Ribociclib plus Endocrine Therapy in Early Breast Cancer

Authors (Top 5): D. Slamon, O. Lipatov, Z. Nowecki, N. McAndrew, B. Kukielka‑Budny

Journal Name, Year, Volume, Issue: The New England Journal of Medicine, 2024, Volume 390, Issue 12

Type of Study: International, open-label, randomized, phase 3 trial

DOI: 10.1056/NEJMoa2305488

Quick Reference Summary

Ribociclib plus nonsteroidal aromatase inhibitor (NSAI) significantly improved 3-year invasive disease-free survival to 90.4% compared to 87.1% with NSAI alone (P = 0.003). This represents a 3.3 percentage point absolute increase and a 25% relative risk reduction in invasive disease, recurrence, or death.

Core Clinical Question

Does the addition of ribociclib to nonsteroidal aromatase inhibitor therapy improve invasive disease-free survival in patients with hormone receptor-positive, HER2-negative stage II or III early breast cancer compared to NSAI alone?

Background

Disease Overview:

HR-positive, HER2-negative breast cancer is the most common subtype, accounting for 70-75% of cases. Predominantly diagnosed at early stages (I-III). Treated with surgery followed by adjuvant endocrine therapy for 5 to 10 years.

Prior Data:

Recurrence Rates:

• 27% in stage II patients
• 46-57% in stage III patients
• Up to 20 years post-diagnosis

CDK4/6 Inhibitors:

• Ribociclib has shown significant progression-free and overall survival benefits in HR+/HER2- advanced breast cancer.
• Previous trials (PENELOPE-B, PALLAS) in early breast cancer showed varying results, with some not demonstrating significant invasive disease-free survival benefits.

Current Standard of Care:

Adjuvant endocrine therapy (e.g., letrozole, anastrozole) for HR-positive, HER2-negative early breast cancer.

Knowledge Gaps Addressed by Study:

Whether the survival benefits of ribociclib observed in advanced breast cancer extend to early-stage HR-positive, HER2-negative breast cancer.

Study Rationale:

Based on the established benefits of CDK4/6 inhibitors in advanced disease, the trial aims to evaluate the efficacy and safety of ribociclib in preventing recurrence in early breast cancer patients at high risk.

Methods Summary

Study Design:

International, open-label, randomized, phase 3 trial.

Setting and Time Period:

• Enrollment: January 10, 2019 – April 20, 2021
• Interim Analysis Data Cutoff: January 11, 2023

Population Characteristics:

• Participants: 5,101 patients with HR-positive, HER2-negative stage II or III early breast cancer.
• Demographics: 73.4% White, 13.2% Asian, 1.7% Black.
• Gender: Predominantly women; inclusion of men was minimal.

Inclusion/Exclusion Criteria:

Inclusion:

• Anatomical stage II or III breast cancer
• High genomic risk (e.g., Recurrence Score ≥26)
• Adequate organ function
• Premenopausal women and men received goserelin

Exclusion:

• Previous CDK4/6 inhibitor therapy
• Clinically significant, uncontrolled heart disease
• Cardiac repolarization abnormalities

Intervention Details:

• Ribociclib Group:
  • Ribociclib 400 mg/day orally for 3 weeks on, 1 week off, continuously for 36 months
  • Plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day) for ≥5 years

Control/Comparison Group Details:

• NSAI Alone:
  • Nonsteroidal aromatase inhibitor (letrozole or anastrozole) as described above

Primary and Secondary Outcomes:

• Primary Outcome: Invasive disease-free survival (IDFS)
• Secondary Outcomes:
  • Distant disease-free survival
  • Recurrence-free survival
  • Overall survival
  • Safety and quality of life

Statistical Analysis Approach:

• Kaplan–Meier method for survival estimates
• Stratified log-rank test for comparisons
• Hazard ratios estimated using stratified Cox proportional-hazards model
• Sample Size Calculations:
  • Approximately 500 events required for ~85% power to detect HR of 0.76

