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Clinical Trial
. 2025 Jul 15;31(14):2899-2909.
doi: 10.1158/1078-0432.CCR-24-2740.

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

Timothy A Yap  1 , Jonathan W Goldman  2 , Shaveta Vinayak  3 , Antoaneta Tomova  4 , Erika Hamilton  5 , Yoichi Naito  6 , Antonio Giordano  7 , Igor Bondarenko  8 , Toshinari Yamashita  9 , Li Zhou  10 , Allison Moreau  10 , Heather Neumann  10 , Jessica Tougias  11 , Feng Liu  10 , Jennifer Park  10 , Maria Delioukina  10 , Komal Jhaveri  12   13
Affiliations
Clinical Trial

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

Timothy A Yap et al. Clin Cancer Res. .

Abstract

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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Conflict of interest statement

T.A. Yap reports other support from the University of Texas MD Anderson Cancer Center; personal fees from AbbVie, Acrivon, Adagene, Almac, Alterome Therapeutics Inc., Aduro, Amgen Inc., Amphista, Astex, Athena, Atrin, Avenzo, Avoro, Axiom, Baptist Health Systems, BioCity Pharma, Bloom Burton, Boxer, BridGene Biosciences, Bristol Myers Squibb, C4 Therapeutics, Calithera, Cancer Research UK, Carrick Therapeutics, Circle Pharma, Cybrexa, Daiichi Sankyo, Dark Blue Therapeutics, Debiopharm, Diffusion, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Ellipses Pharma, Entos, FoRX Therapeutics AG, Genesis Therapeutics, Genmab, Glenmark, GLG, Globe Life Sciences, Grey Wolf Therapeutics, GSK, Guidepoint, Idience, Ignyta, I-MAB, Impact Therapeutics, Institut Gustave Roussy, Intellisphere, Janssen, Joint Scientific Committee for Phase I Trials in Hong Kong, Kyn, Kirin, Lumanity, MEI Pharma, Mereo, Merit, Monte Rosa Therapeutics, Natera, Nested Therapeutics, Nexys, Nimbus, Novocure, Odyssey Therapeutics, OHSU, OncoSec, Ono Pharma, Onxeo, PanAngium Therapeutics, Pegascy, PER, Piper Sandler, Plexium Inc., Prolynx, Protai Bio, Radiopharma Theranostics, resTORbio, Ryvu Therapeutics, SAKK, Schrödinger, Servier, Synnovation, Synthis Therapeutics, TCG Crossover, TD2, Terremoto Biosciences, Tessellate Bio, Theragonostics, Terns Pharmaceuticals, Thryv Therapeutics, Tolremo, Tome, Trevarx Biomedical, Varian, Veeva, Versant, Vibliome, Voronoi Inc., Xinthera, Zai Labs, and ZielBio; grants and personal fees from Artios, AstraZeneca, Bayer, BeiGene, Blueprint, Clovis, EMD Serono, F-Star, Ideaya Biosciences, Innunesensor, Kyowa, Merck, Pfizer, Pliant Therapeutics, Prelude Therapeutics, Repare, Roche, Sanofi, and Tango; grants from BioNTech, Bristol Myers Squibb, Boundless Bio, Constellation, CPRIT, Cyteir, Department of Defense, Eli Lilly, Exelixis, Forbius, GlaxoSmithKline, Genentech, Gilead, Golfers Against Cancer, Haihe, ImmuneSensor, Insilico Medicine, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Novartis, NIH/NCI, Ribon Therapeutics, Rubius, Scholar Rock, Seattle Genetics, Synnovation, Tesaro, V Foundation, Vivace, Zenith, and Zentalis; and other support from Seagen outside the submitted work; in addition, T.A. Yap reports being Vice President and Head of Clinical Development in the Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, which has a commercial interest in DNA Damage Response and other inhibitors (IACS30380/ART0380 was licensed to Artios). J.W. Goldman reports grants from Pfizer during the conduct of the study as well as grants from Pfizer outside the submitted work. E. Hamilton reports grants and other support from Pfizer during the conduct of the study as well as grants and other support from Arvinas, AstraZeneca, BeiGene, Daiichi Sankyo, Gilead Sciences, Lilly, Mersana, Novartis, Pfizer, Roche/Genentech, and Stemline Therapeutics; grants from