Background: Wee1 is a tyrosine kinase implicated in the inhibitory phosphorylation of CDK1/CDC2-bound cyclin B complex responsible for G2 arrest. Wee 1 kinase inhibition results in premature mitotic entry and double strand DNA breaks in preclinical models. AZD1775 is a selective, adenosine-triphosphate (ATP) competitive, small molecule inhibitor of Wee1 kinase that directly inhibits phosphorylation of CDC2 at Tyr15. Partial responses (PR) were observed in patients (pts) with BRCAm+ solid tumors following treatment with AZD1775 in a single agent, Phase I trial (J Clin Oncol. 2015;33(30):3409-15). Clinical benefit in pts with BRCAm+ solid tumors was further evaluated in this trial, conducted as a subprotocol of the NCI-MATCH trial.
Study Design: Eligible pts met all criteria for the NCI-MATCH master protocol and provided tissue specimen for central next generation sequencing, which revealed a known pathogenic mutation in BRCA 1 or 2. Pts with ovarian cancer were required to have received prior poly ADP ribose polymerase (PARP) inhibitor treatment. AZD1775 was administered orally, 300 mg once daily, 5 days on and 2 days off, 2 weeks on and 1 week off; cycle length 21 days. Cycles were repeated until disease progression or unacceptable toxicity. Radiologic assessment was performed every 3 cycles. Dose of AZD1775 was held and modified for grade ≥ 3 toxcities; which were required to resolve to ≤ Grade 2 prior to starting next cycle.
Results: 33 pts were enrolled; 31 received study treatment. Male:female (11/20), age range 36-79 yrs.; ECOG PS 0/1 5/26; 67% had > 3 prior therapies. Tumor types: breast (9), ovarian/fallopian tube/mixed (5/1/1), pancreas (4), gallbladder (1), GI tract (4), melanoma (1), solitary fibrous tumor (1), mesothelioma (1), salivary gland (1), anaplastic oligodendroglioma (1), lung (1). BRCA 1/2 13/18. Clinical benefit: response rate 3.2% (90% CI 0.15%-14.4%); 6-month PFS rate 19% (90% CI 10%-36%): 1 PR (serous fallopian tube cancer); 4 SD > 6 months (ovarian cancer (3), solitary fibrous tumor (1). Median number of cycles: 2 (range 1- 18).Treatment discontinued for disease progression/adverse event/ patient withdrawal/other 17/6/3/3; 2 pts remain on study (4 and 20 cycles). Prior PARP exposure: Gyn cancer 71%; Breast cancer 22%. Prior platinum: Gyn cancer 100%; breast cancer 56%. Common side effects: myelosuppression, fatigue, nausea, vomiting, diarrhea.
Conclusions: Single agent AZD1775, at the dose and schedule evaluated, was well tolerated. Modest single agent activity was observed in heavily pretreated patients with BRCA 1/2 mutated solid tumors. Evaluation of AZD1775 in combination with PARP inhibitors and/or chemotherapy may be warranted in less heavily pretreated patients with BRCA 1/2 mutated solid tumors.
Citation Format: Shivaani Kummar, Shuli Li, Kim Reiss, James M. Ford, Edith P. Mitchell, James A. Zwiebel, Naoko Takebe, Robert J. Gray, Lisa M. McShane, Larry V. Rubinstein, David Patton, Paul Mickey Williams, Stanley R. Hamilton, Adam Brufsky, Barbara A. Conley, Carlos L. Arteaga, Lyndsay N. Harris, Peter J. O'Dwyer, Alice P. Chen, Keith T. Flaherty. NCI-MATCH EAY131 -Z1I: Phase II study of AZD1775, a wee-1 kinase inhibitor, in patients with tumors containing BRCA1 and BRCA2 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT138.