Results of the NATALEE Trial

Educational Objectives

The goal of this program is to improve management of breast cancer using cyclin-dependent kinase (CDK) inhibitors. After hearing and assimilating this program, the clinician will be better able to:

1. Analyze major clinical trials that have investigated the use of CDK4/6 inhibitors in breast cancer.
2. Recognize the key factors that guide treatment decisions for patients with T2N0 breast cancer.

Summary

Introduction: Dr. Finn and Dr. Slayman conducted basic science studies on inhibitory concentration curves, indicating how much medication is required to stop cell growth; they observed that some cell lines exhibited high resistance, while others showed sensitivity to the medication, which was later identified as palbociclib; a significant portion of the sensitive cell lines were estrogen-positive and human estrogen receptor 2 (HER2)-negative; the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors affect the G1 to S phase transition, which is regulated by the retinoblastoma protein; when the retinoblastoma protein is unphosphorylated, a restriction point is created, halting cell cycle progression; prolonged arrest leads to senescence, preventing further cell growth; when phosphorylated, it loses its ability to block the cell cycle’s progression, allowing uncontrolled cell division; CDK4 and CDK6 are the enzymes responsible for phosphorylating the retinoblastoma protein; Finn et al (2009) demonstrated that CDK inhibitors effectively reduce phosphorylated retinoblastoma protein levels in cell lines, confirming that these inhibitors act directly on their intended target; CDK4/6 inhibitors effectively reduced cell growth in endocrine-sensitive and tamoxifen-resistant cell lines, suggesting their potential to overcome resistance mechanisms

Initial evidence: clinical trials of CDK4/6 inhibitors in metastatic breast cancer included PALOMA-2 (Im et al [2019]), MONALEESA-2 (Hortobagyi et al [2018]), and MONARCH-3 (Goetz et al [2017]); initially, these trials showed similar improvements in progression-free survival (PFS), leading to the perception that the medications were interchangeable; however, subsequent analyses of overall survival (OS) revealed differences; the PALOMA-2 trial did not show a significant improvement, while MONALEESA-2 and MONALEESA-7 (in premenopausal patients) demonstrated notable benefits; the MONARCH-3 trial showed a clinically meaningful, though not statistically significant, improvement; these discrepancies were initially attributed to variations in study design and patient populations; it is now recognized that the medications have distinct pharmacodynamic properties, eg, abemaciclib is a broad kinase inhibitor, ribociclib (RIB) exhibits higher selectivity for CDK4 and a longer time on target

Trials: PALLAS trial (Gnant et al [2022]) — utilized the full dose of palbociclib, as approved for metastatic disease, in combination with tamoxifen or an aromatase inhibitor for 2 yr, following local and initial systemic therapy in patients with early-stage breast cancer; monarchE study (Johnston et al [2020]) — evaluated the use of abemaciclib for 2 yr alongside endocrine therapy in patients with high-risk disease (≥4 positive lymph nodes, or 1-3 positive nodes with additional high-risk factors, eg, high-grade tumors, high-risk Oncotype DX scores, or a Ki-67 index >20%); NATALEE trial (Slamon et al [2023]) — used RIB at a reduced dose (400 mg instead of 600 mg) in combination with a nonsteroidal aromatase inhibitor, with or without ovarian suppression; all received an aromatase inhibitor, partly because of interaction between tamoxifen and RIB; treatment duration was 3 yr; PALLAS trial — initially failed to demonstrate improvements in invasive disease-free survival (DFS) or distant DFS; monarchE trial — showed significant improvements in invasive DFS and distant recurrence-free survival; the survival advantage continued even after the medication was discontinued, indicating a durable response; quality of life was similar between the treatment and control groups across various patient subgroups; dose modifications did not compromise efficacy, which is particularly relevant for elderly patients; PENELOPE-B trial (Loibl et al [2021]) — focused on patients with residual disease after neoadjuvant chemotherapy; results of the study did not show a sustained benefit after treatment cessation

NATALEE trial: allowed enrollment ≤12 mo after diagnosis and permitted prior endocrine therapy; included node-positive patients and high-risk node-negative patients, defined by factors, eg, Ki-67 >20%, high-risk genomic profiling, or grade 3 tumors; patients with anatomic stage 2B and 3 disease were also eligible; RIB was administered for 3 yr; the primary endpoint was invasive DFS, with secondary endpoints including OS, patient-reported outcomes, and correlative science

Primary results: demonstrated improvement in invasive and distant DFS; at 3 yr, there was a 3.1% absolute benefit for invasive DFS and a 2.2% absolute benefit for distant DFS in the overall patient population

Subgroup analyses: including stage II vs stage III, node-negative vs node-positive, menopausal status, age, and Ki-67 levels, showed consistent benefits across all groups; consistent benefits were observed across menopausal status

Safety profile of RIB: consistent with previous reports from metastatic studies; the most common reason for discontinuation was liver-related adverse events (grade 3 at ≈8%), but there were no grade 5 events; there was a slight increase in QT prolongation compared with the control group, but grade 3 or higher events were rare (<1%)

