Looking Ahead After Kisqali’s FDA Approval for Adjuvant Treatment of Early Breast Cancer

Kisqali (ribociclib), a CDK4/6 inhibitor, has made significant strides in the treatment of HR-positive, HER2-negative early breast cancer, although several follow-up studies are being conducted to provide more information about its additional benefits and dosing strategies, experts said.

A session at the San Antonio Breast Cancer Symposium focused on adjuvant Kisqali, which was recently approved by the Food and Drug Administration (FDA) in September 2024. Experts discussed the studies gathering more information on the therapy and where more focus is needed to best treatment patients with this disease.

NATALEE Trial Design

A four-year landmark analysis of data from the NATALEE trial was presented at the 2024 European Society for Medical Oncology Congress in September 2024. The trial included 5,101 patients who were randomly assigned to receive Kisqali at 400 milligrams daily as part of a three-weeks-on, one-week-off schedule for three years, plus nonsteroidal aromatase inhibitor (NSAI; 2,549 patients) or NSAI alone (2,552 patients). Treatment with NSAI consisted of Femara (letrozole) or Arimidex (anastrozole) for at least five years plus Zoladex (goserelin) for male patients and female patients who are premenopausal.

Adult patients with HR-positive, HER2-negative early breast cancer were eligible for enrollment on the trial. Those with prior endocrine therapy at 12 months or earlier before randomization were able to enroll. Investigators stratified patients based on anatomical stage, menopausal status, receipt of previous chemotherapy and geographic location.

Regarding patient demographics, Dr. Jennifer Gao, Associate Director for Education at the FDA Oncology Center of Excellence, discussed that patient demographics at the start of the study were mostly balanced. When comparing both treatment groups, there were 19 men enrolled in the trial, in addition to women who were either pre- or post-menopausal. There were also more patients that had stage 3 disease compared with stage 2 disease. Most patients had node-positive disease and received prior treatment for breast cancer.

“Of note, the NATALEE trial did enroll few racial and ethnic minority patients, and this was a post-marketing commitment,” Gao said.

Findings From the NATALEE Trial

In one of the analyses conducted in the NATALEE trial, the invasive disease-free survival rate was statistically significant, although 20% of patients completed three years of adjuvant Kisqali, which resulted in a high level of censoring, Gao said.

“Due to these findings, FDA requested that the NATALEE trial continue, and that the final [invasive disease-free survival] results be submitted to the FDA for review,” Gao added. “And at that final [invasive disease-free survival result], 43% of patients had completed the three years of adjuvant [Kisqali], and the final [invasive disease-free survival] results are consistent with those of the interim analysis.”

Researchers of the NATALEE trial also assessed overall survival as a secondary focus in the study. Also, there was not enough data to assess this at the time of analysis.

“Although overall survival is immature, and descriptive and exploratory, it trended in the direction of favoring the addition of [Kisqali] based on the point estimates,” Gao said.

The side effect profile of Kisqali was consistent with previous data in the metastatic setting, Gao explained during the session. The side effects of special interest, which are listed in Kisqali’s prescribing information, include hepatobiliary toxicity, neutropenia, QT prolongation, interstitial lung disease and pneumonitis.

Regulatory Considerations

Kisqali was approved by the FDA in September 2024 for the adjuvant treatment of patients with HR-positive, HER2-negative stage 2 and 3 early breast cancer at a high risk for recurrence. Despite its approval, the FDA asked the pharmaceutical company to conduct an analysis that includes a “sufficient number of patients of racial and ethnic minorities that reflects the diversity of patients in the United States, especially those who are Black or African American,” Gao explained. The final report of these findings is due to the FDA by March 2030.

The FDA also asked, as part of a postmarketing commitment, for the company to provide findings from an additional overall survival analysis. This report is due to the FDA by December 2026. 

As it stands now, there are three different CDK4/6 inhibitors approved by the FDA in different settings: Kisqali, Verzenio (abemaciclib) and Ibrance (palbociclib). The trials that helped each of these drugs gain FDA approval have nuances regarding their designs, such as eligibility criteria and duration of adjuvant therapy.

Regarding treatment duration, Kisqali was given for three years compared with two years in the adjuvant Verzenio and Ibrance trials, Gao explained.

“At the time that the trial was designed, this is the duration that the company chose and provided some information in the preclinical setting with thoughts about possibility of benefit if the duration were to be given for three years,” Gao said. “At this time, I think we don't have a good sense of what the exact optimal duration of treatment is, but again, at the time of the design of the NATALEE trial, three years was proposed and felt to be reasonable based on the available information.”

Discussions Around Kisqali

There was a question-and-answer portion of this session, during which Gao and other discussants addressed certain comments about drug development, optimal doses and other topics around Kisqali.

One audience member asked a question about whether there are other drugs approved that have a lower dosage in the adjuvant setting compared with the metastatic setting. This sparked a conversation around the process of a drug receiving approval by the FDA, with comments from Dr. Antonio Wolff, medical oncologist at Johns Hopkins, Chief Operating Officer of the Translational Breast Cancer Research Consortium and co-chair of the NCI Breast Cancer Steering Committee.

“Any of you who have done drug development, we find ourselves a little bit stuck on the concept of the MTD, the maximum tolerated dose, and that's the dose that is recommended to go into phase 2, and ultimately in phase 3,” Wolff explained. “And that's how drugs are approved at the end. And I think to a degree, the FDA finds itself a little bit stuck. And I think it would be wonderful if we begin to popularize and push ourselves, push industry, push investigators to actually not look into MTD, but in the minimally effective dose.”

Wolff added that a lot of these studies are conducted after a drug is approved by the FDA and used to treat patients, sometimes taking nearly five years to obtain the additional data.

“I think all of you who take care of patients, all of you do have the experience of patients, many patients after a couple of cycles, … I am yet to see an example of a situation where I have a patient who is having a clinical benefit from a drug, when I dose reduce, that the drug, quote, unquote, appears to stop working,” Wolff added. “And I also have the anecdote of, in many cases, starting dose patients at a lower dose for various reasons, frailty, you name it.”

Victoria Goldberg, a patient advocate living with metastatic breast cancer for 10 years, also participated in the session and commented on the dosing of certain drugs. In particular, she referenced how she does not know of any patients treated with Verzenio who have been on the therapy for a while are on the full dose given its impact on quality of life.

Goldberg applauded the researchers of the NATALEE trial for assessing Kisqali with a dose reduction.

“[Kisqali] is not an easy drug at all,” Goldberg said. “People see neutropenia, which is a problem. There is liver toxicity. That's a big issue as well. And again, many, many patients who are on this drug in metastatic setting are dose reduced.”

She added that the focus around dose reduction is “paramount” for patients.

“There is wonderful initiative, … the Patient-Centered Dosing Initiative, that's suggesting exactly that,” Goldberg explained. “Let's stop doing the maximum tolerable dose. We're in the world of precision medicine. At this point, there could be other decisions made based on the person specifically and the dose that would work for that particular person. And I'm thrilled to be here and hear that this is something that the medical community is in agreement with us.”

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