Endocrine therapy plus CDK 4/6i represents an effective treatment, regardless of HER2 status (low/zero). Second-line agents did not differ significantly in terms of TTD. Endocrine resistant cancers exhibit poor response to CDK 4/6i.

Moreover, the overexpression of PLAU in tumor epithelial cells facilitates its interaction with the receptor PLAUR, predominantly expressed on macrophages, thereby influencing the abnormal epithelial-immune interactome in HNSCC. Notably, the JPX inhibitor Axitinib and the PLAU inhibitor Palbociclib may not only exert their effects on the JPX/miR-193b-3p/PLAU axis that impacts the malignant tumor behaviors and the epithelial-immune cell interactions but also exhibit synergistic effects in terms of suppressing tumor cell growth and arresting cell cycle by targeting epidermal growth factor receptor (EGFR) and cyclin-dependent kinase (CDK4/6) for the treatment of HNSCC.

This study confirms first-line CDK 4/6i effectiveness, with abemaciclib and ribociclib showing prolonged PFS vs. palbociclib. This study could not confirm a ranking of the three CDK 4/6i.

Dose reduction of CDK4/6 inhibitors within the first 12 weeks of treatment was associated with significantly higher mortality and shorter treatment duration. These findings contrast with previous analyses showing no effect of dose reduction, likely due to considering immortal time bias in this study.

P1, N=6, Recruiting, West China Hospital | Trial primary completion date: Oct 2024 --> Oct 2025

To identify biomarkers associated with CDK4/6 inhibitor response or resistance, we combined bioinformatic-database analyses, artificial intelligence-assisted literature review, and manual literature review (Embase and OVID Medline; search window: January 2012-October 2022) to compile data to comprehensively describe the CDK4/6 inhibitor biomarker landscape. Based on these results, and validation by external experts, we identified 15 biomarkers of clinical importance (AR , AURKA, ERBB2, ESR1, CCNE1, CDKN1A/B, CDK2, CDK6, CDK7, CDK9, FGFR1/2, MYC, PIK3CA/AKT, RB1 and STAT3) that could guide future breast cancer research.

P1/2, N=55, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2026 --> Dec 2029 | Trial primary completion date: Dec 2025 --> Dec 2028

P1, N=35, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2024 --> Mar 2024

P1, N=64, Recruiting, Regor Pharmaceuticals Inc. | N=18 --> 64

P2, N=120, Recruiting, BeBetter Med Inc

P3, N=1684, Active, not recruiting, West German Study Group | Recruiting --> Active, not recruiting

P2, N=35, Recruiting, Peking University

P4, N=40, Recruiting, The First Affiliated Hospital of Chongqing Medical University; The First Affiliated Hospital of Chongqing Medical University

P4, N=40, Not yet recruiting, The First Affiliated Hospital of Zhengzhou University; The First Affiliated Hospital of Zhengzhou University

P3, N=400, Not yet recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

P2, N=60, Recruiting, The First Affiliated Hospital of Xi'an Jiaotong University; The First Affiliated Hospital of Xi'an Jiaotong University

P1, N=36, Completed, Beijing Friendship Hospital ,Capital Medical University; Beijing Friendship Hospital ,Capital Medical University

P3, N=460, Not yet recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd.

P2, N=80, Not yet recruiting, UNICANCER

P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027

P2, N=52, Completed, Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori | Unknown status --> Completed | N=150 --> 52

P1, N=17, Active, not recruiting, Peter MacCallum Cancer Centre, Australia | Trial primary completion date: Jun 2024 --> Jun 2025

P2, N=90, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Jan 2026 --> Jun 2025

P1, N=28, Not yet recruiting, Memorial Sloan Kettering Cancer Center

Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer.

Our data demonstrate that FMD overcomes resistance and potentiates the anti-tumor effect of CDK4/6i by inhibiting mTORC1 signaling via lowering the levels of IGF1 and RAS, providing the rationale for clinical investigation of a potential FMD-CDK4/6i strategy in breast cancer.

P3, N=500, Recruiting, American Society of Clinical Oncology | Not yet recruiting --> Recruiting

Dalpiciclib plus fulvestrant is effective and comparatively safe in postmenopausal women with hormone receptor-positive and HER2-negative breast cancers. Dalpiciclib, buparlisib, fulvestrant, and ribociclib cause neutropenia, severe depression, adverse gastroenterological effects, and adverse hepatological effects, respectively.

Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT.

4i also demonstrated a high potential for oral bioavailability due to its adherence to Lipinski's rule of five. The molecular docking studies of 4i analog showed good binding mode with CDK6 active pocket through the formation of multiple interactions with its key amino acids.

No abstract available

No abstract available

FP reduced cell proliferation and induced apoptosis by inducing mitochondrial dysfunction and oxidative stress, as well as increasing BAX/BCL2 and pCDK1 levels. These results suggest that toxicity to the reproductive system should be considered when FP is used in clinical applications.

P2, N=23, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

Furthermore, the side effects were manageable and no dose reductions were necessary during treatment. These findings suggest that the combination of CDK4/6i and ET in the treatment of HR+/HER2-advanced breast cancer cannot be underestimated.

Patients with lower body weight are more susceptible to the adverse events of abemaciclib, increasing their risk of treatment discontinuation. In such patients, strict monitoring of adverse events and consideration of more frequent medical visits are necessary from the start of abemaciclib therapy.

Outcomes in this large, heterogeneous, real-world population are generally consistent with previously reported results from clinical trials and other real-world studies, further supporting the use of palbociclib + ET in patients with HR+/HER2- ABC.

P1, N=34, Recruiting, University of Utah | Trial primary completion date: Aug 2024 --> Apr 2024

P2, N=47, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting

However, in developing countries like India, where most patients come from rural areas, using innovator palbociclib may not be feasible for many. With the availability of generic palbociclib under the Government Health Scheme, patients of metastatic hormone receptor-positive breast cancer will receive the protocol-based treatment.

P1, N=40, Not yet recruiting, Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

P1, N=54, Active, not recruiting, Abramson Cancer Center at Penn Medicine | Phase classification: P1/2 --> P1 | Trial completion date: Apr 2024 --> Dec 2024 | Trial primary completion date: Apr 2024 --> Dec 2024