PF-07220060

Overview

Atirmociclib (PF-07220060) is an investigational, oral, next‑generation cyclin‑dependent kinase 4 (CDK4)–selective inhibitor being developed primarily for hormone receptor–positive, HER2‑negative (HR+/HER2−) advanced/metastatic breast cancer (mBC). Multiple trials are ongoing, including a global randomized study of PF‑07220060 plus fulvestrant versus fulvestrant or everolimus/exemestane after prior CDK4/6 inhibitor therapy (NCT06105632). This study was presented as a phase 3 design at ASCO 2024 (TPS1129), while current sponsor listings describe it as phase 2; as of August–September 2025 the trial is active but not recruiting. (ascopubs.org)

Mechanism of action

Atirmociclib is a highly selective inhibitor of CDK4 that spares CDK6, aiming to inhibit the cyclin D–CDK4/RB/E2F axis and arrest G1‑S cell‑cycle progression. Preclinical work reports markedly greater selectivity for CDK4 over CDK6 compared with first‑generation CDK4/6 inhibitors (approximately 20‑fold vs palbociclib and ~4‑fold vs abemaciclib/ribociclib). (pfizeroncologydevelopment.com)

Efficacy

• Phase 1/2a (first‑in‑human) PF‑07220060 + endocrine therapy (letrozole or fulvestrant) after prior CDK4/6 inhibitor:
• At ASCO 2023 (data cutoff Nov 1, 2022), among 26 patients with HR+/HER2− mBC (21 with measurable disease), confirmed objective responses were seen in 6/21 (29%; 1 CR, 5 PR). Clinical benefit rate (CBR: CR+PR+≥24‑week SD) was 52%, and median PFS was 24.7 weeks; 31% remained on treatment ≥60 weeks. (ascopubs.org)

• An ESMO Breast Cancer 2024 mini‑oral (Abstract 184MO; updated dataset to Nov 1, 2023) reported 1 CR and 7 PR in 25 patients with measurable disease (CBR 64%) and median PFS 8.1 months. (dailyreporter.esmo.org)

• Combination strategy with a selective CDK2 inhibitor (PF‑07104091) to overcome resistance:

• Early phase Ib/II dose‑escalation data in heavily pretreated HR+/HER2− mBC showed an ORR of 27.8%, disease control rate 55.6%, and median PFS 8.3 months; neutropenia was the most common grade ≥3 AE. Dose‑expansion is ongoing (NCT05262400). Preclinical ESMO 2024 work supported the biological rationale for CDK4+CDK2 blockade. (mdanderson.org)

No randomized efficacy results in humans have been reported as of October 2025. The international randomized study (NCT06105632; TPS1129) is ongoing. (ascopubs.org)

Safety

• In the ASCO 2023 first‑in‑human study (post‑CDK4/6i HR+/HER2− mBC), the most frequent treatment‑emergent AEs with PF‑07220060 + endocrine therapy were diarrhea (50%; 0% grade 3), neutropenia (50%; 15% grade 3), and nausea (39%; 4% grade 3). Dose‑limiting toxicities included grade 3 thrombocytopenia at 500 mg BID monotherapy and grade 3 leukopenia/neutropenia at 400 mg BID + fulvestrant; 300 mg BID was selected for expansion. (ascopubs.org)

• ASCO 2024 update (Parts 1B–1C post‑CDK4/6i; Parts 2B–2C CDK4/6i‑naïve): the most common AEs included neutropenia (pooled 1B–1C: 54.5% [18.2% grade 3]; Part 2B: 61.8% [23.5% grade 3]; Part 2C: 36.1% [11.1% grade 3]), leukopenia, and anemia. No grade >3 TEAEs were reported in these cohorts; discontinuations due to AEs occurred in 3.0%–8.3%, and relative dose intensity was ~98%–100%, supporting continuous dosing. (ascopubs.org)

• In the early CDK4+CDK2 combination trial, neutropenia was the most common grade ≥3 AE; overall safety was characterized as manageable. (mdanderson.org)

Ongoing trials (selected)

• NCT04557449 (Phase 1/2a): PF‑07220060 as monotherapy and with endocrine therapy in advanced solid tumors, enriched for HR+/HER2− mBC. Ongoing dose‑expansion. (pfizeroncologydevelopment.com)
• NCT06105632 (FOURLIGHT‑1): randomized PF‑07220060 + fulvestrant versus fulvestrant or everolimus/exemestane after prior CDK4/6 inhibitor; sponsor site currently lists Phase 2; originally presented as Phase 3 (TPS1129). (pfizeroncologydevelopment.com)
• NCT05262400 (Phase 1b/2): PF‑07220060 + PF‑07104091 (CDK2 inhibitor) ± endocrine therapy in HR+/HER2− mBC and other tumors. (pfizeroncologydevelopment.com)

Further reading

• First‑in‑human PF‑07220060 + ET, ASCO 2023 abstract (efficacy and safety): https://ascopubs.org/doi/abs/10.1200/JCO.2023.41.16_suppl.3009 (ascopubs.org)
• Updated safety across post‑CDK4/6i and CDK4/6i‑naïve cohorts, ASCO 2024 abstract 3108: https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.3108 (ascopubs.org)
• International randomized study design (TPS1129), ASCO 2024: https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.TPS1129 (ascopubs.org)
• Pfizer molecule page (mechanism, rationale): https://www.pfizeroncologydevelopment.com/molecule/cdk4-inhibitor (pfizeroncologydevelopment.com)
• AACR 2024 preclinical abstract (CDK4 selectivity data): https://aacrjournals.org/cancerres/article/84/6_Supplement/595/739776 (aacrjournals.org)
• Sponsor trial listings: NCT04557449 and NCT06105632 pages on Pfizer’s oncology development site. https://www.pfizeroncologydevelopment.com/clinical_trial/NCT04557449 and https://www.pfizeroncologydevelopment.com/clinical_trial/NCT06105632 (pfizeroncologydevelopment.com)
• CDK4+CDK2 combination early clinical data and rationale (MD Anderson/ESMO 2024; trial NCT05262400):
• Research highlight: https://www.mdanderson.org/newsroom/md-anderson-research-highlights-special-edition--ESMO-2024.h00-159700701.html (mdanderson.org)
• Trial overview (sponsor site): https://www.pfizeroncologydevelopment.com/clinical_trial/nct05262400 (pfizeroncologydevelopment.com)

Notes: Atirmociclib remains investigational; no regulatory approvals have been granted, and all efficacy/safety findings to date are preliminary and derived from early‑phase and/or non‑randomized cohorts. (pfizeroncologydevelopment.com)

Last updated: Oct 2025