Kisqali Approval: Weighing the Risks vs. Benefits for Early-Stage Breast Cancer

In a long awaited update, The Food and Drug Administration (FDA) has just approved the drug Kisqali (ribociclib) in combination with an aromatase inhibitor (AI) as treatment for people with HR+/HER2- stage II and III early breast cancer (EBC) at high risk of recurrence.

The approval follows positive results from the Phase III NATALEE trial, a randomized trial that included more than 5,000 patients across 20 countries recruited between January 2019 and April 2021.

The NATALEE (New Adjuvant Trials with LEE011) trial is a pivotal study evaluating the use of Kisqali, a CDK4/6 inhibitor, combined with standard endocrine therapy in patients with early-stage hormone receptor-positive (HR+), HER2-negative breast cancer. 

Unlike previous trials that focused on metastatic disease, NATALEE included a broader population, such as node-negative patients, expanding its clinical relevance. The trial’s key objective was to assess whether this combination could reduce the risk of cancer recurrence in high-risk, early-stage breast cancer patients. 

It was discovered that Kisqali “significantly reduced the risk of recurrence by 25 percent vs. endocrine therapy (ET) alone,” and “consistent benefit and a well-tolerated safety profile [were] seen across all subgroups in pivotal Phase III NATALEE trial, including patients with node-negative disease,” according to a September 2024 news release on the approval.

Absolute benefit is still something of a hot topic for debate among the oncologists interviewed by SurvivorNet Connect.

Study Design and Population

NATALEE involved a large, diverse cohort of over 5,000 participants with stage II and III HR+/HER2- breast cancer. Patients received ribociclib (400 mg) alongside endocrine therapy for three years, which is a longer duration of CDK4/6 inhibitor use compared to the standard two-year regimen seen in trials like MonarchE. 

In an interview with SurvivorNet Connect, Dr. Heather McArthur, the clinical director of breast cancer at UT Southwestern in Dallas, Texas, says: “The NATALEE trial enrolled patients with high risk hormone receptor positive early stage breast cancer and randomized them to receive standard endocrine therapy with or without the CDK 4/6 inhibitor ribociclib, which was given for a course of three years.”

The inclusion of patients with node-negative disease, traditionally considered to have a lower risk of recurrence, adds to the significance of this study, broadening its potential impact on clinical practice. 

“NATALEE also enrolled patients with node-negative disease. There was not a statistically significant benefit for those patients with node-negative disease, but there was certainly a trend that there was a consistent benefit in that population,” Dr. McArthur adds.

Key Findings 

The trial achieved its primary endpoint by demonstrating a significant reduction in the risk of invasive disease recurrence. Ribociclib, when added to endocrine therapy, lowered the relative risk of recurrence by 25% compared to endocrine therapy alone. 

This result is particularly meaningful for patients who are at high risk of recurrence, offering a new therapeutic option in a setting where only endocrine therapy was previously considered. 

Notably, the trial confirmed that ribociclib is beneficial not only for high-risk patients but also for those who traditionally have been considered lower-risk, like those with node-negative disease. 

Safety and Tolerability 

NATALEE’s dosing strategy for ribociclib (400 mg) differs from that of metastatic settings, where higher doses (600 mg) are typically used. This adjustment aimed to optimize the balance between efficacy and tolerability, minimizing adverse effects like neutropenia, which is a common challenge with CDK4/6 inhibitors. 

“And of course when you add additional medications into the fold, because again these patients are already receiving five to 10 years of endocrine therapy, it adds to the toxicity. So these are becoming more nuanced conversations in the clinic in terms of risk-benefit calculations and of course safety and toxicity profiles factor into those conversations,” Dr. MacArthur says SurvivorNet. 

Early data suggest that this lower dose was well-tolerated, allowing more patients to complete the full three-year treatment course, which may enhance long-term outcomes. 

Clinical Implications 

The NATALEE trial’s results have the potential to reshape the management of early-stage breast cancer. CDK4/6 inhibitors like ribociclib, which have already proven their efficacy in metastatic disease, may soon become a standard part of treatment for a wider range of patients with early-stage disease. 

This is a significant departure from current clinical practice, where only endocrine therapy is recommended for many patients. If adopted into clinical guidelines, ribociclib could help prevent recurrence in patients at both high and moderate risk of recurrence, marking a shift toward more aggressive adjuvant therapy. 

In addition to its potential for recurrence reduction, NATALEE introduces the possibility of longer CDK4/6 inhibitor treatment in early-stage breast cancer, which may further improve long-term survival. However, the longer duration of treatment also raises questions about patient adherence and long-term side effects, which will need to be carefully monitored in clinical practice. 

Comparison with Current Practices 

Current standards of care for early-stage HR+/HER2- breast cancer primarily involve endocrine therapy, with chemotherapy reserved for higher-risk cases. 

The trial’s results also differentiate ribociclib from other CDK4/6 inhibitors, such as abemaciclib, which was tested in the MonarchE trial. Ribociclib’s longer duration of therapy (three years) and lower dose make it a potentially more tolerable option for long-term use, though head-to-head comparisons with other CDK4/6 inhibitors will be needed to determine the best therapeutic approach for individual patients. 

Future Perspectives 

The NATALEE trial represents a significant step forward in the treatment of early-stage breast cancer. As ribociclib and other CDK4/6 inhibitors are integrated into clinical practice, future studies will focus on optimizing treatment duration, managing long-term side effects, and identifying which patients benefit most from these therapies. 

Additionally, the use of CDK4/6 inhibitors in combination with other targeted therapies, such as immunotherapy, may be explored as researchers continue to refine personalized treatment strategies for breast cancer patients. 

Moreover, follow-up analyses from NATALEE will be crucial to determine whether the observed benefits in recurrence translate into improvements in overall survival. Understanding the long-term impact of ribociclib on patient outcomes will help guide treatment decisions and inform future updates to clinical guidelines.