Verzenio (abemaciclib)

Based on preclinical studies showing synergism with simultaneous inhibition of the estrogen receptor (ER), CDK4/6 and PI3K pathways and based on window of opportunity studies showing that metformin suppresses PI3K/mTOR signaling in endometrial cancer (EC), we conduct a non-randomized phase 2 study of letrozole/abemaciclib/metformin in ER positive endometrioid EC (NCT03675893). There are no objective responses among TP53 mutated ECs and among NSMP (no specific molecular profile) tumors with RB1 or CCNE1 alterations; CTNNB1 mutations correlate with clinical benefit. Pharmacokinetic analyses demonstrate that administration of letrozole and abemaciclib with metformin result in a more than 3-fold increase in metformin exposure.

We report that ONC201 and highly potent second generation ClpP agonists (TR-57, TR-107), promote induction of senescence in triple-negative breast cancer (TNBC) cell lines...By contrast, cells treated with the cell cycle inhibitor and senescence inducer, abemaciclib rapidly regained p-Rb and Myc expression and cell proliferation following washout...Combining a ClpP agonist with a PARP inhibitor (olaparib) produced an additive effect. In summary, we show that ClpP activators stably induce an irreversible senescence in a ClpP-dependent manner that synergizes with venetoclax in TNBC cells.

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

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.

We present a case of a 59-year-old postmenopausal female with metastatic hormone receptor-positive breast cancer who started treatment with fulvestrant and ribociclib after progression on anastrozole...Ribociclib was held, and after no improvement in 28 days, she was treated with a 6-day course of prednisone 1 mg/kg, with significant improvement in her liver enzymes...Following normalization of her liver enzymes, she was rechallenged with abemaciclib with no recurrent hepatotoxicity. Ribociclib hepatotoxicity can be successfully treated with withdrawal of the medication and a short course of corticosteroids if liver enzymes do not improve following a 28-day withdrawal, highlighting a potential immune-mediated mechanism. Additionally, rechallenge with another cyclin-dependent kinase 4 and 6 inhibitor is a safe and effective strategy that should be considered.

These findings highlight the potential of oral 5-FU derivatives as effective and safe treatment options to use after progression on CDK4/6i plus ET for patients with HR+/HER2- MBC.

P1/2, N=792, Recruiting, Hoffmann-La Roche | N=580 --> 792 | Trial completion date: May 2028 --> Sep 2030 | Trial primary completion date: May 2028 --> Sep 2030

Endocrine sensitivity/resistance and ET partner were major determinants of outcome with CDK4/6i plus ET in HR+/HER2- ABC, informing individualized treatment selection and sequencing.

The CDK4/6is included in this study were palbociclib, ribociclib, and abemaciclib. Treatment with CDK4/6is was not generally associated with worsening HRQoL among patients with MBC, except for the symptom-related, patient-reported measures of diarrhea and upset by hair loss. Understanding HRQoL impacts can help support health care decisions and treatment using CDK4/6is for patients with MBC.

P=N/A, N=1, Active, not recruiting, Pfizer | Recruiting --> Active, not recruiting | N=5087 --> 1

P1, N=42, Recruiting, National Cancer Institute (NCI) | Trial completion date: Nov 2025 --> Nov 2026 | Trial primary completion date: Nov 2025 --> Nov 2026

Abemaciclib (ABE), a selective CDK4/6 inhibitor, inhibits the activity of different drug efflux pumps in several types of cancer...In conclusion, ABE treatment differentially regulated the inhibition of efflux pump activities in GBM cells in terms of TMZ resistance. Our findings may provide new insights into the potential use of ABE as a therapeutic agent to overcome MDR in TMZ-resistant GBM.