116 Impact of Neoadjuvant Chemotherapy (NACT) Response on Clinical Outcomes With Ribociclib (RIB) in HR+/HER2− EBC: A Subgroup Analysis From the Phase 3 NATALEE Trial

Background

Initial trials establishing efficacy benefit of chemotherapy in patients with hormone receptor–positive (HR+)/HER2-negative (HER2–) early breast cancer pre-date the use of CDK4/6 inhibitors (CDK4/6i). Potential chemotherapy de-escalation in this population is of significant interest. Given the invasive disease-free survival (iDFS) benefit with ribociclib plus a nonsteroidal aromatase inhibitor (NSAI) vs NSAI alone seen in NATALEE, we evaluated the impact of neoadjuvant chemotherapy response on clinical outcomes.

Methods

We evaluated patients who had received neoadjuvant chemotherapy in NATALEE (n = 2180) and outcomes based on neoadjuvant chemotherapy response. A composite scoring system was used to categorize patients as neoadjuvant chemotherapy responders or non-responders based on change in tumor size, nodal status, and Ki-67 from baseline to surgery (Table). Patients with composite scores totaling 1 or more were considered responders. iDFS was analyzed using a multivariate Cox model stratified by region, menopausal status, nodal status, and stage.

Results

At baseline, the responder vs non-responder group had larger tumors (T4, 18.3% vs 13.4%; T3, 32.0% vs 28.1%; T2, 44.4% vs 42.0%; T1, 4.6% vs 11.6%), greater nodal status (N3, 14.5% vs 6.0%; N2, 21.5% vs 14.0; N1, 50.3% vs 58.7%; N0, 10.4% vs 15.3%), and a greater proportion of premenopausal patients (56.0% vs 47.3%). For patients treated with ribociclib plus NSAI (n = 1085), the iDFS benefit was similar in responders and non-responders (4-year iDFS, 86.5% vs 82.4%; hazard ratio, 0.972; 95% CI, 0.688-1.372). However, for patients treated with NSAI alone (n = 1095), iDFS benefit was greater among responders (4-year iDFS, 85.7% vs 74.8%; hazard ratio, 0.62; 95% CI, 0.445-0.864). No impact with grade or histology was found for responders vs non-responders in either arm when adjusted for responder status and other covariates.

Conclusions

Neoadjuvant chemotherapy non-responders had worse iDFS with NSAI alone, but there was no difference in iDFS between responders and non-responders with ribociclib plus NSAI.Given the overall improved iDFS associated with ribociclib plus NSAI, these data suggest that CDK4/6i warrants further investigation as a chemotherapy de-escalation strategy in HR+/HER2– early breast cancer.

Previously presented at 2025 ESMO: McAndrew N, et al. October 17-21, 2025; Berlin, Germany. Poster 366P. Reused with permission.