Abstract:
:Targeting the ataxia telangiectasia and RAD3-related (ATR) enzyme represents a promising anticancer strategy for tumors with DNA damage response (DDR) defects and replication stress, including inactivation of ataxia telangiectasia mutated (ATM) signaling. We report the dose-escalation portion of the phase I first-in-human trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5 to 80 mg twice daily in 21 patients with advanced solid tumors. The MTD was 40 mg twice daily 3 days on/4 days off. Most common adverse events were manageable and reversible hematologic toxicities. Partial responses were achieved in 4 patients and stable disease in 8 patients. Median duration of response was 315.5 days. Responders had ATM protein loss and/or deleterious ATM mutations and received doses ≥40 mg twice daily. Overall, BAY 1895344 is well tolerated, with antitumor activity against cancers with certain DDR defects, including ATM loss. An expansion phase continues in patients with DDR deficiency. SIGNIFICANCE: Oral BAY 1895344 was tolerable, with antitumor activity in heavily pretreated patients with various advanced solid tumors, particularly those with ATM deleterious mutations and/or loss of ATM protein; pharmacodynamic results supported a mechanism of action of increased DNA damage. Further study is warranted in this patient population.See related commentary by Italiano, p. 14.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Yap TA,Tan DSP,Terbuch A,Caldwell R,Guo C,Goh BC,Heong V,Haris NRM,Bashir S,Drew Y,Hong DS,Meric-Bernstam F,Wilkinson G,Hreiki J,Wengner AM,Bladt F,Schlicker A,Ludwig M,Zhou Y,Liu L,Bordia S,Plummer R,Lagkadindoi
10.1158/2159-8290.CD-20-0868subject
Has Abstractpub_date
2020-09-28 00:00:00eissn
2159-8274issn
2159-8290pii
2159-8290.CD-20-0868pub_type
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