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Endobronchial Ultrasound-guided Intratumoral Injection of Cisplatin for the Treatment of Isolated Mediastinal Recurrence of Lung Cancer
Published on: February 12, 2017
Phase 1 study of the ATR inhibitor berzosertib in combination with cisplatin in patients with advanced solid tumours
Geoffrey I Shapiro1, Robert Wesolowski2, Craig Devoe3
1Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA. geoffrey_shapiro@dfci.harvard.edu.
Background:
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.
Methods:
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).
Results:
Thirty-one patients received berzosertib (90-210 mg/m2) and cisplatin (40-75 mg/m2) 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/m2 (days 2 and 9) and cisplatin 75 mg/m2 (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.
Conclusions:
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.
Clinical Trials Identifier:
NCT02157792.
Insights
Berzosertib combined with cisplatin shows promising early results for advanced solid tumors. This combination therapy is well-tolerated and warrants further investigation in Phase 2 trials.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Berzosertib is a novel, potent, and selective ATR inhibitor.
- ATR inhibitors represent a new class of targeted cancer therapies.
Purpose of the Study:
- To assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of berzosertib in combination with cisplatin.
- To determine the recommended Phase 2 dose (RP2D) for this combination therapy.
Main Methods:
- Adult patients with advanced solid tumors refractory to standard care received escalating doses of cisplatin and berzosertib.
- Treatment was administered every 3 weeks (Q3W) on a defined schedule.
- Safety, tolerability, pharmacokinetics, and efficacy were evaluated.
Main Results:
- Thirty-one patients were treated across seven dose levels.
- The recommended Phase 2 dose was identified as berzosertib 140 mg/m² (days 2 and 9) and cisplatin 75 mg/m² (day 1) Q3W.
- Four patients achieved partial responses, including two confirmed responses, despite prior platinum resistance.
Conclusions:
- Berzosertib plus cisplatin demonstrated a manageable safety profile and preliminary clinical activity in patients with advanced solid tumors.
- The combination warrants further evaluation in Phase 2 clinical trials for patients with advanced solid tumors.
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