Results from the phase 3 NATALEE trial investigating ribociclib plus endocrine therapy may change practice for the treatment of hormone receptor–positive or HER2-negative early breast cancer, according to an expert from the University of Chicago Medicine.
Adding ribociclib (Kisqali) to endocrine therapy yielded clinically and statistically significant improvement in invasive disease-free survival (iDFS) in patients with hormone receptor–positive or HER2-negative early breast cancer vs endocrine alone, according to findings from the phase 3 NATALEE trial (NCT03701334) presented during the 2023 American Society of Clinical Oncology Annual Meeting.1
At the January 11, 2023, data cutoff, patients 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 second interim efficacy analysis.
“We saw a 25% relative reduction in the risk of invasive breast cancer when ribociclib was added. Based on the number of patients that are challenged with this subtype of disease, that could result in a significant efficacy improvement,” Dennis J. Slamon, MD, 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 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.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.
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.
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.
“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.
iDFS using STEEP criteria represented the primary end point of the study. Secondary end points included recurrence-free survival, distant disease-free survival (DDFS), overall survival (OS), 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.
Baseline patient characteristics were well-balanced between the 2 arms; the median age was 52 years in both the investigational and the endocrine therapy arms. Most patients in both arms underwent prior endocrine therapy (72% vs 71%), prior adjuvant or neoadjuvant chemotherapy (88% vs 88%), had an ECOG performance status of 0 (83% vs 84%), were postmenopausal women (56% vs 56%), and had stage III disease (60% vs 59%).
In the combination arm, nodal status at diagnosis consisted of NX (11%), N0 (27%), N1 (41%), and N2/N3 (19%). These figures were 10%, 29%, 41%, and 18%, respectively, in the endocrine therapy arm.
Additional findings from the study revealed that the iDFS benefit was present across all key prespecified subgroups. Notably, patients with N0 disease (HR, 0.630; 95% CI, 0.341-1.165) as well as those with N1 through N3 disease (HR, 0.771; 95% CI, 0.630-0.944). Patients with stage II (HR, 0.761; 95% CI, 0.525-1.103) and stage III (HR, 0.740; 95% CI, 0.592-0.925), as well as those with prior exposure to neoadjuvant (HR, 0.785; 95% CI, 0.610-1.011) or adjuvant chemotherapy (HR, 0.671; 95% CI, 0.486-0.927), all derived an iDFS benefit with the addition of ribociclib.
Ribociclib with endocrine therapy also led to an improvement in DDFS compared with endocrine therapy alone. The 3-year DDFS rates were 90.8% vs 88.6%, respectively (HR, 0.739; 95% CI, 0.603-0.905; P = .0017). Additionally, an OS benefit was also reported with the addition of ribociclib (HR, 0.759; 95% CI, 0.539-1.067; P = .0563). Slamon noted that the median OS follow-up was 30.4 months, and that additional follow-up is planned in this area.
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.
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.
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.
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.
Patients discontinued treatment with endocrine therapy at a rate of 21% and 24% in the investigational and control arms, respectively. Reasons for discontinuation included AEs (5% and 4%), patient or clinician decision (10% and 12%), disease relapse (6% and 7%), being lost to follow-up (0.3% and 0.5%), death (0.2% and 0.1%), and other (0.5% and 0.6%).
Specifically in the combination arm, 19% of patients discontinued study treatment due to AEs. Including ongoing treatment, 57% of patients underwent at least 2 years of therapy and 20% completed 3 years of ribociclib treatment.
“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 Nanda, 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.”