First-in-Human Trial of the Oral Ataxia Telangiectasia and RAD3-Related (ATR) Inhibitor BAY 1895344 in Patients with Advanced Solid Tumors

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-inhuman trial of oral ATR inhibitor BAY 1895344 intermittently dosed 5-80 mg twice daily (BID) in 21 patients with advanced solid tumors. The maximum tolerated dose was 40 mg BID 3 days on/4 days off. Commonest adverse events were manageable and reversible hematological 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 BID. 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 pre-treated 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.

Chemotherapy Induces Senescence-Like Resilient Cells Capable of Initiating AML Recurrence

“…However, in the other three cases killing was supra-additive since these cells were relatively resistant to either Ara-C or VE821, yet still manifested >95% killing in the presence of the combination. These results were confirmed using a second, more potent ATR inhibitor BAY-1895344, which is also in clinical trials (61)…”

Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations)

“…ATR inhibition has been shown to be synthetically lethal with ATM deficiency in preclinical models, translating to responses to monotherapies that have been reported with agents such as BAY1895344 and M6620. 25 , 36 The complete loss of ATM protein is ideally confirmed by protein immunohistochemistry, but this is not yet a standard laboratory test. Genetic testing is not as certain, although LOH can sometimes be confirmed.…”

“…ATM deficiency is expected to sensitize malignant cells to ATR inhibition, which has been demonstrated both in preclinical models and in clinical trials. [22][23][24][25] Additionally, in preclinical pancreatic and lung cancer models, ATM deficiency also sensitizes to PARP inhibition, suggesting that combined ATR and PARP inhibition may be useful. 26,27 In contrast, other studies showed low sensitivity of ATMdeficient prostate cancers to PARP inhibition.…”

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

“…Enhancing replicative damage by blunting the RepStress response pathways with ATR inhibitors is discussed below [8,[63][64][65][66][67]. Synthetic lethality for the PARP inhibitors and platinum derivatives in HRD cancers is being applied for cancer treatment [68,69] and recent studies in animal models suggest such synthetic lethality for TOP1 inhibitors [10,58].…”