A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer

Ruth Plummer, Emma Dean, Hendrik Tobias Arkenau, Charles Redfern, Alexander I. Spira, Jason M. Melear, Ki Y. Chung, Jordi Ferrer-Playan, Thomas Goddemeier, Giuseppe Locatelli, Jennifer Dong, Patricia Fleuranceau-Morel, Ivan Diaz-Padilla, Geoffrey I. Shapiro

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. Materials and methods: Adult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m2 (days 2 and 9) and gemcitabine 1000 mg/m2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. Results: Thirty-eight patients received at least one dose of study treatment. The most common treatment-emergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7–22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0–61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0–43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0–73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90% CI: 2.0–34.0%) in patients with intermediate TMB, and 0% (0/3, 90% CI: 0.0–53.6%) in patients with low TMB. Conclusions: Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials should involve genomically selected patients.

Original languageEnglish (US)
Pages (from-to)19-26
Number of pages8
JournalLung Cancer
Volume163
DOIs
StatePublished - Jan 2022

Keywords

  • ATR inhibitor
  • Berzosertib
  • DNA-damage response
  • Gemcitabine
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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