Atirmociclib

Overview

Atirmociclib (PF-07220060; Example A94) is an investigational, orally administered, selective cyclin-dependent kinase 4 (CDK4) inhibitor developed by Pfizer. Clinical development has focused primarily on hormone receptor-positive, HER2-negative (HR+/HER2−) advanced or metastatic breast cancer, including disease that progressed during prior CDK4/6-inhibitor therapy. It has also been studied in other solid tumors and in combinations with endocrine therapy and other targeted agents. (asco.org)

Mechanism of action

CDK4–cyclin D promotes cell-cycle progression by phosphorylating retinoblastoma protein, thereby activating the E2F pathway and transition from G1 to S phase. Atirmociclib selectively inhibits CDK4, suppressing retinoblastoma phosphorylation and tumor-cell proliferation. Its greater selectivity for CDK4 over CDK6 is intended to preserve CDK6-dependent hematopoiesis and potentially reduce neutropenia relative to dual CDK4/6 inhibitors. Preclinical experiments demonstrated antitumor activity and less inhibition of hematopoietic progenitor cells, although these advantages require confirmation in comparative clinical trials. (pubmed.ncbi.nlm.nih.gov)

Efficacy

In the first-in-human phase 1/2a study (NCT04557449), 26 patients with HR+/HER2− metastatic breast cancer previously treated with a CDK4/6 inhibitor received atirmociclib plus letrozole or fulvestrant. Among 21 patients with measurable disease, the confirmed objective response rate was 28.6%—one complete and five partial responses—and the clinical-benefit rate was 52.4%. Median progression-free survival was 24.7 weeks. (asco.org)

With longer follow-up in a heavily pretreated cohort, the reported confirmed response rate was 32% (8/25 evaluable patients) and median progression-free survival was 8.1 months; these updated figures were disclosed in a company scientific presentation rather than a peer-reviewed publication. (investors.pfizer.com)

In the randomized 264-patient phase 2 FOURLIGHT-1 study, atirmociclib plus fulvestrant reduced the investigator-assessed risk of progression or death by 40% versus fulvestrant or everolimus plus exemestane (hazard ratio 0.60; 95% CI 0.440–0.825; p=0.0007). Median progression-free survival and response-rate results had not yet been publicly reported, and overall-survival data were immature. These findings were announced as topline company results on March 17, 2026 and had not yet undergone presentation or peer review. (pfizer.com)

Safety

In the phase 1/2a endocrine-therapy cohorts, the most frequent treatment-related toxicities included neutropenia, leukopenia, anemia, diarrhea and nausea. In a 39-patient fulvestrant expansion cohort, treatment-related neutropenia occurred in 38.5%, leukopenia in 33.3% and anemia in 25.6%; the most frequent grade 3 events were neutropenia and leukopenia, each in 12.8%. No grade 4 or higher treatment-related events or febrile neutropenia were reported, and no patient discontinued atirmociclib because of a treatment-related event. (pfizeroncologydevelopment.com)

In FOURLIGHT-1, 6.4% of patients discontinued atirmociclib because of treatment-emergent adverse events. Detailed event rates were not included in the topline announcement, which described the safety profile as manageable and reported no new safety signals. (pfizer.com)

Further reading

• First-in-human phase 1/2a clinical abstract, Journal of Clinical Oncology
• Updated phase 1/2a safety poster, ASCO 2024
• Preclinical study in Cancer Cell
• Medicinal-chemistry and discovery paper
• FOURLIGHT-1 phase 2 topline results

Last updated: Sep 2026