Abstract B079: Single agent AZD 1775, a Wee1 inhibitor, shows activity in BRCA deficient patients

Abstract

Abstract Background: Modulation of BRCA1 and ATR has been postulated as an activation mechanism of checkpoint 1 (Chk1), which in turn triggers homologous recombination repair through modulation of BRCA2-Rad51, and the initiation of cell cycle checkpoints through phosphorylation and activation of Wee1. Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of cyclin-dependent kinase 1 (CDK1/CDC2)-bound cyclin B, resulting in G2 cell cycle arrest in response to DNA damage. AZD1775 is a first-in-class selective inhibitor of Wee1 kinase that directly prevents phosphorylation of CDC2 at Tyr15. Model data show single-agent antitumor activity in multiple cancer cell lines across the NCI-60 and in both p53 intact and deficient tumor xenografts. We are conducting a phase I trial of AZD1775 in patients (pts) with refractory solid tumors, both with and without germline BRCA1/2 mutations (BRCA+), evaluating two different dosing schedules. We have previously reported on initial antitumor activity and proof-of-mechanism (Do et al, J Clin Oncol. 2015). This abstract reports the efficacy seen in the BRCA+ population. Methods: AZD1775 was administered orally twice daily (BID) for 5 doses [D1-3 and 8-10, Cohort A (A)] or once daily for 5 days [D1-5 and 8-12, Cohort B (B)] during weeks 1 and 2 of a 21-day cycle; 3+3 design. Primary objectives: establish safety, tolerability and PK of AZD1775. Secondary objectives: determine the effect of AZD1775 on markers of DNA damage and apoptosis in tumor tissue/circulating tumor cells, and antitumor activity. Dose-limiting toxicity (DLT) was determined during Cycle 1. Response defined by RECIST 1.1 on CT. Results: A total of 17 BRCA+ pts have enrolled; 9 pts on A (one pt withdrew for other therapy), and 8 pts on B. Nine pts with BRCA1, 7 pts with BRCA2: ovarian (9 pts), breast (2), pancreas (1), prostate (1), Fallopian tube (1), and peritoneal (1) cancer. Partial responses (PR) were confirmed on 2/8 pts (25%) in A with BRCA1 papillary serous ovarian cancer and squamous cell carcinoma of tongue. Two additional PRs (25%) were confirmed in BRCA1 serous ovarian cancer pts in B. Two further BRCA1 ovarian pts trended near PR. All 4 responders received prior platinum therapy; 3/3 ovarian cancer pts received and responded to prior PARP inhibitor therapy. No differences were noted in severity or rate of toxicity in pts with/without BRCA+: common grade 3/4 toxicities include anemia (6 pts, 37%), lymphopenia (5, 31%), neutropenia (4, 25%), and thrombocytopenia (3, 18%), occurring in responders and nonresponders. Conclusions: AZD1775 has single-agent antitumor activity in a BRCA deficient population, especially BRCA1. Responses were observed in pts with prior exposure to platinum and a PARP inhibitor. Additional accrual on a safety expansion cohort is ongoing, and assessment of PD biomarkers is planned for paired biopsies (NCT01748825). Citation Format: Geraldine OSullivan Coyne, Shivaani Kummar, Naoko Takebe, Khanh Tu Do, Robert Meehan, Richard Piekarz, Jennifer Zlott, Lamin Juwara, Mary Quinn, Elad Sharon, Howard Streicher, Lawrence Rubinstein, Chana Levine, James H. Doroshow, Alice P. Chen. Single agent AZD 1775, a Wee1 inhibitor, shows activity in BRCA deficient patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B079.