P1/2, N=45, Recruiting, West China Hospital | Not yet recruiting --> Recruiting | Trial completion date: Apr 2028 --> Sep 2028 | Initiation date: Apr 2025 --> Sep 2025 | Trial primary completion date: Apr 2027 --> Sep 2027

Early clinical data demonstrated activity of BLU-222, a potent and selective CDK2 inhibitor, both as monotherapy (CCNE1 amplified) and in combination with ribociclib and fulvestrant in patients with HR+/HER2- breast cancer. These findings provide evidence that CDK2i combined with CDK4/6i can address multiple known mechanisms of resistance to CDK4/6i, enhancing antitumor responses in preclinical breast cancer models.

In the two cases we reported, first-line palbociclib therapy shows adequate and timely responses for premenopausal HR+/HER2- metastatic breast cancer patients. Although not widely utilized, frontline therapy with palbociclib combined with endocrine treatments may be a choice for HR+/HER2- metastatic breast cancer patients experiencing severe visceral metastasis.

Combining palbociclib, trastuzumab, and ET was safe and improved significantly PFS, compared to TPC in previously treated HER2-positive, PAM50 luminal A/B ABC patients.

P2, N=14, Active, not recruiting, Case Comprehensive Cancer Center | Recruiting --> Active, not recruiting | N=29 --> 14

P2, N=35, Not yet recruiting, Sun Yat-sen University

CDK4/6 inhibitors have distinct toxicity profiles. Effective AE management and dose adjustments are crucial for maintaining efficacy, emphasizing the need for AE prediction models to optimize CDK4/6i use in HR + HER2 - aBC.

In addition, 48a demonstrated superior growth-inhibitory activity compared to the warhead, palbociclib, in several leukemia cells and displayed favorable microsomal stability...Furthermore, 48a reduced tumor burden and CDK6 levels in an in vivo xenograft model. Collectively, these findings highlight the potential of KLHDC2-mediated degraders as a novel strategy for selective CDK6 degradation and underscore the promise of KLHDC2 as an alternative E3 ligase platform for targeted protein degradation.

A palbociclib lead-in prior to retifanlimab had a high rate of immune-related toxicities. Correlative analyses identified changes in tumor and immune cells attributable to treatment. A study of concurrent dosing of the combination is ongoing.

Immunofluorescence assays depicted an upregulation of BAX and downregulation of Bcl2 protein expression. In the cell cycle study, the RR-PAL-NPs showed remarkable G0/G1 phase arrest due to the decreased phosphorylation of retinoblastoma protein.

Furthermore, we prepared polymeric nanomicelles (MCs) encapsulated with palbociclib (PLB) using the solvent casting technique and surface decorated with an antiprogrammed cell death-ligand 1 (PD-L1) antibody to target hypoxic breast tumor...The clinical dye indocyanine green (ICG) has been utilized to evaluate the targeting efficiency of MCs toward breast tumors using USG/PAI imaging, demonstrating that targeted micelles has enhanced tumor localization. Furthermore, DiD dye has been employed to investigate organ biodistribution through IVIS imaging.

Ribociclib is associated with an increased risk of hepatotoxicity, with the potential for grade 3-4 in a small number of patients. Our analysis suggested a potential association between grade 3-4 hepatotoxicity and reduced OS, warranting further investigation. Regular monitoring of liver function tests during ribociclib treatment may help clinicians identify high-risk patients requiring closer follow-up.