scholarly journals Palbociclib - from Bench to Bedside and Beyond

Breast Care ◽  
2016 ◽  
Vol 11 (3) ◽  
pp. 177-181 ◽  
Author(s):  
Marcus Schmidt
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Endocrine Therapy ◽  
Early Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Hormone Receptor Positive ◽  
The Us ◽  
Accelerated Approval ◽  
Epidermal Growth

Endocrine therapy is the cornerstone in the treatment of hormone receptor-positive breast cancer. During the last decades, much has been learned about the subtle regulation of the cell cycle. In this tightly regulated network, cyclin-dependent kinases (CDKs) play a pivotal role. Especially CDK4/6 is the key regulator of the G1-S transition. Realizing its importance, specific inhibitors of CDK4/6 were developed. The drug most advanced in clinical development in this class is palbociclib (PD 0332991). This review highlights preclinical data and brings into focus early clinical trials that led to an accelerated approval by the US Food and Drug Administration (FDA) as first-line treatment in combination with letrozole in advanced hormone receptor-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Furthermore, ongoing clinical trials with palbociclib in advanced and in early breast cancer are outlined. In conclusion, inhibition of CDK4/6 using palbociclib in combination with endocrine therapy is an efficacious treatment option in hormone receptor-positive/HER2-negative advanced breast cancer. Ongoing clinical trials will show whether palbociclib is ready for prime time in early breast cancer.

Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)

2022 ◽  
Author(s):  
Erica L. Mayer ◽  
Christian Fesl ◽  
Dominik Hlauschek ◽  
Laura Garcia-Estevez ◽  
Harold J. Burstein ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Human Epidermal Growth Factor ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

scholarly journals Therapeutic Strategies for the Management of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Positive (HR+/HER2+) Breast Cancer: A Review of the Current Literature

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3317
Author(s):  
Eirini Thanopoulou ◽  
Leila Khader ◽  
Morena Caira ◽  
Andrew Wardley ◽  
Johannes Ettl ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Human Epidermal Growth Factor ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

Enormous advances have been made in the understanding and treatment of human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) in the last 30 years that have resulted in survival gains for affected patients. A growing body of evidence suggests that hormone receptor-positive (HR+)/HER2+ BC and HR-negative (HR−)/HER2+ BC are biologically different, with complex molecular bidirectional crosstalk between the estrogen receptor and HER2 pathway potentially affecting sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ BC. Subgroup analyses from trials enrolling patients with HER2+ BC and the results of clinical trials specifically designed to evaluate therapy in patients with HR+/HER2+ BC are helping to guide treatment decisions. In this context, encouraging results with strategies aimed at delaying or reversing drug resistance, including extended adjuvant therapy and the addition of drugs targeting alternative pathways, such as cyclin-dependent kinase (CDK) 4 and 6 inhibitors, have recently emerged. We have reached the point where tailoring the treatment according to risk and biology has become the paradigm in early BC. However, further clinical trials are needed that integrate translational research principles and identify and consider specific patient subgroups and biomarkers.

scholarly journals Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy

Breast Cancer ◽  
2021 ◽  
Author(s):  
Kenichi Inoue ◽  
Norikazu Masuda ◽  
Hiroji Iwata ◽  
Masato Takahashi ◽  
Yoshinori Ito ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Confidence Interval ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Phase 3 ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

Abstract Background This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). Methods Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ≤ 12 months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. Results In Japan, 95 patients were randomized (abemaciclib, n = 64; placebo, n = 31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3 months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380–1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3 months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390–1.463). Conclusions Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. Clinical trial registration NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703.

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