bims-cyhorp 2022-09-18 papers

Issue of 2022–09–18
four papers selected by
Piotr Okupski,

Drugs Real World Outcomes. 2022 Sep 12.

Real-World Patient Characteristics, Utilization Patterns, and Outcomes of US Patients with HR+, HER2- Metastatic Breast Cancer Treated with Abemaciclib.

Emily Nash Smyth, Julie Beyrer, Kimberly R Saverno, Elizabeth Hadden, Hamed Abedtash, Angelo DeLuca, Garreth W Lawrence, Sarah Rybowski.

BACKGROUND: Abemaciclib is the most recent oral cyclin-dependent kinase 4 and 6 inhibitor (CDK4 & 6i) to receive US Food and Drug Administration (FDA) approval to treat hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC). Administrative claims data were used to describe patient characteristics and select clinical and economic outcomes in US patients treated in routine clinical practice. Prior analyses from electronic health records data indicate approximately 25% of patients received either palbociclib or ribociclib for MBC before initiating abemaciclib treatment; this work further explored these findings and associated outcomes.
METHODS: This retrospective study analyzed medical and pharmacy claims from the IBM® MarketScan® Research Databases between 1 January 2007 to 31 January 2020. Patients with HR+, HER2- MBC newly initiating abemaciclib between 1 September 2017 and 31 October 2019 were included and grouped by concomitant therapy (+aromatase inhibitor (AI), +fulvestrant (F), 200 mg abemaciclib monotherapy (Mono), or +other), and outcomes were analyzed by prior CDK4 & 6i use. Patient and treatment characteristics were summarized with descriptive statistics. Kaplan-Meier methods assessed time-to-discontinuation (TTD; i.e., persistency) and time-to-chemotherapy (TTC). Adherence (defined by the medication possession ratio) and drug wastage were determined.
RESULTS: This analysis included 454 patients (mean age 57.7 years), with 35.0% (n = 159) in the +F group, 29.3% (n = 133) in the +AI group, 10.4% (n = 47) in the 200 mg Mono group, and 25.3% (n = 115) in the +other group. Prior chemotherapy and CDK 4 & 6i use were present in 23.8% and 49.8% of all patients, respectively. Visceral metastases were present at abemaciclib initiation in 50.4% in the +AI group; 49.7% in the +F group; and 55.3% in the 200 mg Mono group. Liver metastases were present in 33.7% of the overall population. Among patients without prior CDK4 & 6i use, the median TTD for patients receiving abemaciclib + AI was not reached [95% CI 430-not reached (NR) days], abemaciclib + F [531 days (95% CI 281-NR)], and abemaciclib mono [141 days (95% CI 80-NR)]. Median TTC for abemaciclib + AI and abemaciclib + F groups were not reached and the median TTC for abemaciclib mono was 535 days (95% CI 181-NR). Medication adherence was 88.7% and medication wastage costs among those with at least one dose modification were $808.12 and $452.2 per patient per month based on amount paid and wholesale acquisition cost (WAC), respectively. Mean length of follow-up for all patients was 350 days (SD 187).
CONCLUSION: These real-world data complement clinical trial results by examining abemaciclib use among patients treated in routine clinical practice. The sizeable number of patients treated with prior CDK4 & 6i, chemotherapy, and/or visceral metastases at abemaciclib initiation suggest that many patients had very advanced disease and/or were in later stages of their treatment. These data confirm a higher percentage of patients treated with previous CDK4 & 6i than reported previously, reinforcing the importance of the ongoing, prospective clinical trials evaluating outcomes following progression on CDK4 & 6i.

DOI: https://doi.org/10.1007/s40801-022-00327-1

Front Oncol. 2022 ;12 956464

CDK4/6 inhibitors versus PI3K/AKT/mTOR inhibitors in women with hormone receptor-positive, HER2-negative metastatic breast cancer: An updated systematic review and network meta-analysis of 28 randomized controlled trials.

