PS5-09-27: A phase i/ii single-arm trial of azenosertib (zn-c3) combined with carboplatin and pembrolizumab in patients with metastatic triple-negative breast cancer (zap-it)

Abstract Background: Despite recent advances in breast cancer treatment, metastatic triple negative breast cancer (mTNBC) remains incurable. WEE1 is a tyrosine kinase that inhibits cyclin dependent kinase 1, thus arresting the cell cycle at the G2 checkpoint and providing an opportunity for DNA damage repair. WEE1 is highly expressed in several cancer types, including breast cancer. A phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in 34 patients with mTNBC treated with 0-1 prior lines of chemotherapy showed an ORR of 26% (Keenan. CCR 2021). Although the combination missed the pre-specified ORR cutoff of 30%, tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration. Azenosertib is a novel, selective, and orally bioavailable small-molecular inhibitor of the WEE1 tyrosine kinase, with strong evidence of in vitro and in vivo activity in different solid tumor types. Most common side effects (≥G3) of ZN-c3 intermittent dosing with carboplatin AUC 5 were thrombocytopenia (36%), anemia (29%), neutropenia (7%), fatigue (7%), no nausea, vomiting or diarrhea (Liu et al. ASCO 2023). The ZAP-IT trial is evaluating the safety and efficacy of azenosertib with carboplatin and pembrolizumab in patients with mTNBC. Methods: This is an ongoing single-arm, open-label, phase Ib/II study designed to evaluate the safety and efficacy of azenosertib in combination with carboplatin and pembrolizumab in patients with mTNBC, defined as ER 10% or PR 10%, and HER2- negative by IHC and/or FISH; patients are eligible irrespective of tumor PD-L1 status. Patients must have received 1-3 prior systemic therapies in the advanced setting, have not had disease progression on prior platinum, and must have received at least one antibody drug conjugate. In the phase I portion of this study, patients will receive a predetermined dose of carboplatin on days 1 and 8 of every 21 days, a predetermined dose of pembrolizumab once every 21 days and a predetermined starting dose level of azenosertib 5 days on 2 days off. Paired research biopsies will be required at baseline and at Cycle 2 of therapy in phase 2 patients with an optional end of treatment biopsy. The primary objective of the phase Ib is to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of azenosertib when used in combination with carboplatin and pembrolizumab in patients with TNBC. The primary endpoint of the phase II is to assess the efficacy, as defined by objective response rate (ORR) per RECIST 1.1 criteria, of the combination of azenosertib, carboplatin, and pembrolizumab in patients with mTNBC. A maximum of 78 patients will be enrolled. To our knowledge this is the first and only ongoing study testing the combination of a WEE1 inhibitor with carboplatin and a checkpoint inhibitor for the treatment of breast cancer. Citation Format: F. Lynce, N. Tayob, N. Chen, A. Grinshpun, R. Davis, M. K. DeMeo, A. G. Waks, R. Nanda, J. L. Guerriero, G. Shapiro, S. M. Tolaney. A phase i/ii single-arm trial of azenosertib (zn-c3) combined with carboplatin and pembrolizumab in patients with metastatic triple-negative breast cancer (zap-it) abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-27.