Abstract 1915
Background
ATR inhibition (ATRi) exploits high levels of replication stress and G1/S cell cycle checkpoint dysfunction frequently seen in cancers, increasing DNA damage and inducing mitotic crisis. ATRi may also potentiate DNA-damaging anticancer therapies to improve clinical activity.
Methods
We present results from the monotherapy phase of a study of AZD6738, an oral ATRi in patients with advanced solid tumours (NCT02223923). Endpoints were MTD, safety, tolerability, pharmacokinetics (PK) and preliminary efficacy. MTD and PK were previously presented.
Results
Forty-six patients enrolled and received at least 1 dose AZD6738 to February 2019, 24 completed ≥1 cycle (28 days) of treatment in the dose-escalation phase, 20 commenced treatment in expansion phase, testing 2 different schedules at MTD (160 mg BD). The median number of cycles was 3 (range 2-12) in dose-escalation phase and 4 (1-12) in the dose-expansion cohort. 17/26 (65%) patients in dose escalation and 7/20 (35%) in dose-expansion had G ≥ 3 treatment-related adverse events (TRAEs). An intermittent schedule (2-week-on, 2-week-off) was better tolerated than continuous dosing, with G ≥ 3 TRAEs in 4/6 (67%) receiving continuous and 3/15 (20%) with intermittent dosing. The most common TRAEs were fatigue, anaemia, nausea and thrombocytopenia; 20 (77%) of patients in dose escalation and 16 (80%) in expansion discontinued AZD6738 due to progressive disease (PD). 5 (19%) patients in dose-escalation and 1 (5%) in dose-expansion discontinued due to toxicity. Best overall response was confirmed partial response (PR) in 3 (7%) participants, unconfirmed PR in 1 (2%), stable disease (SD) in 22 (48%) and PD in 12 (26%). Early clinical PD or toxicity prevented radiological assessment in 8 (17%). 5/24 (21%) participants in dose-escalation and 5/20 (25%) in dose-expansion had SD of ≥ 4 cycles (16 weeks) duration.
Conclusions
AZD6738 is well tolerated at 160 mg BD on a 2-week-on, 2-week-off schedule. ATRi monotherapy resulted in confirmed PR and a high proportion of prolonged SD. Future cohorts will enrich for DNA damage response-deficient tumours. A parallel dose-escalation study of AZD6738 combined with palliative radiotherapy is underway. Funding: CRUKD/14/007.
Clinical trial identification
NCT02223923; EudraCT: 2013-003994-84.
Editorial acknowledgement
Legal entity responsible for the study
Royal Marsden NHS Foundation Trust and The Institute of Cancer Research: Royal Cancer Hospital.
Funding
Cancer Research UK, ECMC Combinations Alliance, AstraZeneca.
Disclosure
S.A. Smith: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. E. Dean: Full / Part-time employment: AstraZeneca. J. Spicer: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self): Lilly; Honoraria (self): Lytix Biopharma; Honoraria (self): Pierre Fabre; Honoraria (self): Roche; Honoraria (self), Advisory / Consultancy: Shionogi; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Quintiles; Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: AstraZeneca. M.D. Forster: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Sharpe & Dohme; Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly. K.J. Harrington: Advisory / Consultancy: Amgen; Advisory / Consultancy: AstraZeneca-Medimmune; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Lytix Biopharma; Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dohme; Advisory / Consultancy: Merck; Advisory / Consultancy: Oncos Therapeutics; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Viralytics; Research grant / Funding (self): Oncolytics Biotech. All other authors have declared no conflicts of interest.