new cases of female breast cancer will be diagnosed in 2024, and about 42,250 individuals will die of the disease, largely due to metastatic recurrence. About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor (HR)-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy.
Cyclin Dependent Kinases (CDK) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. Cyclin Dependent Kinases 4 and 6 (CDK4 and CDK6) phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity and phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in hormone receptor positive breast cancer, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation and associated with increased expression of CDK4. The understanding of the role of Cyclin Dependent Kinases in the cell cycle, has paved the way for the development of CDK inhibitors.
Abemaciclib (VERZENIO®) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity that prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. 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, but potentially less toxic than earlier pan-CDK inhibitors. At higher doses, only Abemaciclib causes significant cancer cell death, compared with other CDK4/6 inhibitors, suggesting that this drug may be affecting proteins, other than CDK4/6. Additionally, preclinical studies have demonstrated that Abemaciclib may have additional therapeutic benefits for a subset of tumors that are unresponsive to treatment or have grown resistant to other CDK4/6 inhibitors.
For the patient group with advanced or metastatic HR-positive, HER2-negative breast cancer, Abemaciclib has FDA approval in combination with an Aromatase Inhibitor as initial endocrine-based therapy, in combination with Fulvestrant, with disease progression following endocrine therapy, and as monotherapy with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. Abemaciclib has activity in the Central Nervous System, and is included in the ASCO guidelines among the active agents in ER-positive/HER2-amplified breast cancer with brain metastasis. Abemaciclib has been shown to be an effective therapy after treatment with Palbociclib, another CDK4/6 inhibitor.
postMONARCH is a global, randomized, double-blind, placebo-controlled Phase III trial conducted to evaluate the efficacy and safety of Abemaciclib in combination with Fulvestrant compared to a placebo plus Fulvestrant in patients with HR-positive/HER2-negative advanced breast cancer, who experienced disease progression on a prior CDK4/6 inhibitor plus endocrine therapy. In this study, 368 patients (N=368) were randomized in a 1:1 ratio to receive either Abemaciclib plus Fulvestrant (N=182) or placebo plus Fulvestrant (N=186). The eligibility criteria included disease progression on a CDK4/6 inhibitor plus Aromatase Inhibitor as initial therapy for advanced disease, or relapse on or after CDK4/6 inhibitor plus endocrine therapy as adjuvant therapy for early breast cancer. No prior treatment for advanced disease aside from the initial regimen was allowed. The majority (99%) had progressed on a CDK4/6 inhibitor plus endocrine therapy as initial therapy for advanced disease. Prior CDK4/6 inhibitor treatments included Palbociclib (59%), Ribociclib (33%), and Abemaciclib (8%). Approximately 99% of patients had progressed on CDK4/6 inhibitor plus endocrine therapy as initial treatement for advanced breast cancer. The two treatment groups were well balanced. The median age was 59 years and stratification factors included duration of prior CDK4/6 inhibition, visceral metastases, and geographic region. Approximately 60% of patients had visceral metastasis and Imaging studies were performed every 8 weeks for the first 12 months and then every 12 weeks. The Primary endpoint was investigator-assessed Progression Free Survival (PFS). Secondary endpoints encompassed PFS assessed by Blinded Independent Central Review (BICR), Overall Survival (OS), Objective Response Rate (ORR), and Safety. The study analysis was event-driven, with the primary outcome targeting 258 events, and with an interim analysis planned at 70% of events.
At the interim analysis, with 70% of the planned events, Abemaciclib plus Fulvestrant demonstrated a statistically significant improvement in investigator-assessed PFS compared to placebo plus Fulvestrant (HR=0.66; P=0.01). Upon completion of the primary analysis with 258 events, the HR for PFS was 0.73 reflecting a 27% reduction in the risk of disease progression or death. The 6-month PFS rates were 50% for the Abemaciclib group versus 37% for the placebo group. The benefit of Abemaciclib was more pronounced with BICR-assessed PFS, showing a HR of 0.55 representing a 45% reduction in the risk of disease progression or death. In patients with measurable disease, the ORR was 17% for the Abemaciclib group compared to 7% for the placebo group (P=0.0145 by investigator assessment and P=0.0008 by BICR). OS data remained immature with a 20.9% event rate at the time of analysis.
Subgroup Analyses suggested that patients with prior CDK4/6 inhibitor use for more than 12 months had a median PFS of 7.0 months versus 5.4 months in the placebo group (HR=0.70; 95% CI = 0.52–0.94). For those with treatment durations up to 12 months, the median PFS was 5.5 months versus 3.0 months (HR=0.80; 95% CI = 0.50–1.29). The benefit was greater in patients without visceral metastases (HR=0.53; 95% CI = 0.34–0.83), though there was still a benefit observed in those with visceral metastases (HR=0.87; 95% CI = 0.64–1.17). Benefit was observed regardless of presence of ESR1 mutations or PI3K pathway alterations.
The safety profile of Abemaciclib plus Fulvestrant was consistent with known profiles. Grade 3 neutropenia occurred in 25% of patients receiving the combination therapy. Adverse events led to discontinuation in 6% of patients on the Abemaciclib arm, compared with none in the placebo group. The most common Grade 3 or higher adverse events included neutropenia, anemia, and leukopenia.
In summary, the postMONARCH trial supports the use of Abemaciclib plus Fulvestrant as an effective treatment for patients with HR-positive/HER2-negative advanced breast cancer who have progressed on prior CDK4/6 inhibitor plus endocrine therapy, offering a viable option and underscoring the value of continued CDK4/6 inhibition beyond progression in the evolving landscape of breast cancer treatment.
This combination offers significant improvement in PFS, especially in patients with longer durations of prior CDK4/6 inhibition and those without visceral metastases and may be a preferred strategy in the second-line setting for patients who have progressed on initial CDK4/6-based therapies, particularly when biomarker-specific therapies are not available.
Abemaciclib plus fulvestrant vs fulvestrant alone for HR+, HER2- advanced breast cancer following progression on a prior CDK4/6 inhibitor plus endocrine therapy: Primary outcome of the phase 3 postMONARCH trial. Kalinsky K, Bianchini G, Hamilton EP, et al. J Clin Oncol 42, 2024 (suppl 17; abstr LBA1001). DOI 10.1200/JCO.2024.42.17_suppl.LBA1001
