Findings presented at a press briefing during the 2023 ASCO Annual Meeting revealed that the primary end point was met in the phase 3 NATALEE trial.
In patients with hormone receptor–positive/HER2-negative early breast cancer, treatment with ribociclib (Kisqali) plus endocrine therapy led to a statistically and clinically meaningful improvement in invasive disease-free survival (iDFS) compared with endocrine therapy alone, meeting the primary end point of the phase 3 NATALEE trial (NCT03701334).1
Findings were presented at a press briefing during the 2023 American Society of Clinical Oncology Annual Meetingshowed that those who received the CDK4/6 inhibitor in combination with standard-of-care endocrine therapy (n = 2549) achieved a 3-year iDFS rate of 90.4% compared with 87.1% among patients treated with endocrine therapy alone (n = 2552; HR, 0.748; 95% CI, 0.618-0.906; P = .0014). The benefit was consistent across patient subgroups, regardless of disease stage, menopausal status, or nodal status. The median duration of follow-up for iDFS was 27.7 months for both arms at the time of this interim analysis.
"These landmark results will fundamentally change how we treat patients with stage II and III HR+/HER2- early breast cancer who are in need of new, well-tolerated options that prevent their cancer from coming back," said Dennis J. Slamon, M.D., Director of Clinical/Translational Research, UCLA Jonsson Comprehensive Cancer Center and chairman and executive director of Translational Research In Oncology (TRIO), in a press release."Addressing this unmet need across such a broad patient population could help streamline treatment decisions for healthcare providers and keep many more at-risk patients cancer-free without disrupting their daily lives."
NATALEE was a multicenter, randomized, open-label trial comparing ribociclib plus endocrine therapy with endocrine therapy alone in adult patients with hormone receptor–positive/HER2-negative early breast cancer. Eligible patients needed to have anatomic stage group II or III disease following surgical resection, an ECOG performance status of 1 or 0, and have available archival tissue from surgical resection. Those who received prior treatment with a CDK4/6 inhibitor, those with distant breast cancer metastases beyond regional lymph nodes, and those with clinically significant heart disease were included. Prior endocrine therapy up to 12 months was permitted.1,2
Following resection, disease characteristics were defined for a broad patient population that included those with no nodal involvement because many patients with stage II/III hormone receptor–positive/HER2-negative early breast cancer are at risk of recurrence up to decades after their initial diagnosis, Slamon explained.1
Specifically, patients who had stage IIA 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 IIB, disease must be N0 or N1 and for anatomical stage III, disease must be N0, N1, N2, or N3.1
Patients received ribociclib at a dose of 400 mg daily in a 3-weeks-on-1-week off manner for 3 years. In both arms, standard-of-care endocrine therapy consisted of letrozole or anastrozole for a duration of at least 5 years plus goserelin in men and premenopausal women.1
“The approved dose of ribociclib 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 any adverse events [AEs] to 400 mg, they appeared to have equivalent efficacy.”
Slamon also noted that the 3-year duration of treatment was crucial to prolong cell cycle arrest and drive more tumor cells into irreversible senescence.1
iDFS using STEEP criteria represented the primary end point of the study. Secondary end points included recurrence-free survival, distant disease-free survival, overall survival, patient-reported outcomes, pharmacokinetics, and safety and tolerability. Locoregional recurrence-free survival and gene expression and alterations in circulating tumor DNA/RNA samples were exploratory end points.
In the safety population, patients who received the combination (n = 2524) commonly experienced any-grade AEs including arthralgia (36.5%), nausea (23.0%), headache (22.0%), fatigue (21.9%), diarrhea (14.2%), and venous thromboembolism (1.4%). In the endocrine therapy arm (n = 2444), these AEs occurred at rates of 42.5%, 7.5%, 16.5%, 12.7%, 5.4%, and 0.6%, respectively.1
In terms of AEs of grade 3 or greater patients in the investigational arm experienced arthralgia (1%), nausea (0.2%), headache (0.4%), fatigue (0.7%), diarrhea (0.6%), and venous thromboembolism (0.6%). These AEs were present in 1.3%, 0.04%, 0.2%, 0.2%, 0.1%, and 0.2% of patients in the endocrine therapy arm, respectively.1
AEs of special interest included neutropenia, liver-related AEs, 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.1
Compared with pooled data from MONALEESA trials of ribociclib 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 the investigational arm, any-grade liver-related AEs were reported in 25.4% of patients with 8.3% experiencing grade 3 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.1
“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,” Rita Nandal, MD, 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. Ribociclib In the context of the NATALEE trial was effective [and] it was well tolerated. I expect that these trial results will change practice.”
1. Slamon DJ, Stroyakovskiy D, Yardley DA, et al. Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2− early breast cancer: primary results from the phase III NATALEE trial. J Clin Oncol. 2023;41(suppl 17):LBA500.
2. A trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer (NATALEE). ClinicalTrials.gov. Updated December 30, 2022. Accessed May 31, 2023. https://clinicaltrials.gov/ct2/show/NCT03701334