Verzenio (abemaciclib)

Theranostic SSTR2-targeting via [68Ga]DOTATATE for PET imaging and β-emitting [177Lu]DOTATATE for the treatment of meningiomas are currently under active investigation. A nuanced approach is needed for the treatment of refractory meningiomas. Targeted therapies show promise.

Abemaciclib was more frequently taken with an aromatase inhibitor (63%) than with fulvestrant (27%). Adherence to abemaciclib-based therapy is high in a real-life setting, pending the adequate and proactive management of patients. The careful evaluation of patients and detailed information about expected adverse events are essential to ensure adherence to this antineoplastic agent.

Moreover, dalpiciclib is being investigated in HR+/HER2- BC treatment. This article will summarize clinical efficacy, recommendations, and differences in toxicity profile between palbociclib, ribociclib, and abemaciclib and will also discuss the possibility of using dalpiciclib in the treatment of breast cancer.

P1/2, N=73, Recruiting, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano | Not yet recruiting --> Recruiting | Trial primary completion date: Mar 2025 --> Mar 2027

Nineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane + everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant + LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab + pertuzumab (with prophylactic loperamide). The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E-H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F. Overall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC.

P1/2, N=191, Recruiting, Tango Therapeutics, Inc. | Not yet recruiting --> Recruiting

Taken together, we describe CDK4/6i-dependent mechanisms resulting in early-onset resistance to CDK4/6i + ET, using clinically relevant drug concentrations, in preclinical breast cancer cell models. The characterization of these preclinical models post progression on CDK4/6 inhibitor + ET treatment highlights the potential that the specific sequencing of CDK4/6 inhibitors could offer to overcome acquired resistance to CDK4/6i + ET. Abemaciclib + fulvestrant is currently under clinical investigation in patients with HR+, HER2- breast cancer and progression on prior CDK4/6i + ET (NCT05169567, postMONARCH).

This update included 82 unique studies, 42.7% for palbociclib, 7.3% for ribociclib, and 3.7% for abemaciclib; 46.3% assessed multiple CDK4/6i. These data are important to guide clinical decision-making, as they include patients who are not adequately represented in clinical trials. Studies with longer follow-up are needed to assess long-term benefits of all three CDK4/6i therapies in HR+/HER2- A/MBC.

The introduction of the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors abemaciclib and ribociclib to the adjuvant setting marks a significant advancement in the treatment of hormone-receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer (HR+, HER2- EBC). The paper also highlights strategies to enhance patient medication adherence and the involvement of multidisciplinary care teams to support treatment delivery. As research continues to evolve, additional follow-ups of the monarchE and NATALEE trials and future trials will further refine patient selection and treatment sequencing, ultimately improving outcomes and enhancing the quality of life for patients with HR+, HER2- EBC.

Based on current published data, abemaciclib is the preferred CDK4/6 inhibitor that should be used in eligible patients (unless contraindicated). To ensure optimal dose intensity and adherence to treatment schedule, use of literature and patient information material can improves compliance. Treatment modification requires early reporting of adverse effects, a responsibility of the patient and caregiver (relatives).

However, there has been a decrease in studies reporting adverse reactions to abemaciclib-related kidney injuries. Thus, this study was aimed at assessing its safety profile using a large-scale pharmacovigilance database.MethodsAbemaciclib-related adverse drug reaction reports from the Food and Drug Administration Adverse Event Reporting System were obtained and scrutinized, and adverse drug reactions were selected using reporting odds ratio, the proportional reporting ratio methods, empirical Bayes geometric mean and UK Medicines and Healthcare products Regulatory Agency methods.ResultsWe selected 10,757 matched reports associated with abemaciclib, among which we found eight adverse reactions about kidney injuries correlated with abeamciclib, such as increased blood creatinine, renal disorder, decreased glomerular filtration rate, increased blood urea, hydronephrosis, abnormal renal function test, increased creatinine renal clearance and increased cystatin C. A demographic analysis of reported cases of abemaciclib-associated renal injury revealed that the majority were female, aged ≥46 years and had taken the drug ≥30 days.ConclusionThis study highlights the characteristics of adverse reactions with abemaciclib and those associated with renal damage, which are crucial for safety studies on the clinical use of this drug.

We performed adisproportionality analysis to evaluate CDKI-related adverse events (AEs) inolder adults administered abemaciclib, palbociclib, and ribociclib. Our results aligned with clinicalobservations, emphasizing possible CDKI-related AEs. Conducting future clinicalresearch is essential to confirm AE-related differences among CDKIs in olderindividuals.