Hangcheng Xu, Yan Wang, Yiqun Han, Yun Wu, Jiayu Wang, Binghe Xu.

Background: Updated evidence was required to compare the efficacy and safety of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors for patients with hormone receptor-positive and HER2-negative metastatic breast cancer.
Methods: A systematic review and network meta-analysis was conducted utilizing data from randomized controlled trials (RCTs) that contained interventions of CDK4/6 inhibitors or PI3K/AKT/mTOR inhibitors. Progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) were primary outcomes of interest. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% credible intervals (CrIs) were used to assess the survival outcomes and safety profiles, respectively.
Results: A total of 28 RCTs with 12,129 participants were included. Pooled analysis showed that CDK4/6 inhibitors significantly prolonged PFS than PI3K/AKT/mTOR inhibitors (HR, 0.81; 95% CrI, 0.69-0.94), whereas no significant differences were detected regarding OS. After balancing the treatment lines and metastatic sites, the superiority of CDK4/6 inhibitors only appeared in the visceral and non-visceral subgroups. Among CDK4/6 inhibitors, abemaciclib was significantly better than others in ≥3 grade neutropenia (OR, 0.04; 95% CrI, 0.01-0.15). The incidence of stomatitis and digestive disorders was different among diverse kinds of PI3K/AKT/mTOR inhibitors. Discrepancies appeared regarding TRAEs of hepatotoxicity, diarrhea, and hyperglycemia among different interventions.
Conclusions: CDK4/6 inhibitors showed better efficacy in PFS, but the benefits disappeared when taking treatment line into consideration. Specific and discrepant safety profiles were found in two categories of agents.
Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO, identifier CRD42022321172.

Keywords: CDK4/6 inhibitors; HER2-negative; PI3K/AKT/mTOR inhibitors; hormone receptor-positive; metastatic breast cancer; network meta-analysis

DOI: https://doi.org/10.3389/fonc.2022.956464

Front Oncol. 2022 ;12 959322

Design, synthesis, and anticancer activity of three novel palbociclib derivatives.

Tian Li, An-Di Zhou, Li-Fei Bai, Xiao-Yang Zhang, Yu-Ting Zhou, Hai-Li Yang, Le-Tian Xu, Xin-Qin Guo, Xi-Yu Zhu, Dong-Jin Wang, Hong-Wei Gu, Xiao-Ming Wang.

Cancer is one of the most serious diseases threatening human health, so it is particularly important to develop effective tumor-targeting drugs. As the first CDK4/6 inhibitor, palbociclib effectively inhibits tumor proliferation by blocking the cell cycle to the G1 phase. 10-HCPT is a Topo I inhibitor; however, its clinical application has been greatly limited due to its high toxicity. Based on the successful development of double target inhibitors, three novel palbociclib derivatives (HP-1, HP-2, and HP-3) were designed and synthesized from Palbociclib and 10-HCPT, and their biological activities were investigated. At first, the possible binding sites of the three compounds to Topo I and CDK4/6 were predicted by molecular docking. Then, we evaluated the anti-proliferative effects of the three palbociclib derivatives. In general, human lung cancer cells were more sensitive to HP-1, HP-2, and HP-3, especially NCI-H460. In addition, cell cycle arrest and apoptosis induction were investigated by flow cytometry. The three palbociclib derivatives, especially HP-1, had obvious cell cycle arrest phenomenon on NCI-H460 cells and induced apoptosis of NCI-H460 cells significantly. In the end, it was proved that these three drugs had obvious cyclin-dependent kinase inhibitory activities. In short, all the data showed that HP-1, HP-2, and HP-3 could play anti-cancer roles by acting on dual targets and had the characteristics of high efficiencies and low toxicities, which opened up a new idea for the study of palbociclib derivatives.

Keywords: 10-hydroxy camptothecin; CDK4/6; Topo I; anticancer activity; palbociclib derivatives

DOI: https://doi.org/10.3389/fonc.2022.959322