Adjuvant Ribociclib and Endocrine Therapy in Patients with HR+/HER2 Negative Early Breast Cancer: Phase III NATALEE Trial

By Dr. Shipra Gandhi

from Roswell Park Comprehensive Cancer Center

 

Findings from the MonarchE clinical trial¹ led to the approval of combination abemaciclib with AI in the adjuvant setting for patients with HR-positive HER2-negative breast cancer with 1-3 LN with high-risk features: grade 3 or Ki67 >=20% or tumor size >=5 cm in size or patients with four or more lymph nodes. To date, abemaciclib is the only CDK4/6 inhibitor to have demonstrated a clinical benefit in this high-risk node-positive population, especially with a median follow-up of 4 years, 2 years after completion of adjuvant abemaciclib, showing a carry-over effect of abemaciclib efficacy. This data with adjuvant abemaciclib is especially important given that the results of two other adjuvant Palbociclib clinical trials (PALLAS and PENELOPE) were negative.

 

At this year’s ASCO, results from an interim analysis of invasive disease-free survival from phase III NATALEE² clinical trial were presented by Slamon et al. NATALEE trial evaluated adjuvant ribociclib in a broader population of patients, with stage II or III HR-positive HER2-negative early-stage breast cancer, including patients with no nodal involvement.

 

In this trial, men and pre- or post-menopausal women were randomized 1:1 to ribociclib (400 mg/day; 3 wk on/1 wk off for 3 y) + ET (letrozole 2.5 mg/day or anastrozole 1 mg/day, for ≥ 5 y) or ET alone. Men and pre-menopausal women also received goserelin. Eligible pts had an ECOG PS of 0-1 and BC anatomic stage IIA (either N0 with additional risk factors or 1-3 axillary lymph nodes [N1]), stage IIB, or stage III per AJCC (8th ed); prior (neo)adjuvant ET was allowed if initiated ≤ 12 months before randomization.

 

5101 pts were randomized (ribociclib+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), the median follow-up was 34 months (min, 21 months). 3- and 2-y ribociclib treatment was completed by 515 pts (20.2%) and 1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (ribociclib+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (ribociclib + ET, n = 189; ET alone, n = 237). Ribociclib + ET demonstrated significantly longer iDFS than ET alone (HR, 0.748; 95% CI, 0.618-0.906; P = .0014); 3-y iDFS rates were 90.4% vs 87.1%. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored ribociclib. Ribociclib at 400 mg had a favorable safety profile with no new signals.

 

Of note, the NATALEE trial enrolled patients with lymph node-negative disease, allowing these patients the option of receiving CDK4/6 inhibitors. However, the follow-up is only 34 months, and 80% of patients continue on ribociclib. Therefore, long-term follow-up data may be needed to confirm this benefit of adjuvant ribociclib. The trial findings help to expand our patient population who could benefit from adjuvant CDK4/6 inhibition.

 

References:

1. Johnston et al. Abemaciclib plus endocrine therapy for hormone-receptor positive, HER2-negative, node-positive, high risk breast cancer (monarchE). Lancet Oncology 2022.
2. Slamon et al. Ribociclib plus endocrine therapy as adjuvant treatment in patients with HR+HER2- early breast cancer: Primary results from the phase III NATALEE trial. ASCO 2023.