AtlasMedx, Black Diamond, Bliss BioPharmaceuticals, Compugen, Context Therapeutics, Cullinan, Curis, CytomX, Dana-Farber Cancer Institute, Dantari, Deciphera, Duality Biologics, eFFECTOR Therapeutics, Eisai, Ellipses Pharma, Elucida Oncology, EMD Serono, Fochon Pharmaceuticals, FujiFilm, G1 Therapeutics, H3 Biomedicine, Harpoon, Hutchinson MediPharma, Immunogen, Immunomedics, Incyte, Infinity Pharmaceuticals, Inspirna, InvestisBio, Jacobio, Karyopharm, K-Group Beta, Kind Pharmaceuticals, Leap Therapeutics, Loxo Oncology, Lycera, Mabspace Biosciences, Macrogenics, MedImmune, Merus, Millennium, Molecular Templates, Myriad Genetic Laboratories, Nucana, Olema, OncoMed, Oncothyreon, ORIC Pharmaceuticals, Orinove, Orum Therapeutics, PharmaMar, Pieris Pharmaceuticals, Pionyr Immunotherapeutics, Plexxikon, Prelude Therapeutics, Profound Bio, Radius Health, Regeneron, Relay Therapeutics, Repertoire Immune Medicine, Rgenix, Seagen, Sermonix Pharmaceuticals, Shattuck Labs, Silverback Therapeutics, StemCentRx, Sutro, Syndax, Syros, Taiho, TapImmune, Tesaro, Tolmar, Torque Therapeutics, Treadwell Therapeutics, Verastem, Zenith Epigenetics, and Zymeworks; and other support from Circle Pharma, Entos, Incyclix Bio, IQVIA, Janssen, Jazz Pharmaceuticals, Jefferies LLC, Johnson & Johnson, Medical Pharma Services, Pyxis Oncology, Samsung Bioepis, Shorla Pharma, Tempus Labs, Theratechnologies, and Zentalis Pharmaceuticals. Y. Naito reports grants and personal fees from Chugai, Pfizer, Eisai, AstraZeneca, Ono, Takeda, Taiho, Daiichi Sankyo, Gilead, and Myriad; personal fees from Eli Lilly, PDR Pharma, Novartis, Guardant, Bayer, Nihon Kayaku, Bristol, and MSD; and grants from Roche, AbbVie, and Boehringer Ingelheim outside the submitted work. A. Giordano reports personal fees from Pfizer and other support from Pfizer outside the submitted work. T. Yamashita reports grants and personal fees from Chugai, Eisai, Daiichi Sankyo, Taiho, Nippon Kayaku, AstraZeneca, Pfizer, Eli Lilly, and MSD; personal fees from Kyowa Kirin and Novartis Pharma; and grants from Ono, Gilead Sciences, and Seagen during the conduct of the study. L. Zhou reports employment with Pfizer and ownership of Pfizer stock. M. Delioukina reports employment with Pfizer. K. Jhaveri reports personal fees from Novartis, Genentech/Roche, Blueprint Medicines, Zymeworks, Bicycle Therapeutics, Lilly Pharmaceuticals, Olema Pharmaceuticals, AstraZeneca, Daiichi Sankyo, Seattle Genetics, AbbVie, Eisai, Scorpion Therapeutics, Gilead, Merck, Menarini, and Blueprint Medicine and other support from Pfizer, Gilead, AstraZeneca, Lilly, Genentech, Scorpion, Zymeworks, Puma Biotechnology, and Novartis outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1.
Figure 1.
Overall study schema. a25 mg twice daily (BID) was the RDE. bOne patient was untreated. AI, aromatase inhibitor; CDK, cyclin-dependent kinases; CDK4/6i, CDK4/6 inhibitor; ET, endocrine therapy; Ful, fulvestrant; HER2−, human epidermal growth receptor 2-negative; HR+, hormone receptor-positive; IR, immediate release; Let, letrozole; mBC, metastatic breast cancer; MR, modified release; RDE, recommended dose for expansion; TNBC, triple negative breast cancer.
Figure 2.
Figure 2.
Median plasma PF-06873600 concentration–time profile. A, Following single oral doses on cycle 1 day 1. B, Following multiple oral doses on cycle 1 day 15. *Part 1 PF-06873600 25 mg twice daily (BID) IR combined with part 1A PF-06873600 25 mg BID IR, part 1A PF-06873600 25 mg BID biomarker, and part 1C PF-06873600 MR 20 mg lead-in IR 25 mg BID. IR, immediate release; MR, modified release.
See this image and copyright information in PMC

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