Updates: Dr. Fauci presented the 4-yr update, showing that the survival curves continued to separate; the absolute benefit of RIB increased to 4.9% at 4 yr vs 2.7% at 3 yr; consistent benefits were also observed across all reported subgroups, including stage II, stage III, and node-negative individuals; the US Food and Drug Administration approved RIB shortly after the 4-yr European Society for Medical Oncology results were announced; the differences in study design between the monarchE (abemaciclib) and NATALEE (RIB) trials raise questions about the optimal treatment duration and drug choice; there is uncertainty regarding whether 2 yr of abemaciclib or 3 yr of RIB is more effective; direct comparisons between the trials are difficult because of variations in patient populations and control arms; some clinicians may prefer the shorter 2-yr duration of abemaciclib; patients generally tolerate the 3-yr RIB regimen well, and longer CDK4/6 inhibition may lead to greater tumor senescence; practical considerations also influence treatment decisions; abemaciclib is associated with more prominent diarrhea, while RIB carries a higher risk for drug-drug interactions, necessitating careful monitoring and pharmacy consultation

Recurrence: a common concern is whether RIB is necessary for T2N0 patients; the NATALEE trial targeted high-risk T2N0 patients, not all T2N0 cases; analysis of the Flatiron database showed that high-risk T2N0 patients had a 13% 7-yr risk for distant recurrence, similar to node-positive patients, while low-risk T2N0 patients had a 3% risk; careful risk stratification is important in T2N0 breast cancer; evidence suggests that biological risk, not just anatomic stage, should guide treatment decisions; in the NATALEE trial, 8% of node-negative patients experienced recurrence ≤3 yr, highlighting the inadequacy of classifying these patients as low risk; 4-yr analysis showed 5.1% absolute benefit in recurrence prevention for the node-negative group, similar to the benefit seen in the node-positive group

Systemic therapy: most patients received chemotherapy, with roughly equal proportions receiving it in the neoadjuvant and adjuvant settings; patients who received neoadjuvant chemotherapy were generally at higher risk, exhibiting more advanced-stage and higher-grade disease; efficacy outcomes were similar regardless of prior chemotherapy use or sequencing (neoadjuvant vs adjuvant); patients who did not receive chemotherapy had favorable 3-yr recurrence rates, likely because of less aggressive tumor biology; longer follow-up is necessary to determine the long-term benefits of CDK4/6 inhibitors in this subgroup; analysis of prior endocrine therapy revealed that, while most patients started treatment ≤26 wk before enrollment, some had been receiving it for several months; patient characteristics were similar between these groups, suggesting that the timing of endocrine therapy initiation did not significantly influence patient selection; there was no difference in efficacy between patients who started endocrine therapy immediately with RIB and those who had been on it for a longer period before enrollment; delaying initiation of RIB to stabilize patients on endocrine therapy does not compromise outcomes

Readings

Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi:10.1186/bcr2419; Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. doi:10.1200/JCO.2017.75.6155; Gnant M, Dueck AC, Frantal S, et al. Adjuvant palbociclib for early breast cancer: the pallas trial results (ABCSG-42/AFT-05/BIG-14-03). J Clin Oncol. 2022;40(3):282-293. doi:10.1200/JCO.21.02554; Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer [published correction appears in Ann Oncol. 2019 Nov 1;30(11):1842. doi: 10.1093/annonc/mdz215.]. Ann Oncol. 2018;29(7):1541-1547. doi:10.1093/annonc/mdy155; Im SA, Mukai H, Park IH, et al. Palbociclib plus letrozole as first-line therapy in postmenopausal Asian women with metastatic breast cancer: results from the phase III, randomized PALOMA-2 study. J Glob Oncol. 2019;5:1-19. doi:10.1200/JGO.18.00173; Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE). J Clin Oncol. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514; Loibl S, Marmé F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the penelope-b trial. J Clin Oncol. 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639; Slamon DJ, Fasching PA, Hurvitz S, et al. Rationale and trial design of NATALEE: a phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer [published correction appears in Ther Adv Med Oncol. 2023 Sep 29;15:17588359231201818. doi: 10.1177/17588359231201818.]. Ther Adv Med Oncol. 2023;15:17588359231178125. Published 2023 May 29. doi:10.1177/17588359231178125.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. McAndrew has been an advisor for Astra Zeneca, Novartis Pharmaceuticals, and Mersana Pharmaceuticals; and has received honoraria from GoodRX. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. McAndrew was recorded at the 12th Annual USC Multi-Disciplinary Breast Cancer Symposium, held January 25, 2025, in Los Angeles, CA, and presented by Keck School of Medicine of the University of Southern California (USC). For information on upcoming CME activities from this presenter, please visit Keckusc.cloud-cme.com. Audio Digest thanks the speakers and Keck School of Medicine of USC for their cooperation in the production of this program.

CME/CE INFO

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The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

OB721002

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.