NoLEEta: No chemotherapy in intermediate-risk HR+ HER2− early breast cancer treated with ribociclib in the adjuvant setting—A non-inferiority phase III trial.

Abstract

TPS645 Background: Historically, the treatment paradigm for hormone receptor-positive, HER2-negative early breast cancer (HR+ HER2− eBC) has relied on endocrine therapy (ET) and adjuvant chemotherapy. However, the absolute benefit of adjuvant chemotherapy is closely tied to baseline risk, being notably modest in intermediate risk eBC, while associated with significant short- and long-term toxicities. The phase III NATALEE trial demonstrated the efficacy of an adjuvant three-year treatment with ribociclib and ET in prolonging invasive disease-free survival (iDFS) in patients with high-risk HR+ HER− eBC. Contrarily to similar studies of CDK4/6 inhibitors in this setting, NATALEE included a group of patients with intermediate clinical risk (pT1-2 pN1, pT3-4 pN0 or pT2 pN0 with histological grade 3 or grade 2 with Ki67≥ 20%). These patients are usually treated with adjuvant chemotherapy based on the tumor clinicopathological characteristics or the results of a genomic signature. Nevertheless, the absolute benefit of adjuvant chemotherapy in these patients is uncertain (and likely reduced) in the context of an adjuvant treatment strategy that includes a CDK4/6 inhibitor. The NoLEEta trial aims at demonstrating that patients with intermediate-risk HR+ HER2− eBC treated with ribociclib and ET could be spared chemotherapy side effects while ensuring similar survival outcomes. Methods: NoLEEta is an international, randomized, open-label, non-inferiority phase III trial. Main inclusion criteria are: HR+ HER2− eBC after curative surgery, at intermediate risk of relapse (pT0-2 pN1, pT3-4 pN0, pT2 pN0 G3 or pT2 pN0 G2 with Ki67≥20%), eligible for adjuvant chemotherapy (per investigator decision, based on clinicopathological parameters or using a genomic signature). Eligible patients are randomized (1:1) to either receive ribociclib and ET (investigational arm without chemotherapy) or chemotherapy followed by ribociclib and ET (control arm). Primary endpoint is invasive breast cancer-free survival (iBCFS), defined in accordance with the STEEP system as the interval between randomization and the earliest occurrence of ipsilateral invasive breast tumor recurrence, local–regional invasive recurrence, distant recurrence, invasive contralateral breast cancer, or death from any cause. Secondary endpoints include invasive disease-free survival, distant disease-free survival, overall survival, interval and type of iBCFS events, incidence and severity of adverse events, and health-related quality of life. Enrollment in NoLEEta started in December 2025, with a target objective of 3902 randomized patients across 8 countries. One interim analysis is planned. Clinical trial information: NCT07237256 .