Ibrance (palbociclib)

The PFS benefit was more pronounced in those individuals who received abemaciclib or ribociclib as second CDK4/6i. Continuation of CDK4/6 inhibition was associated with higher rates of grade 3 and 4 neutropenia (range: 25-40%) and anemia (range: 1.7-11%). In conclusion, switching CDK4/6i and ET conferred a statistically significant improvement of PFS in comparison to ET alone in patients with progression or recurrence on prior CDK4/6i-containing therapy.

P=N/A, N=25, Active, not recruiting, Centre Oscar Lambret | Recruiting --> Active, not recruiting | Trial completion date: Sep 2023 --> Sep 2025 | Trial primary completion date: Sep 2023 --> Sep 2025

Metronomic IT delivery of palbociclib enhances drug efficacy and safety, improves survival, and offers a promising treatment strategy for PBTs with CSF dissemination.

Recent studies indicate that adding inavolisib, a PI3Kα inhibitor, to palbociclib/fulvestrant benefits patients with endocrine-resistant HR+/HER2- metastatic breast cancer with a PIK3CA mutation. Alpelisib and capivasertib are both US Food and Drug Administration (FDA) approved in combination with fulvestrant in patients with endocrine-resistant HR+/HER2-, PIK3CA-mutant metastatic breast cancer, both with activity in the post-CDK4/6 setting...Toxicity profiles of all agents necessitate careful patient selection. Several mutant-selective and pan-mutant-selective novel inhibitors are under investigation with the potential to improve tolerability and efficacy.

CDK4/6 inhibitors such as palbociclib block cell cycle progression and improve outcomes for many ER+/HER2- breast cancer patients...Understanding the molecular mechanisms that allow treated tumor cells to evade arrest is critical for identifying targets of future therapies. Ultimately, we seek to further SPCA as a tool of precision medicine, targeting treatments by individual tumors, and extending this computational framework to interpret other cyclical biological processes represented by high-dimensional data.

P=N/A, N=419, Completed, MedSIR | Active, not recruiting --> Completed | Trial primary completion date: Oct 2024 --> May 2024

P2, N=60, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Dec 2024 --> Jun 2025

Knockdown of NSRP1 reduces CDK4/6i (palbociclib) sensitivity of MCF7 cells while overexpression of NSRP1 sensitizes MCF7-PalR cells towards palbociclib treatment...In addition, including NSD2 exon 2 elevates NSD2 protein expression to activate the IFN signaling pathway. This study unveils the critical role of NSRP1 in regulating the IFN signaling pathway and the CDK4/6i resistance, which could be a promising biomarker for predicting therapy response.

Dosing schedules other than the standard 3/1 schedule can be used to continue palbociclib with HR+/HER2-MBC while ensuring therapeutic efficacy. Alternative dosing schedules look promising and need further research (preferably, prospective studies) with a larger sample size and longer follow-up to validate treatment efficacy.

P1, N=6, Recruiting, West China Hospital | Initiation date: Dec 2024 --> Aug 2024

These results support a potential role of the palbociclib-letrozole combination as treatment for hormone receptor-positive advanced/recurrent endometrial cancer. Based on these encouraging results, phase III evaluation of letrozole combined with a CDK4/6 inhibitor is planned.

Pseudo-Scr elevation appears to be a class effect of CDK4/6i, with similar rates of Scr elevation observed across the three agents currently FDA approved.

P1/2, N=136, Terminated, Sanofi | Trial completion date: Dec 2027 --> Nov 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Dec 2027 --> Nov 2024; Sponsor decision to prematurely stop the study, not linked to any safety concern.

P1, N=31, Active, not recruiting, Eisai Inc. | Trial completion date: Aug 2025 --> Mar 2026

P1/2, N=29, Recruiting, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University | Trial primary completion date: Dec 2023 --> May 2024

Our findings provide compelling evidence that targeting PP5 can significantly enhance the therapeutic outcomes of radiotherapy in NSCLC. This research offers valuable insights into new combination therapy strategies, highlighting the potential of PP5 as a novel therapeutic target to overcome radioresistance.

Cyclin D-dependent kinase 4/6 inhibitors palbociclib, ribociclib and abemaciclib, in combination with aromatase inhibitors anastrozole and letrozole or oestrogen receptor degrader fulvestrant, are being assessed as candidates for therapeutic drug monitoring. DLLME proved to be the most ecologically acceptable method due to the high degree of miniaturisation (AGREEprep score 0.44), PLR enabled very high sample throughput and cost-effectiveness (BAGI 72.5), while SPE showed the best analytical performance (redness score 100). All three methods are suitable for their designated purpose, and the choice of the ideal method can be made based on the scope of application, available funds and equipment and desired ecological footprint.

