Yale’s Chief of Breast Oncology Shares Risk Stratification & Recommendations for CDK4/6 Inhibitors

Written by Kaique Filardi

At this year’s European Society of Medical Oncology (ESMO) conference, new data from the NATALEE study provided exciting new insights into the best practices for treating breast cancer with CDK4/6 inhibitors.

“In this year’s European Society of Medical Oncology or ESMO meeting, additional follow-up data on the NATALEE study were presented, which showed that with patients with high risk breast cancer, both node (-) as well as node (+) stage II or stage III breast cancer, the addition of adjuvant ribociclib [brand name: Kisqali] for three years concurrent to endocrine therapy actually led to a significant reduction in disease recurrence,” Dr. Maryam Lustberg, chief of Breast Medical Oncology at Yale Cancer Center, tells SurvivorNet Connect

The Importance for High-Risk Patients

This additional data on the CDK4/6 inhibitor not only added one more drug to offer to patients, but also increased the possibilities of mitigating different adverse effects and expanded the CDK4/6 inhibitor indication. 

“The benefit to patients is that it expands eligibility criteria from the prior indication with [Verzenio], which was a much higher risk population. With this new adjuvant [Kisqali] indication, more patients are actually eligible for receiving adjuvant CDK4/6 inhibitors,” Dr. Lustberg adds.

“The reason that’s important is that we know that patients with hormone receptor-positive breast cancer are at risk of both early and late recurrences of the disease. And this is an important targeted therapy option to try to address that.”

Choosing Between the CDK4/6 Inhibitors 

Kisqali (ribociclib) has been approved for a broader indication following the 2024 ESMO Congress. It is now indicated for patients with HR+/HER2- stage II and III early breast cancer who are at high risk of recurrence, including those with node-negative disease.

The approval was based on data from the NATALEE trial, which demonstrated a 28.5% reduction in the risk of recurrence when Kisqali was added to endocrine therapy compared to endocrine therapy alone. This benefit was consistent across all patient subgroups, highlighting its potential to significantly improve outcomes for a diverse group of patients facing a high risk of recurrence.

“So, there are patients who qualify for Kisqali who do not meet indications for Verzenio particularly that node negative high-risk population. So for that patient population, the only choice would be Kisqali if we follow the label,” Dr. Lustberg explains.

For patients with node-positive, high-risk breast cancer, both Kisqali and Verzenio are viable options, but they cater to slightly different patient populations based on the clinical trials they were studied in.

Verzenio is indicated specifically for patients with node-positive disease and high-risk features, such as having four or more positive lymph nodes or 1-3 nodes with additional high-risk factors like a large tumor size or high tumor grade. The monarchE trial demonstrated a 30% reduction in the risk of recurrence for this high-risk group.

Verzenio is usually given for two years and is administered continuously, twice daily​

“For patients who are node positive and high risk, they do have a choice between the two agents. And I think the way I would utilize that in my practice is to make patients know that they do have choices and review the toxicity profile between the two agents and we can decide things together.”

Addressing Potentially Adverse Effects

The choice of CDK 4/6 inhibitors also should take into account the potential adverse effects of each available drug. All three available options — Ibrance (palbociclib), Kisqali (ribociclib), and Verzenio (abemaciclib) — are considered viable, with the selection guided by their efficacy and distinct side effect profiles. Ibrance and Kisqali are more commonly associated with neutropenia, whereas Verzenio is linked to a higher incidence of diarrhea.

“Verzenio is associated with a higher chance of diarrhea but also tends to have less cytopenias or low count issues associated with it. It tends to have less risk of cardiac EKG changes and less risk of liver function test changes,” Dr. Lustberg explains. 

Additionally, Kisqali has a greater likelihood of causing liver function test abnormalities and QTc prolongation, making it less suitable for patients with existing risk factors, such as those taking QTc-prolonging medications.

“Kisqali does not have nearly as much diarrhea,” Dr. Lustberg adds. “But we do need to do careful EKG monitoring early on to make sure that this interval in the cardiac rhythm, called the QTc interval, is not getting prolonged and we do careful monitoring of liver function tests, and there is a higher chance of white count or platelets dropping, which we can always adjust for and it’s not a problem.”