Ethics and Funding Information:

• Funded by Novartis (NATALEE ClinicalTrials.gov number: NCT03701334)
• Conducted in accordance with the Declaration of Helsinki and Good Clinical Practice
• Approved by institutional review boards or independent ethics committees
• All patients provided written informed consent

Detailed Results

Participant Flow and Demographics:

• Total Patients Randomized: 5,101 (2,549 to ribociclib+NSAI, 2,552 to NSAI alone)
• Baseline Characteristics: Well-balanced across treatment groups
  • Median Age: 52 years
  • Menopausal Status: 55.7% postmenopausal
  • Anatomical Stage: 19.6% stage IIA, 20.5% stage IIB, 59.6% stage III
  • Nodal Status at Diagnosis: 28.1% N0, 41.1% N1, 18.6% N2/N3

Primary Outcome Results:

• Invasive Disease-Free Survival (3 years):
  • Ribociclib+NSAI: 90.4%
  • NSAI Alone: 87.1%
  • Hazard Ratio: 0.75 (95% CI, 0.62 to 0.91; P = 0.003)

Secondary Outcome Results:

• Distant Disease-Free Survival (3 years):
  • Ribociclib+NSAI: 90.8%
  • NSAI Alone: 88.6%
  • Hazard Ratio: 0.74 (95% CI, 0.60 to 0.91; P = 0.003)
• Recurrence-Free Survival (3 years):
  • Ribociclib+NSAI: 91.7%
  • NSAI Alone: 88.6%
  • Hazard Ratio: 0.72 (95% CI, 0.58 to 0.88; P = 0.003)
• Overall Survival:
  • Ribociclib+NSAI: 2.4% deaths
  • NSAI Alone: 2.9% deaths
  • Hazard Ratio: 0.76 (95% CI, 0.54 to 1.07; P = 0.083) (Not statistically significant)

Subgroup Analyses:

• Consistent benefits across prespecified subgroups, including stage II and III
• No significant interaction by age, menopausal status, or other demographics

Adverse Events/Safety Data:

• Any Adverse Event:
  • Ribociclib+NSAI: 97.9%
  • NSAI Alone: 87.1%
• Grade ≥3 Adverse Events:
  • Ribociclib+NSAI: 56.9%
  • NSAI Alone: 16.1%
• Most Common Adverse Events:
  • Ribociclib+NSAI: Neutropenia (62.1%), Arthralgia (36.5%)
  • NSAI Alone: Arthralgia (42.5%), Neutropenia (4.5%)
• Serious Adverse Events:
  • Ribociclib+NSAI: 13.3%
  • NSAI Alone: 9.9%
• Notable Safety Findings:
  • QT Interval Prolongation: 5.2% with ribociclib+NSAI vs. 1.2% with NSAI alone (P < 0.001)
  • Liver-Related Adverse Events: 18.9% vs. 10.6% respectively (P < 0.001)
  • Death Not Related to Disease Progression: 2.4% vs. 3.0% respectively

Results Tables

Outcome	Ribociclib + NSAI Group	NSAI Group	Difference (95% CI)	P-value
Invasive Disease-Free Survival	90.4%	87.1%	+3.3% (P = 0.003)	0.003
Distant Disease-Free Survival	90.8%	88.6%	+2.2% (P = 0.003)	0.003
Recurrence-Free Survival	91.7%	88.6%	+3.1% (P = 0.003)	0.003
Overall Survival	2.4% deaths	2.9% deaths	-0.5% (P = 0.083)	0.083

Authors' Conclusions

Primary Conclusions: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer.

Authors' Interpretation of Results: The addition of ribociclib offers a clinically meaningful benefit in preventing disease recurrence without introducing new safety concerns.

Clinical Implications Stated by Authors: Ribociclib can be integrated into the standard adjuvant endocrine therapy regimen for high-risk early breast cancer patients to enhance survival outcomes.

