Abstract
3007 Background: The ATR kinase is a key regulator of the DNA damage response (DDR) machinery, activated by DNA damage and replication stress. BAY 1895344 is a novel, potent, and selective ATR inhibitor with anti-tumor activity in preclinical models with DDR defects. Methods: Pts with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without DDR defects, received BAY 1895344 BID, 3 days (d) on/4 d off continuously in 3-weekly cycles. Results: As of December 20, 2018, 18 pts with colorectal (4), breast (3), prostate (2), and ovarian (2) cancers were enrolled across 6 cohorts (5 mg, 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg BID). Median prior lines of treatment was 5. No dose-limiting toxicities (DLTs) were reported in the 5-40 mg cohorts. 2/3 pts had DLTs in the 80 mg cohort (grade [G] 4 neutropenia, G4 neutropenia and G4 thrombocytopenia) and 2/7 had DLTs in the 60 mg cohort (G4 neutropenia, G2 fatigue). 40 mg BID 3 on/4 off was defined as the maximum tolerated dose. Most common treatment-emergent adverse events included anemia, neutropenia, nausea, and fatigue. Pharmacokinetics appeared dose proportional. Pharmacodynamic analyses showed modulation of pH2AX and/or pKAP1 in paired tumor biopsies at exposures associated with preclinical anti-tumor activity. In 13 pts with and without DDR defects treated at dose levels ≥40 mg BID, the objective response rate was 30.7%, including 2/2 pts at 40 mg (appendix and urothelial cancer), 1/8 pts at 60 mg (breast), and 1/3 pts at 80 mg (endometrial). All responders had ATM protein loss of expression and/or ATM mutation; median treatment duration was 347 d (range 293-364 d). A BRCA1-mutant, olaparib-resistant ovarian cancer pt (60 mg) had a CA125 response and stable disease >10 months. 41 additional pts have been enrolled in ongoing expansion cohorts in cancers with DDR defects (prostate, breast, gynecologic, colorectal) or ATM protein loss (all comers) with responses observed. Conclusions: The ATR inhibitor BAY 1895344 is tolerated at biologically active doses with anti-tumor activity against cancers with certain DDR defects, including ATM protein loss. Clinical trial information: NCT03188965.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.