Atirmociclib (selective CDK4 inhibitor) + letrozole drives 88% Ki-67 CCCA at Day 14 in HR+/HER2− early breast cancer

Atirmociclib (PF-07220060) is an oral, CDK4-selective inhibitor designed to deepen cell-cycle arrest with potentially less dose-limiting toxicity than less-selective CDK4/6 inhibition; in the randomized Phase 2 FourLight-2 “window-of-opportunity” study (NCT06465368), postmenopausal women with untreated HR+/HER2− breast cancer and baseline Ki-67 ≥10% received 14 days of atirmociclib 300mg BID + letrozole 2.5mg QD vs letrozole alone (n=59 vs n=62; Ki-67 evaluable n=51 vs n=56). Centrally assessed complete cell-cycle arrest (CCCA; Ki-67 ≤2.7%) at Day 14 was 88.2% (95% CI 76.6–94.5) with atirmociclib+letrozole vs 17.9% (95% CI 10.0–29.8) with letrozole, with median relative Ki-67 change −97.3% vs −72.4%; the CCCA gap held across tumor grade, T stage, and baseline Ki-67 subgroups. Safety over 14 days was mostly grade 1/2 (diarrhea 19% vs 2%, fatigue 15% vs 10%, nausea 14% vs 5%), with no grade 3/4 treatment-related TEAEs and no discontinuations—while this pharmacodynamic signal clearly exceeds aromatase inhibitor monotherapy (and is broadly in the same “CCCA saturation” neighborhood reported with palbociclib+letrozole over longer NET durations, albeit with different designs/timepoints), it remains a biomarker endpoint rather than a demonstrated improvement in pCR/EFS/OS.