P2, N=9, Terminated, University of Alabama at Birmingham | Trial completion date: Apr 2026 --> Sep 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Apr 2025 --> Jul 2024; Abemaciclib efficacy

P2, N=100, Recruiting, Universitaire Ziekenhuizen KU Leuven | Trial completion date: Oct 2026 --> Jan 2028 | Trial primary completion date: Oct 2026 --> Jan 2028

To improve outcomes, ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa) added to tamoxifen or aromatase inhibitors like exemestane have shown significant disease-free survival (DFS) and, in some cases, overall survival (OS) benefits...Trials with abemaciclib and ribociclib have shown promise in high-risk EBC. For BRCA-mutant patients, the PARP inhibitor olaparib, as demonstrated in the OlympiA trial, significantly improved invasive DFS and OS when used as adjuvant therapy for one year...These advancements reflect a shift toward personalized adjuvant therapy, integrating targeted treatments like CDK4/6 inhibitors and PARP inhibitors, optimizing ET with OFS, and balancing efficacy with quality of life through de-escalation strategies. This tailored approach aims to improve long-term outcomes for HR-positive EBC patients.

P1, N=24, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Jul 2025 --> Oct 2024

The PBPK model successfully simulated the PK profiles and CDK4/6 occupancy for ABE and its three metabolites in plasma and CSD, and determined the optimal dosing in brain MBC. Overall,The PBPK model can provide important insights for personalized dosing strategies, contributing to improved treatment efficacy and safety for patients, particularly those with brain MBC.

In patients with heavily pretreated metastatic RCC, abemaciclib monotherapy had no clinically meaningful activity without new toxicity signals. This data will offer important insight into interpretation of results for ongoing trials exploring CDK4/6 inhibition in combination with HIF-2α inhibitors and immunotherapy.

P2, N=60, Recruiting, University of Washington | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Mar 2025 --> Mar 2027

Targeted therapeutic drugs, such as Abemaciclib (targeting the RB1 pathway) with an IC50 value of 1.744 µM, and Alflutinib Mesylate (targeting the EGFR pathway) with an IC50 value of 0.9150 µM, exhibited significant cytotoxic effects in the MPT2 organoid models. This study highlights the novel application of PDOs for studying the molecular landscape of MPTs and identifying effective therapeutic targets, offering a promising platform for guiding personalized treatment strategies for this rare and challenging cancer.

P1, N=265, Active, not recruiting, Relay Therapeutics, Inc. | Trial completion date: Jul 2024 --> May 2025 | Trial primary completion date: Jun 2024 --> Mar 2025

The biochemical assays revealed that abemaciclib hindered the progression of breast cancer cells MDA-MB-231 and MCF-7 and enhanced RT (10 Gy) by provoking cell cycle arrest throughout the restraint of CDK4 and CDK6 expression and increasing apoptosis, in addition to decreasing the PI3K/AKT/mTOR and NF-κβ/TGF-β pathway expression; inhibiting CK18 and COX2 activity; boosting the protein concentration of BAX and P53; and decreasing Bcl-2, IL-6, IL-1β, MMP2, and MMP9, modulating oxidative stress markers. These results implied potential effects of radiation and CDK4/6i abemaciclib on breast cancer cell lines.

P1, N=18, Recruiting, Fred Hutchinson Cancer Center | Trial completion date: Mar 2026 --> Mar 2029 | Trial primary completion date: Mar 2025 --> Mar 2027

P=N/A, N=3250, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P1, N=50, Active, not recruiting, Nader Sanai | Recruiting --> Active, not recruiting | Trial completion date: Feb 2025 --> Feb 2028

CAMBRIA-1 and CAMBRIA-2 are comparing the next-generation oral SERD camizestrant versus standard-of-care endocrine therapy (aromatase inhibitors or tamoxifen) in patients with ER-positive/HER2-negative early breast cancer, who are at intermediate or high risk of disease recurrence...CAMBRIA-2 is comparing 7 years of upfront adjuvant camizestrant versus endocrine therapy, with abemaciclib permitted in both treatment arms for the first 2 years. The primary endpoint for both studies is invasive breast cancer-free survival. Secondary endpoints include invasive disease-free survival, distant recurrence-free survival, overall survival, pharmacokinetics, patient-reported outcomes, safety and tolerability.Tweetable abstract: CAMBRIA-1 and CAMBRIA-2 are ongoing, randomized, open-label trials of adjuvant camizestrant, either as an upfront treatment or as a treatment after standard endocrine therapy, in patients with HR+/HER2- early breast cancer at intermediate to high risk of disease recurrence.Clinical Trial Registration: NCT05774951 (CAMBRIA-1); NCT05952557 (CAMBRIA-2).

