First-in-human trial of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor BAY 1895344 in patients (pts) with advanced solid tumors.

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.

DNA damage checkpoint kinases in cancer

“…The ATR inhibitor BAY1895344 has recently shown to have anti-tumour activity and is well tolerated at active doses in cancers with defects in DDR, such as loss of ATM (Ref. 192) (NCT03188965).…”

Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer

“…DLTs occurred only at the maximum tested doses and were connected to myelosuppression (G4), and nausea, and fatigue (both G2), whereas the biologically active doses were well tolerated. Objective responses were especially evident in patients with DDR defects including ATM loss/mutation and BRCA1 mutation [ 124 ]. Currently, there is no additional information related to M4344 in clinical trials (there are two phase I trials with recruiting status).…”

“…This could suggest good tolerability for healthy tissues but a greater importance of a combination strategy with DNA damaging agents. For instance, monotherapy (berzosertib, ceralasertib, and BAY1895344) resulted in no DLTs with an acceptable level of myelosuppression [ 118 , 121 , 124 ]. Besides, these three inhibitors are highly selective without potential off-target toxicity.…”

“…The preliminary preclinical data for ATR, CHK1, and WEE1 inhibitors enabled the prediction of which inhibitor would prosper from a particular genetic aberration (see chapter "Rationale in the design of clinical trials") [ 104 , 106 , 166 , 167 ]. Some ATRi successfully translated their presumption from basic research into the clinics, and their clinical responses were mostly dependent on the mutation/loss of ATM [ 118 , 122 , 124 ]. However, the combination of ceralasertib with olaparib was ATM‑independent and preferably profited from the HR defects represented by BRCA1/2 mutations [ 123 ].…”

Meeting report from the Prostate Cancer Foundation PSMA theranostics state of the science meeting

“…158 The ATM inhibitor AZD0156 has also been shown to potentiate both radiation and olaparib responses in preclinical xenograft tumor models. 159 The ATR inhibitor BAY 1895344 has demonstrated some antitumor activity in a single agent phase 1 study in solid tumors 160 ; this agent could be considered for combination with 177 Lu-PSMA-617. The RNA polymerase I inhibitor CX-5461 has also demonstrated synergy with talazoparib in preclinical models of ovarian cancer 161 breakthrough treatments for many cancers including melanoma, lung cancer and others because of the marked and durable responses and unprecedented survival benefit.…”