Implementing geriatric assessment for dose optimization of CDK4/6 inhibitors in older breast cancer patients
Creators: name: Valachis, Antonis
name: Biganzoli, Laura
name: Christopoulou, Athina
name: Fjermeros, Kamilla
name: Fountzila, Elena
name: Geisler, Jürgen
name: Gomez-Bravo, Raquel
name: Karihtala, Peeter
name: Kosmidis, Paris
name: Koutras, Angelos
name: Linardou, Helena
name: Lindman, Henrik
name: Martínez-Ballestero, Iván
name: Rodríguez, Anna Belén
name: Meattini, Icro
name: Munoz-Mateu, Montserrat
name: Othman, Mukhrizah
name: Psyrri, Amanda
name: Risi, Emanuela
name: Schiza, Aglaia
name: Spathas, Nikolaos
name: Utriainen, Meri
name: Visani, Luca
name: Ballesteros, Soledad
name: Basdekis, Ioannis
name: Hay, Susanne Dieroff
name: Fotis, Theo
name: Fricker, Samuel
name: de Graaf, Gimon
name: Jenset, Marit
name: Kanters, Tim
name: Lampropoulos, Kostas
name: Markou, Christiana
name: Mastoraki, Kalliopi
name: Nanou, Christina
name: Aviles, José Manuel Reales
name: Santaholma, Marianne
name: Kosmidis, Thanos
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Medicine
subject: Pharmacology
subject: Biotechnology
subject: Chemical Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Cancer
subject: Hematology
subject: Infectious Diseases
subject: FOS: Health sciences
subject: Virology

description: Current evidence from both randomized trials and real-world studies suggests that older patients with advanced hormone receptor-positive/HER2-negative (HR+/HER2) breast cancer derive clinical benefit from the addition of CDK4/6 inhibitors to endocrine therapy. However, a higher risk for adverse events due to CDK4/6 inhibitors among older patients is evident, leading to a trend of initiating CDK4/6 inhibitors at lower dose in clinical practice, though without evidence. The aim of the IMPORTANT-trial, a pragmatic, multinational, open-label, partly decentralized randomized trial is to investigate whether lower starting dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer who are assessed as vulnerable or frail based on comprehensive geriatric assessment. <b>Clinical Trial Registration:</b>NCT06044623 (ClinicalTrials.gov); Registration date: 13 September 2023. In patients with advanced hormone receptor- (HR-) positive/HER2-negative breast cancer, the combination of endocrine therapy with CDK4/6 inhibitors is the standard of care as initial treatment approach. Older cancer patients are underrepresented in clinical trials, including pivotal trials on CDK4/6 inhibitors. Real-world evidence studies have showed that older patients are at increased risk for adverse events when treated with implementation of CDK4/6 inhibitors; lower initial dose is common in clinical practice, though without evidence. Comprehensive geriatric assessment (CGA) seems to be a reliable tool for the optimization of treatment strategy in older cancer patients. IMPORTANT is pragmatic, multi-national, open-label, partly de-centralized randomized trial investigating whether a lower initial dose of CDK4/6 inhibitors combined with endocrine therapy is comparable to a full dose in older (≥70 years old) patients with advanced HR+/HER2- breast cancer that are assessed as vulnerable or frail based on CGA. Eligible patients are older female or male patients (≥70 years old) with advanced HR-positive/HER2-negative breast cancer, not amenable for curative treatment and without prior therapy for advanced disease. The follow-up strategy in terms of treatment efficacy and toxicity resembles the current follow-up strategy in clinical practice without additional blood tests or radiological examinations. The follow-up will include toxicity evaluation before each treatment cycle as well as clinical and radiological evaluation of treatment efficacy every 3 months. Patient-reported outcomes will be captured through self-questionnaires during the study period. A total of 495 patients are to be enrolled with 30-month accrual period with aim to recruit 149 patients for the fit cohort to be treated and followed, and 346 patients for the vulnerable/ frail cohort to be randomized. Patients will be categorized based on self-reported CGA to fit or vulnerable/frail depending on domains of age metrics that are impaired. Patients categorized as vulnerable/frail will be randomized (1:1) to -1 level lower initial dose or full dose of CDK 4/6 inhibitors combined with endocrine therapy. Stratification factors during randomization are the type of CDK4/6 inhibitor used (palbociclib vs ribociclib vs abemaciclib), the type of endocrine therapy (aromatase inhibitors vs fulvestrant) and the level of vulnerability based on CGA (vulnerable vs frail). The primary end point is time-to-treatment failure; secondary end points include overall treatment utility, investigator-assessed progression-free survival, overall survival, time to chemotherapy initiation, toxicity, quality-of-life (QoL), time to QoL deterioration and cost-effectiveness.