P1, N=32, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=54 --> 32

P1, N=6, Recruiting, West China Hospital | Initiation date: Oct 2023 --> Dec 2024

While some benefit, albeit modest, has been observed from switching to a different CDK4/6i after progression (e.g. ribociclib after palbociclib in the MAINTAIN trial and abemaciclib after both palbociclib and ribociclib in the postMONARCH trial), the current evidence (mainly with palbociclib) clearly argues against maintaining the same CDK4/6i. However, selected patients with indolent disease, prolonged exposure to previous CDK4/6i treatment (especially palbociclib) and without actionable molecular alterations, may be suitable for suchmaintenance strategy beyond progression. In this challenging and rapidly evolving treatment landscape, ongoing studies can refine the optimal approach and identify clinical and molecular factors to select the best treatment for the right patient.

P1, N=214, Active, not recruiting, Jiangsu Simcere Pharmaceutical Co., Ltd. | Recruiting --> Active, not recruiting

CD8RGs play an important role in regulating the TME of PAAD. Five hub genes-BCL11A, KLK11, GNG7, PHOSPHO1, and VCAM1-are closely associated with the prognosis of PAAD patients, providing new references for the exploration of biomarkers. Furthermore, our findings offer novel insights for clinical decision-making.

Gene set enrichment analysis (GSEA) in the NeoPalAna trial demonstrated a significant enrichment of the TFAP2C-DDR1 gene set from patitens after palbociclib treatment, suggesting the possible activation of the TFAP2C-DDR1 axis following palbociclib exposure. Overall, this study provides crucial insights into the novel molecular landscape of palbociclib resistance in breast cancer, suggesting TFAP2C-DDR1 axis inhibition as a promising strategy to overcome resistance.

It discusses the therapeutic applications in breast cancer as well as in solid tumors and hematopoietic malignancies. Additionally, the paper presents an analysis of palbociclib resistance acquired during therapy and explores new approaches, such as modifications to palbociclib that enhance its desired activity or open up new therapeutic possibilities (PROTACs).

Palbociclib showed an anti-proliferative effect, with increased immune infiltration in residual tumors with CCCA.Trial registration: Palbociclib Plus Letrozole in Hormone Receptor Positive Residual Disease After Neoadjuvant Chemotherapy (PROMETEO II) ClinicalTrial.gov number NCT04130152. Study registration; October 17, 2019.

This retrospective study included 193 patients who received either ribociclib or palbociclib in combination with first-line ET. Multivariate analysis identified the symptomatic disease and liver metastasis as independent predictors of shorter mPFS (HR; 1.835, 95% CI; 1.146-2.939 and HR; 2.433, 95% CI; 1.329-4.454, respectively). Our analysis revealed that although symptomatic individuals who underwent CDK4/6 inhibitor plus ET experienced a significant reduction in mPFS durations compared to asymptomatic patients, the 22-month mPFS indicated that CDK4/6 inhibitor plus ET is an effective treatment option.

Concomitant use of PPIs with ribociclib or palbociclib did not affect the efficacy of either CDK4/6 inhibitor. PPIs can be administered alongside these medications when clinically indicated.

Furthermore, DDO-6079 decreased the thermostability of CDK6, reversed the resistance of CDK6 to palbociclib (a successful CDK4/6 inhibitor) in colorectal cancer cells and exhibited efficacy in vivo. Together, the results revealed that DDO-6079 is a first-in-class small molecule CDC37 inhibitor that disrupts the HSP90-CDC37-kinase chaperone complex and provides a new way to block kinase maturation.

Findings from this real-world study indicate patients with HR+/HER2- ABC treated with palbociclib plus ET maintain their QoL for at least 18 months.

The combination of CDK4/6i and ET significantly improves PFS and OS compared to ET alone in both Asian and non-Asian patients with HR+/HER2-aBC. Although the magnitude of benefit appears to be independent of ethnicity, future clinical trials should devise a standardized method for stratifying patients by ethnicity to more effectively assess potential differences in treatment benefits.

P2, N=45, Recruiting, Massachusetts General Hospital | N=30 --> 45 | Trial completion date: Sep 2025 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

By using the novel PDX platform, the results presented in this study demonstrate that the treatments with Palbociclib or Dabrafenib/Trametinib significantly reduced tumor size. In conclusion, PDX models offer a deeper understanding of eGBM at the genomic level and facilitate the identification of potential therapeutic targets. Further translational studies of this novel PDX model hold promise for advancing the diagnosis and treatment of this specific subtype of glioblastoma.

Introduction The INGE-B trial (NCT02894398) aimed to confirm the efficacy and safety data from the PALOMA trials for patients treated first line (1L) with palbociclib (PAL) and letrozole or 1L and later line with PAL and fulvestrant. Conclusion The INGE-B trial demonstrated good efficacy and tolerability of PAL with letrozole (1L) or fulvestrant (first and later line) in accordance with the PALOMA-trials. In addition, the so far lacking proof of efficacy and safety of PAL in combination with anastrozole or exemestane in 1L and with letrozole in later line was provided by INGE-B.

P2, N=200, Not yet recruiting, Peking University Shenzhen Hospital

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.

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

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

P1, N=20, Terminated, Hoffmann-La Roche | Phase classification: P3 --> P1

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

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.

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