Atirmociclib and fulvestrant for patients with HR+/HER2- advanced/metastatic breast cancer who progressed on a prior cyclin-dependent kinase 4/6 inhibitor: primary analysis of the randomized FourLight-1 trial.

Background

Atirmociclib is a potential first-in-class, highly selective cyclin-dependent kinase (CDK) 4 inhibitor, demonstrating significantly greater selectivity over CDK6. In a phase 1/2a study, atirmociclib plus endocrine therapy was well tolerated and showed encouraging antitumor activity in patients with HR+/HER2- advanced/metastatic breast cancer (mBC). We present results from a randomized study of atirmociclib plus fulvestrant versus investigator's choice of therapy (ICT) in patients with HR+/HER2- mBC whose disease progressed on prior adjuvant or first-line CDK4/6 inhibitor treatment. PATIENTS AND

Methods

FourLight-1 is an open-label, phase 2 study. Patients were randomized 1:1 to atirmociclib (300 mg orally, twice daily, continuously) plus fulvestrant or ICT (fulvestrant alone or everolimus plus exemestane). The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), and safety.

Results

At the data cutoff (12 January 2026), 263 patients were enrolled (atirmociclib, n = 126; ICT, n = 137; median age: 57 years). PFS was significantly improved with atirmociclib versus ICT (stratified hazard ratio: 0.60; 95% CI, 0.440-0.825; 1-sided P = 0.0007; median: 9.4 vs 6.6 months). A consistent PFS benefit was observed across most subgroups. Patients with baseline measurable disease in the atirmociclib arm had a higher ORR versus the ICT arm (21 [19.3%] vs 13 [11.3%]; nominal 2-sided P = 0.0901) and median DOR was numerically longer (14.8 vs 9.3 months, respectively); CBR was 61.9% versus 46.0%, respectively. The most common any-grade treatment-emergent adverse events (TEAEs) in the atirmociclib arm were neutropenia (47.2%), leukopenia (33.6%), and diarrhea (28.0%); 6.4% of patients discontinued atirmociclib due to TEAEs.

Conclusions

Atirmociclib plus fulvestrant showed significant and clinically meaningful PFS improvement in patients who progressed on prior CDK4/6 inhibitor treatment with a manageable safety and tolerability profile.