Abstract
ObjectivesBerzosertib (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 methodsAdult 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. ResultsThirty-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. ConclusionsBerzosertib 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.
Highlights
For patients with advanced non-small cell lung cancer (NSCLC) and no targetable mutations, cytotoxic chemotherapies, including DNAdamaging or anti-mitotic agents, achieve response rates of 7–21%, as per Response Evaluation Criteria in Solid Tumors (RECIST), when used as single agents in the second- and/or third-line treatment setting [1,2,3,4,5,6,7].Ataxia-telangiectasia-mutated (ATM) and Rad3-related protein ki nases (ATR) play critical roles in the DNA-damage response (DDR) by regulating the cell cycle checkpoint control and repairing damaged DNA by homologous recombination [8]
Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC
In response to DNA replication stress, induced or exacerbated by chemotherapies such as gemcitabine, ATR is recruited to regions of exposed single-stranded DNA to mediate replication fork stabilization, whereas ATM responds to DNA doublestrand breaks [9]
Summary
For patients with advanced non-small cell lung cancer (NSCLC) and no targetable mutations, cytotoxic chemotherapies, including DNAdamaging or anti-mitotic agents, achieve response rates of 7–21%, as per Response Evaluation Criteria in Solid Tumors (RECIST), when used as single agents in the second- and/or third-line treatment setting [1,2,3,4,5,6,7].Ataxia-telangiectasia-mutated (ATM) and Rad3-related protein ki nases (ATR) play critical roles in the DNA-damage response (DDR) by regulating the cell cycle checkpoint control and repairing damaged DNA by homologous recombination [8]. For patients with advanced non-small cell lung cancer (NSCLC) and no targetable mutations, cytotoxic chemotherapies, including DNAdamaging or anti-mitotic agents, achieve response rates of 7–21%, as per Response Evaluation Criteria in Solid Tumors (RECIST), when used as single agents in the second- and/or third-line treatment setting [1,2,3,4,5,6,7]. In response to DNA replication stress, induced or exacerbated by chemotherapies such as gemcitabine, ATR is recruited to regions of exposed single-stranded DNA to mediate replication fork stabilization, whereas ATM responds to DNA doublestrand breaks [9]. A recent proof-of-concept phase 2 study evaluating the berzosertib–topotecan combination reported an objective response rate of 36% (9/25), with a median duration of response of 6.4 months, in patients with SCLC, including those with platinum-resistant disease [13]
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