First-In-Human Phase 1/2a Study of the First-In-Class CDK2/4/6 Inhibitor PF-06873600 Alone or with Endocrine Therapy in Patients with Breast Cancer

Abstract Purpose: The discovery that cyclin E overexpression is a key CDK4/6 inhibitor resistance mechanism has reinvigorated interest in targeting CDK2, and simultaneous inhibition of CDK2/4/6 as a novel therapeutic approach. This first-in-human study assessed 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 1–50 mg twice daily (BID) (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 HR+/HER2– mBC. Pharmacodynamics and translational readouts were assessed by phosphorylated Rb and Ki67 in tumor biopsies and circulating tumor DNA (ctDNA). Results: The RDE of PF-06873600 was 25mg BID. During dose escalation, six of 42 (14.3%) evaluable patients had treatment-related dose-limiting toxicities. Most common all-causality adverse events (N=151) were nausea (62.9%), anemia (44.4%) and fatigue (43.7%). Reductions in Ki67-positive cells, pRb H-score, and ctDNA levels were observed. Three RECIST partial responses (PRs) were observed in Part 1. In Part 2A there were three PRs (objective response rate [ORR] 6.7%, 95% CI: 1.4–18.3%) and, in Part 2C, five PRs (ORR 22.7%, 95% CI: 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 HR+/HER2– mBC. ClinicalTrials.gov identifier: NCT03519178