atirmociclib (PF-07220060) / Pfizer - LARVOL DELTA

Long-term safety and efficacy of first-line atirmociclib + letrozole for the treatment of patients with HR+/HER2− metastatic breast cancer (mBC) (ESMO 2025) - P2 | "Conclusions At 24.8 months of follow-up, ATI + LET continues to show favorable safety/tolerability and promising efficacy when used as 1L treatment in pts with HR+/HER2− mBC. A randomized phase 3 trial of ATI + LET has been initiated based on these data."

Clinical • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK6 • HER-2

Phase Ib/II first-in-class novel combination trial of next generation CDK4-selective inhibitor PF-07220060 and next generation CDK2-selective inhibitor PF-07104091 in HR+ HER2- metastatic breast cancer and advanced solid tumors (ESMO 2024) - P1/2 | "BC pts could start fulvestrant at Cycle 3. PF-60/PF-91 combination was generally well tolerated with promising antitumor activity in heavily pretreated post-CDK4/6i mBC pts, including 5 PRs in mBC pts with ESR1 mutations and mPFS 8.3 months. Dose expansions are enrolling CDK4/6i-treated and naïve mBC pts."

Metastases • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

International phase 3 clinical trial evaluating PF-07220060 plus fulvestrant in patients with HR+/HER2− advanced/metastatic breast cancer with progression after a prior CDK4/6 inhibitor. (ASCO 2024) - P3 | "Approximately 500 patients will be randomly assigned (1:1) to receive PF-07220060 (orally and continuously in a 28-day cycle) plus fulvestrant (intramuscular injection on days 1 and 15 of cycle 1 and then on day 1 of each cycle thereafter) or investigator's choice of fulvestrant alone or everolimus plus exemestane, which must be declared before randomization. JCO. 2023; 41:3009."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • BRCA • ER • HER-2 • PIK3CA • PTEN

The next-generation CDK4-selective inhibitor atirmociclib (PF-07220060) in combination with letrozole as first-line treatment in patients with HR+/HER2+ metastatic breast cancer (SABCS 2024) - "Combination of atirmociclib + letrozole showed favorable safety/tolerability and promising early activity as first-line treatment in patients with HR+/HER2– mBC."

Clinical • Combination therapy • Metastases • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • CDK6 • CDKN2A • HER-2

First-in-human first-in-class phase 1/2a study of the next generation CDK4-selective inhibitor PF-07220060 in patients (pts) with advanced solid tumors, enriched for HR+ HER2- mBC who progressed on prior CDK4/6 inhibitors and endocrine therapy. (ASCO 2023) - P1/2 | " At data cut off (Nov 1, 2022), 34 pts with advanced solid tumors received PF-07220060 in monotherapy dose escalation (Part 1A: 100–500 mg BID), and 26 pts with HR+/HER2- mBC in combination (300mg/400mg BID) with letrozole or fulvestrant (Parts 1B + 1C). PF-07220060 + ET showed efficacy in pts with HR+/HER2- mBC who progressed on prior CDK4/6i+ET. Tolerability of PF-07220060 alone and in combination with ET was encouraging. Dose expansions with PF-07220060 + ET in pts with HR+/HER2- mBC post CDK4/6i and in CDK4/6i naïve pts are ongoing."

Clinical • Metastases • P1/2 data • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • Leukopenia • Neutropenia • Oncology • Solid Tumor • Thrombocytopenia • HER-2

First-in-human phase I/IIa study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 in combination with endocrine therapy (ET) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC) who progressed on prior CDK4/6 inhibitors (CDK4/6i): Safety and efficacy update (ESMO-BC 2024) - P1/2 | "Results At data cutoff (Nov 1, 2023), 33 pts received PF-07220060 (300mg/400mg BID) in combination with letrozole or fulvestrant (Parts 1B + 1C). Confirmed objective responses (PRs) were observed irrespective of ESR1 or PI3K pathway mutations. Conclusions PF-07220060 + ET showed a favorable safety profile with few hematologic adverse events and infrequent dose modifications, and promising efficacy despite prior CDK4/6i treatment, irrespective of key mutations."

Clinical • Combination therapy • Metastases • P1/2 data • Breast Cancer • Hematological Disorders • HER2 Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • CDK6 • CDKN2A • ER • HER-2

Morpheus-TNBC: A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Metastatic or Locally Advanced Breast Cancer (clinicaltrials.gov) - P1/2 | N=792 | Recruiting | Sponsor: Hoffmann-La Roche | N=580 ➔ 792 | Trial completion date: May 2028 ➔ Sep 2030 | Trial primary completion date: May 2028 ➔ Sep 2030

Enrollment change • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PD-L1 • PIK3CA

