bims-cyhorp 2023-03-26 papers

Issue of 2023–03–26
six papers selected by
Piotr Okupski,

J Oncol Pharm Pract. 2023 Mar 22. 10781552231163121

CDK4/6 inhibitors in metastatic breast cancer, a comparison of toxicity and efficacy across agents in a real-world dataset.

William Buller, Lalit Pallan, Teresa Chu, Leila Khoja.

INTRODUCTION: CDK4/6 inhibitors (ribociclib, palbociclib and abemaciclib) are 1st line therapy in metastatic breast cancer (MBC). No comparative data exists between agents regarding toxicity or efficacy.
METHODS: A retrospective study was performed at our tertiary referral centre evaluating patients on a CDK4/6 inhibitor for MBC between July 2017 and December 2021. Toxicity was evaluated along with variability in full blood counts and liver function over the first 12 weeks of therapy.
RESULTS: Two hundred and seventeen patients were treated (palbociclib 59%, abemaciclib 25% and ribociclib 16%). 86% received the agent as 1st line therapy. Most patients were white women with a median age of 61 years (32-95) and ECOG 0/1. Twelve patients were switched to an alternative CDK4/6 inhibitor due to toxicity and two did not tolerate this. Toxicity profiles of agents were consistent with published trials. However, there was greater overlap in hepatitis, diarrhoea and bone marrow suppression. Blood results indicated a minimum of four weeks treatment before development of neutropenia. Forty percent of patients went onto have subsequent lines of therapy. The progression-free survival per agent was palbociclib 27.9 months (95% CI 23-32.5), ribociclib 29 months (95% CI 21.5-37.0) and abemaciclib 20.6 months (95% CI 15.0-26.0). The overall survival was palbociclib 38.0 months (95% CI 33.5-42.5), ribociclib 33.9 months (95% CI 26.7-41.1) and abemaciclib 27.3 months (95% CI 22.5-32.1).
CONCLUSIONS: Toxicity across CDK4/6 inhibitors overlaps. The optimal sequence of therapies post CDK4/6 inhibitors remains unknown but rechallenge with an alternative agent is possible.

Keywords: CDK4/6 inhibitor; Metastatic breast cancer; toxicity

DOI: https://doi.org/10.1177/10781552231163121

J Oncol Pharm Pract. 2023 Mar 22. 10781552231165434

Osteonecrosis of the jaw under palbociclib: A case series description.

Chabnam Yosofi, Sophie Cairon-Lejeune, Claudia Lefeuvre-Plesse, Elisabeth Polard, Marie Briet, Solène-Florence Kammerer-Jacquet, Louise Triquet, Lucie-Marie Scailteux.

INTRODUCTION: Cases of osteonecrosis of the jaw have been reported by dental surgeons to the pharmacovigilance center in Rennes, France, occurring among patients treated with palbociclib, a cyclin-dependent kinase 4/6 inhibitor. Although this event was not expected with the drug, a safety signal was raised. Describing a local case series, the aim of our study was to identify specific patterns that might suggest a triggering role for these drugs, and to discuss pathophysiological hypotheses.
MATERIALS AND METHODS: A retrospective case series of patients exposed to cyclin-dependent kinase 4/6 inhibitors between 2016 and 2020 with a diagnosis of osteonecrosis of the jaw at the Rennes Dental Care Center was analyzed. The descriptive analysis was conducted on patient demographics, breast cancer characteristics, osteonecrosis of the jaw, biological data, and exposure to cyclin-dependent kinase 4/6 inhibitors.
RESULTS: We identified eight cases, most of them at stages 0-1 (62.5%). Four patients were still exposed to palbociclib at the time of diagnosis and four had discontinued the treatment before the diagnosis. Chronological imputability could not be excluded given the drug's half-life and the variable intervals of dental monitoring from one patient to another. All patients had at least one dental osteonecrosis risk factor (including dental extraction, dentures, and denosumab exposure at the time of diagnosis). Neutropenia and mucositis were not systematically reported at the time of diagnosis. The anatomopathological characteristics were nonspecific.
CONCLUSION: We did not identify a specific pattern that could suggest a triggering role of palbociclib in the development of ONJ.

Keywords: Cyclin-dependent kinase inhibitor; adverse drug reaction; osteonecrosis of the jaw; palbociclib

DOI: https://doi.org/10.1177/10781552231165434

Oncologist. 2023 Mar 22. pii: oyad035. [Epub ahead of print]

Real-World Evaluation of Disease Progression After CDK 4/6 Inhibitor Therapy in Patients With Hormone Receptor-Positive Metastatic Breast Cancer.

