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What to Know About the New Approval for Abemaciclib in Patients With Early Breast Cancer

Laura M. Spring, MD

Instructor in Medicine
Harvard Medical School
Attending Physician, Medical Oncology (Breast Program)
Massachusetts General Hospital
Boston, Massachusetts


Laura M. Spring, MD, has disclosed that she has received funds for research support from Merck and Tesaro and consulting fees from Avrobio and Novartis.


View ClinicalThoughts from this Author

Released: November 29, 2021

Abemaciclib in HR-Positive, HER2-Negative Early Breast Cancer
The CDK4/6 inhibitor abemaciclib was approved by the FDA in October 2021 as adjuvant treatment in combination with endocrine therapy (ET) for patients with hormone receptor (HR)‑positive, HER2‑negative, node‑positive early breast cancer who are at high risk of recurrence with a Ki-67 score ≥20%. This approval was based on data from the phase III monarchE trial, which was a randomized, open-label, 2-cohort trial in which patients with HR-positive, HER2-negative, node-positive, resected early breast cancer who were considered at high risk of recurrence received 2 years of standard ET with or without abemaciclib. The first Ki-67 cohort included high-risk patients, defined as having ≥4 positive lymph nodes or 1‑3 positive lymph nodes along with an additional high-risk feature (grade 3 histology and/or tumor size >5 cm). The second cohort included patients with less significant clinicopathologic characteristics (1-3 positive nodes, no grade 3, and tumor size <5 cm) but with a documented Ki-67 score ≥20%.

Ki-67 is a marker of cellular proliferation that is widely viewed as a prognostic biomarker, with high levels associated with poorer outcomes. Although cohort 1 did not require Ki-67 testing, the abemaciclib approval was based on a secondary predefined analysis of the subset of cohort 1 patients who did have Ki-67 testing and a score ≥20%, which has caused some confusion. MonarchE explored whether Ki-67 was predictive of abemaciclib benefit or only a prognostic biomarker. Among trial participants with Ki-67 testing performed, results suggest that Ki-67 was not actually predictive; the addition of abemaciclib to ET significantly improved invasive disease-free survival (iDFS) regardless of Ki-67 results.

However, we know from this study and others that patients with high Ki-67 are at greater risk of recurrence, so the initial approval has focused on those very high-risk patients who have both high-risk clinicopathologic features (as outlined above) and a Ki-67 score ≥20%. Only a relatively small subset of our patients meet those criteria. Because the monarchE trial did find an iDFS benefit with the addition of abemaciclib in the overall study population, it is possible that we may see the label expanded after longer follow-up. In fact, in a rapid recommendation update on November 15, 2021, the American Society of Clinical Oncology guideline panel for “Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer” recommended that abemaciclib plus ET may be considered for the broader intent-to-treat population of patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence (defined as having ≥4 positive axillary lymph nodes or 1-3 positive axillary lymph nodes and either histologic grade 3 disease, tumor size >5 cm, or Ki-67 index ≥20%). [link: https://www.asco.org/practice-patients/guidelines/breast-cancer#/11081]

Ki-67 Testing in the Clinic
Practically, the FDA approval means that high-risk patients must have Ki-67 results to be eligible to receive abemaciclib. Ki-67 testing is routinely done at some, but not all, institutions. Oncologists should have a conversation with their pathologists about how to implement routine Ki-67 testing for at least high‑risk patients for whom they might consider abemaciclib. One challenge is that Ki-67 testing can be difficult and hard to interpret because it is somewhat subjective. Also, many centers may not be using the FDA-approved companion diagnostic Ki-67 test. Based on the recent American Society of Clinical Oncology guideline update, Ki-67 testing in this setting may become less relevant.

