Abemaciclib Reduces the Risk of Recurrence in Early Breast Cancer

In treating early breast cancer at high risk of recurrence, abemaciclib (Verzenio in the USA, Yulareb in Turkey) has raised many questions alongside the excitement it has generated.

In the treatment of hormone-positive breast cancer, one of the new-generation drugs introduced with its approval is the cell-cycle CDK4 / 6 inhibitor abemaciclib, when added to standard endocrine therapy in high-risk hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative breast cancer, reduced the early risk of recurrence significantly, as shown at the ESMO Virtual Congress 2020 and simultaneously published in the Journal of Clinical Oncology in a phase-3 clinical trial.

MonarchE enrolled 5600 patients and compared 2-year results of abemaciclib plus endocrine therapy versus endocrine therapy alone. Using abemaciclib was found to reduce the risk of disease-free survival by 25% (p = 0.0096; HR, 0.75;95% CI, 0.60 - 0.93).

At year 2, disease-free survival was 92.2% in the abemaciclib arm versus 88.7% in the endocrine-therapy-alone group.

The First Advance in 20 Years

The trial's lead investigator, Dr. Stephen Johnston, said, "This is the first advance in breast cancer adjuvant (postoperative protective) treatment in more than 20 years.".

We know that the highest risk of breast cancer recurrence is in the first 2 years after treatment. The main question is whether treatment is needed for 2 years or longer. Another clinical trial is examining recurrence rates in year 3 with another drug, and we will have to wait longer to see its results.

Could this approach become the new treatment standard for this group? Could HR+, HER2-negative, early-stage, high-risk patients receive this combination (a CDK4 / 6 inhibitor plus endocrine therapy) without chemotherapy?

Study Details

Abemaciclib first received approval in 2017 after endocrine therapy or chemotherapy when the cancer had progressed in HR+, HER2-negative advanced breast cancer, as a single agent or with fulvestrant, based on the MONARCH-2 trial data, from the FDA (see the related FDA approval). Subsequently, in 2018, it received first-line approval with an aromatase inhibitor based on the MONARCH-3 trial.

MonarchE examined the effect of abemaciclib as first-line adjuvant therapy in HR-positive, HER2-negative early breast cancer.

Who Was Considered at High Risk of Recurrence?

• Positive lymph nodes in the surgical pathology,
• a primary tumor size ≥5 cm,
• a histological grade 3 tumor (geade 3)
• and / or a Ki67 index ≥% 20 were considered high-risk features.

The choice of endocrine drug was left to the physician, and endocrine therapy continued for 5-10 years as clinically indicated.

MonarchE included 5637 patients: 2808 in the abemaciclib plus endocrine therapy group and 2829 in the endocrine-therapy-alone group.

The groups were well balanced in baseline characteristics. The great majority (approximately 85%) were under 65, and 56.5% were postmenopausal.

In addition, %37 had previously received neoadjuvant chemotherapy, and approximately 58% had received adjuvant chemotherapy.

Distant metastasis-free survival risk also decreased by 28% with abemaciclib plus endocrine therapy compared with endocrine therapy alone (93.6% versus 90.3%, respectively, at year 2).

Distant organ metastases developed in only 92 patients in the combination arm versus 142 receiving endocrine therapy alone, a particularly notable difference.

Bone recurrence occurred in 32 patients receiving abemaciclib and 81 receiving endocrine therapy alone; liver recurrence occurred in 29 and 42 patients, respectively.

Results showed that the most common adverse effects in the abemaciclib arm were diarrhea, (82%), neutropenia (45%), fatigue (38%); in contrast, in the control group, arthralgia (31%), hot flashes (21%) and fatigue (15%) were the most common adverse effects.

A venous thromboembolic event (vascular blockage) was recorded in 2.3% of abemaciclib patients versus 0.5% receiving endocrine therapy alone. Interstitial lung disease rates were 2.7% and 1.2%, respectively.

Despite a trial design allowing dose reduction from 150 mg twice daily to 100 mg if needed, 463 (16.6%) patients stopped abemaciclib because of adverse effects. Of these, 306 continued endocrine therapy. This will be an important issue to consider in clinical practice.

However, diarrhea frequency and severity decreased substantially over time, and only 4.8% of the abemaciclib group stopped treatment because of this adverse effect.

Questions That Remain...

Some clinical trials with apparently positive results raise as many questions as they answer, and monarchE is no exception.

For example, the negative findings of the very similar PALLAS trial, also presented at ESMO, remain a puzzle. It assessed adding another CDK4 / 6 inhibitor, palbociclib, to adjuvant endocrine therapy in HR+, HER2-negative early breast cancer.

The main issue here is the very short follow-up of 2 years.

Second, will improvements in disease-free survival lead to what really matters: better overall survival? Again, time will tell, but oncologists, patients, regulatory and reimbursement bodies care deeply about the answer.

What About Late Recurrence?

Also, what will be the optimal duration if a CDK4 / 6 inhibitor is used as adjuvant therapy?

Another issue is that, for CDK4 / 6 inhibitors, the patients who benefit most cannot yet be predicted because biomarkers have not yet been identified. These drugs are very expensive. A 2-year adjuvant course is beyond the reach of most patients worldwide who might be candidates for CDK4 / 6 inhibitor treatment.

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