Kisqali Plus Endocrine Therapy Improves Early Breast Cancer Outcomes

Adding Kisqali (ribociclib) to endocrine therapy improved invasive disease-free survival — which is the time a patient lives without signs of invasive disease — in patients with hormone receptor-positive, HER2-negative early breast cancer compared those who were treated with endocrine therapy alone.

These findings from the phase 3 NATALEE trial were presented at a press briefing ahead of the 2023 American Society of Clinical Oncology Annual Meeting.

Patients who received the CDK4/6 inhibitor in combination with standard-of-care endocrine therapy (2,549 patients) achieved a three-year invasive disease-free survival rate of 90.4% compared with 87.1% among patients treated with endocrine therapy alone (2,552 patients). The benefit was consistent across patient subgroups, regardless of disease stage, menopausal status or whether or not disease was present in lymph nodes. The median duration of follow-up for invasive disease-free survival was 27.7 months for both arms at the time of this interim analysis.

“We saw a 25% relative reduction in the risk of invasive breast cancer when (Kisqali) was added. Based on the number of patients that are challenged with this subtype of disease, that could result in a significant efficacy improvement,” Dr. Dennis J. Slamon, the director of Clinical/Translational Research and Revlon/UCLA Women’s Cancer Research Program at the UCLA Jonsson Comprehensive Cancer Center in Los Angeles, California, said during the presentation.

NATALEE was a multicenter, randomized, open-label trial comparing Kisqali plus endocrine therapy with endocrine therapy alone in adult patients with hormone receptor–positive/HER2-negative early breast cancer.

Following resection, disease characteristics were defined for a broad patient population that included those with no nodal involvement (meaning that cancer was found in the lymph nodes) because many patients with stage 2/3 hormone receptor–positive/HER2-negative early breast cancer are at risk of recurrence up to decades after their initial diagnosis, Slamon explained.

Specifically, patients who had stage2A disease included those with N1 disease or those with N0 disease that was grade 2 with evidence of high-risk characteristics, which included Ki-67 expression of 20% or higher, an Oncotype DX Breast Recurrence Score of at least 26, or high-risk characteristics via genomic risk profiling. For anatomical stage 2B, disease must be N0 or N1 and for anatomical stage 3, disease must be N0, N1, N2 or N3.

Patients received Kisqali at a dose of 400 mg daily in a three-weeks-on-one-week off manner for three years. In both arms, standard-of-care endocrine therapy consisted of Femara (letrozole) or Arimidex (anastrozole) for a duration of at least five years plus Zoladex (goserelin) in men and premenopausal women.1

“The approved dose of (Kisqali) for metastatic disease is 600 mg,” Slamon said. “Testing in NATALEE was decreased to 400 mg. The rationale there was, if we were hoping to improve efficacy, we also wanted to see if we could improve safety. We had data from the metastatic trials (showing) that when patients were dose reduced, because of (side effects) to 400 mg, they appeared to have equivalent efficacy.”

Invasive disease-free survival was the main goal of the study. Secondary end points included recurrence-free survival (time a patient lives without their disease recurring), distant disease-free survival (time to distant metastases), overall survival (time until death of any cause), patient-reported outcomes, observing how the drug moves through the body and safety and tolerability.

In a group of trial participants used to observe safety of the drugs, patients who received the combination (2,524 patients) commonly experienced any-grade side effects ncluding joint pain (36.5%), nausea (23.0%), headache (22.0%), fatigue (21.9%), diarrhea (14.2%), and venous thromboembolism (1.4%). In the endocrine therapy group (2,444), these side effects occurred at rates of 42.5%, 7.5%, 16.5%, 12.7%, 5.4% and 0.6%, respectively.

In terms of moderate to severe side effects, patients in the Kisqali/endocrine therapy group experienced joint pain (1%), nausea (0.2%), headache (0.4%), fatigue (0.7%), diarrhea (0.6%), and venous thromboembolism (0.6%). These side effects were present in 1.3%, 0.04%, 0.2%, 0.2%, 0.1%, and 0.2% of patients in the endocrine therapy arm, respectively.

Side effects of special interest included neutropenia (decrease in a type of white blood cells), liver-related side effects, QT interval prolongation and interstitial lung disease (ILD)/pneumonitis.

Any-grade neutropenia was present in 62.1% of patients in the combination arm, including 0.3% who experienced febrile neutropenia. Grade 3 neutropenia was reported in 43.0% of patients and grade 3 febrile neutropenia was reported in 0.3% of patients. In the endocrine arm 4.5% experienced neutropenia of any grade, with 0.8% of patients experiencing a grade 3 event and no patients experiencing febrile neutropenia.

Compared with pooled data from MONALEESA trials of Kisqali at a 600-mg dose in advanced breast cancer, the 400-mg starting dose had lower rates of neutropenia. The all-grade rate of neutropenia was 74% with 60% of events being grade 3 or higher.

In Kisqali-containing group, any-grade liver-related side effects were reported in 25.4% of patients with 8.3% experiencing grade 3 (moderate) events. In the control arm these rated were 10.6% and 1.5% for any-grade and grade 3 events, respectively. ILD/pneumonitis of grade 1 or 2 was reported in 1.5% of patients in the experimental arm and in 0.8% of patients in the control arm, with 0.8% of patients having a grade 3 event.

Any grade QT interval prolongation was present in 5.2% of patients in the investigational arm, including 4.2% of patients who experienced electrocardiogram QT interval prolongation. These events occurred at a grade 3 or greater severity in 1.0% and 0.2% of patients, respectively. In the control arm, any-grade events were reported in 1.2% and 0.7% of patients, respectively, and grade 3 or greater events occurred at rates of 0.5% and 0%, respectively. Of note, no cases of torsades de pointes were reported in NATALEE.

“We know that a substantial portion of patients with early-stage, hormone receptor–positive breast cancer can go on to recur, and these recurrences can be quite delayed,” Dr. Rita Nanda, the director of the Breast Oncology Program and an associate professor of medicine at the University of Chicago Medicine in Illinois said during a discussion of the findings. “For our patients with node-negative disease, to this point we haven’t seen any improvements with the addition of a CDK4/6 inhibitor to endocrine therapy for early-stage breast cancer. (Kisqali) In the context of the NATALEE trial was effective (and) it was well tolerated. I expect that these trial results will change practice.”

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