Abstract 595: Preclinical development of the CDK4 selective inhibitor PF-07220060: Increased CDK4 versus CDK6 inhibition leads to improved anti-tumor efficacy at therapeutic concentrations
Authors: Anders Lars , Pascual Bernadette , Boras Britton , Cianfrogna Julie , Garza Scott , Li Na , Yuan Jing Tang , Moen Mark , Huser Nanni , Gallego Gary , Jalaie Mehran , Ninkovic Sacha , Cho-Schultz Sujin , Shen Hong , Kath John , Dress Klaus , Diehl Wade , Nair Sajiv , Jones Rhys , Lafontaine Jennifer , Murtaza Anwar , Sacaan Aida , Chintharlapalli Sudhakar , VanArsdale Todd 
Published: March 2024

Abstract
PF-07220060 is a selective inhibitor of CDK4, displaying ~20-fold and ~4-fold increased selectivity for CDK4 versus CDK6 when compared to palbociclib and abemaciclib/ribociclib, respectively. This translates to less PF-07220060 associated neutropenia in beagle dogs and humans when compared to dual CDK4/6 inhibitors. Because neutropenia is the primary culprit necessitating limited and often interrupted clinical dosing of dual CDK4/6 inhibitors, the advantage of PF-07220060 lies in the flexibility to escalate the drug’s exposure in patients and thus realize near-complete target coverage of the CDK4 oncogene in tumors that are dependent on this kinase. Here we select tumor types/indications that show dependency on CDK4 but not CDK6 and includes cells derived from luminal breast cancer and androgen-receptor positive metastatic prostate cancer. Additionally, we investigate certain drugs with which PF-07220060 may be combined to maximize its efficacy in these tumor indications. PF-07220060 sensitizes HR+ HER2- breast cancer to the estrogen inhibitor, fulvestrant and the degrader, ARV-471 (vepdegestrant). PF-07220060 + vepdegestrant showed significantly longer tumor regrowth delay vs monotherapy groups and vs Palbo + vepdegestrant and vs PF-07220060 + fulvestrant*. Similarly, PF-07220060 sensitizes prostate cancer to the androgen receptor antagonist, enzalutamide. In HR+ HER2- breast cancer cells, the senescent cell fraction was markedly increased by co-treatment with PF-07220060 and fulvestrant versus either drug alone, albeit the combination did not trigger tumor cell death. Further addition of the PI3K inhibitor alpelisib was sufficient to enforce tumor shrinkage in vivo. Alternatively, inhibition of CDK4 plus CDK2 also led to tumor shrinkage in xenograft models of HR+, HER2- breast cancer. Finally, our preclinical data indicate that the propensity of CDK6 to compensate for CDK4 inhibition in these tumor types is limited. Compensation by CDK6 was seen in only a fraction of the evaluated in vitro and in vivo models. Even so, in these instances, PF-07220060’s efficacy remained comparable to palbociclib’s when both drugs were used at their therapeutic doses. We conclude that PF-07220060’s anti-tumor efficacy is broadly superior to currently approved dual CDK4/6 inhibitors.
Citation Format: Lars Anders, Bernadette Pascual, Britton Boras, Julie Cianfrogna, Scott Garza, Na Li, Jing Tang Yuan, Mark Moen, Nanni Huser, Gary Gallego, Mehran Jalaie, Sacha Ninkovic, Sujin Cho-Schultz, Hong Shen, John Kath, Klaus Dress, Wade Diehl, Sajiv Nair, Rhys Jones, Jennifer Lafontaine, Anwar Murtaza, Aida Sacaan, Sudhakar Chintharlapalli, Todd VanArsdale. Preclinical development of the CDK4 selective inhibitor PF-07220060: Increased CDK4 versus CDK6 inhibition leads to improved anti-tumor efficacy at therapeutic concentrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 595.