Future Research Recommendations: Longer follow-up is necessary to assess overall survival benefits and long-term safety of ribociclib in this patient population.

Literature Review

The study places its findings in the context of existing research, noting that previous trials (PENELOPE-B, PALLAS) did not demonstrate significant invasive disease-free survival benefits with CDK4/6 inhibitors in early breast cancer, whereas the monarchE trial showed a benefit with abemaciclib. The NATALEE trial's results with ribociclib align with monarchE, suggesting a class effect of CDK4/6 inhibition in early-stage, high-risk patients.

Critical Analysis

A. Strengths:

• Large Sample Size: Included over 5,000 patients, enhancing the reliability of results.
• Randomized Controlled Design: Minimizes selection bias and confounding factors.
• International, Diverse Population: Enhances external validity across different demographics and healthcare settings.
• Well-Balanced Baseline Characteristics: Ensures comparability between treatment groups.
• Rigorous Statistical Analysis: Appropriate methodologies used for primary and secondary outcomes.
• Comprehensive Safety Assessment: Detailed reporting of adverse events, allowing for a thorough evaluation of safety profiles.

B. Limitations:

• Interim Analysis: Results are based on a prespecified interim analysis; longer follow-up is needed for overall survival data.
• Underrepresentation of Certain Demographics: Black patients were underrepresented, potentially limiting generalizability to this population.
• Younger Patient Population: Median age in the trial was younger than the typical age at diagnosis in the United States, which may affect applicability to older populations.
• Shorter Follow-Up for Primary Outcome: While invasive disease-free survival was significantly improved, the overall survival data remains immature.
• Adherence and Dose Reductions: High rates of dose reductions and discontinuations might reflect real-world adherence challenges.

C. Literature Context:

A. Previous Studies and Meta-Analyses:

• monarchE Trial: Demonstrated benefit with abemaciclib in a high-risk population (Hortobagyi GN, et al. J Clin Oncol. 2018; 36:1738-48).
• PENELOPE-B and PALLAS Trials: Did not show significant benefits with palbociclib and ribociclib, respectively, in early breast cancer (Sledge GW Jr, et al. J Clin Oncol. 2020; 38:3987-98; Pistilli B, et al. J Clin Oncol. 2022; 40:1518-30).

B. Contrasting Methodological Quality:

• monarchE vs. NATALEE: monarchE used abemaciclib with a different patient enrichment strategy, while NATALEE used ribociclib with a reduced starting dose for improved safety.

C. Comparisons with Guidelines:

• Current guidelines recommend considering CDK4/6 inhibitors in high-risk HR+/HER2- early breast cancer based on monarchE findings. NATALEE supports expanding this recommendation to include ribociclib.

D. This Trial's Contribution:

• Adds Evidence: Confirms the efficacy of CDK4/6 inhibition in improving invasive disease-free survival in early breast cancer.
• Supports Class Effect: Aligns with monarchE, suggesting benefits extend beyond abemaciclib to ribociclib.
• Enhances Safety Profile Understanding: Demonstrates that a lower ribociclib dose maintains efficacy while potentially reducing adverse events.

Clinical Application

• Practice Change: Incorporate ribociclib in combination with NSAI as adjuvant therapy for patients with HR-positive, HER2-negative stage II or III early breast cancer at high risk of recurrence.
• Applicable Patient Populations: Particularly beneficial for patients with node-positive disease or high genomic risk indicators.
• Implementation Considerations: Monitor for neutropenia and QT prolongation; manage dose reductions as necessary to maintain safety and adherence.
• Integration with Existing Evidence: Supports the use of CDK4/6 inhibitors in early breast cancer, complementing existing data from monarchE.

How To Use This Info In Practice

Recommendation: Consider adding ribociclib to standard adjuvant endocrine therapy in high-risk HR-positive, HER2-negative early breast cancer patients to improve invasive disease-free survival, while closely monitoring for adverse events.