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.
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.
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.
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.
NCT02223923; EudraCT: 2013-003994-84.
Royal Marsden NHS Foundation Trust and The Institute of Cancer Research: Royal Cancer Hospital.
Cancer Research UK, ECMC Combinations Alliance, AstraZeneca.
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.