Malinda T West, Shaun M Goodyear, Evthokia A Hobbs, Andy Kaempf, Thomas Kartika, Jessica Ribkoff, Brie Chun, Zahi I Mitri.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER-) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2- patients with MBC.
METHODS: We retrospectively reviewed the medical records of patients with HR+/HER2- MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models.
RESULTS: We identified 140 patients with HR+/HER2- MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN.
CONCLUSION: This study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2- MBC.

Keywords: CDK 4/6 inhibitor resistance; PTEN mutation; hormone receptor positive metastatic breast cancer

DOI: https://doi.org/10.1093/oncolo/oyad035

Mol Omics. 2023 Mar 20.

Role of identified proteins in the proteome profiles of CDK4/6 inhibitor-resistant breast cancer cell lines.

Binayak Kumar, Peeyush Prasad, Ragini Singh, Ram Krishna Sahu, Ashutosh Singh, Srikrishna Jayadev Magani, Suresh Hedau.

Abemaciclib (Ab) and palbociclib (Pb) are CDK4/6 inhibitors used to cure advanced breast cancer (BC). However, acquired resistance is a major challenge. The molecular mechanisms and signature proteins of therapy resistance for Ab and Pb drugs need to be explored. Here we developed resistant cells for Ab and Pb drugs in MCF-7 cell lines and explored the mechanisms and signature proteins of therapy resistance in BC. Proteome profiling was performed using the label-free proteome-orbitrap-fusion-MS-MS technique. Gene ontology (GO)-terms, KEGG pathways and network analysis were performed for the proteome data. Drug-resistant cells showed increased drug tolerance, enhanced colony formation potential and an increased gap-healing tendency for the respective drug. Up-regulation of survival genes (BCL-2 and MCL-1) and down-regulation of apoptosis inducers were observed. Drug-resistance markers (MDR-1 and ABCG2 (BCRP)) along with ESR-1, CDK4, CDK6, and cyclin-D1 genes were up-regulated in resistant cells. A total of 237 and 239 proteins were found to be differentially expressed in the Ab and Pb-resistant cells, respectively. Down-regulated proteins induce apoptosis signalling and nucleotide metabolisms and restrict EGFR signalling; however, up-regulated proteins induce Erk, wnt-β-catenin, VEGFR-PI3K-AKT, glucose transportation, and hypoxia signalling pathways and regulate hydrogen peroxide signalling pathways. The panel of identified proteins associated with these pathways might have characteristics of molecular signature and new drug targets for overcoming drug resistance in breast cancer.

DOI: https://doi.org/10.1039/d2mo00285j

Pharmacoeconomics. 2023 Mar 23.

Abemaciclib in Combination with Endocrine Therapy for Adjuvant Treatment of Hormone Receptor-Positive, HER2-Negative, Node-Positive Early Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

Giovany Orozco Leal, Nigel Armstrong, Ashleigh Kernohan, Charlotte Ahmadu, Diarmuid Coughlan, Kevin McDermott, Steven Duffy, Susan O'Meara, Tomos Robinson, Luke Vale, Jos Kleijnen.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Eli Lilly) of abemaciclib (Verzenios) to submit evidence for the clinical and cost effectiveness of this drug in combination with endocrine therapy (ET) for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence, as part of the Institute's Single Technology Appraisal (STA) process. Kleijnen Systematic Reviews Ltd, in combination with Newcastle University, was commissioned to act as the independent Evidence Review Group (ERG). This paper summarised the Company Submission (CS), presents the ERG's critical review of the clinical and cost-effectiveness evidence in the CS, highlights the key methodological considerations, and describes the development of the NICE guidance by the Appraisal Committee. The ERG produced a critical review of the evidence for the clinical and cost-effectiveness evidence in the CS and also independently searched for relevant evidence and modified the manufacturer decision analytic model to examine the impact of altering some of the key assumptions. A systematic literature review identified the MonarchE trial, an ongoing, open-label, randomised, double blind trial involving 5637 people comparing abemaciclib in combination with ET versus ET alone. The trial included two cohorts that used different inclusion criteria to define high risk of recurrence. The ERG considered Cohort 1 as an adequate representation of this population and the AC concluded that Cohort 1 was generalisable to National Health Service clinical practice. Trial results showed improvements in invasive disease-free survival for the abemaciclib arm, which was considered an appropriate surrogate outcome. The ERG believed that the modelling structure presented in the de novo economic model by the company was appropriate but highlighted several areas of uncertainty that had the potential to have a significant impact on the resulting incremental cost-effectiveness ratio (ICER). Areas of uncertainty included the extrapolation of long-term survival curves, the duration of treatment effect and treatment waning, and the proportion of patients who receive other CDK4/6 treatments for metastatic disease after receiving abemaciclib. ICER estimates were £9164 per quality-adjusted life-year gained for the company's base-case and £17,810 for the ERG's base-case. NICE recommended abemaciclib with ET as an option for the adjuvant treatment of HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.

DOI: https://doi.org/10.1007/s40273-023-01259-6