Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Berzosertib (formerly M6620, VX-970) is a highly potent and selective, first-in-class ataxia telangiectasia-mutated and Rad3-related protein kinase (ATR) inhibitor. We assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib plus cisplatin.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Adult patients with advanced solid tumours refractory or resistant to standard of care therapies received ascending doses of cisplatin (day 1) and berzosertib (days 2 and 9) every 3 weeks (Q3W).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Thirty-one patients received berzosertib (90–210 mg/m<jats:sup>2</jats:sup>) and cisplatin (40–75 mg/m<jats:sup>2</jats:sup>) across seven dose levels. The most common grade ≥3 treatment-emergent adverse events were neutropenia (20.0%) and anaemia (16.7%). There were two dose-limiting toxicities: a grade 3 hypersensitivity reaction and a grade 3 increase in alanine aminotransferase. Berzosertib 140 mg/m<jats:sup>2</jats:sup>(days 2 and 9) and cisplatin 75 mg/m<jats:sup>2</jats:sup>(day 1) Q3W was determined as the recommended Phase 2 dose. Cisplatin had no apparent effect on berzosertib pharmacokinetics. Of the 31 patients, four achieved a partial response (two confirmed and two unconfirmed) despite having previously experienced disease progression following platinum-based chemotherapy.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Berzosertib plus cisplatin is well tolerated and shows preliminary clinical activity in patients with advanced solid tumours, warranting further evaluation in a Phase 2 setting.</jats:p></jats:sec><jats:sec><jats:title>Clinical Trials Identifier</jats:title><jats:p>NCT02157792.</jats:p></jats:sec>