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

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

Tim Schutte  1 , Alaa Embaby  2 , Neeltje Steeghs  3 , Stevie van der Mierden  4 , Willemien van Driel  5 , Martin Rijlaarsdam  3 , Alwin Huitema  6 , Frans Opdam  3
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Free article

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

Tim Schutte et al. Cancer Treat Rev. 2023 Apr.
Free article

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.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be seen as a potential conflict of interest to the presented work. Each author provided a detailed conflict of interest statement according to the Journals policy. N Steeghs received research grants (All outside the submitted work, all payment to the Netherlands Cancer Institute) from: Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, Takeda. N. Steeghs received consulting fees (All outside the submitted work, all payment to the Netherlands Cancer Institute) from Boehringer Ingelheim, Cogent Biosciences, Ellipses Pharma, Luszana.

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