Safety and Tolerability of Abemaciclib for Early-Stage Disease
The main adverse event associated with abemaciclib is a fairly high incidence of diarrhea, although most events are low grade. Patients who received abemaciclib also showed increased rates of some cytopenias and fatigue compared with those who had ET alone. A patient’s willingness to tolerate those adverse events can vary based on the setting, particularly an adjuvant vs metastatic setting. As with most agents, optimal management of adverse events is crucial to allow patients to maintain a high quality of life while on therapy. Aggressive early management of diarrhea is important for patients receiving abemaciclib, as is dose reduction, when needed.

Treatment After Disease Recurrence
Abemaciclib is the first approval in the adjuvant setting in several years, and it represents a great advance for our patients with HR‑positive, HER2‑negative early breast cancer. We always need to think about what comes next, though. The most recent monarchE report had a median follow-up of 27 months, but a longer follow-up is needed to clarify whether abemaciclib is actually preventing recurrence or simply masking it. Either way, we have to consider how we will treat patients with disease recurrence on or following abemaciclib.

Similar to how I would think about recurrence on a different agent, such as an aromatase inhibitor, it is important to consider when recurrence happened: during abemaciclib, within 1 year of treatment, or >1 year after abemaciclib treatment. If disease recurrence occurs during or shortly after the use of abemaciclib, I would likely consider either changing the estrogen therapy backbone and/or switching to a non‑CDK4/6 option.

We are awaiting more data to understand if there can be continued benefit with CDK4/6 blockade after progression or recurrence on a CDK4/6 inhibitor. We have some retrospective data, and there are some currently enrolling and recently completed trials that look at the use of CDK4/6 inhibitors with a new ET after progression on a prior CDK4/6 inhibitor in the metastatic setting. The results of those studies will help guide what we do in the future.

Additional considerations for selecting next therapy include genomic testing results. For patients with a PIK3CA mutation, alpelisib with fulvestrant at the time of recurrence would be reasonable. The mTOR inhibitor everolimus combined with fulvestrant might be another possible targeted approach, especially for patients without a PIK3CA mutation. In the long run, we will need clinical trials in this setting to fill in some of these data gaps.

Other Considerations for Abemaciclib Use
These questions are especially important to consider in the context of studies of other CDK4/6 inhibitors. The other major CDK4/6 study in the adjuvant setting is the phase III PALLAS trial of palbociclib added to ET. This trial did not meet its primary endpoint of improved iDFS, leading to much discussion about whether the lack of benefit with palbociclib is due to the study design, treatment adherence, or a reflection of an actual difference with the CDK4/6 inhibitor used. 

Abemaciclib has a broader profile than palbociclib or ribociclib. For example, it also appears to inhibit CDK2 and CDK1. It is also the only CDK4/6 inhibitor currently approved in breast cancer as monotherapy, at least in the advanced setting, which may reflect its broader activity. I will be interested to see the results of the NATALEE trial of adjuvant ribociclib. Of interest, NATALEE is evaluating 3 years of treatment, but monarchE and PALLAS both used 2 years. Duration of therapy and the appropriate timing of therapy in the adjuvant setting remain open questions in the field. For monarchE, patients were allowed to have already received up to 12 weeks of ET after their last non-ET before randomization and had to enroll within 16 months of surgery. The abemaciclib label does not specify timing, but how closely we need to adhere to the study criteria to see the same benefit is not clear.

It is always a challenge with a new approval to decide how to apply it to patients who are already in the midst of therapy. Deciding whether to use abemaciclib needs to be a patient‑centered discussion, especially for a patient who is further along in their treatment course, because the idea of adding another new therapy may not be appealing. As healthcare professionals, we need to be very honest with our patients about what we don’t know, but abemaciclib may be appealing to explore for our highest‑risk patients.

Your Thoughts?
Now that we have this new FDA approval for our patients in the early disease setting, I have started discussing abemaciclib with my patients with high Ki-67 who would have fit the criteria for the monarchE study, with the goal of offering the therapy when appropriate.

Are you using abemaciclib with ET as adjuvant treatment for your patients with HR-positive, HER2-negative disease? How will you decide whether to use abemaciclib in your eligible patients? I encourage you to answer the polling question and join the discussion in the comments box below.

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