FOURLIGHT-1: A Study to Learn About the Study Medicine Called PF-07220060 in Combination With Fulvestrant in People With HR-positive, HER2-negative Advanced or Metastatic Breast Cancer Who Progressed After a Prior Line of Treatment (clinicaltrials.gov) - P2 | N=333 | Active, not recruiting | Sponsor: Pfizer | Trial primary completion date: Sep 2025 ➔ Mar 2026

Trial primary completion date • Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Discovery of NKT5097: a first-in-class, highly potent and selective, orally bioavailable CDK2/4 dual degrader for cancer therapy (SABCS 2025) - "NKT5097 also demonstrates a 68-fold increase in selectivity for CDK2 over CDK1 in comparison to PF-07104091, and a 33-fold increase in selectivity for CDK4 over CDK6 compared to PF-07220060 in functional cellular assays...Additionally, combination of NKT5097 with fulvestrant leads to deeper degradation of CDK2 and CDK4 in vitro, resulting in better tumor growth inhibition in HR+ breast cancer models...Therefore, as the first-in-class CDK2/4 dual degrader, NKT5097 presents a unique opportunity to serve as a backbone therapy for HR+HER2- breast cancer and other cancers with CDK2 and/or CDK4 dysregulation. NKT5097 is currently being investigated in a phase I clinical study."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • CCNE1 • CDK1 • CDK2 • CDKN2A • HER-2

Pharmacodynamic effects of the first-in-class CDK4-selective inhibitor atirmociclib (PF-07220060) in combination with endocrine therapy in tumors of patients with HR+/HER2− metastatic breast cancer (SABCS 2025) - P2 | "Atirmociclib, in combination with fulvestrant, showed strong effects in inhibiting cell cycle-related pharmacodynamic protein biomarkers and gene sets in HR+/HER2− mBCtumors, consistent with its mechanism of CDK4 inhibition. The analyses also revealed potential immune-modulatory effects of atirmociclib, including increased macrophage infiltration and enhanced antigen presentation pathway gene expression."

Clinical • Combination therapy • Metastases • PK/PD data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CAFs • CD4 • CD8 • FOXM1 • HER-2

Gdc-4198, a next-generation CDK4/2 inhibitor, induces durable cell cycle arrest and overcomes CDK2-driven adaptation to CDK4 inhibition (SABCS 2025) - "While CDK4/6 inhibitors (CDK4/6i) have changed the therapeutic landscape of hormone receptor-positive (HR+) breast cancer, resistance to these therapies is a major challenge limiting their clinical benefit...Immunofluorescence data from HR+ breast cancer cells revealed that the shift in cell cycle distribution induced by GDC-4198 was differentiated from the effects of CDK4/6i and can most closely be reproduced by a combination of atirmociclib (a CDK4 inhibitor) and tagtociclib (a CDK2 inhibitor)...Additional studies in patient-derived cell lines obtained in the setting of metastatic HR+ breast cancer following progression on letrozole/ribociclib, as well as in patient-derived cell lines with acquired in vitro resistance to palbociclib, confirmed the enhanced antitumor activity of GDC-4198 compared to current CDK4/6i or atirmociclib...Pharmacokinetic and pharmacodynamic analyses indicated favorable drug exposure and pharmacodynamic modulation in tumor tissues consistent..."

Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • CCNE1 • CDK2

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

Discovery of Atirmociclib (PF-07220060): A Potent and Selective CDK4 Inhibitor. (PubMed, J Med Chem) - "Central to our strategy were efficiency-based optimization (LipE and LipMetE), structure-based drug design, and molecular dynamics simulation. The culmination of these efforts resulted in the discovery of PF-07220060 (atirmociclib), which possessed high potency and levels of selectivity for CDK4 over CDK6 that translated to minimal impact on neutrophils while driving efficacy in a mouse ZR75-1 xenograft model."

Journal • Breast Cancer • Hematological Disorders • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Neutropenia • Oncology • Solid Tumor • CDK6 • HER-2

Investigating CDK2 and CDK4 Inhibition in IDH-Mutant Glioma with CDKN2A Deletion (SNO 2025) - "To test this, we assessed the response of IDH-mutant glioma cell lines (with and without CDKN2A deletion) to CDK2 inhibitors (INX-315, Tagtociclib), a CDK4 inhibitor (Atirmociclib), and their combination. Broader inhibitors, including Abemaciclib and PF-06873600 (CDK4/6 and CDK2/4/6 inhibitors, respectively), we measured the effect of the drug on cell viability and confirmed the impact of the drug on pathway activity by western blot mediators of CDK-Rb activity...These results suggest that CDK6 activity, or synergistic inhibition across CDK2/4/6, may be critical for efficacy. The lack of efficacy with selective inhibitors highlights on non-redundant roles of CDK in G1/S checkpoint regulation and underscores the complexity of CDK targeting in glioma."

