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
Mené sur 78 patientes atteintes d'un cancer du sein de stade avancé, d'un cancer du sein triple négatif ou d'un cancer de l'ovaire, cet essai de phase I/IIA détermine la dose maximale tolérée de PF-06873600 (un inhibiteur de CDK2/4/6) seul et en combinaison avec un traitement endocrinien, puis analyse ses caractéristiques pharmacodynamiques et pharmacocinétiques
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
Clinical Cancer Research , résumé 2025