Tumors with G1/S checkpoint deficiencies (e.g. TP53 mutations) rely on WEE1 kinase activity to arrest cell cycle progression at the G2 checkpoint, allowing for DNA repair before entry into mitosis. In preclinical models, WEE1 inhibition leads to mitotic catastrophe and cell death when combined with inhibitors of DNA damage response pathways. AZD1775 is a highly selective small molecule WEE1 inhibitor in development for the treatment (tx) of advanced solid tumors. Here, we report results from lead-in portions of two Phase 2 studies: carboplatin (C)/pemetrexed (P) + AZD1775 v. C/P in 1st-line metastatic non-squamous (NS) NSCLC (NCT02087241); and docetaxel (D) + AZD1775 v. D in recurrent NSCLC (NCT02087176).
Both lead-in portions were designed to assess early safety and efficacy (response rate (RR) per RECIST 1.1). Tumor specimens were tested retrospectively for TP53 mutations using Next-Generation Sequencing. Patients (pts) with TP53-mutated (TP53+) and wild-type tumors were eligible. 1st-line metastatic tx: C AUC 6 + P 500mg/m2 IV day (d) 1, every 21d; recurrent tx: D 75mg/m2 IV d1 + granulocyte-colony stimulating factor 6mg SC d4 every 21d. All pts received AZD1775 225mg PO BID d1-3 x 5 doses. After a planned safety analysis of the 1st-line trial, dose and schedule were modified to reduce toxicity.
Data are presented in the table. Both studies were closed early owing to prioritization of other ongoing monotherapy and combination development programs, including strategies to optimize pt selection based on emerging genomic data. This limited the assessment of efficacy. One 1st-line pt (TP53 status unknown) remains on maintenance tx (Cycle 19) with AZD1775 and P.
|First-line Group (N = 14)||Recurrent Group (N = 32)|
|Median Age||63 years||62 years|
|TP53 + , n (%)||4 (29)||17 (53)|
|Male, n (%)||6 (43)||19 (59)|
|Partial Response (PR), n (%)||4 (29) including 1 pt on AZD1775 alone for 1 year and 1 pt on AZD1775 and pemetrexed for over 1 year||3 (9)|
|TP53+ pts with PR||1 pt, 1/4 total (25)||3 pts, 3/17 total (18)|
|Stable Disease, n (%)||6 (43)||21 (66)|
|TP53+ pts with SD||3 pts, 3/4 total (75)||10 pts, 10/17 total (59)|
|Progressive Disease, n (%)||1 (7)||1 (7)|
|TP53+ pts with PD||0||1 pt, 1/17 total (6)|
|Not Evaluable, n||3 pts||5 pts|
|Most Common Grade 3/4 Toxicities (> 10%)||Neutropenia (36%)||Neutropenia (28%)|
|Diarrhea (36%)||Thrombocytopenia (28%)|
|Thrombocytopenia (29%)||Leukopenia (22%)|
|Nausea (14%)||Abdominal Pain (13%)|
|Vomiting (14%)||Diarrhea (13%)|
|Anemia (14%)||Asthenia (13%)|
|Atrial Fibrillation (14%)||Fatigue (13%)|
|Febrile Neutropenia (14%)|
Toxicities included myelosuppression and diarrhea. AZD1775 development is ongoing across multiple tumor settings as monotherapy, in combination with olaparib, and in biomarker-specific cohorts.
Clinical trial identification
Legal entity responsible for the study
Sarah Cannon Research Institute
D.R. Spigel: AstraZeneca-Travel funding. A. Sadiq: AstraZeneca-honoraria. C. Cook, G.M. Mugundu, N.M. Laing, T. French: AstraZeneca-employee and stock owner. All other authors have declared no conflicts of interest.