P2, N=18, Active, not recruiting, Duke University | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

Ribociclib, with its broader applicability and impact on the decision making for axillary lymph node surgery, may be the preferred option in high-risk populations. The review also addresses unanswered clinical questions and highlights the need for ongoing research to optimize the adjuvant therapy strategies.

Additionally, diarrhea improved after symptomatic treatment. We believe that the combination of trastuzumab, hormone suppression, and abemaciclib is a practicable and effective treatment for HER2-positive and HR-positive metastatic BC in premenopausal patients who cannot tolerate the first-line chemotherapy.

A few cases were identified in which abemaciclib eligibility was not properly determined due to ALND omission. This suggests that omitting ALND following SNB, when two of fewer positive nodes are detected, may not significantly impact the determination of abemaciclib eligibility.

CDK4/6 inhibitors differed in their safety profile reports; for example, neutropenia mainly occurs with palbociclib and ribociclib, diarrhea and venous thromboembolism mainly occur with abemaciclib, and QTc prolongation mainly occurs with ribociclib. Individualized drug administration according to patients' conditions is needed in clinical practice.

Cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are widely used in combination with endocrine therapy for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The patient developed erythematous, edematous plaques and papules on her hands and forearms, which resolved after discontinuation of the drug and treatment with topical corticosteroids. This report highlights the need for awareness of cutaneous side effects associated with CDK4/6 inhibitors, particularly abemaciclib.

In this study, our Food and Drug Administration (FDA)-approved drug screening reveals that abemaciclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, dramatically promotes the proteasome-dependent degradation of YAP1, thereby inhibiting tumor progression in CRC cells and patient-derived xenograft models...Histological analysis shows a positive correlation between DUB3 and YAP1 expression in CRC specimens. Collectively, our study uncovers a novel oncogenic role of the CDK4/6-DUB3 pathway, which promotes YAP1 stabilization and tumor-promoting function, highlighting that targeting CDK4/6 offers a potential therapeutic strategy for CRC with aberrantly upregulated DUB3 and YAP1.

P1/2, N=43, Recruiting, Memorial Sloan Kettering Cancer Center

P1/2, N=316, Recruiting, Hoffmann-La Roche | N=510 --> 316

P1/2, N=400, Recruiting, Stemline Therapeutics, Inc. | Trial completion date: Aug 2026 --> Dec 2028 | Trial primary completion date: Dec 2024 --> Dec 2026

P=N/A, N=3250, Not yet recruiting, Novartis Pharmaceuticals

P2, N=51, Recruiting, Fondazione Oncotech | Not yet recruiting --> Recruiting

The phase 3 EMBER-3 trial1 demonstrated that when compared to standard therapy, imlunestrant improved progression-free survival (PFS) in advanced ER+/HER2- breast cancer with ESR1 mutations. When combined with abemaciclib, it significantly improved PFS for the entire population. However, the absence of a biomarker-based control group limits broader conclusions, highlighting the need for trials incorporating specific standards in ER+/HER2- breast cancer.

P1/2, N=103, Completed, Multiple Myeloma Research Consortium | Recruiting --> Completed | N=228 --> 103 | Trial completion date: Feb 2024 --> Dec 2024 | Trial primary completion date: Feb 2022 --> Dec 2024

Under the diagnosis of left breast cancer with cT2N3cM1(OSS), Stage Ⅳ, Luminal B like, we started treatment with anastrozole, leuprorelin, abemaciclib and denosumab. It also has a longer intracerebral retention time than other CDK4/6 inhibitors. Combination therapy with abemaciclib may be a useful treatment option for HR-positive, HER2-negative breast cancer with brain metastases.

To address this challenge, three pH- and glutathione-responsive poly(amino acid) nanogels composed of methoxy poly(ethylene glycol) of various lengths and poly(L-glutamic acid-co-L-cystine) (mPEG-P(Glu10-co-Cys25)) were developed to efficiently deliver the CDK4/6i abemaciclib (ABE) to TNBC cells...Furthermore, NG2000/ABE enhanced immune checkpoint therapy for TNBC, achieving a tumor inhibition rate of 89.66 %. These findings demonstrate the potential of poly(amino acid) nanoformulations for delivering CDK4/6 inhibitors as molecularly targeted immunotherapy for TNBC in clinical applications.