Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review

Tim Schutte; Alaa Embaby; Neeltje Steeghs; Stevie van der Mierden; Willemien van Driel; Martin Rijlaarsdam; Alwin Huitema; Frans Opdam

doi:10.1016/j.ctrv.2023.102531

Clinical development of WEE1 inhibitors in gynecological cancers: A systematic review

Cancer Treat Rev. 2023 Apr:115:102531. doi: 10.1016/j.ctrv.2023.102531. Epub 2023 Mar 3.

Authors

Tim Schutte¹, Alaa Embaby², Neeltje Steeghs³, Stevie van der Mierden⁴, Willemien van Driel⁵, Martin Rijlaarsdam³, Alwin Huitema⁶, Frans Opdam³

Affiliations

¹ Department of Internal Medicine and Department of Medical Oncology, Amsterdam UMC, Location VUmc, Amsterdam, Netherlands. Electronic address: t.schutte@amsterdamumc.nl.
² Department of Clinical Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands.
³ Department of Medical Oncology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands.
⁴ Scientific Information Service, The Netherlands Cancer Institute, Amsterdam, Netherlands.
⁵ Department of Gynecological Oncology, The Netherlands Cancer Insitute - Antoni van Leeuwenhoek, Amsterdam, Netherlands.
⁶ Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek, Amsterdam, Netherlands; Department of Pharmacology, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.

PMID: 36893690
DOI: 10.1016/j.ctrv.2023.102531

Abstract

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% and 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.

Keywords: Adavosertib; Gynecological malignancies; Gynecological oncology; Ovarian cancer; WEE1 inhibitors WEE1i; Zn-C3.

Publication types

Systematic Review
Review

MeSH terms

Antineoplastic Agents* / therapeutic use
Cell Cycle Proteins
Female
Genital Neoplasms, Female* / drug therapy
Genital Neoplasms, Female* / genetics
Humans
Protein-Tyrosine Kinases

Substances

Antineoplastic Agents
WEE1 protein, human
Protein-Tyrosine Kinases
Cell Cycle Proteins