Purpose:

The discovery that cyclin E overexpression is a key cyclin-dependent kinase (CDK) 4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2 and the simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of PF-06873600, the first-in-class inhibitor of CDK2/4/6.

Patients and Methods:

Dose escalation included 78 patients with advanced breast cancer, triple-negative breast cancer, or ovarian cancer who received oral PF-06873600 at doses ranging from 1 to 50 mg twice daily (part 1A, n = 51) or PF-06873600 with endocrine therapy (part 1B, n = 16; part 1C, n = 11) to determine the recommended dose for expansion (RDE). Dose expansion (part 2A, n = 45; part 2C, n = 28) assessed preliminary antitumor activity, safety, and tolerability at the RDE in combination with fulvestrant in patients with hormone receptor+/HER2− metastatic breast cancer. Pharmacodynamics and translational readouts were assessed by measuring phosphorylated Rb and Ki67 in tumor biopsies and ctDNA.

Results:

The RDE of PF-06873600 was 25 mg twice daily. During dose escalation, 6 of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. The most common all-causality adverse events (N = 151) were nausea (62.9%), anemia (44.4%), and fatigue (43.7%). Reductions in Ki67-positive cells, phosphorylated Rb histo-score, and ctDNA levels were observed. Three RECIST partial responses (PR) were observed in part 1. In part 2A, there were three PRs (objective response rate, 6.7%; 95% confidence interval, 1.4%–18.3%), and in part 2C, there were five PRs (objective response rate, 22.7%; 95% confidence interval, 7.8%–45.4%).

Conclusions:

PF-06873600 demonstrated a benefit–risk profile consistent with the CDK4/6 inhibitor class of drugs, with preliminary clinical activity in hormone receptor+/HER2− metastatic breast cancer.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
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First page of First-in-Human Phase I/IIa Study of the First-in-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer<alt-title alt-title-type="short">CDK2/4/6 Inhibitor PF-06873600 in Breast Cancer</alt-title>

Supplementary data

Supplementary Table S1

Supplementary Table S1. Representativeness of study participants.

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Supplementary Table S2

Supplementary Table S2. Summary of treatment-emergent adverse events (>15%) by preferred term and maximum CTCAE grade (treatment-related, all cycles)—safety analysis set, Part 2.

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Supplementary Table S3

Supplementary Table S3. Descriptive summary of plasma PF-06873600 immediate release formulation PK parameters—PK parameter analysis set.

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Supplementary Table S4

Supplementary Table S4. Descriptive summary of plasma PF-06873600 PK parameters following the immediate release, modified release short duration, and modified release long duration formulations (Part 1C)—PK parameter analysis set.

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Supplementary Figure S1

Supplementary Figure S1. Change from baseline in tumor biomarkers following monotherapy or combination treatment - biomarker analysis set.

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Supplementary Figure S2

Supplementary Figure S2. ctDNA molecular response.

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Supplementary Figure S3

Supplementary Figure S3. Median ctDNA change and PFS.

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Supplementary Figure S4

Supplementary Figure S4. Waterfall plot for best percent change from baseline in sum of diameters for target lesions based on investigator assessment (RECIST v1.1) - full analysis set, Part 2.

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