Brain Cancer • Glioma • Solid Tumor • CDKN2A

A Study to Compare Two Tablet Formulations of Study Medicine Atirmociclib in Healthy Participants (clinicaltrials.gov) - P1 | N=35 | Completed | Sponsor: Pfizer | Not yet recruiting ➔ Completed

Trial completion

Study About Whether Atirmociclib/PF-07220060 Proportionally Increases Exposure as Dose Increases in Healthy Participants (clinicaltrials.gov) - P1 | N=72 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

A Study to Learn About How the Study Medicines Called Itraconazole and Probenecid Change How the Body Processes PF-07220060 (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: Pfizer | Not yet recruiting ➔ Recruiting

Enrollment open

Investigating CDK2 and CDK4 Inhibition in IDH-Mutant Glioma with CDKN2A Deletion (WFNOS 2025) - "To test this, we assessed the response of IDH-mutant glioma cell lines (with and without CDKN2A deletion) to CDK2 inhibitors (INX-315, Tagtociclib), a CDK4 inhibitor (Atirmociclib), and their combination. Broader inhibitors, including Abemaciclib and PF-06873600 (CDK4/6 and CDK2/4/6 inhibitors, respectively), we measured the effect of the drug on cell viability and confirmed the impact of the drug on pathway activity by western blot mediators of CDK-Rb activity...These results suggest that CDK6 activity, or synergistic inhibition across CDK2/4/6, may be critical for efficacy. The lack of efficacy with selective inhibitors highlights on non-redundant roles of CDK in G1/S checkpoint regulation and underscores the complexity of CDK targeting in glioma."

Brain Cancer • Glioma • Solid Tumor • CDKN2A

Anticipated Upcoming Events (GlobeNewswire) - "Initiate the Phase 1b/2 study evaluating palazestrant with atirmociclib in ER+/HER2- metastatic breast cancer in Q4 2025; Present trial-in-progress poster entitled 'OPERA-02: a phase 3 randomized, double-blind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2- advanced breast cancer' at the San Antonio Breast Cancer Symposium (SABCS) in December 2025; Report top-line data from OPERA-01 in the second half of 2026."

P3 data: top line • Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

OP-1250-003: Phase 1b Study of OP-1250 (Palazestrant) in Combination With Ribociclib, Alpelisib, Everolimus, or Atirmociclib in ER+, HER2- Breast Cancer (clinicaltrials.gov) - P1 | N=190 | Recruiting | Sponsor: Olema Pharmaceuticals, Inc. | Active, not recruiting ➔ Recruiting | Trial completion date: Sep 2026 ➔ Jan 2028 | Trial primary completion date: Aug 2026 ➔ Dec 2027

Enrollment open • Trial completion date • Trial primary completion date • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Randomized phase 2 trial of preoperative atirmociclib plus letrozole on Ki-67 tumor expression in HR+/HER2− early breast cancer (ESMO 2025) - P2 | "Secondary endpoints include safety, ctDNA measurements, Ctrough and peri-biopsy plasma atirmociclib concentration, and Ki-67 staining. Enrollment is ongoing in the US, Europe and Asia (NCT06465368)."

Clinical • P2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Randomized phase 3 clinical trial evaluating atirmociclib plus letrozole versus a CDK4/6 inhibitor plus letrozole as first-line treatment for patients with HR+/HER2− advanced/metastatic breast cancer (ESMO 2025) - P3 | "Overall survival is a key secondary endpoint; other secondary endpoints include objective response, duration of response, clinical benefit rate, safety, patient-reported outcomes, and changes in circulating tumor DNA. Enrollment is ongoing in the US, Europe and Asia, with additional global sites planned (NCT06760637)."

Clinical • Metastases • P3 data • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Study About Whether Atirmociclib/PF-07220060 Proportionally Increases Exposure as Dose Increases in Healthy Participants (clinicaltrials.gov) - P1 | N=72 | Not yet recruiting | Sponsor: Pfizer

New P1 trial

C4391001: Study to Test the Safety and Tolerability of PF-07220060 in Participants With Advance Solid Tumors (clinicaltrials.gov) - P2 | N=362 | Active, not recruiting | Sponsor: Pfizer | Recruiting ➔ Active, not recruiting | Phase classification: P1 ➔ P2

Enrollment closed • Phase classification • Breast Cancer • Castration-Resistant Prostate Cancer • Estrogen Receptor Positive Breast Cancer • Genito-urinary Cancer • Hormone Receptor Positive Breast Cancer • Liposarcoma • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Sarcoma • Solid Tumor • CCND1 • CD4 • CDKN2A

A Study to Learn About the Study Medicine PF-07220060 Together With Letrozole Compared to Letrozole Alone in Women Post Menopause (clinicaltrials.gov) - P2 | N=121 | Completed | Sponsor: Pfizer | Recruiting ➔ Completed | Trial completion date: Oct 2025 ➔ Jul 2025 | Trial primary completion date: Oct 2025 ➔ Jul 2025

Trial completion • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor