354P - Synergistic preclinical efficacy through combination of the CDK4 and CDK2 selective inhibitors, PF-07220060 and PF-07104091, respectively, in HR+ HER2- breast cancer

Background

PF-07220060 (CDK4i) is a first-in-class CDK4 selective inhibitor, with superior efficacy and improved safety profile when compared to dual CDK4/6 inhibitors. PF-07220060 is currently being evaluated in a Phase 3 clinical trial in HR+/HER2- breast cancer. PF-07220060 provides the flexibility to increase its exposure and thus realize near complete target coverage of the CDK4 oncogene in HR+/HER2- breast cancer. PF-07104091 (CDK2i) is a first-in-class CDK2-selective inhibitor, also under clinical investigation in patients with HR+/HER2- breast cancer.

Methods

We interrogated the mechanisms of resistance to PF-07220060 in an in vivo model of HR+/HER2- breast cancer. Unbiased molecular analysis of the resistant tumors was conducted and in vitro as well as in vivo follow-up studies performed. Various dosing regimens with the combination of CDK4i (PF-07220060) and CDK2i (PF-07104091), were tested in naïve and palbociclib resistant in vivo models to identify minimum doses that could still achieve significant tumor growth inhibition (TGI).

Results

Molecular analysis of PF-07220060 resistant tumors showed upregulation of numerous candidate resistance mediators, including cyclin E1. Expression of CDK6 remained undetectable. Co-treatment of PF-07220060 with the selective CDK2i, PF-07104091, inhibited RB1 phosphorylation and sensitized HR+/HER2- breast tumors to PF-07220060. Combinatorial benefit was characterized by tumor regression rather than tumor stasis. Despite lowering one or both inhibitor concentrations, there were no differences in TGI observed between the different dosing regimens. At clinically relevant dosing, the anti-tumor efficacy of PF-07104091 in combination with PF-07220060 was superior to PF-07104091 plus palbociclib.

Conclusions

Combining the highly selective CDK2i (PF-07104091) and CDK4i (PF-07220060) for HR+/HER2- breast cancer circumvents inhibition of CDK6, resulting in less hematologic toxicity. Further, increased anti-tumor efficacy and tumor regression seen with this combination (unlike with the single agents, or the combination of CDK2i and palbociclib) provide the rationale for the current clinical trial NCT05262400.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Pfizer INC.

Funding

Pfizer INC.

Disclosure

L. Anders; T. Van Arsdale; S. Chintharlapalli; B. Boras; J. Cianfrogna; N. Huser; B. Pascual; C. Shen; M. Qiu; A. Sacaan; R. Jones: Financial Interests, Institutional, Full or part-time Employment: Pfizer.