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

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.