Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review
A partir d'une revue systématique de la littérature (26 articles), cette étude analyse les données des essais cliniques évaluant l'efficacité, du point de vue du taux de réponse objective, du taux de bénéfice clinique, de la survie globale et de la survie sans progression, et la toxicité des inhibiteurs de WEE1, en particulier l'adavosertib, pour traiter les patientes atteintes d'un cancer gynécologique
Résumé en anglais
Introduction: The anti-tumor activity of WEE1 inhibitors (WEE1i) in gynecological malignancies has recently been demonstrated in clinical trials and its rationale is based on biological/molecular features of gynecological cancers. With this systematic review, we aim to outline the clinical development and current evidence regarding the efficacy and safety of these targeted agents in in this patient group.
Methods: Systematic literature review of trials including patients with gynecological cancers treated with a WEE1i. The primary objective was to summarize the efficacy of WEE1i in gynecological malignancies regarding objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS) and progression-free survival (PFS). Secondary objectives included toxicity profile, Maximum Tolerated Dose (MTD), pharmacokinetics, drug-drug interactions and exploratory objectives such as biomarkers for response.
Results: 26 records were included for data extraction. Almost all trials used the first-in-class WEE1i adavosertib; one conference abstract reported about Zn-c3. The majority of the trials included diverse solid tumors (n=16). Six records reported efficacy results of WEE1i in gynecological malignancies (n=6). Objective response rates of adavosertib monotherapy or in combination with chemotherapy ranged between 23%-43% in these trials. Median PFS ranged from 3.0 to 9.9 months. The most common adverse events were bone marrow suppression, gastrointestinal toxicities and fatigue. Mainly alterations in cell cycle regulator genes TP53 and CCNE1 were potential predictors of response.
Conclusion: This report summarizes encouraging clinical development of WEE1i in gynecological cancers and considers its application in future studies. Biomarker driven patient selection might be essential to increase the response rates.
