Ribociclib and endocrine therapy as adjuvant treatment in patients with HR+/HER2- early breast cancer: Primary results from the phase III NATALEE trial.

Abstract

LBA500 Background: RIB + ET has demonstrated significant survival benefits in pre- and postmenopausal pts with HR+/HER2− metastatic BC. To investigate whether RIB + ET also improves outcomes in early BC (EBC), the Phase III NATALEE trial (NCT03701334) evaluated adjuvant RIB + ET in a broad population of pts with stage II or III HR+/HER2− EBC at risk for recurrence, including pts with no nodal involvement (N0). As extended duration of tx is crucial to prolong cell cycle arrest and drive more tumor cells into senescence or death, a 3-y duration of RIB tx at a dose of 400 mg was chosen to improve tolerability while maintaining efficacy. Results from a prespecified interim analysis of invasive disease–free survival (iDFS; primary endpoint) are presented. Methods: Men and pre- or postmenopausal women were randomized 1:1 to RIB (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 premenopausal 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 mo before randomization. Stratification factors were menopausal status, disease stage, prior (neo)adjuvant chemotherapy, and geographic region. This prespecified interim analysis of iDFS, defined per STEEP criteria, was planned after ≈ 425 iDFS events (≈ 85% of planned total events). iDFS was evaluated by Kaplan-Meier methods, and statistical comparison was made by a stratified log-rank test, with a protocol-defined Lan-DeMets (O'Brien-Flemming) stopping boundary of a 1-sided P < .0128 for superior efficacy. Results: From 10 Jan 2019 to 20 April 2021, 5101 pts were randomized (RIB+ET, n = 2549; ET alone, n = 2552). As of the data cutoff (11 Jan 2023), median follow-up was 34 mo (min, 21 mo). 3- and 2-y RIB tx was completed by 515 pts (20.2%) and 1449 pts (56.8%), respectively; 3810 (74.7%) remained on study tx (RIB+ET, n = 1984; ET alone, n = 1826). iDFS was evaluated after 426 events (RIB + ET, n = 189; ET alone, n = 237). RIB + 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%. iDFS benefit was generally consistent across stratification factors and other subgroups. Secondary endpoints of overall survival, recurrence-free survival, and distant disease–free survival consistently favored RIB. RIB at 400 mg had a favorable safety profile with no new signals. Conclusions: Ribociclib added to standard-of-care ET demonstrated a statistically significant, clinically meaningful improvement in iDFS with a well-tolerated safety profile. The NATALEE results support ribociclib + ET as the treatment of choice in a broad population of pts with stage II or III HR+/HER2− EBC, including pts with N0 disease. Clinical trial information: NCT03701334 .

Treatment of residual disease following neoadjuvant therapy in breast cancer

“…This trial included patients receiving neoadjuvant therapy who remained at high risk for recurrence based on presence of residual disease or because of high‐risk features at diagnosis. Patients receiving endocrine therapy with ribociclib had improved 3‐year iDFS (90.4% vs. 87.1%) versus endocrine therapy alone 46 . Though promising, longer follow‐up is required to confirm long‐term outcomes and whether particular subsets of patients benefit most.…”

“…Ongoing studies of CDK 4/6i in HR+/HER2‐ early breast cancer include the phase III NATALEE study of 5100 patients with HR+/HER2‐ stage II‐III at risk for recurrence (including patients with N0 disease) treated with endocrine therapy with or without ribociclib for 36 months 46 . This trial included patients receiving neoadjuvant therapy who remained at high risk for recurrence based on presence of residual disease or because of high‐risk features at diagnosis.…”

What's new in surgical oncology breast

“…5 The NATALEE study, also presented at the 2023 ASCO meeting, was designed to compare invasive disease-free survival (DFS) using adjuvant ribociclib plus an AI versus an AI alone. 6 With median follow-up of 27 months, the risk of invasive disease was reduced by 25% with the addition of ribociclib to an AI. When combined with the recent results of the MonarchE trial using adjuvant abemaciclib plus endocrine therapy for node-positive, high-risk early breast cancer, these practice-changing trials supported the addition of a CDK 4/6 inhibitor to an AI as adjuvant therapy for patients with ER+HER2-early breast cancer, regardless of axillary lymph node status.…”

“…Ribociclib is a CDK 4/6 inhibitor that improved overall survival and maintained quality of life in patients with metastatic breast cancer 5 . The NATALEE study, also presented at the 2023 ASCO meeting, was designed to compare invasive disease‐free survival (DFS) using adjuvant ribociclib plus an AI versus an AI alone 6 . With median follow‐up of 27 months, the risk of invasive disease was reduced by 25% with the addition of ribociclib to an AI.…”

Update Breast Cancer 2023 Part 3 – Expert Opinions of Early Stage Breast Cancer Therapies

“…Die Abschätzung des Nutzen-Risiko-Verhältnisses basierend auf der Vielzahl der durchgeführten Studien scheint die Dauer von 7-8 Jahren Gesamttherapiedauer als Favoriten zu bestimmen[18 - 26]. Ein genomischer Test scheint nicht vonnöten zu sein (Fragen 78 und 79), um die Dauer der endokrinen Therapie festzulegen.Bislang gibt es positive Studien für 2 CDK4/6-Inhibitoren, die monarchE-Studie[27 -29] und die NATALEE/TRIO-033-Studie[30]. Abemaciclib ist für Patientinnen mit einem hohen Risiko bereits zugelassen.…”