What are the results of the NATALEE (New Adjuvant Trial with Abemaciclib, Letrozole, and External control) trial for postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer?

NATALEE Trial in Breast Cancer

The NATALEE trial demonstrated that adding ribociclib 400 mg/day (3 weeks on/1 week off) for 3 years to adjuvant endocrine therapy significantly improved invasive disease-free survival by 3.3% at 3 years (HR 0.75,95% CI 0.62-0.91, P=0.003) in patients with stage II-III HR-positive/HER2-negative early breast cancer, representing the broadest population studied in any adjuvant CDK4/6 inhibitor trial. 1, 2

Trial Design and Patient Population

NATALEE (NCT03701334) was a multicenter, randomized, open-label Phase III trial that enrolled 5,101 patients (2,549 in ribociclib arm, 2,552 in control arm) with HR-positive/HER2-negative early breast cancer. 2, 3, 4

Eligibility Criteria

• Included women (regardless of menopausal status) and men aged ≥18 years with anatomical stage IIA (N0 with grade 2-3 and/or Ki-67 ≥20%, or N1), stage IIB, or stage III disease. 1, 2, 3
• Patients with initial diagnosis ≤18 months prior to randomization were eligible, and those receiving standard (neo)adjuvant endocrine therapy initiated ≤12 months before randomization could enroll. 3, 4
• This represents the broadest eligibility criteria of any adjuvant CDK4/6 inhibitor trial, notably including select node-negative patients with high-risk features. 1, 3

Treatment Arms

• Ribociclib arm: 400 mg/day orally (3 weeks on/1 week off) for 36 months plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day) for ≥60 months, with goserelin 3.6 mg every 28 days for premenopausal women and men. 2, 4
• Control arm: NSAI alone (letrozole or anastrozole) for ≥60 months, with goserelin for premenopausal women and men. 2, 4
• The 400 mg dose represents a reduction from the 600 mg dose used in metastatic disease, intended to improve tolerability while maintaining efficacy. 3, 4

Key Efficacy Results

Primary Endpoint: Invasive Disease-Free Survival

• At median follow-up of 34 months, ribociclib plus NSAI showed statistically significant improvement in iDFS (HR 0.749,95% CI 0.628-0.892, P=0.0012). 1, 4
• The 3-year iDFS rates were 90.7% (95% CI 89.3-91.8%) with ribociclib versus 87.6% (95% CI 86.1-88.9%) with NSAI alone, representing an absolute improvement of 3.1%. 1, 4
• At 5-year follow-up (median 55.4 months), the iDFS benefit persisted (HR 0.716,95% CI 0.618-0.829), with absolute improvement increasing to 4.5% between treatment arms. 5

Secondary Endpoints

• Distant disease-free survival and recurrence-free survival both favored ribociclib plus NSAI over NSAI alone. 4, 5
• Overall survival data remain immature at the primary analysis, with only 172 deaths (3.5%) across both arms. 2, 4
• At 5-year follow-up, a numerical improvement in OS favoring ribociclib was observed (HR 0.800,95% CI 0.637-1.003, nominal P=0.026), though not yet statistically significant. 5

Subgroup Analyses

• Consistent iDFS benefit was observed across prespecified subgroups, including stage II versus III disease and node-positive versus node-negative disease. 4, 5
• In the node-negative subgroup, ribociclib demonstrated substantial benefit (HR 0.606,95% CI 0.372-0.986). 5

Safety Profile

Treatment Completion and Discontinuation

• At final iDFS analysis, ribociclib was stopped for 1,996 patients (78.3%); 1,091 (42.8%) completed the full 3 years of treatment, and 528 (20.7%) remained on treatment. 4
• No new safety signals were observed with longer follow-up, and adverse events remained stable over time. 4, 5

Common Adverse Events

• The most common adverse reactions in ≥20% of patients included neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. 6
• Ribociclib carries specific safety concerns including QT prolongation (5.2% of patients), neutropenia (43.8%), and hepatotoxicity (8.3-8.9%). 7, 8

Clinical Practice Implications

Guideline Recommendations

• NCCN guidelines (2024) state that results from NATALEE showed statistically significant improvement in iDFS with ribociclib plus adjuvant endocrine therapy for stage II and III HR-positive/HER2-negative breast cancer, though additional follow-up is needed to characterize long-term efficacy. 1
• ESMO guidelines (2024) note that pending FDA or EMA approval, ribociclib could potentially be another option for intermediate- and high-risk disease, with a 3.3% improvement in 3-year iDFS. 1
• Currently, abemaciclib remains the only FDA-approved CDK4/6 inhibitor for adjuvant therapy (Category 1, preferred option), while ribociclib approval in this setting is pending. 1

Patient Selection Considerations

• ASCO guidelines (2025) indicate that ribociclib efficacy was evaluated in patients with any axillary lymph node macroinvolvement, as well as node-negative patients with tumors >5 cm or 2-5 cm tumors that were grade 2 with Ki-67 ≥20% or high genomic risk score. 1
• For patients with pT1 disease, grade 3, HR-positive cancers, SLNB may be prudent given higher likelihood of positive nodes, in which case ribociclib would be considered if positive SLN is found. 1
• The decision to use ribociclib stems primarily from assessment of the primary breast tumor characteristics rather than nodal status alone. 1

Comparison with Other CDK4/6 Inhibitors

Abemaciclib (MonarchE)

• Abemaciclib 150 mg twice daily for 2 years reduced absolute risk of recurrence at 4 years by 6.4% (HR 0.664,95% CI 0.578-0.762, P<0.0001) in patients with ≥4 positive nodes or 1-3 positive nodes with high-risk features (grade 3 or size ≥5 cm). 1
• Abemaciclib is currently the only FDA-approved CDK4/6 inhibitor for adjuvant therapy and is a Category 1, preferred option. 1

Palbociclib

• Two trials of adjuvant palbociclib in HR-positive/HER2-negative early breast cancer did not show benefit in invasive DFS. 1

Key Differences

• NATALEE used a lower ribociclib dose (400 mg vs 600 mg in metastatic disease) and longer treatment duration (3 years vs 2 years for abemaciclib). 3, 4
• NATALEE included a broader patient population, including select node-negative patients, compared to MonarchE's higher-risk population. 1, 3

Important Clinical Caveats

Drug Interactions

• Ribociclib is a potent CYP3A4 inhibitor, requiring careful attention to drug interactions, particularly with CYP3A4-metabolized medications like alprazolam. 7
• Concurrent use with CYP3A4-metabolized benzodiazepines should be avoided; alternatives include lorazepam, oxazepam, or non-benzodiazepine anxiolytics. 7

Special Populations

• Ribociclib should be used with extreme caution in elderly patients (≥65 years) due to increased sensitivity and higher drug exposure. 7
• The combination should be avoided entirely in patients with hepatic impairment, as both ribociclib and many concurrent medications undergo hepatic metabolism. 7
• Patients with cardiac risk factors or those taking QT-prolonging medications may be better candidates for alternative CDK4/6 inhibitors like palbociclib or abemaciclib. 8

Monitoring Requirements

• Regular monitoring for neutropenia, hepatotoxicity, and QT prolongation is essential throughout treatment. 7, 8, 6