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-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.This article is highlighted in the In This Issue feature, p. 1.

Figure 1.

Pharmacokinetic and pharmacodynamic results. A, BAY 1895344 geometric mean plasma concentration over time after single-dose administration at cycle 1, day 1. B, BAY 1895344 geometric mean plasma concentration over time after multiple-dose administration at cycle 1, day 10. C, Example of on-treatment increase of tumor γ-H2AX and pKAP1 at baseline and cycle 1, day 10 in a patient with a BRCA1 germline mutation and high-grade serous platinum-refractory ovarian cancer. D, Percentage of γ-H2AX positive cells at baseline and post-treatment in biopsy pairs (n = 17). E, Percentage of γ-H2AX positive cells at baseline and post-treatment in biopsy pairs from patients with (n = 12) or without (n = 5) ATM protein expression. F, PD-L1 expression in baseline tumor biopsy samples. G, Comparison of PD-L1 expression at baseline with on-treatment paired biopsies in patients with ovarian (n = 6) and endometrial cancer (n = 2). NS, not significant.

Figure 2.

Efficacy and clinical response results of BAY 1895344 in the dose-escalation part. A, Change in target lesion size, best response, ATM aberration status, and mutation status in the 20 patients with available data from post-baseline assessments. ^aAlternating dose; ^bOngoing with study treatment; ^c2 patients who achieved stable disease as RECIST best response had investigator-assessed clinical disease progression at the same time point and were therefore reported as having progressive disease. B, Durability of response in the 17 patients treated on the 3 days on/4 days off schedule who had post-baseline tumor assessments. C, Tumor reduction of −54% in a patient with tumor ATM protein loss by IHC and a germline ATM mutation with hormone receptor positive, human epidermal growth factor receptor 2-negative platinum-refractory breast cancer and 11 prior lines of systemic therapy. D, Tumor shrinkage of −19% and a significant cancer antigen 125 reduction in a patient with a BRCA1 germline mutation and high-grade serous platinum-refractory ovarian cancer, also refractory to prior poly (ADP-ribose) polymerase inhibition and immunotherapy. PD, progressive disease; PR, partial response; SD, stable disease.