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

by Selleckchem | Jan 24 2024

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.

Comments:

Your systematic review provides a comprehensive overview of the clinical trials exploring WEE1 inhibitors (WEE1i) in treating gynecological malignancies. The focus on outlining their efficacy, safety, and potential future applications is valuable in understanding their role in this patient group.

The primary objective of summarizing efficacy based on objective response rates, clinical benefit rates, overall survival, and progression-free survival sheds light on the effectiveness of WEE1i in treating gynecological cancers. It's promising to note the varied response rates and survival outcomes observed across different trials using adavosertib, the primary WEE1i investigated.

The identification of common adverse events, such as bone marrow suppression, gastrointestinal toxicities, and fatigue, underscores the importance of monitoring and managing these side effects in clinical settings. Additionally, the potential role of specific gene alterations, like TP53 and CCNE1, as predictors of response highlights the need for biomarker-driven approaches for patient selection, potentially enhancing response rates.

Your conclusion appropriately emphasizes the encouraging developments in using WEE1i for gynecological cancers and hints at the necessity for refining patient selection through biomarkers. This could significantly impact future studies and clinical applications of WEE1 inhibitors in this specific patient cohort.